NZ624323B2 - Methods for treating cancers using oral formulations of cytidine analogs - Google Patents

Abstract

Provided is the use of oral formulations of cytidine analogs in the treatment of cancer. In a preferred embodiment an oral formulation of the cytidine analog 5-azacytidine is used in combination with a platinum agent, such as carboplatin, for the treatment of non-small cell lung cancer (NSCLC).

Description

METHODS FOR TREATING CANCERS USING ORAL FORMULATIONS OF CYTIDINE ANALOGS This application claims priority to US. Provisional Patent Application No. 61/554,344, filed November 1, 201 l, which is hereby incorporated by reference in its entirety.

I. FIELD Provided herein are methods for ng, preventing, or managing cancers using a cytidine analog, or a salt, solvate, or hydrate thereof. Also provided are methods for using a cytidine analog, or a salt, solvate, or hydrate thereof, to treat, prevent, or manage diseases and disorders including ers related to abnormal cell proliferation, hematologic disorders, and immune disorders, among others. In certain of the methods, the cytidine analog is formulated in an oral dosage form and administered orally. In n of the methods, the cytidine analog is administered alone or in combination with one or more anti-cancer agents. 11. BACKGROUND Cancer is a major worldwide public health problem; in the United States alone, approximately 0 cancer-related deaths were expected in 2005. See, e.g., Jemal et al., CA Cancer J. Clin. 55(1): 10-30 (2005). Many types of cancer have been described in the medical literature. Examples e cancer of the blood, bone, lung (e.g., non-small-cell lung cancer and small-cell lung ), colon, breast, prostate, ovary, brain, and intestine.

The incidence of cancer ues to climb as the general population ages and as new forms of cancer develop. A continuing need exists for effective therapies to treat subjects with cancer.

Nucleoside analogs have been used clinically for the treatment of viral infections and certain cancers. Most nucleoside analogs are classified as anti-metabolites. After they enter the cell, nucleoside analogs are successively orylated to side 5'-mono- phosphates, di-phosphates, and tri-phosphates.

The nucleoside analogs 5-azacytidine (also known as 4-aminoB-D- ribofilranosyl- l ,3 ,5-triazin-2( lH)-one; National Service Center designation 28 l 6; CAS ry Number 3202; azacitidine; Aza and AZA; and currently marketed as VIDAZA®) and 2’-deoxyazacytidine (also known as 2'-deoxycytidine, decitabine, 5- aza-CdR, Dac, and DAC, and currently ed as DACOGEN®) are DNA methyltransferase (DNMT) inhibitors that have been approved by the US. Food and Drug Administration for the ent of myelodysplastic syndromes (MDS). Azacitidine and decitabine are cytidine analogs; a ural difference between these cytidine analogs and their related natural nucleosides is the presence of a nitrogen at position 5 of the cytosine ring in place of a carbon. Azacitidine may be defined as having a molecular formula of CgH12N405, a lar weight of 244.21 grams per mole, and a structure as shown below.

Decitabine may be defined as having a molecular formula of 4O4, a molecular weight of 228.21 grams per mole, and a structure as shown below.

J12 NH2 le \ N NIJ§N MAO kN/go HO HO O O H H OH OH OH Azacitidine Decitabine After its incorporation into replicating DNA, 5-azacytidine or 2'- deoxycytidine can form a covalent complex with DNA transferases. DNA methyltransferases are responsible for de novo DNA methylation and for reproducing established methylation patterns in daughter DNA strands of replicating DNA. Inhibition of DNA methyltransferases can lead to DNA thylation, thereby restoring normal functions to morphologically dysplastic, immature cells by re-expression of genes involved in normal cell cycle regulation, differentiation and death. The cytotoxic effects of ne analogs can cause the death of rapidly dividing cells that are no longer responsive to normal cell growth control mechanisms. 5-Azacytidine, unlike 5-aza-2'-deoxycytidine, also incorporates into RNA. The cytotoxic effects of idine may result from multiple mechanisms, including inhibition of DNA, RNA and protein synthesis, incorporation into RNA and DNA, and activation of DNA damage pathways. 5-Azacytidine and 5-aza-2'-deoxycytidine have been tested in clinical trials and showed significant activity, such as, for example, in the treatment of myelodysplastic mes (MDS), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), and non Hodgkin’s lymphoma (NHL). See, e.g., io et al., Curr. Opin. Invest. Drugs 3(4): 627-33 (2002). 5-Azacytidine has undergone NCI-sponsored trials for the treatment ofMDS and has been approved for treating all FAB subtypes of MDS. See, e.g., Komblith et al., J. Clin. Oncol. 20(10): 2441-2452 (2002); Silverman et al., J. Clin. Oncol. 20(10): 2429-2440 (2002). 5-Azacytidine may alter the natural course ofMDS by diminishing the transformation to AML through its cytotoxic activity and its inhibition ofDNA methyltransferase. In a Phase III study, 5-azacytidine administered subcutaneously significantly prolonged al and time to AML transformation or death in subjects with higher-risk MDS. See, e.g., P. Fenaux et al. , Lancet 011001., 2009, 10(3):223-32; Silverman et al., Blood 106(11): Abstract 2526 .

Other members of the class of cytidine analogs include, for example: l-B-D- arabinofuranosylcytosine abine or ; pseudoisocytidine (psi ICR); o-2'- deoxycytidine (FCdR); 2'-deoxy-2',2'-difluorocytidine (Gemcitabine); 5-aza-2'-deoxy-2',2'- difluorocytidine; 2'-deoxy-2'-fluorocytidine; l-B-D-ribofuranosyl-2(1H)-pyrimidinone (Zebularine); dideoxyfluoro-3'-thiacytidine (Emtriva); 2'-cyclocytidine (Ancitabine); l-B-D-arabinofuranosyl-S-azacytosine (Fazarabine or ara-AC); 6-azacytidine (6-aza-CR); 5,6- dihydro-S-azacytidine (dH-aza-CR); N4-pentyloxycarbonyl-5'-deoxyfluorocytidine (Capecitabine); N4-octadecyl-cytarabine; and c acid cytarabine. 5-Azacytidine and certain other ne analogs are approved for subcutaneous (SC) or intravenous (IV) administration to treat certain erative disorders. Oral dosing of cytidine analogs would be more desirable and convenient for patients and doctors, e.g., by eliminating inj -site reactions that may occur with SC administration and/or by permitting improved patient compliance. However, oral delivery of cytidine analogs has proven difficult due to combinations of chemical instability, enzymatic instability, and/or poor permeability. For example, cytidine analogs have been considered acid labile and unstable in the acidic gastric environment. us attempts to develop oral dosage forms of cytidine analogs have required enteric coating of the drug core to protect the active ceutical ingredient (API) from what was understood and accepted to be therapeutically unacceptable hydrolysis in the stomach, such that the drug is ably absorbed in specific regions of the lower gastrointestinal tract, such as the jejunum in the small intestine. See, e.g., Sands, et al., US. Patent ation No. 2004/0162263 (App. No. /698,983). In addition, a generally accepted belief in the art has been that water leads to detrimental hydrolytic degradation of cytidine analogs during formulation, subsequently affecting the stability of the API in the dosage form. As a result, coatings applied to the drug core for prospective oral ry of cytidine analogs have previously been limited to c solvent-based systems to minimize exposure of the API to water.

III SUMMARY [0009a] The t invention particularly relates to the use of 5-azacytidine, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the manufacture of a composition for oral administration for the treatment of non-small cell lung cancer in a subject, wherein the ent further comprises administering at least one additional eutic agent comprising a platinum agent. This and other embodiments are described further below. Where an embodiment is described as a method of treating, preventing or managing, or similar language, it should also be understood as referring to the use of the compound in the cture of a medicament for use in that treating, preventing or managing.

Provided herein are methods for treating, preventing, or managing cancers using a ne , or a salt, solvate, or hydrate thereof. Also provided are methods for using a cytidine analog, or a salt, e, or hydrate thereof, to treat, prevent, or manage diseases and disorders, including disorders related to abnormal cell proliferation, hematologic disorders, and immune disorders, among . In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is ed or refractory. In one ment, the cancer is a cancer of the breast, lung, head and neck, ovary, testicle, prostate, gastrointestinal system, stomach, pancreas, liver, colon, kidney, bladder, brain, skin, or bone, among others. In one embodiment, the cancer is a cancer of the blood or the lymph. In particular embodiments, the cancer is a relapsed or refractory solid tumor. In particular embodiments, the cancer is a cancer of the bladder, ovary, pancreas, lung, colon, head and neck, breast, or skin. In particular embodiments, the cancer is a cancer of the bladder, ovary, pancreas, lung, or colon.

In one embodiment, the cytidine analog is formulated in an oral dosage form provided herein (e.g., a tablet or a capsule). In one embodiment, the cytidine analog is administered orally to a subject in need thereof. In one embodiment, the ne analog is administered to a subject in need thereof for a sustained period of time. In one embodiment, the cytidine analog is administered to a subject in need thereof cyclically (e.g., dosing for one or more days, followed by a g period). In one embodiment, the cytidine analog is administered to a subject in need thereof over multiple dosing cycles. - 4 – (Followed by page 4A) In one embodiment, the cytidine analog is administered alone as a single agent to a subject in need thereof. In one embodiment, the cytidine analog is administered in combination with one or more additional anti-cancer agent(s), including, but not d to, carboplatin, paclitaxel, or Abraxane® (paclitaxel protein-bound particles), among others. In one embodiment, the onal anti-cancer agent is an alkylating agent, a cytotoxic agent, an anti-angiogenic agent, an anti-tubulin agent, an etabolite, a kinase inhibitor, a biologics agent, or any other known anti-cancer agent (e.g., an anti-cancer agent ed herein elsewhere). In certain embodiments, in addition to the cytidine analog or the one or more additional anti-cancer agent(s), an anti-emetic is administered to a subject in need thereof. - 4A – - (Followed by page 5) WO 67043 In one embodiment, the cytidine analog is administered orally or parenterally. In one embodiment, the cytidine analog is stered orally. In particular embodiments, 5- azacytidine is administered orally. In one embodiment, the additional anti-cancer agent is administered orally or parenterally. In one embodiment, the cytidine analog is administered via the same route as the one or more additional anti-cancer agent(s). In one ment, the ne analog is administered via a different route as the one or more additional anti-cancer agent(s) (e.g., one administered orally and the other administered parenterally).

In one embodiment, the cytidine analog is administered in a particular dosing cycle. In one embodiment, the cytidine analog and the one or more additional anti-cancer agent(s) (including, but not d to, carboplatin, paclitaxel, or Abraxane®) are co- administered in a particular dosing cycle. In particular embodiments, the cytidine analog is first administered to a subject in need thereof for one or more days (e.g., for 7 days or more), and the one or more additional anti-cancer s) is/are stered to the subject (e.g., starting on Day 8 or later of the treatment cycle). In particular ments, when the one or more additional ancer agent(s) is/are administered to the subject, the cytidine analog is also administered to the subject. In particular embodiments, when the one or more onal anti-cancer agent(s) is/are administered to the subject, the cytidine analog is not administered to the subject simultaneously.

In one embodiment, provided herein are pharmaceutical compositions comprising a cytidine analog, wherein the compositions release the API substantially in the stomach upon oral administration. In one embodiment, provided herein are pharmaceutical compositions comprising a cytidine analog, wherein the compositions release the API ntially in the stomach and the upper intestine upon oral administration. Also provided are methods for making the compositions, and methods for using the compositions to treat, prevent, or manage diseases and disorders including cancer, disorders related to abnormal cell proliferation, solid tumors, and hematologic disorders.

In certain embodiments, the cytidine analog is 5-azacytidine. In other ments, the cytidine analog is 5-aza-2'-deoxycytidine (decitabine or 5-aza-CdR). In yet other embodiments, the cytidine analog is, for example: -arabinofuranosylcytosine (Cytarabine or ara-C); pseudoisocytidine (psi ICR); 5-fluoro-2'-deoxycytidine (FCdR); 2'- deoxy-2',2'-difluorocytidine (Gemcitabine); 5-aza-2'-deoxy-2',2'-difluorocytidine; 5-aza-2'- deoxy-2'-fluorocytidine; l-B-D-ribofuranosyl-2(lH)-pyrimidinone (Zebularine); 2',3'-dideoxy- -fluoro-3'-thiacytidine (Emtriva); 2'-cyclocytidine abine); l-B-D-arabinofuranosyl-S- azacytosine (Fazarabine or ara-AC); 6-azacytidine (6-aza-CR); 5,6-dihydroazacytidine (dH-aza-CR); tyloxycarbonyl-5'-deoxyfluorocytidine (Capecitabine); N4-octadecyl- cytarabine; elaidic acid cytarabine; or their derivatives or related analogs.

Certain embodiments herein provide compositions that are single unit dosage forms comprising a cytidine analog. n embodiments herein provide compositions that are non-enteric-coated. n embodiments herein provide compositions that are tablets comprising a cytidine analog. Certain embodiments herein provide itions that are capsules comprising a cytidine analog. In n embodiments, the single unit dosage forms optionally further contain one or more excipients. In certain embodiments, the s optionally further contain one or more excipients. In other embodiments, the capsules ally further contain one or more excipients. In certain embodiments, the composition is a tablet that effects an ate release of the API upon oral administration. In other embodiments, the composition is a tablet that effects a controlled release of the API substantially in the stomach. In other ments, the composition is a tablet that effects a controlled release of the API substantially in the h and the upper intestine. In certain embodiments, the composition is a capsule that effects an immediate release of the API upon oral administration. In other embodiments, the composition is a capsule that s a controlled release of the API substantially in the stomach. In other embodiments, the composition is a capsule that effects a controlled release of the API substantially in the stomach and the upper intestine. In particular embodiments, the tablet contains a drug core that ses a ne analog, and optionally fiarther contains a coating of the drug core, n the coating is applied to the drug core using an aqueous solvent, such as, for example, water, or non-aqueous solvent, such as, for example ethanol.

Certain embodiments herein provide methods of making formulations of cytidine s intended for oral ry. Further provided are articles of manufacture containing packaging material, an oral formulation of a cytidine analog, and a label that indicates that the formulation is for the treatment, prevention, or ment of certain diseases or disorders including, e.g., a cancer, a er related to abnormal cell proliferation, a solid tumor, a hematologic disorder, or an immune disorder.

Certain embodiments herein provide methods of using the formulations provided herein to treat, prevent, or manage diseases or disorders including, e.g., cancer, disorders related to abnormal cell proliferation, solid tumors, hematologic disorders, or immune disorders. In certain embodiments, the formulations of cytidine analogs are orally administered to subjects in need thereof to treat, prevent, or manage a cancer; or a hematological disorder, such as, for example, MDS, AML, ALL, CML, NHL, leukemia, lymphoma, or multiple myeloma; or a solid tumor, such as, for example, sarcoma, melanoma, carcinoma, or cancer of the colon, breast, ovary, gastrointestinal system, kidney, bladder, lung (e.g., non-small-cell lung cancer and small-cell lung cancer), le, prostate, stomach, pancreas, liver, head and neck, brain, skin, or bone, among others. In particular embodiments, the cancer is a cancer of the bladder, ovary, pancreas, lung, colon, head and neck, breast, or skin. In ular embodiments, the cancer is a cancer of the r, ovary, pancreas, lung, or colon. In certain embodiments, the cancer is refractory. In certain embodiments, the cancer is relapsed. In certain ments, the cancer is atic. In certain embodiments, the formulations of cytidine analogs are orally stered to subjects in need thereof to treat, prevent, or manage an immune disorder. In certain embodiments, the oral formulations provided herein are co-administered with one or more therapeutic agents to provide a synergistic therapeutic effect in subjects in need thereof. In certain ments, the oral formulations provided herein are co-administered with one or more therapeutic agents to provide a resensitization effect in subjects in need thereof. The co-administered agents may be a cancer therapeutic agent, as described herein. In certain embodiments, the co-administered agent(s) may be dosed, e.g., orally or by injection. In certain embodiments, the cytidine and/or the co-administered agent(s) may be dosed cyclically.

In particular embodiments, ed herein are tablets containing 5-azacytidine and methods for making and using the tablets to treat, prevent, or manage cancer, disorders related to abnormal cell eration, solid tumors, or hematologic disorders. In certain embodiments, the tablets optionally further contain one or more excipients such as, for example, glidants, diluents, lubricants, colorants, disintegrants, ating agents, binding agents, polymers, and/or coating agents. Examples of ingredients useful in preparing certain formulations provided herein are bed in, e.g., Etter et al., US. Patent Publication No. 2008/0057086 (App. No. ,958), and Etter et al., US. Patent ation No. 2009/0286752 (App. No. 12/466,213), both of which are incorporated herein by reference in their entireties.

Specific embodiments herein provide, inter alia, pharmaceutical compositions sing a therapeutically effective amount of 5-azacytidine. Specific embodiments herein provide, inter alia, pharmaceutical compositions comprising a therapeutically effective amount of 5-azacytidine, wherein the composition es the 5-azacytidine substantially in the h following oral administration to a subj ect. Further embodiments provide the aforementioned compositions, which: are immediate release compositions; do not have an enteric coating (z'.e., are non-enteric-coated); are tablets; are capsules; further comprise an excipient selected from any excipient disclosed herein; further comprise a permeation enhancer; r comprise d-alpha-tocopheryl hylene glycol 1000 succinate; further comprise a permeation enhancer in the ation at about 2% by weight relative to the total weight of the formulation; are essentially free of a cytidine deaminase inhibitor; are essentially free of ydrouridine; have an amount of 5-azacytidine of at least about 40 mg; have an amount of ytidine of at least about 50 mg; have an amount of 5-azacytidine of at least about 60 mg; have an amount of 5-azacytidine of at least about 80 mg; have an amount of 5-azacytidine of at least about 100 mg; have an amount of 5-azacytidine of at least about 120 mg; have an amount of 5-azacytidine of at least about 150 mg; have an amount of -azacytidine of at least about 200 mg; have an amount of 5-azacytidine of at least about 250 mg; have an amount of 5-azacytidine of at least about 300 mg; have an amount of 5- azacytidine of at least about 350 mg; have an amount of 5-azacytidine of at least about 400 mg; have an amount of 5-azacytidine of at least about 450 mg; have an amount of 5- azacytidine of at least about 500 mg; have an amount of ytidine of at least about 600 mg; have an amount of 5-azacytidine of at least about 1000 mg; have an amount of 5- azacytidine of about 40 mg; have an amount of 5-azacytidine of about 50 mg; have an amount of 5-azacytidine of about 60 mg; have an amount of 5-azacytidine of about 80 mg; have an amount of 5-azacytidine of about 100 mg; have an amount of 5-azacytidine of about 120 mg; have an amount of 5-azacytidine of about 150 mg; have an amount of 5-azacytidine of about 200 mg; have an amount of 5-azacytidine of about 250 mg; have an amount of 5- azacytidine of about 300 mg; have an amount of 5-azacytidine of about 350 mg; have an amount of 5-azacytidine of about 400 mg; have an amount of 5-azacytidine of about 450 mg; have an amount of 5-azacytidine of about 500 mg; have an amount of 5-azacytidine of about 600 mg; have an amount of 5-azacytidine of about 1000 mg; achieve an nder-the-curve value of at least about 200 ng-hr/mL following oral administration to a subject; achieve an area-under-the-curve value of at least about 400 ng-hr/mL following oral stration to a subject; achieve a maximum plasma concentration of at least about 100 ng/mL following oral administration to a subject; achieve a maximum plasma concentration of at least about 200 ng/mL following oral stration to a subject; achieve a time to maximum plasma concentration of less than about 90 minutes following oral administration to a subject; and/or achieve a time to maximum plasma concentration of less than about 60 minutes following oral administration to a subject.

Specific embodiments herein provide, inter alia, methods for treating a subject having cancer or a disease associated with abnormal cell proliferation, comprising orally administering to the subject a pharmaceutical composition comprising a eutically effective amount of 5-azacytidine. Specific embodiments herein provide, inter alia, methods for treating a subject having cancer or a disease associated with abnormal cell proliferation, comprising orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of 5-azacytidine, wherein the composition releases the 5- azacytidine substantially in the stomach following oral administration to the subj ect. Further embodiments herein provide the aforementioned methods, in which: the disease is myelodysplastic syndrome; the disease is acute myelogenous leukemia; the disease is cancer; the disease is a solid tumor; the disease is a cancer of the bladder, ovary, pancreas, lung, colon, head and neck, breast, or skin; the disease is a cancer of the r, ovary, pancreas, lung, or colon; the e is a relapsed or refractory solid tumor; the method r comprises co-administering to the subject in need thereof an additional therapeutic agent selected from any additional therapeutic agent disclosed ; the composition is an immediate release composition; the composition does not have an enteric coating; the composition r comprises a permeation enhancer; the composition further ses the permeation enhancer d-alpha-tocopheryl polyethylene glycol 1000 succinate; the composition r comprises d-alpha-tocopheryl polyethylene glycol 1000 ate in the formulation at about 2% by weight relative to the total weight of the ation; the method r comprises not co-administering a cytidine deaminase tor with the ne analog; the ition is a single unit dosage form; the composition is a tablet; the ition is a capsule; the composition further comprises an excipient selected from any excipient disclosed herein; the amount of 5-azacytidine is at least about 40 mg; the amount of 5-azacytidine is at least about 50 mg; the amount of 5-azacytidine is at least about 60 mg; the amount of 5- azacytidine is at least about 80 mg; the amount of 5-azacytidine is at least about 100 mg; the amount of 5-azacytidine is at least about 120 mg; the amount of 5-azacytidine is at least about 150 mg; the amount of 5-azacytidine is at least about 200 mg; the amount of 5-azacytidine is at least about 250 mg; the amount of 5-azacytidine is at least about 300 mg; the amount of 5- azacytidine is at least about 350 mg; the amount of 5-azacytidine is at least about 400 mg; the amount of 5-azacytidine is at least about 450 mg; the amount of 5-azacytidine is at least about 500 mg; the amount of 5-azacytidine is at least about 600 mg; the amount of ytidine is at least about 1000 mg; the amount of ytidine is about 40 mg; the amount of 5- azacytidine is about 50 mg; the amount of 5-azacytidine is about 60 mg; the amount of 5- azacytidine is about 80 mg; the amount of 5-azacytidine is about 100 mg; the amount of 5- azacytidine is about 120 mg; the amount of 5-azacytidine is about 150 mg; the amount of 5- idine is about 200 mg; the amount of 5-azacytidine is about 250 mg; the amount of 5- azacytidine is about 300 mg; the amount of 5-azacytidine is about 350 mg; the amount of 5- azacytidine is about 400 mg; the amount of 5-azacytidine is about 450 mg; the amount of 5- azacytidine is about 500 mg; the amount of 5-azacytidine is about 600 mg; the amount of 5- azacytidine is about 1000 mg; the method achieves an area-under-the-curve value of at least about 200 ng-hr/mL following oral administration to the subject; the method achieves an nder-the-curve value of at least about 400 ng-hr/mL following oral administration to the subject; the method achieves a maximum plasma concentration of at least about 100 ng/mL following oral administration to the subject; the method achieves a maximum plasma concentration of at least about 200 ng/mL following oral administration to the subject; the method achieves a time to maximum plasma concentration of less than about 90 minutes following oral administration to the subject; and/or the method achieves a time to maximum plasma concentration of less than about 60 minutes following oral administration to the IV. BRIEF PTION OF THE DRAWINGS Figure 1: Dosing and ng schema for Part 1, Arm A of a clinical study on orally dosed 5-azacytidine.

Figure 2: Dosing and sampling schema for Part 1, Arm B of a clinical study on orally dosed 5-azacytidine.

Figure 3: Dosing and sampling schema for Part 1, Arm C of a clinical study on orally dosed 5-azacytidine.

Figure 4: Dose levels and dose escalation rules for Arms A and B of a clinical study on orally dosed 5-azacytidine.

Figure 5: Dose levels and dose escalation rules for Arm C of a clinical study on orally dosed 5-azacytidine.

Figure 6: Modeling of clinical dosing schema in cancer cells. [0028a] Figure 7: Overall study design scheme for a clinical study on orally dosed 5- azacytidine.

V. ED DESCRIPTION Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications and patents referred to herein are incorporated by reference herein in their ties.

A. Definitions As used in the specification and the accompanying claims, the indefinite articles “a” and “an” and the definite article “the” e plural as well as singular referents, unless the context clearly dictates ise.

The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deViations. In certain embodiments, the term ” or “approximately” means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, l%, 0.5%, 0.1%, or 0.05% ofa given value or range.

As used herein, and unless otherwise specified, the terms “treat,3, CCtreating” and “treatment” refer to the eradication or ration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject with such a disease or disorder. In some embodiments, the terms refer to the administration of a compound or dosage form provided herein, with or without one or more onal active agent(s), after the onset of symptoms of the particular disease.

As used herein, and unless otherwise specified, the terms nt, 3, enting” and “prevention” refer to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms f. In certain embodiments, the terms refer to the treatment with or administration of a nd or dosage form provided herein, with or without one or more other additional active agent(s), prior to the onset of symptoms, particularly to subjects at risk of disease or disorders provided herein. The terms encompass the inhibition or reduction of a symptom of the particular disease. Subjects with familial history of a disease are potential candidates for preventive regimens in certain embodiments.

In addition, subjects who have a history of recurring ms are also ial candidates for prevention. In this regard, the term “prevention” may be interchangeably used with the term “prophylactic treatment.” As used , and unless otherwise specified, the terms “manage,3, CCmanaging” and “management” refer to preventing or slowing the ssion, spread or worsening of a e or disorder, or of one or more symptoms thereof. Often, the beneficial s that a subject derives from a lactic and/or therapeutic agent do not result in a cure of the e or disorder. In this regard, the term “managing” encompasses treating a subject who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease.

As used herein, “amelioration” of the symptoms of a ular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or ary, lasting or transient, that can be attributed to or associated with administration of the composition.

As used herein, and unless ise specified, the terms “therapeutically effective amount” and “effective amount” of a compound mean an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or ze one or more symptoms associated with the disease or disorder. A “therapeutically effective amount” and “effective amount” of a compound mean an amount of therapeutic agent, alone or in combination with one or more other agent(s), which provides a therapeutic benefit in the treatment or management of the disease or er. The terms “therapeutically effective amount” and “effective amount” can encompass an amount that improves overall therapy, reduces or avoids ms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease or disorder, or prevent its recurrence. A prophylactically ive amount of a compound means an amount of therapeutic agent, alone or in combination with one or more other agent(s), which provides a prophylactic benefit in the tion of the disease. The term “prophylactically effective amount” can encompass an amount that es overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

As used herein, and unless otherwise specified, the term “subject” is defined herein to include animals such as mammals, including, but not limited to, es (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In specific embodiments, the subject is a human. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a ian subject, such as a human.

“Tumor,” as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. astic,” as used herein, refers to any form of dysregulated or unregulated cell growth, whether malignant or , resulting in abnormal tissue growth. Thus, “neoplastic cells” include malignant and benign cells having ulated or unregulated cell growth.

As used herein, the terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to bome (e.g., ma, leukemia) and solid tumors.

As used herein, and unless ise specified, the term “proliferative” disorder or disease refers to ed cell proliferation of one or more subset of cells in a multicellular organism resulting in harm (i.e., fort or decreased life expectancy) to the multicellular organism. For example, as used , proliferative disorder or disease includes neoplastic disorders and other proliferative disorders.

As used herein, and unless otherwise specified, the term “relapsed” refers to a situation where a subject, that has had a remission of cancer after a y, has a return of cancer cells.

As used herein, and unless otherwise specified, the term “refractory” or “resistant” refers to a circumstance where a subject, even after intensive ent, has residual cancer cells in the body.

As used herein, and unless otherwise specified, the term “drug resistance” refers to the condition when a disease does not respond to the treatment of a drug or drugs. Drug resistance can be either intrinsic, which means the disease has never been sive to the drug or drugs, or it can be acquired, which means the disease ceases responding to a drug or drugs that the disease had previously responded to. In certain embodiments, drug resistance is intrinsic. In certain embodiments, the drug resistance is acquired.

As used herein, and unless otherwise specified, the term “anti-cancer ” “anticancer agent” or “cancer therapeutic agent” is meant to include anti-proliferative agents and chemotherapeutic agents, including, but not limited to, antimetabolites (e.g. ro uracil, methotrexate, azacitidine, decitabine, fludarabine, cytarabine (also known as cytosine arabinoside or Ara-C), and high dose cytarabine), antimicrotubule agents (e.g., vinca alkaloids, such as vincristine and vinblastine; and s, such as axel and docetaxel), alkylating agents (e.g., mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide, carmustine, busulfan, cyclophosphamide, dacarbazine, mide, and nitrosoureas, such as carmustine, lomustine, bischloroethylnitrosurea, and hydroxyurea), platinum agents (e.g., cisplatin, latin, oxaliplatin, satraplatin (JM-2l6), and CI-973), cyclines (e.g., doxorubicin and daunorubicin), antitumor antibiotics (e.g., mitomycin, bleomycin, idarubicin, adriamycin, daunomycin (also known as ubicin, rubidomycin, or cerubidine), and mitoxantrone), topoisomerase inhibitors (e.g., etoposide and camptothecins), purine antagonists or pyrimidine antagonists (e.g., 6-mercaptopurine, 5- fluorouracil, cytarabine, clofarabine, and gemcitabine), cell maturing agents (e.g., arsenic trioxide and tretinoin), DNA repair enzyme inhibitors (e.g, podophyllotoxines, ide, irinotecan, topotecan, and teniposide), enzymes that prevent cell survival (e.g., asparaginase and pegaspargase), histone deacetylase inhibitors (e.g., vorinostat), any other cytotoxic agents (e.g., estramustine phosphate, dexamethasone, prednimustine, and procarbazine), hormones (e.g., thasone, prednisone, methylprednisolone, tamoxifen, leuprolide, flutamide, and megestrol), monoclonal antibodies (e.g., gemtuzumab ozogamicin, alemtuzumab, rituximab, and yttriumibritumomab tiuxetan), immuno-modulators (e.g., thalidomide and lenalidomide), Bcr-Abl kinase inhibitors (e.g., AP23464, AZD0530, CGP76030, PD180970, SKI-606, imatinib, BMS354825 (dasatinib), AMNlO7 inib), and VX-680), hormone agonists or antagonists, partial agonists or partial antagonists, kinase inhibitors, surgery, radiotherapy (e.g., gamma-radiation, neutron bean radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), ine therapy, ical response modifiers (e.g., interferons, interleukins, and tumor necrosis ), hyperthermia and cryotherapy, and agents to ate any adverse effects (e.g., antiemetics).

As used herein, and unless otherwise specified, the terms “co-administration” and “in combination with” include the administration of two or more therapeutic agents aneously, concurrently, or sequentially within no specific time limits unless otherwise indicated. In one embodiment, the agents are present in the cell or in the subject’s body at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms. In certain embodiments, a first agent can be stered prior to (e.g., 5 minutes, 15 minutes, s, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 2012/062845 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), essentially concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the stration of a second eutic agent.

The terms “composition,” “formulation,” and “dosage form,” as used herein are intended to encompass compositions comprising the specified ingredient(s) (in the specified amounts, if indicated), as well as any product(s) which result, directly or indirectly, from combination of the specified ingredient(s) in the specified amount(s). By “pharmaceutical” or “pharmaceutically acceptable” it is meant that any diluent(s), excipient(s) or carrier(s) in the composition, formulation, or dosage form are compatible with the other ingredient(s) and not rious to the recipient thereof. Unless ted otherwise, the terms “composition,” “formulation,” and “dosage form” are used herein interchangeably.

The term iate release,” when used herein in reference to a composition, formulation, or dosage form provided herein, means that the composition, formulation, or dosage form does not comprise a component (e.g., a coating) that serves to delay the l and/or temporal release of some or all of the API from the composition, formulation, or dosage form following oral administration. In certain embodiments, an immediate release composition, formulation, or dosage form is one that releases the API substantially in the stomach following oral administration. In n embodiments, an immediate release composition, formulation, or dosage form is one that releases the API substantially in the stomach or the upper intestine following oral administration. In specific embodiments, an immediate release composition, formulation, or dosage form is one that is not delayed- release. In specific embodiments, an immediate release composition, ation, or dosage form is one that does not comprise an enteric coating.

The term “non-enteric-coated,” when used herein, refers to a pharmaceutical composition, formulation, or dosage form that does not se a coating intended to release the active ingredient(s) beyond the stomach (e.g., in the intestine). In certain embodiments, a non-enteric-coated composition, formulation, or dosage form is designed to release the active ingredient(s) substantially in the stomach. In n embodiments, a non- enteric-coated composition, formulation, or dosage form is designed to e the active ingredient(s) ntially in the h and the upper intestine.

The term “substantially in the stomach,” when used herein in reference to a composition, formulation, or dosage form ed herein, means that at least about 99%, at least about 95%, at least about 90%, at least about 85%, at least about 80%, at least about 75%, at least about 70%, at least about 65%, at least about 60%, at least about 55%, at least about 50%, at least about 45%, at least about 40%, at least about 35%, at least about 30%, at least about 25%, at least about 20%, at least about 15%, or at least about 10% of the ne analog is released in the stomach. The term “released in the stomach” and related terms as used herein refer to the process whereby the cytidine analog is made available for uptake by or ort across cells lining the stomach and then made available to the body.

The term “isotopic composition” refers to the amount of each isotope present in a given atomic position, and “natural ic ition” refers to the naturally occurring ic composition or nce for a given atomic on. Atomic positions containing their natural isotopic composition may also be referred to herein as “non-enriched.” Unless otherwise designated, the atomic positions of the nds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural isotopic ition.

The term “isotopically enriched” refers to an atomic position having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atomic position having an isotopic composition other than the natural isotopic composition of that atom. As used herein, an “isotopologue” is an isotopically enriched compound.

The term “isotopic enrichment” refers to the percentage of incorporation of an amount of a specific isotope at a given atomic on in a molecule in the place of that atom’s natural isotopic composition. For example, deuterium ment of l% at a given position means that l% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%.

The term “isotopic enrichment factor” refers to the ratio between the isotopic ition and the natural isotopic composition of a specified isotope.

With regard to the compounds provided herein, when a particular atomic position is designated as having deuterium or “D,” it is understood that the abundance of deuterium at WO 67043 that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. A on designated as having deuterium typically has a minimum isotopic enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% ium incorporation), at least 4500 (67.5% ium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position.

The isotopic enrichment and isotopic enrichment factor of the compounds provided herein can be determined using conventional ical methods known to one of ordinary skill in the art, including, e.g, mass spectrometry, nuclear magnetic resonance spectroscopy, and llography.

As used herein, and unless ise specified, the term “pharmaceutically acceptable carrier, 3, 6‘pharmaceutically acceptable excipient,3) “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically-acceptable material, composition, or vehicle, such as, e.g., a liquid or solid filler, diluent, ent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable t/risk ratio. In one embodiment, by “pharmaceutical” or aceutically acceptable” it is meant that any diluent(s), excipient(s) or carrier(s) in the composition, ation, or dosage form are compatible with the other ingredient(s) and not deleterious to the ent thereof. See, e.g., Remington, The Science and Practice ofPharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook ofPharmaceutical Excipients, 5th n; Rowe et al., ed., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook ofPharmaceutical Additives, 3rd Edition; Ash and Ash ed., Gower hing Company: 2007; Pharmaceutical malation and Formulation, Gibson ed., CRC Press LLC: Boca Raton, FL, 2004. 2012/062845 As used herein, and unless otherwise specified, the term “hydrate” means a compound provided herein or a salt thereof, which r includes a stoichiometric or non- stoichiometric amount of water bound by non-covalent intermolecular .

As used herein, and unless otherwise specified, the term “solvate” means a solvate formed from the association of one or more solvent molecules to a compound ed herein. The term “solvate” includes hydrates (e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like).

As used herein, and unless otherwise specified, a compound described herein is intended to encompass all possible stereoisomers, unless a particular stereochemistry is ed. Where structural isomers of a compound are interconvertible via a low energy barrier, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism; or so-called valence tautomerism in the compound, e.g., that contain an aromatic moiety.

B. Cytidine Analogs 1. Overview Provided herein are dosage forms, pharmaceutical formulations, and compositions comprising ne analogs that release the API substantially in the stomach upon oral administration. In certain embodiments, the cytidine analog is 5-azacytidine. In certain embodiments, the cytidine analog is 5-aza-2'-deoxycytidine (decitabine or 5-aza-CdR). In certain embodiments, the cytidine analog is, for e: l-[3-D-arabinofi1ranosylcytosine (Cytarabine or ara-C); iso-cytidine (psi ICR); 5-fluoro-2'-deoxycytidine (FCdR); 2'- deoxy-2',2'-difluorocytidine (Gemcitabine); 5-aza-2'-deoxy-2',2'-difluorocytidine; 5-aza-2'- deoxy-2'-fluorocytidine; l-B-D-ribofuranosyl-2(lH)-pyrimidinone (Zebularine); 2',3'-dideoxy- -fluoro-3'-thiacytidine (Emtriva); locytidine (Ancitabine); l-B-D-arabinofuranosyl-S- azacytosine (Fazarabine or ara-AC); 6-azacytidine (6-aza-CR); 5,6-dihydroazacytidine (dH-aza-CR); N4-pentyloxy-carbonyl-5'-deoxyfluorocytidine (Capecitabine); N4-octadecyl-cytarabine; elaidic acid cytarabine; or a conjugated compound comprising a ne analog and a fatty acid (6.g. , an idine—fatty acid conjugate, including, but not limited to, CP-4200 (Clavis Pharma ASA) or a nd disclosed in , such as aza-C-5’-petroselinic acid ester or aza-C-5’-petroselaidic acid ester).

In certain embodiments, cytidine s provided herein include fied derivatives of cytidine analogs, such as, e.g., esterified derivatives of 5-azacytidine. In particular embodiments, esterified derivatives are cytidine analogs that contain an ester moiety (e.g., an acetyl group) at one or more ons on the cytidine analog molecule.

Esterified derivatives may be prepared by any method known in the art. In certain embodiments, esterified derivatives of a cytidine analog serve as prodrugs of the cytidine analog, such that, e.g., following administration of an esterified derivative, the derivative is deacetylated in vivo to yield the cytidine analog. A particular embodiment herein provides 2’,3’,5’-triacetylazacytidine (TAC), which possesses favorable al-chemical and therapeutic properties. See, e. g., International Publication No.

(International Application No. PCT/U$2008/052124); Ziemba, A.J., et al., “Development of Oral Demethylating Agents for the Treatment of Myelodysplastic me” (Abstract No. 3369), In: Proceedings 0fthe 100th Annual g 0fthe American Associationfor Cancer ch; 2009 Apr. 18-22; Denver, Co. Philadelphia (PA): AACR; 2009 (both of which are incorporated by reference herein in their entireties).

In certain embodiments, the ne analogs ed herein include any compound which is structurally related to ne or deoxycytidine and functionally mimics and/or antagonizes the action of cytidine or deoxycytidine. Certain embodiments herein provide salts, cocrystals, es (e.g., hydrates), complexes, prodrugs, sors, metabolites, and/or other derivatives of the cytidine analogs provided herein. For example, particular embodiments provide salts, cocrystals, solvates (e.g., hydrates), complexes, precursors, metabolites, and/or other tives of 5-azacytidine. Certain embodiments provide cytidine analogs that are not salts, cocrystals, solvates (e.g., hydrates), or complexes of the cytidine analogs provided herein. For example, particular embodiments provide 5- azacytidine in a non-ionized, non-solvated (e.g., anhydrous), non-complexed form. Certain embodiments herein provide mixtures of two or more cytidine s provided herein.

Cytidine analogs ed herein may be prepared using synthetic methods and ures referenced herein or otherwise available in the literature. For example, particular methods for synthesizing 5-azacytidine are taught in, e.g, US. Patent No. 7,038,038 and references discussed therein, each of which is incorporated herein by reference. 5- Azacytidine is also available from e Corporation, Warren, NJ. Other cytidine analogs provided herein may be prepared using previously sed synthetic procedures available to a person of ordinary skill in the art.

It should be noted that if there is a discrepancy between a depicted structure and a chemical name given that structure, the depicted structure is to be accorded more weight. In on, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers. Where the compound provided herein contains an alkenyl or alkenylene group, the compound may exist as one geometric (i. e., cis/trans or E/Z) isomer or a e of ric (i.e., cis/trans or E/Z) isomers. Unless ise specified, a compound provided herein is ed to encompass all geometric s.

Where ural isomers are inter-convertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called e tautomerism in the compound that contain, for example, an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. It will be understood that unless otherwise specified, a compound provided herein is intended to encompass all possible tautomers. Similarly, unless otherwise ed, a compound provided herein is intended to encompass all possible stereoisomers.

The compounds provided herein may be enantiomerically pure, such as a single enantiomer or a single reomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a c mixture of two enantiomers; or a mixture of two or more diastereomers. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, by chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation. In some instances, for compounds that o epimerization in vivo, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent to administration of the compound in its (S) form, and vice versa.

When the compound provided herein contains an acidic or basic moiety, it may also be provided as a pharmaceutically able salt (See, Berge et al., J. Pharm. Sci. 1977, 66, l-l9; and “Handbook of Pharmaceutical Salts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA, Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(lS)- camphor-lO-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fiamaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, uronic acid, L-glutamic acid, (x-oxoglutaric acid, glycolic acid, ic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (::)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)—L-malic acid, malonic acid, (::)-DL-mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, alene-l,5-disulfonic acid, l-hydroxynaphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, oric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, c acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

Suitable bases for use in the preparation of pharmaceutically able salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, ary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, amine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, ylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H- imidazole, L-lysine, morpholine, 4-(2—hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, amine, pyrrolidine, ydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, yl-D-glucamine, 2-amino(hydroxymethyl)-l,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a prodrug, which is a functional derivative of a compound provided herein, and is readily convertible into the parent compound in viva. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral stration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various isms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221-294; Morozowich et al. in n of Biopharmaceutical Properties h Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977; “Bioreversible Carriers in Drug in Drug Design, Theory and Application,” Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard, ElseVier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265- 287; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al., Pharm.

Biotech. 1998, 11, 345-365; ult et al., Pract. Med. Chem. 1996, 6; ejad in “Transport Processes in Pharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218, 2000; Balant et al., Eur. J. Drug Metab. cokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; , Clin. harmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, I 7, 179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 0; Fleisher et al., Methods Enzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877; Friis and Bundgaard, Eur. J.

Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv.

Drug Delivery Rev. 1999, 39, 63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497- 507.

In certain embodiments, exemplary cytidine analogs have the structures provided below: NH2 )1in NH2 J‘LHz I I Q \ N O N O N O 0 HO HO HO HO 0 o o\0 o H H H H H H H H OH OH OH OH H OH OH Azacitidine Decitabine Cytarabine (Ara-C) Pseudoisocytidine (psi ICR) NH2 NH2 l x ' A ' x N O N O N O HO HO HO INN/KO H H H H H H 7(0)‘ OH F OH OH OH H8 H Gemcitabine Zebularine FCdR Emtriva fiN HN \N N\N/go kN/go HO HO O O H H H H OH OH OH OH 6-Azacytidine 5Dihydroazacytidine 2. Isotopically Enriched Cflidine Analogs Particular embodiments herein provide isotopically enriched cytidine analogs, prodrugs thereof, synthetic intermediates thereof, and metabolites thereof. For example, specific embodiments herein provide isotopically enriched ytidine. ic enrichment (e.g., deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), codynamics (“PD”), and toxicity es, has been demonstrated previously with some classes of drugs. See, e. g., Lijinsky et. al., Food Cosmet.

Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et. al., Mutation Res. 308: 33 ; Gordon et. al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade, D., Chem. Biol. Interact. 117: 191 (1999).

Without being limited by any particular theory, isotopic enrichment of a drug can be used, for example, to: (1) reduce or eliminate unwanted metabolites; (2) increase the half- life of the parent drug; (3) decrease the number of doses needed to achieve a desired effect; (4) decrease the amount of a dose necessary to achieve a desired effect; (5) increase the formation of active metabolites, if any are formed; and/or (6) decrease the tion of deleterious metabolites in specific s and/or create a more ive drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.

Replacement of an atom for one of its isotopes may often result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect (“KIE”). For example, if a C—H bond is broken during a rate-determining step in a chemical reaction (z'.e. the step with the highest transition state ), substitution of a deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (“DKIE”). See, e.g., Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 ; Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999).

Certain embodiments herein provide deuterium enriched 5-azacytidine analogs, wherein one or more hydrogen(s) in the 5-azacytidine molecule is/are isotopically enriched with ium. In certain ments, provided herein are compounds of formula (I): Y7ids.) HO Y2 (1), wherein one or more Y atom(s) (2'.e., Y1, Y2, Y3, Y4, Y5, Y6, and Y7) is/are en(s) isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen atom(s). In particular embodiments, one, two, three, four, five, six, or seven of the indicated Y ) is/are isotopically enriched with deuterium, and any remaining Y atom(s) is/are non-enriched hydrogen(s).

In certain embodiments, one or more Y atoms on the ribose moiety of Compound (I) are deuterium-enriched. Particular examples include, but are not limited to, the following compounds, in which the label “D” indicates a deuterium-enriched atomic position, z'.e., a sample comprising the given compound has a deuterium enrichment at the ted position(s) above the natural abundance of deuterium: WO 67043 N I2 N I2 \N \N In certain embodiments, the Y atom on the 5-azacytosine moiety of Compound (I) is deuterium-enriched. Particular example includes the following compound, in which the label “D” indicates a deuterium-enriched atomic position, z'.e., a sample comprising the given nd has a deuterium enrichment at the indicated position(s) above the natural abundance of deuterium: In n embodiments, one or more Y atoms on the ribose moiety and the Y atom on the 5-azacytosine moiety of Compound (I) are deuterium-enriched. Particular examples include, but are not limited to, the following compounds, in which the label “D” indicates a deuterium-enriched atomic position, z'.e., a sample comprising the given compound has a deuterium enrichment at the ted position(s) above the natural abundance of deuterium: 1-15 It is understood that one or more deuterium(s) may exchange with hydrogen under physiological conditions.

Certain embodiments herein provide carbon-l3 enriched analogs of 5-azacytidine, wherein one or more (s) in the ytidine le is/are isotopically enriched with carbon-l3. In n embodiments, provided herein are compounds of formula (II): 3 2 \N/ \O HO\8 | O 7\H/ \Hl4 H I I H OH OH (11), wherein one or more of l, 2, 3, 4, 5, 6, 7, or 8 is/are carbon atom(s) isotopically enriched with carbon-l3, and any remaining atom(s) of l, 2, 3, 4, 5, 6, 7, or 8 is/are riched carbon atom(s). In particular embodiments, one, two, three, four, five, six, seven, or eight carbon atom(s) (i.e., atoms 1, 2, 3, 4, 5, 6, 7, and 8) is/are isotopically enriched with carbon-l3, and any remaining carbon atom(s) is/are non-enriched.

In certain embodiments, one or more carbon atom(s) of the ribose moiety of Compound (II) are enriched with carbon-l3. Particular examples include, but are not limited to, the following nds, in which the asterisk (“*”) indicates a carbon-l3 ed atomic position, z'.e., a sample comprising the given compound has a carbon-l3 enrichment at the indicated position(s) above the natural abundance of carbon-l3: 2012/062845 11-10 11-11 In certain embodiments, one or more carbon atom(s) of the 5-azacytosine moiety of Compound (11) are enriched with carbon-l3. Particular examples include, but are not limited to, the following compounds, in which the asterisk “*” indicates a carbon-l3 enriched 2012/062845 atomic on, z'.e., a sample comprising the given compound has a carbon-l3 enrichment at the indicated position(s) above the natural abundance of carbon-l3: NH2 NH2 Nk NKN *ka0 HR. 11-12 11-13 11-14 In certain embodiments, one or more carbon atoms on the ribose moiety and one or more carbon atoms on the 5-azacytosine moiety of Compound (II) are enriched with carbon-l3, z'.e., any combination of -l3 enrichment for the ribose moiety and carbon- 13 ment for the azacitosine moiety is encompassed herein.

In certain embodiments, one or more hydrogen(s) is/are enriched with deuterium(s) and one or more carbon(s) is/are enriched with carbon-l3, i.e., any combination of deuterium enrichment and carbon-l3 enrichment of 5-azacytidine is encompassed herein.

The compounds described herein may be synthesized using any method known to one of ordinary skill in the art. For example, particular nds bed herein are synthesized using standard synthetic organic chemistry techniques known to those of ordinary skill in the art. In some embodiments, known procedures for the synthesis of 5- azacytidine are employed, wherein one or more of the reagents, starting materials, precursors, or intermediates are replaced by one or more isotopically-enriched reagents, ng materials, precursors, or intermediates, including but not limited to one or more deuterium- enriched reagents, starting materials, precursors, or intermediates, and/or one or more carbon- l3-enriched reagents, starting materials, precursors, or intermediates. Isotopically enriched reagents, starting materials, precursors, or intermediates are commercially ble or may be prepared by e chemical reactions known to one of skill in the art. In some embodiments, the routes are based on those disclosed in US. Patent No. 038 and US.

Patent Publication No. 2009/0286752 (App. No. 12/466,213), both of which are incorporated herein by nce in their entireties.

C. Pharmaceutical Compositions In one embodiment, ed herein are pharmaceutical compositions, which comprise a cytidine analog, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, as an active ingredient, in combination with one or more ceutically acceptable excipient or carrier. In one embodiment, the pharmaceutical composition comprises at least one nonrelease controlling excipient or carrier. In one embodiment, the pharmaceutical composition comprises at least one release controlling and at least one ease controlling excipient or carrier.

In certain embodiments, the cytidine analog used in the pharmaceutical compositions provided herein is in a solid form. Suitable solid forms include, but are not limited to, solid forms sing the free base of the cytidine analog, and solid forms comprising salts of the ne analog. In certain embodiments, solid forms provided herein include polymorphs, solvates (including hydrates), and tals comprising the cytidine analog and/0r salts thereof. In certain embodiments, the solid form is a crystal form of the cytidine analog, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

In one embodiment, the pharmaceutical compositions provided herein may be formulated in various dosage forms for oral, parenteral, and topical stration. The ceutical itions may also be ated as modified release dosage forms, including delayed-, ed-, prolonged-, sustained-, -, controlled-, accelerated- and fast-, targeted-, programmed-release, and c retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g, Remington, The Science and Practice ofPharmacy, 2lst Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Modified-Release Drug Delivery Technology, Rathbone et al., eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2003; Vol. 126.

In one embodiment, the pharmaceutical compositions are provided in a dosage form for oral administration. In another embodiment, the pharmaceutical compositions are provided in a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical compositions are provided in a dosage form for topical administration.

In one embodiment, the ceutical compositions provided herein may be provided in a unit-dosage form or le-dosage form. A unit-dosage form, as used herein, refers to a physically discrete unit suitable for administration to human and animal subjects, and packaged dually as is known in the art. Each unit-dose contains a ermined quantity of the active ingredient(s) sufficient to produce the desired eutic effect, in association with the required pharmaceutical rs or excipients. Examples of a unit- dosage form include an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples f. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.

In one embodiment, the pharmaceutical itions provided herein may be administered once or multiple times, at particular intervals of time. It is understood that the e dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is fiarther understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the sional judgment of the person administering or supervising the administration of the formulations. 1. Overview of Oral Dosage Forms In one embodiment, the pharmaceutical compositions provided herein may be provided in solid, lid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and gual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, escent or non-effervescent powders or granules, solutions, emulsions, suspensions, ons, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not d to, s, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.

In one embodiment, provided herein are pharmaceutical ations and compositions comprising a cytidine analog (e.g., 5-azacytidine or another cytidine analog provided herein), and optionally a tion enhancer, wherein the formulations and compositions are prepared for oral administration. In a particular embodiment, the formulations and compositions are prepared for release of the cytidine analog substantially in the stomach. In specific embodiments, the ne analog (e.g., 5-azacytidine or another cytidine analog provided ) and the pharmaceutical ation and composition are used for treating, preventing, or managing es and disorders associated with al cell proliferation, for example, a solid tumor, wherein the cytidine analog, the formulation and ition are prepared for oral administration, preferably for release of the cytidine analog ntially in the stomach. Particular embodiments relate to the use of one or more cytidine analogs (e.g., ytidine or another cytidine analog provided herein) for the preparation of pharmaceutical formulations and compositions for treating ular medical indications, as provided herein. The pharmaceutical formulations and compositions comprising a cytidine analog provided herein are intended for oral delivery of the cytidine analog in ts in need thereof. Oral delivery formats include, but are not limited to, tablets, capsules, s, solutions, suspensions, and syrups, and may also comprise a plurality of granules, beads, powders or pellets that may or may not be encapsulated. Such formats may also be referred to herein as the “drug core” which contains the cytidine analog.

Particular ments herein provide solid oral dosage forms that are tablets or es. In certain embodiments, the formulation is a tablet comprising a cytidine analog.

In certain embodiments, the formulation is a capsule comprising a cytidine analog. In certain embodiments, the tablets or capsules provided herein optionally comprise one or more excipients, such as, for example, glidants, diluents, lubricants, colorants, disintegrants, granulating agents, binding agents, polymers, and coating . In certain embodiments, the ation is an ate release tablet. In certain embodiments, the formulation is a controlled release tablet releasing the API, 6.g. in the stomach. In certain , substantially embodiments, the ation is a hard gelatin capsule. In certain embodiments, the formulation is a soft n capsule. In certain embodiments, the capsule is a hydroxypropyl methylcellulose (HPMC) capsule. In certain embodiments, the formulation is an immediate release capsule. In certain embodiments, the formulation is an immediate or controlled release capsule releasing the API, 6.g. in the stomach. In certain embodiments, , substantially the formulation is a rapidly disintegrating tablet that dissolves substantially in the mouth following administration. In certain embodiments, ments herein encompass the use of a cytidine analog (e.g., 5-azacytidine or another cytidine analog provided herein) for the preparation of a pharmaceutical composition for treating a disease associated with abnormal cell proliferation, wherein the composition is ed for oral administration. 2. Performance of Certain Dosage Forms Provided Herein In certain embodiments, the formulations comprising a cytidine analog, such as, for example, 5-azacytidine or another cytidine analog provided herein, effect an immediate release of the API upon oral administration. In particular embodiments, the formulations comprising a cytidine analog, such as, for example, 5-azacytidine or another ne analog provided herein, comprise a therapeutically or prophylactically effective amount of the cytidine analog (and, optionally, one or more excipients) and effect an immediate e of the API upon oral administration.

In certain embodiments, the formulations comprising a cytidine analog, such as, for example, 5-azacytidine or another ne analog provided herein, effect a controlled release of the API substantially in the stomach upon oral administration. In certain embodiments, the formulations comprising a cytidine analog, such as, for example, 5- azacytidine or another cytidine analog ed herein, comprise a therapeutically or prophylactically effective amount of the cytidine analog and a drug release controlling component which is capable of releasing the cytidine analog substantially in the stomach. In certain embodiments, matrices (e.g. be employed in the formulation , polymer es) may to control the e of the cytidine analog. In certain embodiments, coatings and/or shells may be employed in the ation to control the e of the cytidine analog in the substantially in the stomach.

In certain embodiments, the formulations sing a ne analog, such as, for example, 5-azacytidine or another cytidine analog provided herein, release the API substantially in the stomach upon oral administration. In certain embodiments, the formulations effect an immediate release of the cytidine analog upon oral administration. In n embodiments, the formulations optionally fiarther comprises a drug release controlling component, wherein the drug release controlling component is adjusted such that the release of the ne analog occurs substantially in the stomach. In particular embodiments, the drug e controlling component is adjusted such that the release of the cytidine analog is immediate and occurs ntially in the stomach. In particular embodiments, the drug release controlling component is adjusted such that the release of the cytidine analog is sustained and occurs substantially in the stomach. In certain embodiments, the formulation of a ne analog, such as, for example, 5-azacytidine or another cytidine analog provided herein, releases the API ntially in the stomach, and, subsequently, releases the remainder of the API in the ine upon oral administration.

Methods by which skilled practitioners can assess where a drug is released in the intestinal tract of a t are known in the art, and include, for example, scintigraphic studies, testing in a bio-relevant medium which simulates the fluid in relevant ns of the intestinal tract, among other methods.

] Particular embodiments herein provide pharmaceutical formulations (e.g. immediate release oral formulations and/or formulations that e the API substantially in the stomach) comprising a cytidine analog (e.g., 5-azacytidine or r cytidine analog provided herein) that achieve a particular exposure in the subject to which the formulation is orally administered, as compared to a SC dose of the same cytidine analog. Particular embodiments provide oral formulations that achieve an exposure of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%, as compared to a SC dose.

In certain ments, the formulation (e.g., immediate release oral formulation and/or formulation that release the API substantially in the stomach) comprising a cytidine analog, such as, for example, 5-azacytidine or another cytidine analog provided herein, renders a certain percentage of the cytidine analog in the formulation systemically bioavailable upon oral administration. In certain ments, after the subject is orally administered the formulation, the cytidine analog in the formulation is absorbed substantially in the stomach, and becomes available to the body through systemic exposure. In particular embodiments, the oral bioavailability of a formulation comprising a cytidine analog provided herein is, e.g., greater than about 1%, r than about 5%, greater than about 10%, r than about 15%, greater than about 20%, greater than about 25%, greater than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, r than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or about 100%, of the total amount of the cytidine analog in the formulation. s by which skilled practitioners can assess the oral ilability of a drug formulation in a subject are known in the art. Such methods, include, for example, comparing certain dosing-related parameters, such as, but not limited to, maximum plasma concentration (“Cmax”), time to maximum plasma tration (“Tmax”), or nder- the-curve (“AUC”) determinations.

Particular embodiments herein provide pharmaceutical formulations (e.g. immediate e oral formulations and/or formulations that release the API ntially in the h) comprising a cytidine analog (e.g., 5-azacytidine or another cytidine analog provided herein) that achieve a particular AUC value (6.g. , AUC(0-t) or AUC(0-OO)) in the subject (e.g., human) to Which the formulation is orally administered. Particular embodiments provide oral formulations that achieve an AUC value of at least about 25 ng- hr/mL, at least about 50 ng-hr/mL, at least about 75 ng-hr/mL, at least about 100 ng-hr/mL, at least about 150 ng-hr/mL, at least about 200 ng-hr/mL, at least about 250 ng-hr/mL, at least about 300 ng-hr/mL, at least about 350 ng-hr/mL, at least about 400 ng-hr/mL, at least about 450 ng-hr/mL, at least about 500 mL, at least about 550 ng-hr/mL, at least about 600 ng-hr/mL, at least about 650 ng-hr/mL, at least about 700 ng-hr/mL, at least about 750 ng- hr/mL, at least about 800 ng-hr/mL, at least about 850 ng-hr/mL, at least about 900 ng-hr/mL, at least about 950 ng-hr/mL, at least about 1000 ng-hr/mL, at least about 1100 ng-hr/mL, at least about 1200 ng-hr/mL, at least about 1300 ng-hr/mL, at least about 1400 ng-hr/mL, at least about 1500 ng-hr/mL, at least about 1600 ng-hr/mL, at least about 1700 ng-hr/mL, at least about 1800 ng-hr/mL, at least about 1900 ng-hr/mL, at least about 2000 ng-hr/mL, at least about 2250 ng-hr/mL, or at least about 2500 ng-hr/mL. In particular embodiments, the AUC determination is obtained from a time-concentration pharmacokinetic profile obtained from the blood samples of animals or human eers following dosing.

Particular embodiments herein provide pharmaceutical formulations (e.g. immediate release oral formulations and/or formulations that release the API substantially in the stomach) comprising a cytidine analog (e.g., ytidine or another cytidine analog ed herein) that achieve a particular maximum plasma tration (“Cmax”) in the subject to which the formulation is orally administered. Particular embodiments provide oral formulations that achieve a Cmax of the cytidine analog of at least about 25 ng/mL, at least about 50 ng/mL, at least about 75 ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at least about 200 ng/mL, at least about 250 ng/mL, at least about 300 ng/mL, at least about 350 ng/mL, at least about 400 ng/mL, at least about 450 ng/mL, at least about 500 ng/mL, at least about 550 ng/mL, at least about 600 ng/mL, at least about 650 ng/mL, at least about 700 ng/mL, at least about 750 ng/mL, at least about 800 ng/mL, at least about 850 ng/mL, at least about 900 ng/mL, at least about 950 ng/mL, at least about 1000 ng/mL, at least about 1100 ng/mL, at least about 1200 ng/mL, at least about 1300 ng/mL, at least about 1400 ng/mL, at least about 1500 ng/mL, at least about 1600 ng/mL, at least about 1700 ng/mL, at least about 1800 ng/mL, at least about 1900 ng/mL, at least about 2000 ng/mL, at least about 2250 ng/mL, or at least about 2500 ng/mL.

Particular embodiments herein provide ceutical formulations (e.g. immediate release oral formulations and/or formulations that release the API substantially in the stomach) comprising a cytidine analog (e.g., 5-azacytidine or another cytidine analog provided herein) that achieve a particular time to maximum plasma concentration (“Tmax”) in the subject to which the formulation is orally administered. Particular embodiments provide oral formulations that achieve a Tmax of the cytidine analog of less than about 10 min., less than about 15 min., less than about 20 min., less than about 25 min., less than about min., less than about 35 min., less than about 40 min., less than about 45 min., less than about 50 min., less than about 55 min., less than about 60 min., less than about 65 min., less than about 70 min., less than about 75 min., less than about 80 min., less than about 85 min., less than about 90 min., less than about 95 min., less than about 100 min., less than about 105 min., less than about 110 min., less than about 115 min., less than about 120 min., less than about 130 min., less than about 140 min., less than about 150 min., less than about 160 min., less than about 170 min., less than about 180 min., less than about 190 min., less than about 200 min., less than about 210 min., less than about 220 min., less than about 230 min., or less than about 240 min. In particular embodiments, the Tmax value is measured from the time at which the formulation is orally administered.

Particular embodiments herein e oral dosage forms comprising a cytidine analog, wherein the oral dosage forms have an enteric coating. Particular embodiments provide a permeable or partly permeable (e.g, “leaky”) enteric g with pores. In particular embodiments, the permeable or partly permeable enteric-coated tablet releases the -azacytidine in an immediate release manner substantially in the h. 3. Compositions of Certain Dosage Forms ed Herein Provided herein are dosage forms designed to maximize the absorption and/or efficacious delivery of certain cytidine analogs, e.g, 5-azacytidine or other cytidine analogs provided , upon oral administration, e.g., for e ntially in the stomach.

Accordingly, certain embodiments herein provide a solid oral dosage form of a cytidine analog, such as, for example, 5-azacytidine or r ne analog provided herein, using pharmaceutical excipients designed for immediate release of the API upon oral administration, 6.g. , substantially in the stomach. Particular immediate e formulations comprise a specific amount of a cytidine analog and optionally one or more ents. In certain embodiments, the formulation may be an ate release tablet or an immediate release capsule (such as, e.g., an HPMC capsule).

] Provided herein are methods of making the formulations provided herein comprising a cytidine analog provided herein (e.g., ate release oral formulations and/or formulations that release the API substantially in the stomach). In particular ments, the formulations provided herein may be prepared using conventional methods known to those skilled in the field of pharmaceutical formulation, as described, e.g., in pertinent textbooks. See, e. g., REMINGTON, THE SCIENCE AND PRACTICE OF CY, 20th Edition, cott Williams & s, (2000); ANSEL et al., PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS, 7th Edition, Lippincott Williams & Wilkins, (1999); GIBSON, PHARMACEUTICAL PREFORMULATION AND FORMULATION, CRC Press (2001).

In particular embodiments, formulations provided herein (e.g., immediate release oral formulations, formulations that release the API ntially in the stomach, or rapidly disintegrating formulations that dissolve substantially in the mouth) comprise a cytidine analog, such as, for example, 5-azacytidine or another cytidine analog provided herein, in a specific amount. In particular embodiments, the specific amount of the cytidine analog in the formulation is, e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, least about 240 mg, about 250 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 350 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 450 mg, about 460 mg, about 480 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 3000 mg, about 4000 mg, or about 5000 mg.

In ular embodiments, the specific amount of the cytidine analog in the formulation is, e.g., at least about 10 mg, at least about 20 mg, at least about 40 mg, at least about 60 mg, at least about 80 mg, at least about 100 mg, at least about 120 mg, at least about 140 mg, at least about 160 mg, at least about 180 mg, at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 250 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 340 mg, at least about 350 mg, at least about 360 mg, at least about 380 mg, at least about 400 mg, at least about 420 mg, at least about 440 mg, at least about 450 mg, at least about 460 mg, at least about 480 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 900 mg, at least about 1000 mg, at least about 1100 mg, at least about 1200 mg, at least about 1300 mg, at least about 1400 mg, at least about 1500 mg, at least about 1600 mg, at least about 1700 mg, at least about 1800 mg, at least about 1900 mg, at least about 2000 mg, at least about 2100 mg, at least about 2200 mg, at least about 2300 mg, at least about 2400 mg, at least about 2500 mg, at least about 3000 mg, at least about 4000 mg, or at least about 5000 mg.

In certain embodiments, the formulation is a tablet, wherein the tablet is manufactured using standard, art-recognized tablet sing procedures and ent. In certain embodiments, the method for forming the s is direct compression of a powdered, crystalline and/or granular composition comprising the cytidine analog, alone or in combination with one or more excipients, such as, for example, carriers, additives, polymers, or the like. In certain embodiments, as an alternative to direct compression, the tablets may be ed using wet granulation or dry granulation processes. In certain embodiments, the tablets are molded rather than compressed, starting with a moist or otherwise tractable material. In n embodiments, compression and granulation techniques are used.

In certain embodiments, the formulation is a capsule, wherein the capsules may be manufactured using standard, cognized capsule processing procedures and equipments.

In certain embodiments, soft gelatin capsules may be prepared in which the capsules contain a e of the cytidine analog and vegetable oil or non-aqueous, water miscible materials such as, for example, polyethylene glycol and the like. In certain embodiments, hard gelatin capsules may be prepared containing granules of the cytidine analog in combination with a solid pulverulent carrier, such as, for example, lactose, rose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin. In certain embodiments, a hard gelatin capsule shell may be prepared from a capsule ition comprising n and a small amount of plasticizer such as glycerol. In certain ments, as an alternative to gelatin, the capsule shell may be made of a carbohydrate material. In n embodiments, the capsule composition may additionally include polymers, colorings, ngs and opacif1ers as required. In certain embodiments, the capsule comprises HPMC.

WO 67043 In certain embodiments, the formulation of the cytidine analog, such as, for example, ytidine or another cytidine analog provided herein, is prepared using aqueous solvents without causing significant hydrolytic degradation of the cytidine analog. In particular embodiments, the formulation of the cytidine analog, such as, for example, 5- azacytidine or another cytidine analog ed herein, is a tablet which contains a coating applied to the drug core using aqueous solvents without causing significant hydrolytic degradation of the cytidine analog in the ation. In certain embodiments, water is ed as the solvent for coating the drug core. In certain embodiments, the oral dosage form of the cytidine analog is a tablet containing a film coat applied to the drug core using aqueous solvents. In particular embodiments, water is employed as the solvent for film- coating. In particular ments, the tablet containing the cytidine analog is film-coated using aqueous solvents without effecting ation of the pharmaceutical composition. In particular embodiments, water is used as the film coating solvent without effecting degradation of the pharmaceutical composition. In particular embodiments, an oral dosage form sing 5-azacytidine and an aqueous film coating effects immediate drug release upon oral delivery. In particular embodiments, the oral dosage form comprising 5- azacytidine and an aqueous film g effects controlled drug release to the upper gastrointestinal tract, e.g., the stomach, upon oral administration. In particular embodiments, a tablet with an aqueous-based film coating comprises 5-azacytidine as the API.

In certain embodiments, provided herein is a controlled release pharmaceutical formulation for oral stration of a cytidine analog that es the cytidine analog substantially in the stomach, comprising: a) a specific amount of a cytidine analog; b) a drug release controlling component for controlling the release of the cytidine analog substantially in the upper intestinal tract, e.g., the stomach; and c) optionally one or more ents.

In certain embodiments, the oral dosage form comprising the ne analog is prepared as a controlled e tablet or capsule which includes a drug core comprising the pharmaceutical ition and optional excipients. Optionally, a “seal coat” or “shell” is applied. In certain embodiments, a formulation provided herein comprising a cytidine analog provided herein is a controlled e tablet or e, which comprises a therapeutically effective amount of the cytidine analog, a drug release controlling component that controls the release of the cytidine analog substantially in the stomach upon oral administration, and optionally, one or more excipients.

Particular embodiments provide a drug release controlling component that is a polymer matrix, which swells upon exposure to gastric fluid to effect the gastric retention of the formulation and the sustained release of the cytidine analog from the polymer matrix substantially in the h. In certain embodiments, such formulations may be prepared by incorporating the cytidine analog into a suitable polymeric matrix during formulation.

Examples of such formulations are known in the art. See, e.g., Shell et al., US. Patent Publication No. 2002/0051820 (Application No. 09/990,061); Shell et al., US. Patent Publication No. 2003/0039688 (Application No. 10/045,823); Gusler et al., US. Patent Publication No. 2003/0104053 (Application No. 10/029, 134), each of which is incorporated herein by reference in its entirety.

In certain embodiments, the drug e controlling component may comprise a shell nding the ontaining core, wherein the shell releases the cytidine analog from the core by, e.g., permitting diffusion of the ne analog from the core and promoting gastric retention of the formulation by swelling upon exposure to gastric fluids to a size that is retained in the stomach. In certain embodiments, such ations may be prepared by first compressing a mixture of the cytidine analog and one or more excipients to form a drug core, and compressing r powdered mixture over the drug core to form the shell, or ing the drug core with a capsule shell made of le materials. Examples of such formulations are known in the art. See, e.g., Bemer et al., US. Patent ation No. 2003/0104062 Application No. 10/213,823), incorporated herein by reference in its entirety.

Certain embodiments herein provide oral dosage forms comprising a cytidine analog, wherein the dosage form contains pores in the conventional enteric coating. In particular embodiments, the oral dosage form of the cytidine analog is a tablet that ns a permeable or partly ble (e.g., “leaky”) enteric coating with pores. In particular embodiments, the permeable or partly permeable enteric-coated tablet controls the release of the cytidine analog from the tablet primarily to the upper gastrointestinal tract, 6.g. the stomach. In particular ments, the permeable or partly ble enteric-coated tablet comprises 5-azacytidine. In particular embodiments, the remainder of the cytidine analog is subsequently released beyond the stomach (e.g., in the intestine).

In certain embodiments, the pharmaceutical formulation ed herein is a compressed tablet sing a cytidine analog. In addition to the cytidine , the tablet optionally comprises one or more excipients, including (a) diluents or fillers, which may add necessary bulk to a formulation to prepare tablets of the desired size; (b) binders or adhesives, which may promote adhesion of the les of the formulation, enabling a granulation to be prepared and maintaining the integrity of the final ; (c) disintegrants or disintegrating agents, which, after administration, may promote breakup of the tablets to smaller particles for improved drug availability; (d) anti-adherents, glidants, ants or ating agents, which may enhance flow of the tableting material into the tablet dies, minimize wear of the punches and dies, prevent the sticking of fill material to the punches and dies, and produce s having a sheen; and (e) miscellaneous adjuncts such as colorants and flavorants. After ssion, tablets provided herein may be coated with various materials as described herein.

In certain embodiments, the pharmaceutical formulation provided herein is a multiple compressed tablet of a cytidine analog. Multiple compressed tablets are prepared by subjecting the fill material to more than a single compression. The result may be a multiple- layered tablet or a tablet-within-a-tablet, the inner tablet being the core comprising a cytidine analog and optionally one or more excipients, and the outer portion being the shell, n the shell comprises one or more excipients, and may or may not contain the ne analog.

Layered tablets may be prepared by the l compaction of a portion of fill material in a die ed by onal fill material and compression to form two- or three-layered tablets, depending upon the number of separate fills. Each layer may contain a different therapeutic agent, separate from one another for reasons of chemical or physical incompatibility, or the same therapeutic agent for staged drug release, or simply for the unique appearance of the multiple-layered tablet. Each n of fill may be colored differently to prepare a distinctive looking tablet. In the preparation of tablets having a compressed tablet as the inner core, special machines may be used to place the preformed tablet precisely within the die for the subsequent compression of surrounding fill material.

In certain embodiments, the compressed tablet of a cytidine analog may be coated with a colored or an uncolored sugar layer. The g may be water-soluble and quickly dissolved after oral ingestion. The sugar coating may serve the purpose of protecting the enclosed drug from the environment and providing a barrier to an objectionable taste or smell. The sugar coating may also enhance the appearance of the ssed tablet and permit the imprinting of identifying manufacturer’s information. In n embodiments, sugar-coated tablets may be 50% larger and heavier than the original uncoated tablets. The sugar-coating of tablets may be divided into the following optional steps: (1) waterproofing and sealing (if needed); (2) sub-coating; (3) smoothing and final rounding; (4) finishing and coloring (if desired); (5) imprinting (if needed); and (6) polishing.

In n embodiments, the compressed tablet of a cytidine analog may be film- coated. Film-coated tablets may be compressed tablets coated with a thin layer of a polymer e of g a skin-like film over the tablet. The film is usually colored and has the advantage to be more durable, less bulky, and less time-consuming to apply. By its composition, the coating may be designed to rupture and expose the core tablet at the desired location within the gastrointestinal tract. The film-coating process, which places a thin skin- tight coating of a plastic-like material over the compressed tablet, may produce coated tablets having ially the same , shape, and size as the originally compressed tablet. The film-coating may be colored to make the tablets attractive and distinctive. Film-coating solutions may be non-aqueous or aqueous. In particular embodiments, the ueous solutions may optionally contain one or more of the following types of materials to provide the desired coating to the tablets: (l) a film former e of producing smooth, thin films reproducible under conventional coating conditions and applicable to a variety of tablet shapes, such as, for example, cellulose acetate phthalate; (2) an alloying substance ing water solubility or permeability to the film to ensure penetration by body fluids and therapeutic availability of the drug, such as, for example, polyethylene glycol; (3) a plasticizer to produce flexibility and elasticity of the coating and thus provide durability, such as, for example, castor oil; (4) a surfactant to enhance spreadability of the film during ation, such as, for example, polyoxyethylene sorbitan derivatives; (5) opaquants and colorants to make the appearance of the coated tablets attractive and distinctive, such as, for e, titanium dioxide as an opaquant, and FD&C or D&C dyes as a colorant; (6) sweeteners, flavors, or aromas to enhance the acceptability of the tablet to the subject, such as, for example, saccharin as ners, and vanillin as flavors and aromas; (7) a glossant to provide a luster to the tablets without a separate polishing operation, such as, for example, beeswax; and (8) a volatile solvent to allow the spread of the other components over the tablets while allowing rapid evaporation to permit an effective yet speedy operation, such as, for e, alcohol-acetone e. In certain embodiments, an aqueous ating formulation may contain one or more of the ing: (1) film-forming polymer, such as, for example, cellulose ether polymers as hydroxypropyl methyl-cellulose, hydroxypropyl cellulose, and -cellulose; (2) plasticizer, such as, for example, glycerin, propylene glycol, polyethylene glycol, l phthalate, and dibutyl tate; (3) colorant and opacif1er, such as, for example, FD&C or D&C lakes and iron oxide pigments; or (4) vehicle, such as, for example, water.

In certain embodiments, the ssed tablet of a cytidine analog may be ssion-coated. The coating material, in the form of a granulation or powder, may be ssed onto a tablet core of drug with a special tablet press.

In n embodiments, the ceutical formulation is a gelatin-coated tablet comprising a cytidine analog. A gelatin-coated tablet is a capsule-shaped compressed tablet that allows the coated product to be smaller than a capsule filled with an equivalent amount of powder. The gelatin coating facilitates swallowing and compared to unsealed capsules, gelatin-coated s may be more tamper-evident.

In certain embodiments, the pharmaceutical formulation may be a gual tablet of a cytidine analog. The sublingual tablet is ed to be dissolved beneath the tongue for absorption h the oral mucosa. The gual tablet may dissolve ly and provide rapid release of the drug.

In certain embodiments, the pharmaceutical formulation is an immediate release tablet of a cytidine analog. In certain embodiments, the immediate e tablet is designed, e.g., to disintegrate and release the API absent of any special ontrolling features, such as l coatings and other techniques. In certain embodiments, the formulation is a rapidly disintegrating tablet that, e.g., dissolves substantially in the mouth following administration.

In certain embodiments, the pharmaceutical formulation is an extended release tablet of a cytidine analog. In certain embodiments, the extended release tablet is designed, e.g., to release the API over an extended period of time and substantially in the stomach.

In certain embodiments, compressed tablets may be prepared by wet granulation.

Wet granulation is a widely employed method for the production of compressed tablets, and, in particular embodiments, requires one or more the following steps: (1) weighing and blending the ingredients; (2) preparing a damp mass; (3) screening the damp mass into pellets or granules; (4) drying the granulation; (5) sizing the granulation by dry screening; (6) adding ant and blending; and (7) tableting by compression.

In certain embodiments, compressed tablets may be prepared by dry granulation.

By the dry granulation method, the powder mixture is compacted in large pieces and subsequently broken down or sized into granules. But this method, either the active ingredient or the diluent has cohesive property. After weighing and mixing the ingredients, the powder mixture may be slugged or compressed into large flat tablets or pellets. The slugs then are broken up by hand or by a mill and passed h a screen of desired mesh for sizing. ant is added in the usual manner, and tablets are ed by compression.

Alternatively, instead of slugging, powder compactors may be used to increase the density of a powder by pressing it between high-pressure rollers. The compressed material then is broken up, sized, and lubricated, and tablets are prepared by compression in the usual . The roller compaction method is often preferred over slugging. Binding agents used in roller compaction ations include methylcellulose or hydroxyl-methylcellulose and can produce good tablet hardness and friability.

In n embodiments, compressed s may be prepared by direct compression. Some ar chemicals possess free flowing and cohesive ties that enable them to be ssed directly in a tablet machine without the need of wet or dry granulation. For chemicals that do not possess this quality, special pharmaceutical ents may be used which impart the necessary qualities for the production of tablets by direct ssion. ular tableting excipients include, e.g.: fillers, such as dried lactose, micro-crystals of alpha-monohydrate lactose, e-invert sugar-corn starch mixtures, micro-crystalline cellulose, crystalline maltose, and di-calcium phosphate; disintegrating agents, such as direct-compression starch, sodium carboxymethyl starch, cross-linked carboxymethylcellulose fibers, and cross-linked nylpyrrolidone; lubricants, such as magnesium searate and talc; and glidants, such as filmed silicon dioxide.

In certain embodiments, tablets provided herein may be prepared by molding.

The base for molded tablets is generally a mixture of finely powdered lactose with or without a portion of powdered sucrose. In preparing the fill, the drug is mixed uniformly with the base by geometric dilution. The powder mixture may be wetted with a mixture of water and alcohol sufficient only to dampen the powder so that it may be compacted. The solvent action of the water on a portion of the lactose/sucrose base effects the biding of the powder mixture upon drying. The alcohol portion hastens the drying process.

In certain ments, the pharmaceutical formulations provided herein contain a cytidine analog and, optionally, one or more excipients to form a “drug core.” Optional excipients include, e.g., diluents (bulking agents), lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, coloring , flavoring agents, binding agents, excipient supports, glidants, permeation enhancement excipients, plasticizers and the like, e.g., as known in the art. It will be understood by those in the art that some substances serve more than one purpose in a pharmaceutical composition. For instance, some substances are binders 2012/062845 that help hold a tablet together after compression, yet are also disintegrants that help break the tablet apart once it reaches the target delivery site. Selection of excipients and amounts to use may be readily determined by the formulation scientist based upon experience and eration of standard procedures and nce works available in the art.

In certain embodiments, formulations provided herein se one or more binders. Binders may be used, e.g., to impart cohesive ies to a tablet, and thus ensure that the tablet remains intact after compression. Suitable binders include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, propylene , waxes, and l and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl ose, hydroxypropylmethylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and the like), veegum, carbomer (e.g., carbopol), sodium, dextrin, guar gum, hydrogenated vegetable oil, magnesium aluminum silicate, maltodextrin, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), microcrystalline cellulose, among . Binding agents also include, e.g., acacia, agar, alginic acid, cabomers, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioner’s sugar, copovidone, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl ose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, , lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethylacrylates, povidone, sodium te, sodium carboxymethylcellulose, starch, pregelatinized starch, stearic acid, sucrose, and zein. The binding agent can be, relative to the drug core, in the amount of about 2% W/W of the drug core; about 4% W/W of the drug core, about 6% W/W of the drug core, about 8% W/W of the drug core, about 10% W/W of the drug core, about 12% W/W of the drug core, about 14% W/W of the drug core, about 16% W/W of the drug core, about 18% W/W of the drug core, about % W/W of the drug core, about 22% W/W of the drug core, about 24% W/W of the drug core, about 26% W/W of the drug core, about 28% W/W of the drug core, about 30% W/W of the drug core, about 32% W/W of the drug core, about 34% W/W of the drug core, about 36% W/W of the drug core, about 38% W/W of the drug core, about 40% W/W of the drug core, about 42% W/W of the drug core, about 44% W/W of the drug core, about 46% W/W of the drug core, about 48% W/W of the drug core, about 50% W/W of the drug core, about 52% W/W of the drug core, about 54% W/W of the drug core, about 56% W/W of the drug core, about 58% W/W of the drug core, about 60% W/W of the drug core, about 62% W/W of the drug core, about 64% W/W of the drug core, about 66% W/W of the drug core; about 68% W/W of the drug core, about 70% W/W of the drug core, about 72% W/W of the drug core, about 74% W/W of the drug core, about 76% W/W of the drug core, about 78% W/W of the drug core, about 80% W/W of the drug core, about 82% W/W of the drug core, about 84% W/W of the drug core, about 86% W/W of the drug core, about 88% W/W of the drug core, about 90% W/W of the drug core, about 92% W/W of the drug core, about 94% W/W of the drug core, about 96% W/W of the drug core, about 98% W/W of the drug core, or more, if determined to be appropriate. In certain embodiments, a suitable amount of a particular binder is determined by one of ordinary skill in the art.

In certain ments, formulations ed herein comprise one or more diluents. Diluents may be used, 6.g. to increase bulk so that a practical size tablet is ultimately provided. Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, ol, sodium chloride, dry starch, rystalline cellulose (e.g., AVICEL), microf1ne cellulose, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, n, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT), potassium chloride, sodium chloride, sorbitol and talc, among others. Diluents also include, e.g., ammonium alginate, calcium ate, calcium phosphate, calcium sulfate, cellulose acetate, compressible sugar, confectioner’s sugar, tes, dextrin, dextrose, erythritol, ethylcellulose, se, fumaric acid, glyceryl palmitostearate, t, kaolin, lacitol, lactose, mannitol, magnesium ate, magnesium oxide, extrin, maltose, medium-chain triglycerides, microcrystalline cellulose, microcrystalline silicified cellulose, d cellulose, polydextrose, polymethylacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized , sucrose, sulfobutylether-[3-cyclodextrin, talc, tragacanth, trehalose, and xylitol. Diluents may be used in amounts calculated to obtain a desired volume for a tablet or capsule; in certain embodiments, a diluent is used in an amount of about 5% or more, about 10% or more, about % or more, about 20% or more, about 22% or more, about 24% or more, about 26% or more, about 28% or more, about 30% or more, about 32% or more, about 34% or more, about 36% or more, about 38% or more, about 40% or more, about 42% or more, about 44% or more, about 46% or more, about 48% or more, about 50% or more, about 52% or more, about 54% or more, about 56% or more, about 58% or more, about 60% or more, about 62% or more, about 64% or more, about 68% or more, about 70% or more, about 72% or more, about 74% or more, about 76% or more, about 78% or more, about 80% or more, about 85% or more, about 90% or more, or about 95% or more, weight/weight, of a drug core; between about 10% and about 90% w/w of the drug core; between about 20% and about 80% w/w of the drug core; between about 30% and about 70% w/w of the drug core; n about 40% and about 60% w/w of the drug core. In certain embodiments, a le amount of a particular diluent is determined by one of ordinary skill in the art.

In certain ments, formulations provided herein comprise one or more lubricants. Lubricants may be used, e.g., to facilitate tablet manufacture; examples of suitable lubricants include, for example, vegetable oils such as peanut oil, seed oil, sesame oil, olive oil, corn oil, and oil of theobroma, in, magnesium stearate, calcium stearate, and stearic acid. In n embodiments, stearates, if present, represent no more than approximately 2 weight % of the drug-containing core. Further examples of lubricants include, e.g., calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, magnesium lauryl sulfate, magnesium stearate, myristic acid, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. In particular embodiments, the lubricant is magnesium te. In certain embodiments, the lubricant is present, relative to the drug core, in an amount of about 0.2% w/w of the drug core, about 0.4% w/w of the drug core, about 0.6% w/w of the drug core, about 0.8% w/w of the drug core, about 1.0% w/w of the drug core, about 1.2% w/w of the drug core, about 1.4% w/w of the drug core, about 1.6% w/w of the drug core, about 1.8% w/w of the drug core, about 2.0% w/w of the drug core, about 2.2% w/w of the drug core, about 2.4% w/w of the drug core, about 2.6% w/w of the drug core, about 2.8% w/w of the drug core, about 3.0% w/w of the drug core, about 3.5% w/w of the drug core, about 4% w/w of the drug core, about 4.5% w/w of the drug core, about 5% w/w of the drug core, about 6% w/w of the drug core, about 7% w/w of the drug core, about 8% w/w of the drug core, about 10% w/w of the drug core, about 12% w/w of the drug core, about 14% w/w of the drug core, about 16% w/w of the drug core, about 18% w/w of the drug core, about 20% w/w of the drug core, about 25% w/w of the drug core, about 30% w/w of the drug core, about 35% w/w of the drug core, about 40% w/w of the drug core, between about 0.2% and about 10% w/w of the drug core, between about 0.5% and about 5% w/w of the drug core, or between about 1% and about 3% w/w of the drug core. In certain embodiments, a suitable amount of a particular lubricant is determined by one of ordinary skill in the art.

In certain embodiments, ations provided herein comprise one or more disintegrants. Disintegrants may be used, e.g., to facilitate disintegration of the tablet, and may be, e.g., starches, clays, celluloses, , gums or crosslinked polymers. Disintegrants also include, e.g., alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL, PRIMELLOSE), colloidal silicon dioxide, rmellose sodium, crospovidone (e.g., KOLLIDON, POLYPLASDONE), guar gum, magnesium um te, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., EXPLOTAB) and starch. Additional egrants include, e.g., calcium alginate, chitosan, sodium docusate, hydroxypropyl cellulose, and povidone. In certain embodiments, the disintegrant is, relative to the drug core, present in the amount of about 1% w/w of the drug core, about 2% w/w of the drug core, about 3% w/w of the drug core, about 4% w/w of the drug core, about 5% w/w of the drug core, about 6% w/w of the drug core, about 7% w/w of the drug core, about 8% w/w of the drug core, about 9% w/w of the drug core, about 10% w/w of the drug core, about 12% w/w of the drug core, about 14% w/w of the drug core, about 16% w/w of the drug core, about 18% w/w of the drug core, about 20% w/w of the drug core, about 22% w/w of the drug core, about 24% w/w of the drug core, about 26% w/w of the drug core, about 28% w/w of the drug core, about 30% w/w of the drug core, about 32% w/w of the drug core, greater than about 32% w/w of the drug core, between about 1% and about 10% w/w of the drug core, n about 2% and about 8% w/w of the drug core, between about 3% and about 7% w/w of the drug core, or between about 4% and about 6% w/w of the drug core. In n embodiments, a suitable amount of a particular disintegrant is determined by one of ordinary skill in the art.

In certain embodiments, ations provided herein comprise one or more stabilizers. Stabilizers (also called absorption enhancers) may be used, e.g., to inhibit or retard drug decomposition reactions that include, by way of e, oxidative reactions.

Stabilizing agents include, e.g., d-Alpha-tocopheryl hylene glycol 1000 succinate in E TPGS), acacia, albumin, alginic acid, aluminum stearate, ammonium alginate, ascorbic acid, ascorbyl palmitate, bentonite, ted hydroxytoluene, calcium alginate, calcium stearate, calcium carboxymethylcellulose, carrageenan, ceratonia, colloidal silicon dioxide, cyclodextrins, diethanolamine, edetates, ethylcellulose, ethyleneglycol palmitostearate, glycerin monostearate, guar gum, hydroxypropyl cellulose, hypromellose, invert sugar, lecithin, magnesium aluminum silicate, monoethanolamine, , poloxamer, polyvinyl alcohol, potassium alginate, potassium ilin, povidone, propyl gallate, propylene glycol, propylene glycol alginate, raffinose, sodium acetate, sodium alginate, sodium borate, sodium carboxymethyl cellulose, sodium stearyl fiamarate, sorbitol, stearyl l, sufobutyl-b-cyclodextrin, trehalose, white wax, xanthan gum, xylitol, yellow wax, and zinc acetate. In certain embodiments, the stabilizer is, relative to the drug core, present in the amount of about 1% w/w of the drug core, about 2% w/w of the drug core, about 3% w/w of the drug core, about 4% w/w of the drug core, about 5% w/w of the drug core, about 6% w/w of the drug core, about 7% w/w of the drug core, about 8% w/w of the drug core, about 9% w/w of the drug core, about 10% w/w of the drug core, about 12% w/w of the drug core, about 14% w/w of the drug core, about 16% w/w of the drug core, about 18% w/w of the drug core, about 20% w/w of the drug core, about 22% w/w of the drug core, about 24% w/w of the drug core, about 26% w/w of the drug core, about 28% w/w of the drug core, about % w/w of the drug core, about 32% w/w of the drug core, n about 1% and about % w/w of the drug core, between about 2% and about 8% w/w of the drug core, between about 3% and about 7% w/w of the drug core, or between about 4% and about 6% w/w of the drug core. In certain embodiments, a suitable amount of a particular izer is determined by one of ry skill in the art.

In certain embodiments, formulations provided herein se one or more glidants. Glidants may be used, e.g., to improve the flow properties of a powder ition or granulate or to improve the accuracy of dosing. Excipients that may fianction as glidants include, e.g., colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, , tribasic calcium phosphate, m silicate, powdered cellulose, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, ic calcium phosphate, and talc. In certain embodiments, the glidant is, relative to the drug core, present in the amount of less than about 1% w/w of the drug core, about 1% w/w of the drug core, about 2% w/w of the drug core, about 3% w/w of the drug core, about 4% w/w of the drug core, about 5% w/w of the drug core, about 6% w/w of the drug core, about 7% w/w of the drug core, about 8% w/w of the drug core, about 9% w/w of the drug core, about 10% w/w of the drug core, about 12% w/w of the drug core, about 14% w/w of the drug core, about 16% w/w of the drug core, about 18% w/w of the drug core, about 20% w/w of the drug core, about 22% w/w of the drug core, about 24% w/w of the drug core, about 26% w/w of the drug core, about 28% w/w of the drug core, about 30% w/w of the drug core, about 32% w/w of the drug core, between about 1% and about 10% w/w of the drug core, between about 2% and about 8% w/w of the drug core, between about 3% and about 7% w/w of the drug core, or n about 4% and about 6% w/w of the drug core. In certain embodiments, a suitable amount of a particular glidant is determined by one of ordinary skill in the art.

In one embodiment, formulations provided herein se one or more complexing agents. In certain embodiments, the complexing agents include, but are not limited to, cyclodextrins, including oc-cyclodextrin, [3-cyclodextrin, ypropyl-[3- cyclodextrin, sulfobutylether-[3-cyclodextrin, and sulfobutylether 7-[3-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

] In certain embodiments, formulations provided herein comprise one or more permeation enhancers (also called, e.g., permeability enhancers). In n embodiments, the permeation enhancer enhances the uptake of a cytidine analog through the gastrointestinal wall (6.g. the stomach). In certain ments, the permeation er alters the rate and/or amount of the ne analog that enters the bloodstream. In ular embodiments, d-alpha-tocopheryl polyethylene glycol-1000 succinate (Vitamin E TPGS) is used as a permeation enhancer. In particular embodiments, one or more other suitable permeation enhancers are used, including, 6.g. enhancer known in the art. , any permeation c es of le permeation enhancers include, e.g., those listed below: Example of Product name Chemical Name Supplier Pluronic F 127 Poloxamer F 127 Sigma Lutrol F 68 Poloxamer 188 BASF Carbopol 934-P Carbomer 934-P Spectrum Chemical Tween 80 Polysorbate 80 Sigma Chitosan Chitosan Low Mol Wt Aldrich Capric acid/Na cap Sodium Decanoate Sigma Lauric acid/Na laur Sodium Dodecanoate Sigma Disodium EDTA Ethylenediamine tetraacetic acid Sigma disodium dihydrate Propylene glycol 1, 2 Propanediol Sigma CM Cellulose Carboxymethyl Cellulose Sigma Labrasol Caprylocaproyl macrogol-8 glycerides Gattefosse N,N— Dimethylacetamide (minimum 99%) Sigma Vitamin E TPGS d-Alpha-Tocopheryl Polyethylene n Glycol-1000 Succinate Solutol HS 15 Polyethylene glycol 660 12- BASF hydroxystearate Labrafil M 1944 CS (2) Oleyl Macrogolglyerides Gattefosse Other potential permeation enhancers e, e.g., alcohols, yl ide, glyceryl monooleate, glycofurol, isopropyl myristate, isopropyl ate, lanolin, linoleic acid, myristic acid, oleic acid, oleyl l, palmitic acid, polyoxyethylene alkyl ethers, 2- pyrrolidone, sodium lauryl sulfate, and thymol.

In certain embodiments, the permeation enhancer is present in the formulation in an amount by weight, relative to the total weight of the formulation, of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1% about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.1% about 5.2%, about 5.3%, about .4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about 6%, about 6.1% about 6.2%, about 6.3%, about 6.4%, about 6.5%, about 6.6%, about 6.7%, about 6.8%, about 6.9%, about 7%, about 7.1% about 7.2%, about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8%, about 8.1% about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9%, about 9.1% about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9%, about 10%, greater than about 10%, greater than about 12%, greater than about 14%, greater than about 16%, greater than about 18%, greater than about 20%, greater than about %, r than about 30%, greater than about 35%, greater than about 40%, greater than about 45%, or greater than about 50%. In certain embodiments, the riate amount of a suitable permeation enhancer provided herein is determined by one of skill in the art.

Without intending to be limited to any particular theory, the permeation enhancers provided herein may function by, inter alia, facilitating (e.g. , increasing the rate or extent of) the transport of a ne analog through the gastrointestinal wall. In general, movement through the gastrointestinal wall may occur by, e.g: passive diffiJsion, such as the movement of drug across a membrane in a manner driven solely by the concentration gradient; carrier- mediated diffusion, such as the movement of drug across a cell membrane via a specialized transport system embedded in the cell membrane; paracellular diffusion, such as the nt of a drug across a membrane by going between, rather than through, two cells; and transcellular diffusion, such as the movement of a drug across the cell. Additionally, there are us ar proteins e of preventing intracellular lation of drugs by pumping out drug that enters the cell. These are sometimes called efflux pumps. One such efflux pump is that involving p-glycoprotein, which is present in many ent tissues in the body (e.g., intestine, placental membrane, blood-brain barrier). Permeation enhancers can function by, inter alia, tating any of the ses mentioned above (such as by sing fluidity of membranes, opening tight junctions between cells, and/or inhibiting efflux, among others).

In n embodiments, the compositions provided herein comprising a cytidine analog, e.g., 5-azacytidine or another cytidine analog provided herein, are essentially free of a cytidine deaminase inhibitor (6.g. , do not comprise a cytidine ase tor). In certain embodiments, the compositions provided herein are essentially free of (e.g., do not comprise) the cytidine deaminase inhibitor tetrahydrouridine (THU). Certain embodiments herein provide pharmaceutical compositions comprising a therapeutically effective amount of a cytidine analog (6.g. , 5-azacytidine or another cytidine analog provided herein), wherein the compositions release the cytidine analog substantially in the stomach following oral administration to a subject, and wherein the compositions are essentially free of (e.g., do not comprise) a cytidine deaminase inhibitor (6.g. , THU). Certain embodiments herein e pharmaceutical compositions comprising a therapeutically effective amount of a cytidine analog (6.g. , 5-azacytidine or another cytidine analog provided herein), wherein the compositions e the cytidine analog substantially in the stomach following oral administration to a subject, wherein the compositions are essentially free of (e.g., do not comprise) a cytidine ase tor (e.g., THU), and wherein the compositions achieve a particular biological parameter provided herein (e.g., a particular Cmax value, Tmax value, and/or AUC value provided herein). In particular embodiments, a composition provided herein that is essentially free of a cytidine deaminase inhibitor (e.g., THU) comprises, e.g., less than 200 mg, less than 150 mg, less than 100 mg, less than 50 mg, less than 25 mg, less than 10 mg, less than 5 mg, less than 1 mg, or less than 0.1 mg of the cytidine deaminase inhibitor. 4. Other Embodiments of Oral Dosage Forms In other embodiments, the pharmaceutical compositions provided herein may be provided as ssed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or c-coating tablets, sugar-coated, or film-coated tablets. In one embodiment, enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric- coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in ting the tablets from oxidation. Film-coated s are compressed tablets that are covered with a thin layer or film of a water-soluble material.

Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. In one embodiment, film coating imparts the same general characteristics as sugar g. le compressed tablets are compressed tablets made by more than one compression cycle, including layered s, and press-coated or ated tablets.

In one embodiment, the tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including s, disintegrants, controlled- e polymers, lubricants, ts, and/or colorants. Flavoring and sweetening agents are useful in the formation of chewable tablets and lozenges.

In one embodiment, the pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the led capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft c capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the on of glycerin, sorbitol, or a similar . The soft gelatin shells may contain a preservative to t the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and lid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in US. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. 2012/062845 In one embodiment, the pharmaceutical compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is sed in the form of small globules throughout another liquid, which can be oil-in-water or water-in- oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, fying agent, and vative. Suspensions may e a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically able acetal, such as a di(lower alkyl) acetal of a lower alkyl de, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a hylene glycol may be diluted with a ient quantity of a pharmaceutically able liquid carrier, e.g., water, to be measured conveniently for administration.

In one embodiment, other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) ed herein, and a dialkylated mono- or poly-alkylene glycol, including, l,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycoldimethyl ether, hylene glycoldimethyl ether, polyethylene glycoldimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, propionic acid and its esters, and dithiocarbamates.

In one embodiment, the pharmaceutical compositions provided herein may be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may e diluents, sweeteners, and wetting agents.

Pharmaceutically acceptable carriers and excipients used in the escent granules or powders may include organic acids and a source of carbon dioxide. ng and flavoring agents can be used in the dosage forms provided herein.

] In one embodiment, the pharmaceutical itions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

In one embodiment, the pharmaceutical compositions provided herein may be co- formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action.

In one embodiment, active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in US. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, ,120,548, 5,073,543, 476, 5,354,556, and 5,733,566, each ofwhich is incorporated herein by nce. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, ropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic s, multilayer coatings, microparticles, liposomes, microspheres, or a ation thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active agents provided herein. In one embodiment, provided are single unit dosage forms suitable for oral administration such as, but not d to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.

In one embodiment, controlled-release pharmaceutical products improve drug therapy over that achieved by their non-controlled counterparts. In another embodiment, the use of a controlled-release preparation in medical treatment is terized by a minimum of drug substance being employed to cure or control the ion in a minimum amount of time. ages of controlled-release ations include extended ty of the drug, reduced dosage frequency, and increased patient ance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

In another embodiment, the controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired eutic or prophylactic effect, and gradually and continually release of other amounts of drug to maintain this level of eutic or prophylactic effect over an extended period of time. In one embodiment, in order to maintain a constant level of drug in the body, the drug can be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

. Parenteral Dosage Forms In another ment, the pharmaceutical compositions provided herein may be administered parenterally by injection, on, or implantation, for local or systemic administration. Parenteral administration, as used herein, include enous, rterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

] In one embodiment, the pharmaceutical compositions provided herein may be ated in dosage forms that are suitable for eral administration, ing solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, e. g., Remington, The e and Practice ofPharmacy, supra).

In one embodiment, the pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically able carriers and excipients, including, but not limited to, aqueous es, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local etics, ding and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, otectants, lyoprotectants, ning agents, pH adjusting agents, and inert gases.

In one embodiment, suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers ion, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles e, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, l,3-butanediol, liquid polyethylene glycol (e.g, polyethylene glycol 300 and hylene glycol 400), propylene glycol, in, N—methyl- 2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

In one embodiment, le antimicrobial agents or preservatives e, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, butanol, methyl and propyl oxybenzoates, thimerosal, konium chloride (6.g. , benzethonium chloride), methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable ing agents include, but are not limited to, ate and citrate. Suitable antioxidants are those as described herein, including bisulf1te and sodium metabisulf1te. Suitable local anesthetics include, but are not limited to, procaine hloride. le suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine . Suitable tering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable xing agents include, but are not limited to, cyclodextrins, ing oc-cyclodextrin, [3-cyclodextrin, hydroxypropyl-[3-cyclodextrin, sulfobutylether-[3-cyclodextrin, and sulfobutylether 7-[3- cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

In one embodiment, the pharmaceutical compositions provided herein may be formulated for single or multiple dosage administration. The single dosage formulations are packaged in an ampoule, a vial, or a syringe. The multiple dosage parenteral formulations may contain an antimicrobial agent at bacteriostatic or fiangistatic concentrations. All eral formulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided as to-use sterile solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile suspensions. In yet another embodiment, the ceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical compositions are provided as ready-to-use sterile emulsions.

In one embodiment, the pharmaceutical itions provided herein may be formulated as immediate or modified e dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.

In one embodiment, the pharmaceutical compositions may be formulated as a suspension, solid, semi-solid, or ropic liquid, for administration as an implanted depot.

In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric ne that is insoluble in body fluids but allows the active ingredient in the ceutical compositions diffilse through.

In one embodiment, suitable inner matrixes include polymethylmethacrylate, polybutyl-methacrylate, plasticized or ticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural , polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone s, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed nyl acetate.

In one embodiment, le outer polymeric membranes include polyethylene, polypropylene, ethylene/propylene mers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, nylchloride, vinyl chloride mers with vinyl e, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyloxyethanol copolymer, and ne/vinyl acetate/vinyl alcohol terpolymer.

In specific embodiments, provided herein is a pharmaceutical composition prepared for parenteral administration (6.g. , IV or SC). In one embodiment, the composition comprises 5-azacytidine as a lyophilized powder. In one embodiment, the composition comprises 5-azacytidine and mannitol as a lyophilized powder. In one embodiment, the amount of 5-azacytidine in the composition is about 100 mg. In one embodiment, the weight ratio of ytidine to ol is about 1:1. In one embodiment, the lyophilized powder comprising 5-azacytidine is reconstituted with sterile water for IV or SC administration. In one embodiment, the dose for parenteral stration is about 75 mg/m2. In one embodiment, the dose for parenteral administration is from about 75 mg/m2 to about 100 mg/mz. In specific embodiments, the composition is administered daily for 7 days at a dose of about 75 mg/m2 to about 100 mg/mz. In specific embodiments, the composition is administered daily for 7 days at a dose of about 75 mg/m2 to about 100 mg/mz, and the cycle is repeated every 4 weeks. In one embodiment, the compositions is administered for at least 4 to 6 cycles.

In some embodiments, azacitidine is administered at about 20—200 mg/kg per day (including for e 50 mg/kg, 80 mg/kg, 100 mg/kg, 120 mg/kg, 140 mg/kg, 180 mg/kg).

In some ments, decitabine is administered at about 0.75—4 mg/kg per day (including for example 1.0 mg/kg, 15 mg/kg, 2.00 mg/kg, 2.5 mg/kg, 3.0 mg/kg, 3.5 .

] In some embodiments, azacitidine or decitabine is administered at about 10—200 mg/m2 (including for example about 50—100 mg/m2 or for example about 75 mg/mz). 6. Topical Dosage Forms In yet another embodiment, the pharmaceutical compositions provided herein may be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, ies, bougies, poultices or cataplasm, pastes, powders, ngs, creams, plasters, ceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes as described in, e.g., Remington, The Science and Practice ofPharmacy, supra.

In one embodiment, rectal, urethral, and l suppositories are solid bodies for insertion into body orifices, which are solid at ry atures but melt or soften at body temperature to release the active ient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as bed herein, including te and sodium sulf1te. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and cerides of fatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin. Combinations of the various vehicles may be used. Rectal and vaginal suppositories may be prepared by the compressed method or molding. The typical weight of a rectal and l suppository is about 2 to about 3 g.

In one embodiment, the pharmaceutical compositions provided herein may be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions may be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using ohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a le propellant, such as 2-tetrafluoroethane or l,l,l,2,3,3,3-heptafluoropropane.

The pharmaceutical itions may also be ed as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For asal use, the powder may comprise a bioadhesive agent, ing chitosan or cyclodextrin.

In one embodiment, solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer may be formulated to contain ethanol, aqueous ethanol, or a le alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein, a propellant as t; and/or a surfactant, such as an trioleate, oleic acid, or an oligolactic acid.

In one embodiment, the pharmaceutical compositions provided herein may be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes may be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high re homogenization, or spray drying.

In one embodiment, capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the pharmaceutical itions provided herein; a le powder base, such as lactose or starch; and a performance modifier, such as L-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhaled/intranasal administration may fiarther comprise a suitable flavor, such as menthol and levomenthol, or ners, such as saccharin or saccharin sodium.

In one embodiment, the pharmaceutical compositions provided herein for topical administration may be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release. 7. Additional Therapeutic Agents In some embodiments, provided herein is a pharmaceutical composition comprising one, two, three, or more other cologically active substances (also termed herein “additional therapeutic agents, 3, “second active agents,” or the like) (6.g. other than cytidine ). In some embodiments, the cytidine analog formulations provided herein further comprise one, two, three, or more other pharmacologically active substances (also termed herein “additional therapeutic agents,3, “second active agents,” or the like). In other embodiments, the cytidine analog formulations provided herein is co-administered with one, two, three, or more other pharmacologically active nces. In particular embodiments, the oral formulations provided herein comprise the additional therapeutic agent(s) in a therapeutically effective amount. In ular embodiments, the cytidine analog (e.g., 5- azacytidine or another cytidine analog provided herein) and the onal therapeutic agent(s) are co-formulated together in the same dosage form using methods of co-formulating active pharmaceutical ingredients, including methods disclosed herein and methods known in the art. In other embodiments, the cytidine analog (e.g., 5-azacytidine or another ne analog provided herein) and the additional therapeutic agent(s) are co-administered in separate dosage forms. It is ed that certain combinations work istically in the treatment of particular diseases or disorders, including, e.g., types of cancer and n diseases and conditions ated with, or characterized by, undesired angiogenesis or al cell proliferation, for example, solid tumors. Cytidine analog dosage forms provided herein can also work to alleviate e effects associated with certain second active agents, and some second active agents can be used to alleviate adverse effects associated with cytidine analog dosage forms provided herein. In certain embodiments, the formulations of cytidine analogs provided herein are co-administered with one or more therapeutic agents to provide a resensitization effect in ts in need thereof. onal therapeutic agents can be, e.g., large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, metallic, or organic molecules).

Examples of particular additional therapeutic agents useful in the compositions and methods disclosed herein include, but are not d to, e.g., cytotoxic agents, anti- metabolites, antifolates, HDAC inhibitors (e.g., entinostat, also known as SNDX-275 or MS- 275; or vorinostat, also known as suberoylanilide amic acid (SAHA) or oxy-N- phenyl-octanediamide), DNA intercalating agents, DNA cross-linking agents, DNA alkylating agents, DNA cleaving agents, topoisomerase inhibitors, CDK inhibitors, JAK inhibitors, anti-angiogenic agents, Bcr-Abl inhibitors, HER2 inhibitors, EGFR inhibitors, VEGFR inhibitors, PDGFR inhibitors, HGFR inhibitors, IGFR inhibitors, c-Kit inhibitors, Ras pathway inhibitors, PI3K inhibitors, multi-targeted kinase inhibitors, mTOR inhibitors, anti-estrogens, anti-androgens, aromatase tors, somatostatin analogs, ER modulators, anti-tubulin agents, Vinca alkaloids, taxanes, HSP inhibitors, Smoothened antagonists, rase inhibitors, COX-2 inhibitors, anti-metastatic agents, immunosuppressants, biologics such as antibodies, and hormonal therapies. In particular embodiments, the co- stered therapeutic agent is an immunomodulatory compound, 6.g. , thalidomide, lenalidomide, or pomalidomide. In particular embodiments, the co-administered therapeutic agent is carboplatin. In particular embodiments, the co-administered therapeutic agent is axel (e.g., Abraxane®). See, e.g., US. Patent Nos. 7,758,891, 7,771,751, 7,820,788, 7,923,536, 8,034,375; US. Patent Publication No. 2010/0048499; see also US. Pat. Nos. ,916,596; 6,506,405; 6,749,868, and 579, and US. Pat. Pub. Nos. 2007/0082838; all of which are incorporated herein by reference in their entireties. Other references include PCT Application Publication Nos. W008/057562, W009/126938, W009/126401, W009/126175, incorporated herein by reference. In one embodiment, the co-administered agent may be dosed, e.g., orally or by injection.

In one embodiment, the onal therapeutic agent is a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and a r protein. In some embodiments, the nanoparticle ition comprises nanoparticles comprising paclitaxel and an albumin. In some embodiments, the nanoparticles in the composition described herein have an average diameter of no greater than about 200 nm, including for example no greater than about any one of 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, or 60 nm.

In some embodiments, at least about 50% (for example at least about any one of 60%, 70%, 80%, 90%, 95%, or 99%) of all the nanoparticles in the composition have a diameter of no greater than about 200 nm, including for example no greater than about any one of 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, or 60 nm. In some ments, at least about 50% (for e at least any one of 60%, 70%, 80%, 90%, 95%, or 99%) of all the nanoparticles in the composition fall Within the range of about 20 to about 400, including for example about 20 to about 200 nm, about 30 to about 180 nm, and any one of about 40 to about 150, about 50 to about 120, and about 60 to about 100 nm. In some embodiments, the carrier protein has dral groups that can form disulfide bonds. In some embodiments, at least about 5% (including for example at least about any one of 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%) of the carrier protein in the nanoparticle portion of the composition are crosslinked (for e crosslinked through one or more disulfide bonds).

] In some embodiments, the nanoparticles comprise the taxane (such as paclitaxel) coated with a carrier protein, such as n (6.g. human serum albumin). In some embodiments, the composition comprises taxane in both nanoparticle and non-nanoparticle form, n at least about any one of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the taxane in the composition are in nanoparticle form. In some embodiments, the taxane in the nanoparticles constitutes more than about any one of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the nanoparticles by weight. In some embodiments, the nanoparticles comprise a core of taxane that is substantially free of polymeric als (such as polymeric matrix).

In some embodiments, the rticle composition is substantially free (such as free) of surfactants (such as Cremophor®, Tween 80, or other organic solvents used for the administration of taxanes). In some embodiments, the nanoparticle composition contains less than about any one of 20%, 15%, 10%, 7.5%, 5%, 2.5%, or 1% organic solvent. In some embodiments, the weight ratio of carrier protein (such as n) and taxane in the nanoparticle composition is about 18:1 or less, such as about 15:1 or less, for example about 9:1 or less. In some embodiments, the weight ratio of carrier protein (such as albumin) and taxane in the composition falls within the range of any one of about 1:1 to about 18:1, about 2:1 to about 15:1, about 3:1 to about 13:1, about 4:1 to about 12:1, about 5:1 to about 10:1, about 9: 1. In some embodiments, the weight ratio of carrier protein and taxane in the nanoparticle portion ofthe composition is about any one of 1 :2, 1:3, 1:4, 1:5, 1:9, 1:10, 1:15, or less.

In some embodiments, the particle composition comprises one or more of the above teristics. In some ments, the nanoparticle composition is Abraxane®.

Nanoparticle compositions comprising other taxanes (such as docetaxel and ortataxel) may also comprise one or more of the above characteristics.

In some embodiments, Abraxane® is intravenously stering at a dose of about 80 to about 200 mg/m2 (such as about 100 mg/mz). In some embodiments, Abraxane® is administered weekly. In some embodiments, ne® is administered once every two weeks. In some embodiments, Abraxane® is administered once every three weeks. In some embodiments, Abraxane® is administered as part of a cyclic treatment regimen (e.g., in cycles). In some embodiments, ne® is administered on Days 1 and 8 of a 21-day cycle. In some embodiments, Abraxane® is administered on Days 8 and 15 of a 21-day cycle.

In some embodiment, carboplatin is intravenously administering at the dose of about AUC 2 to AUC 6 (such as AUC 2, AUC 4, AUC 6). In some embodiments, carboplatin is administered . In some ments, carboplatin is administered once every two weeks. In some embodiments, carboplatin is administered once every three weeks.

In some embodiments, carboplatin is administered as part of a cyclic ent regimen (e.g. in cycles).

Other examples of onal therapeutic agents include, but are not limited to, hematopoietic growth factor, a cytokine, an anti-cancer agent, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor F), erythropoietin (EPO), interleukin (IL), interferon (IFN), oblimersen, melphalan, topotecan, pentoxifylline, taxotere, irinotecan, ciprofloxacin, doxorubicin, vincristine, dacarbazine, Ara- C, vinorelbine, prednisone, cyclophosphamide, bortezomib, arsenic trioxide. Such additional therapeutic agents are particularly useful in methods and compositions disclosed herein including, but not limited to, those relating to treatment of multiple myeloma.

Other examples of additional therapeutic agents include, but are not limited to, an antibody (e.g., mab, anti-CD33), poietic growth factor, ne, anti-cancer agent, antibiotic, cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent, corticosteroid, or a pharmacologically active mutant or derivative thereof. See, e.g., S. Nand et al., Leukemia and ma, 2008, 49(l l):214l-47 (describing a Phase II study involving the administration of a combination of hydroxyurea, azacitidine and low dose gemtuzumab ozogamicin to elderly ts with AML and high-risk MDS, and concluding that this combination appears to be a safe and ive regimen in the treatment ofAML and high risk MDS in this group of patients). Such additional therapeutic agents are particularly useful in methods and compositions disclosed herein including, but not limited to, those relating to treatment of the diseases and disorders disclosed herein.

Examples of large le active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Typical large molecule active agents are ical molecules, such as naturally occurring or artificially made proteins. Proteins that are particularly useful include proteins that stimulate the survival and/or proliferation of poietic precursor cells and immunologically active poietic cells in vitro or in vivo. Others stimulate the division and differentiation of committed oid progenitors in cells in vitro or in vivo. Particular proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II (“rIL2”) and canarypox IL-2), IL-lO, IL-l2, and IL-l8; erons, such as interferon a, interferon alfa-2b, interferon l, interferon alfa-n3, interferon beta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO.

] Particular proteins that can be used in the methods and compositions provided herein include, but are not limited to: filgrastim, which is sold in the United States under the trade name Neupogen® (Amgen, Thousand Oaks, CA); sargramostim, which is sold in the United States under the trade name Leukine® (Immunex, Seattle, WA); and recombinant EPO, which is sold in the United States under the trade name Epogen® (Amgen, Thousand Oaks, CA).

Recombinant and mutated forms of GM-CSF can be prepared as described in US. patent nos. 5,391,485; 5,393,870; and 5,229,496; all of which are incorporated herein by reference. Recombinant and mutated forms of G-CSF can be prepared as described in US. patent nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755; all ofwhich are orated herein by reference. ments herein encompass the use of native, naturally occurring, and recombinant proteins. Particular embodiments encompass mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit, in viva, at least some of the cological activity of the ns upon which they are based. Examples of mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the lly ing forms of the proteins. Also encompassed by the term ts” are proteins that lack carbohydrate moieties normally present in their naturally ing forms (6.g. , nonglycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fiasing IgGl or IgG3 to the protein or active portion of the n of interest. See, e.g., Penichet, ML. and Morrison, S.L., J. Immunol. Methods 248:91-101 (2001). dies that can be used in combination with oral formulations disclosed herein include onal and polyclonal dies. Examples of antibodies include, but are not limited to, trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (AvastinTM), umab (OmnitargTM), tositumomab (Bexxar®), edrecolomab (Panorex®), and G250.

Oral formulations disclosed herein can also comprise, be combined with, or used in combination with anti-TNF-(x antibodies.

Large molecule active agents may be administered in the form of anti-cancer vaccines. For example, vaccines that secrete, or cause the secretion of, cytokines such as IL- 2, G-CSF, and GM-CSF can be used in the methods, pharmaceutical compositions, and kits provided herein. See, e.g., Emens, L.A., et al., Curr. Opinion M01. Ther. 3(1):77-84 (2001). 2012/062845 ] In one embodiment, the additional therapeutic agent (e.g., large-molecule compound or small-molecule compound) reduces, eliminates, or prevents an adverse effect associated with the administration (e.g., oral stration) of a cytidine analog provided herein. Depending on the particular cytidine analog and the disease or disorder begin treated, e effects can include, but are not limited to, anemia, penia, febrile neutropenia, thrombocytopenia, hepatotoxicity (e.g., including, but not limited to, hepatoxicity in patients with preexisting hepatic impairment), elevated serum creatinine, renal failure, renal tubular acidosis, hypokalemia, hepatic coma, nausea, vomiting, dyspepsia, abdominal pain, pyrexia, leukopenia, diarrhea, constipation, ecchymosis, petechiae, rigors, weakness, pneumonia, anxiety, insomnia, lethargy, and decrease in , among others known in the art to be associated with particular cytidine analogs.

Like some large molecules, many small-molecule compounds are believed to be capable of providing a synergistic effect when administered with (e.g., before, after or simultaneously) a cytidine analog oral ation disclosed herein. Examples of small molecule second active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids.

Examples of anti-cancer agents e, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; eukin; amine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; a; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; nar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; ubicin hydrochloride; decitabine; aplatin; anine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate ; etanidazole; etoposide; etoposide ate; etoprine; ole hydrochloride; fazarabine; inide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; abine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide e; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol e; melengestrol acetate; melphalan; menogaril; mercaptopurine; rexate; methotrexate sodium; metoprine; meturedepa; mitindomide; rcin; mitocromin; mitogillin; mitomalcin; mitomycin; er; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; ycin; pentamustine; peplomycin sulfate; famide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; cin; puromycin hydrochloride; pyrazofurin; riboprine; saf1ngol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; ozocin; sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone e; triciribine phosphate; trimetrexate; rexate glucuronate; triptorelin; tubulozole hloride; uracil mustard; uredepa; vapreotide; verteporfln; vinblastine sulfate; vincristine sulfate; vindesine; ine sulfate; vinepidine sulfate; vinglycinate sulfate; rosine sulfate; vinorelbine tartrate; idine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.

Other anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; lvene; adecypenol; esin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin l; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; in III derivatives; balanol; batimastat; L antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnaf1de; bistratene A; bizelesin; breflate; bropirimine; tane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived tor; carzelesin; casein kinase inhibitors (ICOS); ospermine; cecropin B; cetrorelix; chlorlns; quinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene ues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; bine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; sfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-S-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen ts; estrogen antagonists; etanidazole; etoposide ate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; f1nasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; nium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene tamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; sine; ilomastat; imatinib (e.g., c®), imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; erons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; adine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; lide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; ilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; um texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; ; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; one; meterelin; methioninase; metoclopramide; MIF inhibitor; istone; miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin ues; mitonaf1de; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; orone; N—acetyldinaline; N—substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense®); 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; etron; etron; ; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; mycin; paclitaxel; paclitaxel analogues; axel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; iptine; pegaspargase; peldesine; pentosan polysulfate ; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; rpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator tor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; sone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; ins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl protein erase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; mes; RII retinamide; rohitukine; romurtide; roquinimex; none Bl; ruboxyl; safingol; pin; ; sarcophytol A; sargramostim; Sdi l mimetics; semustine; senescence derived inhibitor 1; sense ucleotides; signal transduction tors; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin l; squalamine; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafilr; tellurapyrylium; telomerase inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; raline; opoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; zamine; titanocene bichloride; topsentin; toremifene; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; in B; velaresol; veramine; s; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

Specific additional therapeutic agents include, but are not limited to, oblimersen (Genasense®), remicade, docetaxel, celecoxib, lan, thasone (Decadron®), ds, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, bazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-l l, eron alpha, pegylated interferon alpha (e.g., PEG INTRON—A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate, c trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt®), sulindac, and etoposide. 8. E In one embodiment, active ingredients provided herein are not administered to a patient at the same time or by the same route of administration. Provided herein are kits which can fy the administration of appropriate amounts of active ingredients.

In one embodiment, a kit comprises a dosage form of a compound provided herein. Kits can further comprise one or more second active ingredients as bed herein, or a pharmacologically active mutant or derivative thereof, or a combination thereof In other embodiments, kits can r comprise devices that are used to ster the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

In one embodiment, kits can r comprise cells or blood for lantation as well as pharmaceutically acceptable es that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable e in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not d to, corn oil, seed oil, peanut oil, sesame oil, ethyl oleate, isopropyl ate, and benzyl benzoate.

D. Methods of Use In one embodiment, provided herein are methods for treating, preventing or managing cancer by administering a ne analog, or a ceutically acceptable salt, solvate, or hydrate thereof, to a subject having cancer. In one embodiment, the s comprise treating cancer with a ne analog, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, the methods comprise preventing cancer with a cytidine analog, or a pharmaceutically able salt, solvate, or hydrate thereof. In one embodiment, the methods comprise managing cancer with a cytidine analog, or a pharmaceutically acceptable salt, solvate, or e f. In n embodiments, the cytidine analog is 5-azacytidine. In certain embodiments, the ne analog is decitabine.

In certain embodiments, the methods se co-administering one or more additional active agents (e.g., an anti-cancer agent provided herein). In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In ular embodiments, the cancer is a solid tumor (e.g., a relapsed or tory solid tumor).

In one embodiment, provided herein is use of a cytidine analog (e.g., 5- azacytidine or another cytidine analog provided herein), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the manufacture of a medicament for the treatment, prevention, and/or management of cancer (e.g, a ed or refractory solid tumor).

In one embodiment, provided herein is a cytidine analog (e.g, 5-azacytidine or another cytidine analog provided herein), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for use in the treatment, prevention, and/or management of cancer (6.g. , a relapsed or refractory solid tumor).

In one embodiment, provided herein are methods of treating, preventing, or managing certain types of cancer, including but not limited to, a solid tumor or a blood-bome tumor; a refractory cancer or a relapsed cancer; or a refractory solid tumor or a relapsed solid tumor. In one embodiment, ed herein are methods of treating, preventing, or managing certain types of cancer, including but not limited to, cancers of the breast, lung, head and neck, ovary, testicle, prostate, gastrointestinal system, stomach, pancreas, liver, colon, kidney, bladder, brain, skin, or bone. In other embodiments, the cancer is a cancer of the blood or the lymph. 2012/062845 In one embodiment, provided herein are methods of treating, preventing, or managing breast cancer, comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (e.g., additional therapeutic agent described herein).

In one embodiment, ed herein are methods of ng, preventing, or managing lung cancer (e.g., NSCLC or SCLC), comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (e.g., additional therapeutic agent described herein).

In one embodiment, provided herein are methods of treating, preventing, or managing head and neck cancer, comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (e.g., additional therapeutic agent described herein).

In one ment, provided herein are methods of treating, preventing, or managing ovarian cancer, comprising administering a ne analog (e.g., orally) and at least one additional eutic agent (6.g. additional therapeutic agent described herein).

In one embodiment, provided herein are methods of treating, preventing, or managing ular cancer, comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (6.g. additional eutic agent bed herein).

In one embodiment, provided herein are methods of treating, preventing, or managing prostate cancer, comprising administering a cytidine analog (e.g., ) and at least one additional therapeutic agent (6.g. additional therapeutic agent described herein).

In one embodiment, provided herein are methods of treating, preventing, or managing intestinal cancer, sing stering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (e.g, additional therapeutic agent described herein).

In one embodiment, provided herein are methods of treating, preventing, or managing stomach cancer, comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (6.g. additional therapeutic agent bed herein).

In one embodiment, provided herein are methods of treating, preventing, or managing pancreatic cancer, comprising stering a cytidine analog (e.g., ) and at least one additional eutic agent (6.g. additional therapeutic agent described herein).

In one embodiment, provided herein are methods of treating, preventing, or managing liver cancer, comprising administering a cytidine analog (e.g., orally) and at least one onal therapeutic agent (e.g., additional therapeutic agent described herein).

In one embodiment, provided herein are methods of treating, preventing, or managing colorectal cancer, comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (6.g. onal therapeutic agent described ).

In one embodiment, provided herein are methods of treating, preventing, or managing renal cancer, comprising administering a ne analog (e.g., orally) and at least one additional therapeutic agent (e.g., additional therapeutic agent bed herein).

In one embodiment, ed herein are methods of treating, preventing, or managing bladder cancer, comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (6.g. additional therapeutic agent described herein).

In one embodiment, provided herein are methods of treating, preventing, or managing brain cancer, comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (e.g., additional eutic agent described ).

] In one embodiment, provided herein are methods of treating, preventing, or managing skin cancer (e.g., melanoma), comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (e.g., additional eutic agent described herein).

In one embodiment, provided herein are s of treating, preventing, or managing bone cancer, comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (e.g., onal therapeutic agent described herein).

In one embodiment, provided herein are methods of treating, preventing, or managing blood cancer, comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (e.g., additional therapeutic agent described herein).

In one ment, provided herein are methods of treating, preventing, or managing ia, comprising administering a cytidine analog (e.g., orally) and at least one additional eutic agent (e.g., additional therapeutic agent described herein).

In one embodiment, ed herein are methods of treating, preventing, or managing ma, comprising administering a ne analog (e.g., orally) and at least one additional therapeutic agent (e.g., additional therapeutic agent described herein).

In one embodiment, provided herein are methods of treating, preventing, or managing multiple myeloma, comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (6.g. additional therapeutic agent described herein).

In one embodiment, provided herein are methods of treating, ting, or managing myelodysplastic syndrome, comprising administering a cytidine analog (e.g., orally) and at least one additional therapeutic agent (e.g., additional therapeutic agent described herein).

In one embodiment, provided herein are methods of ng, preventing, or managing cancer in the primary tumor, lymph nodes, or distant metastasis, by stering a cytidine analog, or a pharmaceutically acceptable salt, solvate, or hydrate f, to a subject in need thereof. In one embodiment, provided herein are s of treating, preventing, or managing cancer in the primary tumor, lymph nodes, or distant metastasis, by administering -azacytidine, or a pharmaceutically acceptable salt, e, or hydrate thereof, to a subject in need f.

In one embodiment, provided herein are methods of treating, preventing, or managing cancer in a subject having surgically resectable cancer, locally or regionally advanced , or distant metastatic cancer, by administering a cytidine analog, or a ceutically acceptable salt, solvate, or e thereof. In one embodiment, provided herein are methods of treating, ting, or managing cancer in a subject having surgically resectable cancer, locally or regionally advanced cancer, or distant metastatic cancer, by administering 5-azacytidine, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In particular embodiments, provided herein are methods of treating surgically resectable cancer, by administering 5-azacytidine to a subject having cancer. In particular embodiments, provided herein are methods of treating locally or regionally advanced cancer, by administering 5-azacytidine to a subject having cancer. In particular ments, provided herein are methods of treating distant metastatic cancer, by administering 5- azacytidine to a subject having cancer.

In one embodiment, the methods comprise treating, preventing or managing certain stages of cancer, e.g, Stage 0, Stage 1, Stage 11, Stage III, and Stage IV, by administering a cytidine , or a ceutically acceptable salt, solvate, or hydrate thereof, to a subject having cancer. The staging of cancer may be defined according to methods known in the art, for example, according to the guidelines provided by the an Joint Committee on Cancer (AJCC). In one embodiment, the staging of cancer is designated and grouped based on the TNM classification, z'.e., a classification based on the status of primary tumor (e.g., TX, T0, Tis, T1, T2, T3, T4), regional lymph nodes (e.g., NX, N0, N1, N2, N3), and/or distant metastasis (e.g., MX, M0, M1), in a subject having cancer.

] In particular embodiments, methods provided herein comprise stering a cytidine analog to a subject having a solid tumor that is surgically able. In particular embodiments, the methods provided herein comprise administering a cytidine analog to a subject having locally advanced solid tumor. In particular embodiments, methods provided herein comprise administering a cytidine analog to a subject having regionally ed solid tumor. In particular embodiments, the methods provided herein comprise administering a cytidine analog to a subject having a distant metastasis, e.g., at the time of diagnosis.

Particular embodiments provide ng a subject having cancer using one or more of the methods provided herein, together with y. Particular embodiments provide treating a subject having cancer using one or more of the methods provided herein, together with chemotherapy. Particular ments e treating a subject having cancer using one or more of the methods ed , together with immunotherapy. Particular embodiments e treating a subject having cancer using one or more of the s provided herein, together with targeted therapy. Particular embodiments provide treating a subject having cancer using one or more of the s provided herein, together with radiation therapy. Particular embodiments provide treating a subject having cancer using one or more of the methods provided herein, together with two or more of the treatments ed from surgery, chemotherapy, immunotherapy, targeted therapy, and radiation therapy.

Particular ments provide treating a subject having cancer using one or more of the methods provided herein, together with two or more of the treatments selected from surgery, chemotherapy, and ion therapy.

In certain ments, the subject to be treated with one of the methods provided herein has not been treated with anticancer therapy prior to the administration of the cytidine analog. In n ments, the subject to be treated with one of the methods provided herein has been treated with one or more anticancer therapies prior to the administration of the cytidine analog. In certain embodiments, the subject to be treated with one of the methods provided herein has been treated with a cancer therapeutic agent, as described herein. In certain embodiments, the subject to be d with one of the s provided herein has developed drug resistance to anticancer therapy. In certain embodiments, the subject to be treated with the methods provided herein has a relapsed cancer. In n embodiments, the subject to be treated with the methods provided herein has a refractory cancer. In certain embodiments, the subject to be treated with the methods provided herein has a metastatic cancer.

In one embodiment, the methods provided herein encompass treating a subject regardless of patient’s age, although some diseases or disorders are more common in certain age groups. Further provided herein is a method for treating a subject who has undergone surgery in an attempt to treat the disease or condition at issue. Further provided herein is a method for treating a t who has not undergone surgery as an attempt to treat the e or condition at issue. e the subjects with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a particular subject may vary, depending on his/her prognosis. The d clinician will be able to readily determine without undue experimentation, specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual subject with cancer.

In each embodiment ed herein, the method may further comprise one or more diagnostic steps, to determine, e.g., the type of cancer, the presence of particular cell types, the genetic profile of a subject, and/or the staging of the disease in a subject.

In each embodiment provided herein, the method may further comprise a disease evaluation step after the cytidine analog has been administered to the subject, to determine, e. g., changes in one or more molecular markers as described herein elsewhere, changes in tumor size and location, and/or other benchmarks used by those skilled in the art to ine the prognosis of cancer in a subject.

Certain methods herein provide administration of a cytidine analog by, e.g., intravenous (IV), subcutaneous (SC) or oral routes of administration. Certain methods herein provide administration of a cytidine analog by oral route of administration. n embodiments herein provide inistration of a cytidine analog (e.g., 5-azacytidine or r cytidine analog ed herein) with one or more additional active agents to provide a synergistic therapeutic effect in subjects in need thereof The co-administered agent(s) may be a cancer therapeutic agent, as described herein. In certain embodiments, the co- administered agent(s) may be dosed, e.g., orally or by injection (e.g., IV or SC).

Certain embodiments herein provide methods for treating disorders of abnormal cell proliferation comprising stering a cytidine analog using, e.g., IV, SC and/or oral administration methods. Certain embodiments herein provide methods for treating disorders of abnormal cell proliferation comprising administering a cytidine analog using oral administration methods. In certain ments, treatment cycles se multiple doses administered to a t in need f over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or greater than 28 days), ally followed by treatment dosing holidays (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or greater than 28 days). Suitable dosage amounts for the methods provided herein e, e.g., therapeutically effective amounts and prophylactically ive amounts. In specific embodiments, a treatment cycle comprises multiple doses administered to a subject in need thereof once a day or more than once a day, for 3 days, for 5 days, for 7 days, for 14 days, for 21 days, or for 28 days. In specific embodiments, a treatment cycle comprises a resting period of 1 day, 2 days, 3 days, 4 days, 5 days, 7 days, 14 days, 21 days, or 28 days. In specific ments, a t is treated with multiple ent cycles, for example, multiple 7-day, , 21-day, 28-day, , or 42-day treatment cycles for a total period of treatment of about 1, 2, 3, 4, 5, 6, 7, 8, 9,10,11,12,13,14,15,16,17,18,19, 20, 21, 22, 23, or 24 months, or greater than 24 months. In specific embodiments, a subject is treated with multiple treatment cycles, that may be the same or different (e.g., a 7-day treatment cycle followed by a 14-day, 21-day, or 28-day treatment cycle).

In one embodiment, the amount of the ne analog (e.g., 5-azacytidine or another cytidine analog provided herein) administered in the methods provided herein may range, e.g., between about 50 mg/mZ/day and about 2,000 mg/mZ/day, between about 100 mg/mz/day and about 1,000 mg/m2/day, between about 50 mg/m2/day and about 200 mg/mZ/day, between about 50 mg/mZ/day and about 100 mg/mZ/day, between about 100 mg/mz/day and about 500 mg/mz/day, or between about 120 mg/mZ/day and about 250 mg/mZ/day. In certain embodiments, particular dosages are, e.g., about 50 mg/mZ/day, about 75 mg/mZ/day, about 100 day, about 120 mg/mZ/day, about 140 mg/mZ/day, about 150 mg/mZ/day, about 180 mg/mZ/day, about 200 mg/mZ/day, about 220 mg/mZ/day, about 240 mg/mZ/day, about 250 mg/mZ/day, about 260 mg/mZ/day, about 280 mg/mZ/day, about 300 mg/ mZ/day, about 320 mg/mZ/day, about 350 mg/mZ/day, about 380 mg/mZ/day, about 400 mg/mz/day, about 450 day, or about 500 mg/mZ/day. In certain embodiments, particular dosages are, e.g., up to about 100 mg/mZ/day, up to about 120 day, up to about 140 mg/mZ/day, up to about 150 mg/mZ/day, up to about 180 mg/mZ/day, up to about 200 day, up to about 220 mg/mZ/day, up to about 240 mg/mZ/day, up to about 250 mg/mZ/day, up to about 260 mg/mZ/day, up to about 280 mg/mZ/day, up to about 300 mg/ mZ/day, up to about 320 mg/mZ/day, up to about 350 mg/mZ/day, up to about 380 mg/mZ/day, up to about 400 mg/mZ/day, up to about 450 mg/mZ/day, up to about 500 mg/mZ/day, up to about 750 mg/mZ/day, or up to about 1000 mg/mZ/day.

] In one embodiment, the amount of the cytidine analog (e.g., 5-azacytidine or another cytidine analog provided herein) administered in the methods provided herein may range, e.g., between about 5 mg/day and about 2,000 mg/day, between about 10 mg/day and about 2,000 mg/day, n about 20 mg/day and about 2,000 mg/day, between about 50 mg/day and about 1,000 mg/day, n about 100 mg/day and about 600 mg/day, between about 100 mg/day and about 500 mg/day, between about 150 mg/day and about 500 mg/day, n about 250 mg/day and about 350 mg/day, or between about 150 mg/day and about 250 mg/day. In certain embodiments, particular dosages are, e.g., about 10 mg/day, about 20 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 120 , about 150 mg/day, about 180 mg/day, about 200 mg/day, about 240 mg/day, about 250 mg/day, about 280 mg/day, about 300 mg/day, about 320 mg/day, about 350 mg/day, about 360 , about 400 mg/day, about 450 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, about 900 mg/day, about 1,000 mg/day, about 1,200 mg/day, or about 1,500 mg/day. In certain embodiments, particular s are, e.g., up to about 10 mg/day, up to about 20 mg/day, up to about 50 mg/day, up to about 75 mg/day, up to about 100 mg/day, up to about 120 mg/day, up to about 150 mg/day, up to about 200 mg/day, up to about 250 mg/day, up to about 300 , up to about 350 mg/day, up to about 400 mg/day, up to about 450 mg/day, up to about 500 mg/day, up to about 600 mg/day, up to about 700 mg/day, up to about 800 mg/day, up to about 900 mg/day, up to about 1,000 mg/day, up to about 1,200 mg/day, or up to about 1,500 mg/day.

In one embodiment, the amount of the cytidine analog (e.g., ytidine or another cytidine analog provided herein) in the pharmaceutical composition or dosage form provided herein may range, e.g., between about 5 mg and about 2,000 mg, between about 10 mg and about 2,000 mg, between about 20 mg and about 2,000 mg, between about 50 mg and about 1,000 mg, between about 100 mg and about 600 mg, between about 100 mg and about 500 mg, between about 150 mg and about 500 mg, between about 250 mg and about 350 mg, or between about 150 mg and about 250 mg. In certain ments, particular amounts are, e. g., about 10 mg, about 20 mg, about 50 mg, about 75 mg, about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, about 240 mg, about 250 mg, about 300 mg, about 320 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,200 mg, or about 1,500 mg. In certain ments, particular amounts are, e.g., up to about 10 mg, up to about 20 mg, up to about 50 mg, up to about 75 2012/062845 mg, up to about 100 mg, up to about 120 mg, up to about 150 mg, up to about 200 mg, up to about 250 mg, up to about 300 mg, up to about 350 mg, up to about 400 mg, up to about 450 mg, up to about 500 mg, up to about 600 mg, up to about 700 mg, up to about 800 mg, up to about 900 mg, up to about 1,000 mg, up to about 1,200 mg, or up to about 1,500 mg.

In one ment, depending on the disease to be treated and the subject’s condition, the cytidine analog (6.g. , ytidine or another cytidine analog provided herein) may be administered by oral, parenteral (e.g. , intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. In some ments, the cytidine analog may be formulated, alone or together with one or more active agent(s), in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration. In one embodiment, the cytidine analog (e.g., 5-azacytidine or another cytidine analog provided herein) is administered . In another embodiment, the cytidine analog (6.g. , ytidine or another ne analog provided herein) is administered parenterally. In yet another embodiment, the cytidine analog (e.g., 5-azacytidine or another cytidine analog provided herein) is administered intravenously. In yet another ment, the ne analog (6.g. or r cytidine analog provided herein) is , 5-azacytidine administered subcutaneously.

In one embodiment, the ne analog (e.g., 5-azacytidine or another cytidine analog provided herein) can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infiJsion over time or divided bolus doses over time. In one embodiment, the cytidine analog (e.g., 5-azacytidine or another cytidine analog provided herein) can be administered repetitively if necessary, for e, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. For example, stable e for solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more from the last measurement. See, e. g., Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal oft/w National Cancer Institute 92(3): 205-216 (2000). Stable disease or lack f is determined by methods known in the art such as evaluation of patient’s symptoms, al examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.

In one embodiment, the cytidine analog (e.g., 5-azacytidine or another ne analog provided herein) can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID). In one embodiment, the administration can be continuous (2'.e., daily for consecutive days or every day), intermittent, e.g, in cycles (z'.e., including days, weeks, or months of rest when no drug is administered). In one embodiment, the cytidine analog is administered daily, for e, once or more than once each day for a period of time. In one embodiment, the cytidine analog is administered daily for an rrupted period of at least 7 days, in some ments, up to 52 weeks. In one ment, the ne analog is administered intermittently, z'.e. and starting at either regular or irregular intervals. In one , stopping embodiment, the cytidine analog is administered for one to six days per week. In one embodiment, the cytidine analog is administered in cycles (e.g., daily administration for about one, two, three, four, five, six, seven, or eight consecutive weeks, then a rest period with no stration for about one, two, three, or four weeks). In one embodiment, the cytidine analog is stered on alternate days. In one embodiment, the cytidine analog is administered in cycles (6.g. administered daily or continuously for a certain period interrupted with a rest period).

In one embodiment, the frequency of administration ranges from about daily to about monthly. In certain embodiments, the cytidine analog (e.g., 5-azacytidine or another cytidine analog provided herein) is administered once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the cytidine analog is administered once a day. In another embodiment, the cytidine analog is administered twice a day. In yet another embodiment, the cytidine analog is administered three times a day. In still another embodiment, the cytidine analog is administered four times a day.

In one embodiment, the cytidine analog (e.g., 5-azacytidine or another cytidine analog provided herein) is administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, the cytidine analog is stered once per day for one week, two weeks, three weeks, or four weeks. In one embodiment, the cytidine analog is administered once per day for one week. In another ment, the cytidine analog is administered once per day for two weeks. In yet another embodiment, the cytidine analog is administered once per day for three weeks. In still another embodiment, the cytidine analog is administered once per day for four weeks.

In one ment, the cytidine analog (e.g., 5-azacytidine or another cytidine analog provided herein) is administered once per day for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, about 9 weeks, about 12 weeks, about 15 weeks, about 18 weeks, about 21 weeks, or about 26 weeks. In certain embodiments, the cytidine analog is stered intermittently. In certain embodiments, the cytidine analog is administered ittently in the amount of between about 50 mg/mZ/day and about 2,000 mg/m2/day. In certain embodiments, the cytidine analog is administered intermittently in the amount of between about 100 mg/day and about 600 mg/day. In certain embodiments, the cytidine analog is administered continuously. In n embodiments, the cytidine analog is administered continuously in the amount of between about 50 mg/mZ/day and about 1,000 mg/m2/day. In certain embodiments, the cytidine analog is administered continuously in the amount of between about 100 mg/day and about 600 mg/day.

In certain embodiments, the cytidine analog (e.g., ytidine or another ne analog provided herein) is administered to a patient in cycles. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this tial administration. Cycling therapy can reduce the development of resistance, avoid or reduce the side effects, and/or improves the efficacy of the treatment.

In one embodiment, the cytidine analog (e.g., 5-azacytidine or another ne analog provided herein) is administered daily in single or divided doses for about 3 days, about 5 days, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about ten weeks, about fifteen weeks, or about twenty weeks, followed by a rest period of about 1 day to about ten weeks. In one embodiment, the methods provided herein contemplate cycling treatments of about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about eight weeks, about ten weeks, about fifteen weeks, or about twenty weeks. In some embodiments, the cytidine analog is administered daily in single or divided doses for about 3 days, about 5 days, about one week, about two weeks, about three weeks, about four weeks, about five weeks, or about six weeks with a rest period of about 1, 2, 3, 4, ,6,7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 29, or 30 days. In some embodiments, the rest period is 1 day. In some embodiments, the rest period is 3 days. In some embodiments, the rest period is 7 days. In some embodiments, the rest period is 14 days. In some embodiments, the rest period is 28 days. The frequency, number and length of dosing cycles can be increased or decreased.

In one embodiment, the methods provided herein comprise: i) administering to the subject a first daily dose of a cytidine analog; ii) optionally resting for a period of at least one day where the ne analog is not administered to the subj ect; iii) administering a second dose of the cytidine analog to the subject; and iv) repeating steps ii) to iii) a plurality of times.

In certain embodiments, the first daily dose is between about 50 mg/mZ/day and about 2,000 day. In certain embodiments, the second daily dose is between about 50 mg/mZ/day and about 2,000 mg/mZ/day. In n embodiments, the first daily dose is between about 100 mg/day and about 1,000 . In certain embodiments, the second daily dose is between about 100 mg/day and about 1,000 mg/day. In certain embodiments, the first daily dose is higher than the second daily dose. In certain embodiments, the second daily dose is higher than the first daily dose. In one embodiment, the rest period is 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, 12 days, 13 days, 14 days, 15 days, 17 days, 21 days, or 28 days.

In n embodiments, the cytidine analog (e.g., 5-azacytidine or another cytidine analog provided herein) is administered continuously for between about 1 and about 52 weeks. In certain embodiments, the cytidine analog is administered continuously for about 0.5, l, 2, 3, 4, 5, 6, 7, 8, 9, 10, ll, or 12 months. In certain embodiments, the cytidine analog is administered continuously for about 7, about 14, about 21, about 28, about 35, about 42, about 84, or about 112 days. It is understood that the duration of the treatment may vary with the age, weight, and condition of the t being treated, and may be determined empirically using known testing protocols or according to the professional judgment of the person providing or supervising the treatment. The skilled clinician will be able to readily determine, without undue experimentation, an effective drug dose and treatment duration, for treating an individual t having a particular type of . 1. Methods of Using Oral Formulations Provided Herein As described herein, certain embodiments herein provide oral formulations of cytidine s useful in methods relating to, e.g., permitting ent dosing amounts and/or dosing periods; providing alternative pharmacokinetic s, pharmacodynamic profiles, and/or safety profiles; permitting the evaluation of long-term and/or nance therapies; ing treatment regimens that maximize demethylation and/or gene re- sion; providing treatment regimens that prolong uous demethylation; ing new indications for cytidine analogs; and/or providing other potential advantageous benefits.

Provided herein are methods of treating, preventing, or managing patho- physiological conditions sted by abnormal cell proliferation, such as, for example, cancer, including hematological disorders and solid tumors, by orally administering a pharmaceutical formulation comprising a cytidine analog, such as, for example, 5- azacytidine, wherein the formulation releases the cytidine analog ntially in the stomach. Other embodiments herein provide methods of treating, preventing, or managing immune ers. In particular ments, the methods provided herein involve oral administering a formulation that effects an immediate release of the cytidine analog. In certain embodiments, the cytidine analog and one or more therapeutic agents are co- administered to subjects to yield a synergistic therapeutic effect. The co-administered agent may be a cancer therapeutic agent dosed orally or by injection.

In n embodiments, methods provided herein for treating, preventing, or managing disorders related to abnormal cell proliferation comprise orally administering a formulation comprising a therapeutically effective amount of a ne analog. Particular therapeutic indications relating to the methods provided herein are disclosed herein. In certain embodiments, the therapeutically ive amount of the cytidine analog in the pharmaceutical ation is an amount as disclosed herein. In certain embodiments, the e therapeutically effective amount of the cytidine analog in the pharmaceutical formulation will vary depending on, e.g, the age, weight, disease and/or condition of the subject.

In particular ments, the disorders related to abnormal cell eration e, but are not limited to, solid tumors, sarcoma, melanoma, carcinoma, adenocarcinoma, chordoma, breast cancer, colorectal cancer, ovarian cancer, lung cancer (e.g., non-small-cell lung cancer and small-cell lung cancer), testicular cancer, renal cancer, bladder cancer, pancreatic cancer, bone cancer, gastric cancer, head and neck cancer, prostate cancer, MDS, AML, ALL, CML, leukemia, chronic cytic leukemia (CLL), lymphoma (including non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma), and multiple a (MM). In particular embodiments, the disorder related to abnormal cell proliferation is a solid tumor. In particular embodiments, the disorder d to abnormal cell proliferation is a relapsed or refractory solid tumor. In particular embodiments, the disorder related to abnormal cell proliferation is MDS. In particular embodiments, the WO 67043 disorder related to abnormal cell proliferation is AML. In particular embodiments, the disorder related to abnormal cell proliferation is breast cancer. In particular embodiments, the disorder related to abnormal cell proliferation is r cancer. In particular embodiments, the disorder related to abnormal cell proliferation is head and neck . In ular embodiments, the disorder related to al cell proliferation is pancreatic cancer. In particular embodiments, the er related to abnormal cell proliferation is lung cancer (e.g., NSCLC or SCLC). In particular embodiments, the disorder related to abnormal cell eration is ovarian cancer. In ular embodiments, the disorder related to abnormal cell proliferation is colorectal cancer. In particular embodiments, the disorder related to abnormal cell proliferation is skin cancer (6.g. In particular , melanoma). embodiments, the disorder related to abnormal cell proliferation is uterine . In particular embodiments, the disorder related to abnormal cell proliferation is sarcoma.

In one embodiment, methods ed herein for treating, preventing, or managing disorders of abnormal cell proliferation comprise administering a cytidine analog orally. In other embodiments, methods provided herein for treating, preventing, or managing disorders of al cell proliferation comprise administering a cytidine analog using at least two of IV, SC and oral administration methods. For example, particular embodiments herein provide administering an l treatment cycle of a cytidine analog, such as, for example, 5-azacytidine, administered either SC or IV, followed by subsequent orally administered treatment cycles of the cytidine analog. In certain embodiments, treatment cycles comprise multiple doses administered to a subject in need thereof over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9,10,11,12,13,14,15,16,17,18,19, 20, 21, or greater than 21 days), optionally followed by treatment dosing holidays (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or greater than 14 days). Particular embodiments herein provide a treatment schedule comprising SC and/or IV administration for one, two, three, four, five, or more initial cycles, followed by oral administration for subsequent cycles. For example, particular embodiments herein provide a treatment schedule comprising SC administration for cycle 1, followed by oral stration for subsequent cycles. Suitable dosage ranges and amounts for the methods provided herein are provided hout the specification. For example, in n embodiments, the SC dose is about 75 mg/m2. In certain embodiments, the oral dose is about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 350 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 600 mg, or greater than about 600 mg. In certain embodiments, oral doses are calculated to achieve about 80%, 100%, or 120% of SC AUC.

] In certain embodiments, methods of treating disorders of abnormal cell proliferation comprises orally administering a formulation comprising a cytidine analog (e.g., -azacytidine or another cytidine analog provided ) as single or multiple daily doses.

In ular embodiments, a formulation comprising a cytidine analog is orally administered once per day, twice per day, three times per day, four times per day, or more than four times per day. For example, in certain ments, a formulation comprising a cytidine analog is administered using a treatment cycle comprising administration of about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 350 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg of the ne analog once, twice, three, or four times per day for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days. In certain embodiments, the method of ng comprises continuous low-dose administration. In certain embodiments, the formulation comprising the ne analog is administered using a treatment cycle comprising administration of about 200 mg of the cytidine analog once per day for 7 or more days. In certain embodiments, the formulation comprising the cytidine analog is administered using a treatment cycle comprising administration of about 200 mg of the cytidine analog twice per day for 7 or more days. In certain embodiments, the formulation comprising the ne analog is administered using a treatment cycle comprising stration of about 200 mg of the cytidine analog once per day for 14 or more days. In certain embodiments, the formulation comprising the cytidine analog is administered using a treatment cycle comprising administration of about 200 mg of the cytidine analog twice per day for 14 or more days. In certain embodiments, the formulation comprising the cytidine analog is stered using a treatment cycle comprising stration of about 200 mg of the cytidine analog once per day for 21 or more days. In certain embodiments, the formulation comprising the cytidine analog is administered using a treatment cycle comprising administration of about 200 mg of the cytidine analog twice per day for 21 or more days. In certain embodiments, the formulation comprising the cytidine analog is administered using a treatment cycle comprising administration of about 200 mg of the cytidine analog three times per day for 7 or more days. In certain embodiments, the ation comprising the cytidine analog is administered using a treatment cycle comprising stration of about 200 mg of the cytidine analog three times per day for 14 or more days. In certain embodiments, the formulation sing the cytidine analog is administered using a treatment cycle comprising administration of about 300 mg of the cytidine analog once per day for 7 or more days. In certain embodiments, the formulation comprising the cytidine analog is administered using a treatment cycle comprising administration of about 300 mg of the cytidine analog twice per day for 7 or more days. In certain embodiments, the formulation comprising the cytidine analog is administered using a treatment cycle comprising stration of about 300 mg of the cytidine analog once per day for 14 or more days. In certain embodiments, the formulation comprising the cytidine analog is administered using a treatment cycle comprising administration of about 300 mg of the cytidine analog twice per day for 14 or more days. In certain embodiments, the formulation comprising the cytidine analog is administered using a treatment cycle comprising administration of about 300 mg of the cytidine analog once per day for 21 or more days. In n embodiments, the formulation comprising the cytidine analog is administered using a treatment cycle comprising administration of about 300 mg of the cytidine analog twice per day for 21 or more days. In n embodiments, the formulation comprising the cytidine analog is administered using a treatment cycle comprising administration of about 300 mg of the cytidine analog three times per day for 7 or more days.

In n ments, the formulation comprising the cytidine analog is administered using a treatment cycle sing administration of about 300 mg of the cytidine analog three times per day for 14 or more days. In certain embodiments, methods ed herein comprise administering a formulation comprising a cytidine analog using one or more of the cycles provided herein, and repeating one or more of the cycles for a period of, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or greater than 12 months.

In certain embodiments, methods herein comprise stering particular oral formulations provided herein to, e.g, overcome limitations associated with IV or SC administration of cytidine analogs. For e, IV or SC administration may limit the ability to deliver a cytidine analog for longer periods of time on a r basis, y potentially limiting the maximal efficacy of the cytidine analog. Due to the difficulties of WO 67043 complying with the rigors of a prolonged IV or SC dosing le, prolonged SC or IV exposure to a cytidine analog may cause subjects (e.g., subjects with multiple cytopenias) to discontinue from the regimen. See, e. g., Lyons, R.M., et al., Hematologic Response to Three Alternative Dosing Schedules of Azacitidine in Patients With ysplastic mes, J.

Clin. Oncol. (2009) (DOI:10.1200/ JCO.2008.17. 1058), which is incorporated by reference herein in its entirety. Accordingly, in certain embodiments, methods provided herein comprise administering an oral formulation provided herein to overcome these or other limitations associated with SC or IV cytidine analog administration. For example, in certain embodiments, methods provided herein comprise stering daily to a subject an oral formulation provided herein for 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, or more, 21 or more, or 28 or more days.

Certain embodiments herein provide methods comprising administering oral formulations of ne analogs provided herein comprising delivering the cytidine analog (e.g, 5-azacytidine or another cytidine analog ed herein) at a lower dose over a more prolonged period of time, as compared to IV or SC administration. In particular embodiments, such methods se managing dose-related cytopenias (including, e.g., dose-related cytopenias associated with 5-azacytidine) by administering an oral formulation provided . In certain embodiments, s provided herein comprise administering an oral formulation ed herein to achieve an improved safety profile as compared to an IV or SC dose comprising the same cytidine .

As described herein, certain embodiments provide methods for ed treatment of particular es or disorders (6.g. treatment of solid ) by administering an oral formulation provided herein, as compared to IV or SC administration of the cytidine analog. In particular embodiments, certain methods herein provide administering oral formulations provided herein at lower doses for more prolonged periods of time, leading to improved demethylation. For example, certain methods provided herein comprise administering an oral ation provided herein to treat a solid tumor while avoiding certain dose-limiting-toxicity-related side effects associated with dosing the cytidine analog via SC or IV administration. An example of certain toxicity-related drawbacks associated with administration of a cytidine analog are described, e.g., in K. Appleton et al., J. Clin. 011001., Vol. 25(29):4603-4609 (2007), which is incorporated by reference herein in its entirety.

Particular embodiments herein provide methods for ng a subject having a disease or disorder provided herein by orally administering a pharmaceutical composition provided herein, n the treatment results in improved survival of the subject. In certain embodiments, the improved survival is measured as compared to one or more conventional care regimens. Particular embodiments herein provide methods for treating a subject having a disease or disorder provided herein by orally administering a pharmaceutical composition provided herein, n the treatment provides improved effectiveness. In particular embodiments, the improved effectiveness is measured using one or more endpoints for cancer clinical trials, as ended by the US. Food and Drug Administration (FDA). For example, FDA provides Guidance for Industry on Clinical Trial Endpoints for the al of Cancer Drugs and Biologics (http://www.fda.gov/CbElnglns/clintrialend.htm). The FDA endpoints include, but are not limited to, Overall Survival, Endpoints Based on Tumor Assessments such as (i) e-Free Survival (ii) Objective Response Rate, (iii) Time to Progression and ssion-Free Survival and (iv) Time-to-Treatment Failure. Endpoints Involving Symptom nts may e Specific Symptom Endpoints such as (i) Time to ssion of cancer symptoms and (ii) A composite symptom endpoint. Biomarkers assayed from blood or body fluids may also be useful to determine the management of the disease.

In certain embodiments, the methods of ng disorders of al cell proliferation se orally administering a formulation of a cytidine analog with food. In certain embodiments, the methods of treating disorders of abnormal cell proliferation comprise orally administering a formulation of a ne analog without food. In certain embodiments, pharmacological parameters (e.g., Cmax, Tmax) depend on the fed state of the subject. In n embodiments, the ation of the cytidine analog is administered sublingually.

In certain embodiments, the cytidine analog, e.g., 5-azacytidine or another cytidine analog provided herein, is not co-administered with a cytidine deaminase inhibitor.

In certain embodiments, the oral formulation comprising a ne analog as provided herein is not co-administered with THU. Certain embodiments herein provide methods of treating a disease or disorder provided herein (e.g., a disease associated with al cell proliferation) comprising orally administering a cytidine analog provided herein for release substantially in the stomach, wherein the methods achieve a particular biological parameter provided herein (e.g, a particular Cmax value, Tmax value, and/or AUC value provided ), and wherein the s comprise not co-administering a cytidine deaminase inhibitor with the cytidine analog. Certain embodiments herein provide methods of treating a disease or disorder provided herein (e.g., a disease ated with abnormal cell proliferation) comprising orally administering a cytidine analog provided herein for release substantially in the stomach, wherein the methods avoid e effects associated with administering a ne deaminase inhibitor (e.g., THU) by not co-administering the cytidine deaminase inhibitor with the cytidine analog. In particular embodiments, a cytidine deaminase inhibitor (e.g., THU) is inistered with the cytidine analog in an amount of, e. g., less than about 500 mg/d, less than about 200 mg/d, less than about 150 mg/d, less than about 100 mg/d, less than about 50 mg/d, less than about 25 mg/d, less than about 10 mg/d, less than about 5 mg/d, less than about 1 mg/d, or less than about 0.1 mg/d.

Certain embodiments herein provide methods for delivering a cytidine analog to a subject comprising administering to the subject in need thereof an oral formulation comprising a cytidine analog. In particular embodiments, oral formulations comprise (l) a therapeutically effective amount of a cytidine analog; and (2) an optional drug e controlling component capable of releasing the cytidine analog substantially in the h after a subject ingests the oral formulation sing the cytidine analog. n embodiments herein e a method for enhancing the oral bioavailability of a cytidine analog in a subject. Certain embodiments herein provide a method of increasing the oral bioavailability of a cytidine analog comprising orally administering a pharmaceutical composition provided herein. In n methods provided herein, a pharmaceutical composition provided herein is orally administered to a subject, contacts the biological fluids of the subject’s body, and is absorbed in the upper gastrointestinal tract, such as, for example, substantially in the stomach.

Certain embodiments herein provide a method of achieving a particular exposure value provided herein by administering an oral formulation comprising a cytidine analog ed herein. Certain embodiments herein e a method of achieving a particular oral ilability value provided herein by administering an oral formulation comprising a cytidine analog provided herein. Certain embodiments herein provide a method of achieving a particular AUC value provided herein by administering an oral formulation comprising a cytidine analog provided herein. n ments herein provide a method of achieving a particular Cmax value provided herein by administering an oral formulation sing a cytidine analog provided herein. Certain embodiments herein provide a method of achieving a particular Tmax value provided herein by administering an oral formulation comprising a cytidine analog provided herein. n embodiments herein provide methods of ng a ion involving undesirable or uncontrolled cell proliferation by administering an oral ation comprising a cytidine analog as provided herein. Such conditions include, e.g., benign tumors, various types of s such as primary tumors and tumor metastasis, solid tumors (e.g., relapsed or refractory solid tumors), hematological disorders (e.g. leukemia, myelodysplastic syndrome and sickle cell anemia), restenosis (e.g. ry, carotid, and cerebral lesions), abnormal stimulation of endothelial cells (arteriosclerosis), insults to body tissue due to surgery, abnormal wound healing, abnormal angiogenesis, diseases that produce fibrosis of tissue, repetitive motion disorders, ers of tissues that are not highly vascularized, and proliferative responses associated with organ transplants.

In certain embodiments, cells in a benign tumor retain their differentiated features and do not divide in a completely uncontrolled manner. A benign tumor may be localized and/or nonmetastatic. Specific types of benign tumors that can be treated using the s, compositions, and formulations provided herein include, 6.g. , hemangiomas, hepatocellular adenoma, cavernous ioma, focal r hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular rative hyperplasia, trachomas and pyogenic granulomas.

In certain ments, cells in a malignant tumor become undifferentiated, do not respond to the body’s growth control signals, and/or multiply in an uncontrolled manner.

The malignant tumor may be invasive and capable of ing to distant sites (metastasizing). Malignant tumors may be divided into two categories: primary and secondary. Primary tumors arise directly from the tissue in which they are found. A secondary tumor, or asis, is a tumor which is originated ere in the body but has now spread to a distant organ. The common routes for metastasis are direct growth into adjacent structures, spread through the vascular or lymphatic systems, and tracking along tissue planes and body spaces (peritoneal fluid, ospinal fluid, etc.).

Without being limited by a particular theory, methylation can lead to the ing of genes critical to cellular control (2'.e., epigenetic gene silencing), and can be an early event in the development of malignant tumors including, e.g., colorectal cancer or lung cancer. See, e.g., M.V. Brock et al., N. Engl. J. Med, 2008, 358(11):1118-28; P.M. Das et al., M01.

Cancer, 2006, 5(28); G. Gifford et al., Clin. Cancer Res, 2004, 0-26; J.G. Herman et al., N. Engl. J. Med, 2003, 349:2042-54; A.M. Jubb et al., J. Pathology, 2001, l95:lll-34.

Accordingly, in certain embodiments, Without being limited by a particular theory, methods herein e using oral formulations provided herein to prevent or reverse epigenetic gene silencing, e.g., by reversing abnormal DNA methylation. In specific embodiments, oral formulations provided herein are used for early intervention to prevent the development of cancer in patients at risk of developing cancer, e.g., familial polyposis or lung cancer, wherein a cause of the cancer is epigenetic gene silencing. In ular embodiments, such early intervention would be impractical by means other than oral administration (e.g., IV or SC administration). In specific embodiments, oral ations provided herein are used for early intervention to prevent the recurrence of cancer in patients at risk for early relapse, e.g. , colorectal cancer or non-small-cell lung cancer. In certain embodiments, the early intervention is achieved via prolonged oral dosing schedules, using formulations and/or methods as described herein. n embodiments provide methods for administering oral formulations provided herein to reverse the effect of gene silencing, e.g. in patients at risk of gene silencing due to epigenetic changes.

In certain embodiments, specific types of cancers or malignant tumors, either primary or secondary, that can be treated using the methods, compositions, and ations provided herein include, e.g., leukemia, lymphoma, breast cancer, skin , bone cancer, prostate cancer, liver cancer, lung cancer (e.g., non-small-cell lung cancer and small-cell lung cancer), brain cancer, cancer of the larynx, gall bladder, pancreas, rectum, uterine, prostate, parathyroid, d, adrenal, neural tissue, head and neck, colon, stomach, bronchi, , or r, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, melanoma, metastatic skin carcinoma, sarcoma, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, le myeloma, giant cell tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy- cell tumor, adenoma, hyperplasia, medullary oma, pheochromocytoma, mucosal neuronmas, intestinal ganglioneuromas, lastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor, seminoma, ovarian , leiomyoma tumor, cervical squamous cell carcinoma, cervical sia and in situ carcinoma, lastoma, blastoma, oblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fungoides, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and other sarcoma, malignant hypercalcemia, renal cell tumor, polycythermia vera, adenocarcinoma, glioblastoma multiforma, ant melanoma, epidermoid carcinoma, other carcinomas and sarcomas, relapsed or refractory solid tumors, and ed metastatic solid tumors.

] Particular embodiments herein provide using the methods, compositions, and formulations provided herein to treat al cell proliferation due to, e.g. insults to body tissue during surgery for a y of surgical procedures, including, e.g., joint surgery, bowel surgery, and cheloid scarring. Proliferative responses associated with organ transplantation that may be treated using the methods, compositions, and formulations provided herein include those proliferative responses contributing to potential organ rejections or associated complications. Specifically, these proliferative responses may occur during transplantation of the heart, lung (e.g., non-small-cell lung cancer and small-cell lung cancer), liver, kidney, and other body organs or organ systems.

In certain embodiments, the amount of the cytidine analog in the oral formulations provided , the methods of administration thereof, or the methods of treatment as set forth herein, is a specific dosage amount as provided herein. 2. kers In certain embodiments, appropriate kers may be used to determine or predict the effect of the methods provided herein on the e state and to provide guidance as to the dosing schedule. For example, ular embodiments herein provide a method for determining whether a patient diagnosed with cancer has an increased probability of obtaining a greater benefit from treatment with a pharmaceutical composition sing a cytidine analog, e.g., by assessing the patient’s nucleic acid methylation status. In particular embodiments, the cytidine analog is 5-azacytidine. In particular embodiments, the cytidine analog is decitabine. In particular ments, the c acid is DNA or RNA. In particular ments, the r benefit is an overall survival benefit. In particular embodiments, the methylation status is examined in one or more genes, e.g., genes associated with the particular cancer. Specific embodiments involve methods for determining whether baseline DNA methylation levels influence overall survival in patients with cancer treated with a cytidine analog, such as 5-azacytidine or decitabine. Specific ments provide methods for determining whether gene promoter methylation levels influence overall al in patients with cancer.

In one embodiment, provided herein is a method for determining whether a patient diagnosed with cancer has an increased probability of obtaining a greater benefit from treatment with a pharmaceutical composition comprising a cytidine analog by assessing the gene expression profile in the patient. In one embodiment, provided herein is a method for ining whether a patient diagnosed with cancer has an increased probability of obtaining a greater benefit from treatment with a pharmaceutical composition comprising a ne analog by assessing molecular markers, including one or more cell cycle markers, apoptosis markers, and DNA damage markers. In ular ments, the cytidine analog is 5-azacytidine. In particular embodiments, the cytidine analog is decitabine. In particular embodiments, the greater benefit is an overall survival benefit.

In certain ments, appropriate biomarkers may be used to determine or t the effect of the pharmaceutical compositions comprising cytidine analogs on the disease state and to provide guidance to the dosing schedule. For example, particular embodiments herein provide a method of determining whether a patient diagnosed with a solid tumor, leukemia, lymphoma, multiple myeloma, MDS, or AML, has an increased probability of obtaining a greater benefit from treatment with a pharmaceutical composition comprising a cytidine analog by assessing the patient’s nucleic acid methylation status. In particular embodiments, the cytidine analog is azacitidine. In particular embodiments, the cytidine analog is decitabine. In particular embodiments, the nucleic acid is DNA or RNA.

In particular embodiments, the greater benefit is an overall survival benefit. In particular embodiments, the methylation status is examined in one or more genes, e.g., genes ated with the solid tumor, leukemia, ma, multiple myeloma, MDS, or AML. Specific embodiments involve methods for determining whether baseline DNA methylation levels influence overall survival in ts treated with azacitidine. Specific embodiments involve methods for ining whether ne DNA methylation levels ce overall survival in patients treated with decitabine. Specific embodiments provide methods for determining whether gene promoter methylation levels influence overall al in patients.

] For e, specific embodiments herein provide methods for evaluating the influence of gene methylation on prolonged survival in patients with a solid tumor (6.g. a relapsed or refractory solid . In particular embodiments, such evaluation is used to predict overall survival in patients with a solid tumor, e.g., upon treatment with a pharmaceutical composition sing a cytidine analog, as provided herein. In particular embodiments, such evaluation is used for therapeutic decision-making. In specific embodiments, such therapeutic decision-making includes planning or ing a patient’s treatment, 6.g. , the dosing regimen, amount, and/or duration of administration of the cytidine analogue.

Certain embodiments provide methods of identifying individual patients diagnosed with a solid tumor having an increased probability of obtaining an overall survival benefit from cytidine analog treatment, using is of methylation levels, 6.g. in particular genes. In some ments, lower levels of nucleic acid methylation are associated with an increased probability of obtaining improved overall survival following treatment with a cytidine analog. In some embodiments, higher levels of nucleic acid methylation are associated with an increased probability of obtaining improved overall survival following treatment with a cytidine analog. In some embodiments, a particular pattern or signature of nucleic acid methylation of multiple genes are associated with an increased ility of obtaining improved overall survival following treatment with a cytidine analog. In some ments, the increased probability of obtaining improved overall survival following treatment is at least a 5% greater probability, at least a 10% greater ility, at least a 20% greater probability, at least a 30% greater probability, at least a 40% greater probability, at least a 50% greater probability, at least a 60% greater probability, at least a 70% greater probability, at least an 80% greater probability, at least a 90% greater probability, at least a 100% greater probability, at least a 125% greater probability, at least a 150% r probability, at least a 175% greater ility, at least a 200% greater probability, at least a 250% r probability, at least a 300% greater probability, at least a 400% greater probability, or at least a 500% greater probability of obtaining improved overall survival following treatment, e.g., using a pharmaceutical ition comprising a cytidine analog as provided . In particular embodiments, the greater probability of obtaining improved l survival following treatment is a greater probability as compared to the e probability of a particular comparison tion of patients.

In particular embodiments, nucleic acid (e.g., DNA or RNA) hypermethylation status may be determined by any method known in the art. In certain embodiments, DNA hypermethylation status may be determined using the bone marrow aspirates of patients diagnosed with cancer, e.g., by using quantitative real-time methylation specific PCR (“qMSP”). In certain embodiments, the methylation is may involve bisulfite sion of genomic DNA. For example, in certain embodiments, bisulfite treatment of DNA is used to t non-methylated CpG sites to UpG, leaving methylated CpG sites . See, e.g., Frommer, M., et al., Proc. Nat’l Acad. Sci. USA 1992, 89:1827-31.

Commercially available kits may be used for such bisulfite treatment. In certain embodiments, to facilitate methylation PCR, primers are designed as known in the art, 6.g. , outer primers which amplify DNA regardless of methylation status, and nested primers which bind to methylated or non-methylated sequences within the region ed by the first PCR.

See, e.g., Li et al., Bioinformatics 2002, 18: 1427-3 1. In certain embodiments, probes are designed, e.g., probes which bind to the bisulfite-treated DNA regardless of methylation status. In certain embodiments, CpG methylation is detected, e.g., following PCR amplification of bisulfite-treated DNA using outer primers. In certain ments, ed product from the initial PCR reaction serves as a template for the nested PCR reaction using methylation-specific s or non-methylation-specific primers. In certain embodiments, a rd curve is established to determine the percentage of methylated les in a particular sample. Methods for detecting nucleic acid ation (e.g., RNA or DNA methylation) are known in art. See, e.g., Laird, P.W., Nature Rev. Cancer 2003, 3:253-66; Belinsky, S.A., Nature Rev. Cancer 2004, 4: 1-1 1.

In certain embodiments, statistical analyses are performed to assess the influence of particular methylation levels with the potential benefit of treatment with a particular pharmaceutical composition comprising a cytidine analog. In certain embodiments, the influence of methylation on overall survival is assessed, e.g. Cox proportional hazards , using models and -Meier (KM) methodology.

In certain embodiments, any gene associated with a particular solid tumor, ia, lymphoma, multiple myeloma, MDS, or AML may be examined for its methylation status in a patient. Particular genes associated with a solid tumor, leukemia, lymphoma, multiple myeloma, MDS, or AML, which would be suitable for use in the methods disclosed here, may be known in the art.

In specific embodiments, provided herein is a method of identifying a subject who is likely to be responsive to a treatment bed herein, comprising: (a) determining the level of a ker in a ical sample from the subject, wherein the biomarker is bed herein; and (b) comparing the level of the biomarker in the ical sample to a reference level of the biomarker; wherein the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered (e.g., high or low) as compared to the reference level of the biomarker.

In specific embodiments, provided herein is a method of identifying a subject who is likely to be responsive to a treatment described herein, comprising: (a) determining the level of a biomarker in a biological sample from the subject, wherein the biomarker is bed herein; (b) determining the level of the ker in a control sample; and (c) comparing the level of the biomarker in the biological sample from the subject to the level of the biomarker in the control sample; wherein the subject is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered (e.g. , high or low) as compared to the level of the biomarker in the control sample.

In specific ments, provided herein is a method of identifying a subject who is likely to be responsive to a treatment described herein, comprising: (a) obtaining a biological sample from the subject; (b) determining the level of a ker in the biological sample, wherein the biomarker is described herein; and (c) comparing the level of the biomarker in the biological sample to a reference level of the biomarker; wherein the subject is likely to be responsive to the treatment if the level of the ker in the biological sample fiom the subject is altered (e.g., high or low) as compared to the nce level of the biomarker.

In specific ments, provided herein is a method of identifying a subject who is likely to be responsive to a treatment described , comprising: (a) obtaining a biological sample from the subject; (b) determining the level of a biomarker in the biological , wherein the biomarker is described herein; (c) determining the level of the biomarker in a control sample; and (d) comparing the level of the biomarker in the biological sample from the subject to the level of the biomarker in the control sample; wherein the t is likely to be responsive to the treatment if the level of the biomarker in the biological sample from the subject is altered (e.g., high or low) as compared to the level of the biomarker in the l sample.

In specific embodiments, provided herein is a method of predicting the responsiveness of a subject to a treatment described herein, comprising: (a) determining the level of a biomarker in a ical sample from the subject, wherein the biomarker is described herein; and (b) comparing the level of the biomarker in the biological sample to a reference level of the biomarker; wherein the difference between the level of the biomarker in the biological sample from the subject and the reference level of the biomarker (e.g. , higher or lower) correlates with the responsiveness of the subject to the treatment.

] In specific embodiments, ed herein is a method of predicting the responsiveness of a subject to a treatment described herein, sing: (a) determining the level of a biomarker in a biological sample from the subject, wherein the biomarker is described herein; (b) determining the level of the biomarker in a control sample; and (c) comparing the level of the biomarker in the biological sample from the subject to the level of 2012/062845 the ker in the control sample; wherein the difference between the level of the biomarker in the biological sample from the subject and the level of the biomarker in the control sample (e.g., higher or lower) correlates with the responsiveness of the subject to the treatment.

In specific embodiments, provided herein is a method of ting the responsiveness of a subject to a treatment described herein, comprising: (a) obtaining a biological sample from the subject; (b) determining the level of a biomarker in the biological sample, n the biomarker is described herein; and (c) ing the level of the biomarker in the biological sample to a reference level of the biomarker; wherein the difference between the level of the biomarker in the biological sample from the subject and the reference level of the biomarker (e.g., higher or lower) correlates with the responsiveness of the t to the treatment.

In specific embodiments, provided herein is a method of predicting the siveness of a subject to a treatment described , comprising: (a) obtaining a biological sample from the subject; (b) ining the level of a biomarker in the biological sample, wherein the ker is described herein; (c) ining the level of the biomarker in a control sample; and (d) comparing the level of the biomarker in the biological sample from the subject to the level of the biomarker in the control sample; wherein the difference between the level of the biomarker in the biological sample from the subject and the level of the biomarker in the control sample (e.g., higher or lower) correlates with the responsiveness of the subject to the treatment.

In specific embodiments, ed herein is a method of monitoring the efficacy of a treatment described herein, comprising: (a) obtaining a first biological sample from the subject; (b) determining the level of a biomarker in the first biological sample, wherein the biomarker is described herein; (c) administering the treatment compound to the subject; (d) thereafter obtaining a second biological sample from the subject; (e) determining the level of the biomarker in the second biological sample; and (f) comparing the levels of the biomarker in the first and second biological samples; n the subject is responsive to the treatment if the level of the biomarker in the second biological sample of the subject is altered (e.g., high or low) as compared to the level of the ker in the first biological sample of the subject.

In specific embodiments, provided herein is a method of monitoring the compliance of a t with a treatment described herein, comprising: (a) obtaining a biological sample from the subject; (b) determining the level of a biomarker in the biological sample, wherein the biomarker is described ; and (c) comparing the level of the biomarker with the level of the biomarker in a control sample from the subject; wherein the change in the level of the biomarker in the biological sample in comparison with the level of the ker in the control sample (e.g., high or low) indicates the compliance of the subject with the treatment. 3. inistered Therapeutic Agents In one embodiments, methods provided herein for treating cancer comprise co- administering a cytidine analog, such as, for example, 5-azacytidine, with one or more eutic , such as, for example, cancer therapeutic agents, to yield a synergistic therapeutic effect. In one embodiment, the co-administered therapeutic agent is provided herein above (e.g., one or more of the additional eutic agent described herein). In exemplary embodiments, the co-administered eutic agents include, but are not limited to, e.g., cytotoxic agents, anti-metabolites, antifolates, DNA intercalating agents, DNA cross- linking agents, DNA alkylating agents, DNA cleaving agents, topoisomerase inhibitors, HDAC inhibitors such as MGCD0103 (a.k.a. N—(2-aminophenyl)((4-(pyridin yl)pyrimidinylamino)methyl)benzamide), CDK inhibitors, JAK tors, antiangiogenic agents, Bcr-Abl inhibitors, HER2 inhibitors, EGFR inhibitors, VEGFR inhibitors, PDGFR inhibitors, HGFR inhibitors, IGFR inhibitors, c-Kit inhibitors, Ras pathway inhibitors, PI3K inhibitors, multi-targeted kinase inhibitors, mTOR inhibitors, anti-estrogens, anti-androgens, aromatase inhibitors, somatostatin analogs, ER modulators, anti-tubulin agents, vinca ids, taxanes, HSP inhibitors, ened antagonists, telomerase inhibitors, COX-2 inhibitors, anti-metastatic agents, immunosuppressants, biologics such as antibodies, and hormonal ies. In particular embodiment, the co-administered therapeutic agent is thalidomide, lenalidomide, or pomalidomide. In particular ment, the co-administered therapeutic agent is carboplatin. In particular embodiment, the co- administered therapeutic agent is paclitaxel (e.g., Abraxane®). See, e.g., US. Patent Nos. 7,758,891, 7,771,751, 7,820,788, 7,923,536, 8,034,375; US. Patent Publication No. 2010/0048499; all of which are orated herein by reference in their entireties. The co- administered agent may be dosed, e.g., orally or by injection.

In one ment, the route of the administration of the ne analog (e.g., 5- idine or another cytidine analog provided herein) is independent of the route of the administration of a second therapy. In one embodiment, the cytidine analog is administered orally. In another embodiment, the cytidine analog is administered intravenously or subcutaneously. In certain embodiments, the cytidine analog is administered orally, and the second therapy is administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, gually, intramuscularly, rectally, transbuccally, intranasally, liposomally, Via inhalation, lly, intraoccularly, Via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, the cytidine analog and a second therapy are administered by the same mode of stration, 6.g. or , orally, intravenously, aneously. In another embodiment, the cytidine analog is administered by one mode of administration, e.g., orally, whereas the second agent (e.g., an anticancer agent) is administered by another mode of administration, e.g, enously or aneously. In yet another embodiment, the cytidine analog is administered by one mode of administration, e. g., enously or subcutaneously, Whereas the second agent (e.g, an anticancer agent) is administered by another mode of administration, 6.g. , orally.

] In one embodiment, each method provided herein may independently, further comprise the step of administering a second therapeutic agent. In one embodiment, the second therapeutic agent is an anticancer agent. In one embodiment, the anticancer agent is an antimetabolite, including, but not d to, S-fluoro uracil, methotrexate, cytarabine, high dose bine, and fludarabine. In one ment, the anticancer agent is an antimicrotubule agent, including, but not limited to, Vinca alkaloids (e.g., Vincristine and Vinblastine) and taxanes (e.g., paclitaxel, e.g., Abraxane® , and docetaxel). In one embodiment, the anticancer agent is an alkylating agent, including, but not limited to, cyclophosphamide, melphalan, carmustine, and nitrosoureas (e.g., hydroxyurea and bischloroethylnitrosurea). In one embodiment, the anticancer agent is a platinum agent, including, but not limited to, cisplatin, carboplatin, oxaliplatin, satraplatin (JM-216), and CI- 973. In one embodiment, the anticancer agent is an anthracycline, including, but not limited to, doxrubicin and daunorubicin. In one ment, the anticancer agent is an antitumor antibiotic, including, but not limited to, mitomycin, idarubicin, adriamycin, and ycin (also known as daunorubicin). In one embodiment, the anticancer agent is a topoisomerase inhibitor, e.g., etoposide and camptothecins. In one embodiment, the anticancer agent is selected from the group consisting of adriamycin, busulfan, bine, cyclophosphamide, dexamethasone, fludarabine, fluorouracil, hydroxyurea, interferons, oblimersen, platinum derivatives, taxol, topotecan, and Vincristine. 2012/062845 In one embodiment, other therapies or anticancer agents that may be used in combination with the cytidine analog include surgery, radiotherapy (e.g. , gamma-radiation, n beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, biologic response modifiers (e.g., interferons, interleukins, and tumor is factor (TNF)), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., etics), and other ed chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, and ifosfamide), antimetabolites abine, high dose cytarabine, and rexate), purine antagonists and pyrimidine antagonists (6- mercaptopurine, ouracil, cytarabine, and gemcitabine), spindle poisons (vinblastine, vincristine, vinorelbine, docetaxel, and paclitaxel, e.g., Abraxane®), podophyllotoxins (etoposide, irinotecan, and topotecan), antibiotics rubicin, doxorubicin, bleomycin, and cin), nitrosoureas (carmustine and lomustine), inorganic ions (cisplatin and latin), enzymes (asparaginase), and es (tamoxifen, leuprolide, flutamide, and megestrol), imatinib, adriamycin, dexamethasone, and hosphamide. For additional available cancer therapies, see, e.g, /www.nci.nih.gov/; for a list of FDA approved oncology drugs, see, e.g., http://www.fda.gov/, The Merck Manual, 18th Ed. 2006, and PDR: Physician Desk Reference 2010, 64th Ed. 2009; the contents of each of which are hereby incorporated by reference in their entireties.

In one embodiment, t being limited by a particular theory, methylation- based silencing of specific genes limits the anti-tumor effects of cytotoxic agents. In one embodiment, without being limited by a particular theory, a cytidine analog, such as, for example, 5-azacytidine or decitabine, can sensitize tumors to the effects of chemotherapy (e.g., the effect of an anti-cancer agent). In one embodiment, without being limited by a particular theory, the etic effect of a cytidine analog, such as, for example, 5- azacytidine or decitabine, es chemo-sensitivity of cancer cells, after the cancer cells are contacted with the cytidine analog for a period of time. In certain embodiments, without being limited by a particular theory, a cytidine analog is administered to a subject in need thereof for a sustained period of time (6.g. doses or multiple treatment cycles) , multiple before the subject is treated with an additional therapeutic agent (6.g. an anti-cancer agent) to yield a greater synergistic therapeutic effect and/or a reduced toxicity effect. In some embodiments, without being limited by a particular theory, co-administration of a cytidine analog and certain anti-cancer agent (6.g. , a xic agent) from the first day of therapy may produce increased toxicity without added anti-tumor s. In some embodiments, without being limited by a particular theory, sustained exposure of a subj ect to a cytidine analog (6.g. , 5-azacytidine or decitabine or another cytidine analog provided herein) prior to the stration of an onal therapeutic agent (6.g. a cytotoxic agent) yield a synergistic therapeutic effect (6.g. , sensitization of cancer cells to the cytotoxic agent).

In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 100 mg/day for 7 days or more before a second therapeutic agent is administered to the t. In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 100 mg/day for 14 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5- azacytidine is administered orally to a subject in need thereof at a dose of about 100 mg/day for 21 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, ytidine is administered orally to a subject in need thereof at a dose of about 100 mg/day for 28 days or more before a second therapeutic agent is stered to the subject. In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 150 mg/day for 7 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 150 mg/day for 14 days or more before a second therapeutic agent is stered to the subject. In particular embodiments, 5-azacytidine is administered orally to a subject in need f at a dose of about 150 mg/day for 21 days or more before a second eutic agent is administered to the subject. In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 150 mg/day for 28 days or more before a second therapeutic agent is administered to the t. In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 200 mg/day for 7 days or more before a second therapeutic agent is stered to the subject. In particular embodiments, 5- azacytidine is administered orally to a subject in need thereof at a dose of about 200 mg/day for 14 days or more before a second therapeutic agent is administered to the subject. In particular ments, 5-azacytidine is stered orally to a t in need thereof at a dose of about 200 mg/day for 21 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 200 mg/day for 28 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5- azacytidine is administered orally to a subject in need thereof at a dose of about 250 mg/day for 7 days or more before a second therapeutic agent is administered to the t. In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 250 mg/day for 14 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5-azacytidine is administered orally to a t in need thereof at a dose of about 250 mg/day for 21 days or more before a second therapeutic agent is administered to the t. In particular embodiments, 5- azacytidine is administered orally to a subject in need thereof at a dose of about 250 mg/day for 28 days or more before a second therapeutic agent is stered to the subject. In particular embodiments, 5-azacytidine is stered orally to a subject in need thereof at a dose of about 300 mg/day for 7 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 300 mg/day for 14 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5- azacytidine is administered orally to a subject in need f at a dose of about 300 mg/day for 21 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5-azacytidine is stered orally to a subject in need thereof at a dose of about 300 mg/day for 28 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5-azacytidine is administered orally to a subject in need f at a dose of about 350 mg/day for 7 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, ytidine is administered orally to a subject in need thereof at a dose of about 350 mg/day for 14 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 350 mg/day for 21 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5-azacytidine is administered orally to a subject in need f at a dose of about 350 mg/day for 28 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 400 mg/day for 7 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5- azacytidine is stered orally to a subject in need thereof at a dose of about 400 mg/day for 14 days or more before a second therapeutic agent is administered to the t. In particular embodiments, 5-azacytidine is stered orally to a subject in need thereof at a dose of about 400 mg/day for 21 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 400 mg/day for 28 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, 5- azacytidine is administered orally to a subject in need thereof at a dose of about 450 mg/day for 7 days or more before a second therapeutic agent is stered to the subject. In particular embodiments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 480 mg/day for 7 days or more before a second therapeutic agent is administered to the subject. In particular embodiments, ytidine is stered orally to a subject in need thereof at a dose of about 500 mg/day for 7 days or more before a second therapeutic agent is administered to the subject. In particular ments, 5-azacytidine is administered orally to a subject in need thereof at a dose of about 600 mg/day for 7 days or more before a second therapeutic agent is stered to the subject.

In one embodiment, after the second therapeutic agent is administered, the administration ofthe cytidine analog is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 26, 28, or more than 28 days; optionally followed with a g period from the administration ofthe cytidine analog of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 21, 28, or more than 28 days.

] In one embodiment, the second therapeutic agent is stered cyclically, after the first dose. In one embodiment, the methods provided herein comprise: i) administering to the subject a first daily dose of the second eutic agent; ii) optionally resting for a period of at least one day where the second therapeutic agent is not administered to the subject; iii) administering a second dose of the second therapeutic agent to the subject; and iV) repeating steps ii) to iii) a plurality of times. In certain embodiments, the first daily dose is between about 50 mg/m2/day and about 2,000 mg/mZ/day. In certain embodiments, the second daily dose is between about 50 day and about 2,000 mg/m2/day. In certain embodiments, the first daily dose is between about 50 mg/mZ/day and about 200 mg/mZ/day. In certain embodiments, the second daily dose is between about 50 mg/m2/day and about 200 mg/mz/day. In certain embodiments, the first daily dose is between about 100 mg/day and about 1,000 mg/day. In certain embodiments, the second daily dose is between about 100 mg/day and about 1,000 mg/day. In certain embodiments, the first daily dose is higher than the second daily dose. In certain embodiments, the second daily dose is higher than the first daily dose. In n embodiments, the second daily dose and the first daily dose are the 2012/062845 same. In one embodiment, the rest period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, ll days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, or 28 days. In one embodiment, the rest period is at least 2 days and steps ii) through iii) are repeated at least three times. In one embodiment, the rest period is at least 2 days and steps ii) through iii) are ed at least five times. In one embodiment, the rest period is at least 3 days and steps ii) through iii) are repeated at least three times. In one embodiment, the rest period is at least 3 days and steps ii) through iii) are repeated at least five times. In one embodiment, the rest period is at least 7 days and steps ii) through iii) are repeated at least three times. In one embodiment, the rest period is at least 7 days and steps ii) through iii) are repeated at least five times. In one ment, the rest period is at least 14 days and steps ii) through iii) are repeated at least three times. In one embodiment, the rest period is at least 14 days and steps ii) through iii) are repeated at least five times. In one embodiment, the rest period is at least 21 days and steps ii) through iii) are repeated at least three times. In one embodiment, the rest period is at least 21 days and steps ii) through iii) are repeated at least five times. In one embodiment, the rest period is at least 28 days and steps ii) through iii) are repeated at least three times. In one embodiment, the rest period is at least 28 days and steps ii) through iii) are repeated at least five times.

In one embodiment, 5-azacytidine is administered orally for 7 days out of a 28- day cycle. In one embodiment, 5-azacytidine is administered orally for 14 days out of a 28- day cycle. In one embodiment, 5-azacytidine is administered orally for 21 days out of a 28- day cycle. In one ment, 5-azacytidine is administered orally for 7 days out of a 21- day cycle. In one ment, 5-azacytidine is stered orally for 14 days out of a 21- day cycle. In one embodiment, 5-azacytidine is administered orally for 21 days out of a 21- day cycle. In one embodiment, 5-azacytidine is administered orally once daily. In one ment, 5-azacytidine is administered orally twice daily. In one embodiment, 5- idine is administered orally once daily in an amount of about 50 mg/day. In one embodiment, 5-azacytidine is administered orally twice daily in an amount of about 50 mg/day. In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 50 mg/day for 7, 14, or 21 days. In one embodiment, 5-azacytidine is administered orally twice daily in an amount of about 50 mg/day for 7, 14, or 21 days. In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 50 mg/day for more than 21 days. In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 100 mg/day. In one embodiment, 5-azacytidine is administered orally twice daily in an amount of about 100 . In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 100 mg/day for 7, 14, or 21 days. In one ment, 5-azacytidine is administered orally twice daily in an amount of about 100 mg/day for 7, 14, or 21 days. In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 100 mg/day for more than 21 days. In one embodiment, 5- azacytidine is administered orally once daily in an amount of about 150 mg/day. In one embodiment, 5-azacytidine is administered orally twice daily in an amount of about 150 mg/day. In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 150 mg/day for 7, 14, or 21 days. In one embodiment, 5-azacytidine is administered orally twice daily in an amount of about 150 mg/day for 7, 14, or 21 days. In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 150 mg/day for more than 21 days. In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 200 mg/day. In one embodiment, 5-azacytidine is stered orally twice daily in an amount of about 200 mg/day. In one embodiment, 5-azacytidine is stered orally once daily in an amount of about 200 mg/day for 7, 14, or 21 days. In one embodiment, 5-azacytidine is administered orally twice daily in an amount of about 200 mg/day for 7, 14, or 21 days. In one ment, 5-azacytidine is administered orally once daily in an amount of about 200 mg/day for more than 21 days. In one ment, 5- azacytidine is administered orally once daily in an amount of about 250 mg/day. In one ment, 5-azacytidine is administered orally twice daily in an amount of about 250 mg/day. In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 250 mg/day for 7, 14, or 21 days. In one embodiment, 5-azacytidine is administered orally twice daily in an amount of about 250 mg/day for 7, 14, or 21 days. In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 250 mg/day for more than 21 days. In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 300 mg/day. In one embodiment, 5-azacytidine is administered orally twice daily in an amount of about 300 mg/day. In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 300 mg/day for 7, 14, or 21 days. In one ment, 5-azacytidine is administered orally twice daily in an amount of about 300 mg/day for 7, 14, or 21 days. In one embodiment, 5-azacytidine is administered orally once daily in an amount of about 300 mg/day for more than 21 days. In particular embodiments, -azacytidine is administered continuously for 14 days, followed with a 7-day resting period. 4. s Comprising inistering One or More Additional eutic Agents with Oral Formulations Disclosed Herein Particular embodiments herein provide methods of ng diseases or ers disclosed herein (e.g., es or disorders involving abnormal cell proliferation), wherein the s comprise co-administering an oral formulation disclosed herein, such as, for example, an oral formulation comprising ytidine or another cytidine analog provided herein, with one or more additional therapeutic agents (such as, for example, a cancer therapeutic agent) to yield a synergistic therapeutic effect. Particular co-administered therapeutic agents useful in the methods disclosed herein are disclosed throughout the specification. In particular embodiments, the co-administered therapeutic agent is carboplatin. In particular embodiments, the co-administered therapeutic agent is paclitaxel (e.g., Abraxane®). In particular embodiments, the onal therapeutic agent is co- stered in an amount that is a therapeutically effective amount. In particular embodiments, the additional therapeutic agent is co-administered in a te dosage form from the cytidine analog dosage form with which it is co-administered. In particular embodiments, the additional therapeutic agent is co-administered in a dosage form (e.g., a single unit dosage form) together with the cytidine analog with which it is co-administered.

In such cases, the cytidine analog and the additional therapeutic agent may be co-formulated together in the same dosage form using methods of co-formulating active pharmaceutical ingredients, including methods sed herein and methods known in the art.

In particular embodiments, a cytidine analog is administered to a subject in need thereof, for a sustained period of time (e.g., for l, 2, 3, 4, 5, 6, 7, or more than 7 days) before one or more additional therapeutic agent(s) is/are administered to the subject. In particular embodiments, provided herein are methods of treating diseases or disorders disclosed herein (e.g., diseases or disorders involving abnormal cell proliferation, such as a relapsed or refractory solid , wherein the methods comprise: (i) first administering a cytidine analog orally to a subject in need thereof, for l, 2, 3, 4, 5, 6, 7, or more than 7 days; and (ii) administering an additional therapeutic agent (6.g. , an anti-cancer agent provided herein, such as, carboplatin or paclitaxel, e.g., Abraxane®) for one or more days. In certain ment, the second step comprises continued stration of the cytidine analog orally for one or more additional days (e.g., for l, 2, 3, 4, 5, 6, 7, 8, 9, 10, ll, l2, l3, 14, or more than 14 days). oration By Reference: All disclosures (e.g., patents, publications, and web pages) referenced throughout this specification are incorporated by reference in their entireties.

VI. ES A. Example 1 al studies were conducted to evaluate oral azacitidine as a single agent and in combination with Carboplatin or Abraxane® in subjects with relapsed or refractory solid tumors (Figure 7).

One objective of the study was to te the safety and to define the Maximal Tolerated Dose (MTD) or the Maximal Administered Dose (MAD) of oral azacitidine as a single agent and in combination with carboplatin (CBDCA) or paclitaxel protein-bound particles (Abraxane® [ABX]) in subjects with relapsed or refractory solid .

Other objectives of the study included: (1) to examine the impact, if any, of CBDCA or ABX on the pharmacokinetics (PK) of oral azacitidine; (2) to examine the impact, if any, of oral azacitidine on the PK of CBDCA or ABX; (3) to te the pharmacodynamic (PD) s of oral azacitidine as a single agent and in combination with CBDCA and ABX in blood, plasma and tumor tissue; and (4) to make a preliminary assessment of the anti-tumor activity of oral azacitidine as a single agent and in combination with CBDCA and ABX in specific tumor types.

] Additional objectives of the study included: to determine r there is any relationship among baseline tumor molecular characteristics (genetic or epigenetic), PD effects, and umor activity.

The study was an open-label, 3-arm, multi-center, dose-escalation study of oral azacitidine in combination with either CBDCA (Arm A), ABX (Arm B), or as a single agent (Arm C) in subjects with ed or refractory solid tumors (Part 1). Subjects were assigned to each study Arm at the discretion of the investigator. A minimum of 6 subjects were assigned to each study Arm when a dose level (DL) became open for enrollment. If one (1) or zero (0) out of six (6) subjects in a DL experienced dose limiting toxicity (DLT), the dose of oral azacitidine was escalated in the successive DL. A limited number of oral azacitidine DLs were explored to arrive at a recommended Part 2 dose (RP2D) of oral azacitidine for each study Arm. The RP2D may be the MTD, MAD, or a lower dose depending on the tolerability, PK, and PD observed. Part 1 was followed by expansion cohorts at the RP2D in specific tumor types (Part 2). Approximately 60 subjects were enrolled in Part 1, and approximately 100 subjects were enrolled in Part 2. Safety, y, pharmacokinetics, and pharmacodynamics data were evaluated.

In Part 1, Arms A and B, Cycle 1 was 28 days in duration. Subsequent treatment Cycles were 21 days in duration. In Arm C, all Cycles were 21 days in duration.

Part 1 Design: Subjects may continue to receive their ed combination treatment if they have no unacceptable toxicity and if there is no clinical or radiographic evidence of disease progression or the investigator deems that the subject is deriving potential benefit. If combination treatment is suspended for unacceptable toxicity that is believed to be related to CBDCA in Arm A or ABX in Arm B, subjects may continue to take single agent oral idine at their assigned DL once the toxicity resolves to at least grade 1. Subjects in Arm C receive single agent oral azacitidine in all Cycles up to approximately 1 year from the start of therapy or until they experience unacceptable ty or progressive disease, as assessed by the investigator, whichever occurs first. tion of the oral azacitidine dose continues independently in each Arm until the RP2D of oral azacitidine as a single agent and in combination with CBDCA and ABX is defined. The RP2D may be different for each study Arm.

Part 2 Design: ion cohorts of up to 20 subjects for each of several specific tumor types are enrolled at the RP2D for each Arm. In addition to further exploring the safety and PD activity of oral azacitidine alone and in combination with CBDCA or ABX in specific tumor types, this part of the study is ed to make an initial assessment of anti- tumor ty and its potential association with candidate tive biomarkers. Tumor biopsies are performed in Part 2.

Study tion: Men and women, 18 years or older, with histological or cytological confirmation of advanced unresectable solid tumors, including those who have progressed on (or not been able to tolerate) standard anti-cancer therapy, or for whom no other known effective therapy exists, or for those who have declined standard therapy.

Length of Study: The duration of Part 1 of the study from first subject screened to last subject last visit is approximately 1 year. Part 2 of the study lasts imately 18 months making the entire duration of the study imately 2.5 years.

Study Treatments: Part 1: Subjects receive oral azacitidine as a single agent for the first 7 days of study. Beginning on Cycle 1, Day 8, subjects in Arms A and B begin combination treatment with CBDCA or ABX, respectively. Subjects may continue to receive their assigned combination until they ence disease progression or ptable toxicity, whichever occurs first. Subjects in Arm C receive single agent oral azacitidine in all Cycles until they experience unacceptable toxicity or progressive disease, whichever occurs first.

The dose of oral azacitidine in each Arm is escalated (or reduced) based on tolerability with a fixed dose of CBDCA or ABX in the first 28-day Cycle, or as a single agent in the first 2l-day Cycle, until the RP2D is defined.

All study Arms begin at Dose Level 1 (DLl). If DLl is declared tolerable, Dose Level 2 (DL2) opens for enrollment. If DL2 is declared tolerable, this dose and schedule are explored in Part 2 of the study. If DL2 exceeds the maximum tolerated dose (MTD), DLl is explored in Part 2. If DLl exceeds MTD, Dose Level-l (DL-l) opens for enrollment.

] For Arms A and B, if DL-l is declared tolerable, Dose Level-2 (DL-2) opens for enrollment. If DL-2 is declared tolerable, this dose and le are ed in Part 2. If DL-2 exceeds MTD, DL-l is explored in Part 2. If DL-l exceeds MTD, enrollment to that Arm stops (Figure 4).

For Arm C, if DL-l is ed tolerable, that dose and schedule are explored in Part 2. If DL-l s MTD, DL-2 opens for enrollment. If DL-2 is declared tolerable, that dose and le are explored in Part 2. If DL-2 exceeds MTD, ment into Arm C stops (Figure 5).

In certain embodiments, subjects receive a dose of a prophylactic anti-emetic, for example, a 5-HT3 antagonist, prior to each dose of oral azacitidine.

Part 2: Subjects in Part 2 of the study receive oral azacitidine alone (Arm C) or in combination with CBDCA (Arm A) or ABX (Arm B) according to the RP2D established for each Arm in Part 1. All treatment Cycles in Part 2 are 21 days in duration. Each specific tumor type in Part 2 receives treatment according to one of the three Arms. About 14 to 20 patients are enrolled per tumor type. ment of Subject to Study Arms: At the time of enrollment in Part 1, subjects who meet all of the ion criteria and none of the exclusion criteria are assigned to either Arm A (oral azacitidine with CBDCA), Arm B (oral azacitidine with Abraxane®), or Arm C (single agent oral azacitidine). Assignment of ts to each of these study Arms is at the discretion of the investigator, based on the suitability of the regimen(s) for the subject and availability of open enrollment slots. The DLs for Arms A, B, and C are shown in Table 1, Table 2, and Table 3, respectively.

Table 1: Oral Azacitidine and Carboplatin (CBDCA) Dose Levels for Arm A Cycle 1 (28 days) Cycle 2 (21 days) Cycles 3+ (21 days) Oral Oral Oral idine CBDCA CBCDA CBCDA Azacitidine Azacitidine 100 mg AUC4 100 mg AUC 4 100 mg AUC 4 DL–2 Days 1-7, 9-28 Day 8 Days 1-21 Day 1 Days 1-21 Day 1 100 mg 100 mg 100 mg AUC4 AUC 4 AUC 4 DL-1 Days 1-7, 9-14, Days 1-7, Days 1-7, Day 8 Day 1 Day 1 22-28 15-21 15-21 200 mg 200 mg 200 mg AUC4 AUC 4 AUC 4 DL1 Days 1-7, 9-14, Days 1-7, Days 1-7, Day 8 Day 1 Day 1 22-28 15-21 15-21 300 mg 300 mg 300 mg AUC4 AUC 4 AUC 4 DL2 Days 1-7, 9-14, Days 1-7, Days 1-7, Day 8 Day 1 Day 1 22-28 15-21 15-21 Table 2: Oral Azacitidine and Abraxane® (ABX) Dose Levels for Arm B Cycle 1 (28 days) Cycle 2 (21 days) Cycles 3+ (21 days) Oral Oral Oral Azacitidine ABX ABX ABX Azacitidine Azacitidine 100 mg 100 mg/m2 100 mg 100 mg/m2 100 mg 100 mg/m2 DL-2 Days 1-14, Days 8, 15 Days 1-21 Days 1, 8 Days 1-21 Days 1, 8 19-28 100 mg 100 mg 100 mg 100 mg/m2 100 mg/m2 100 mg/m2 DL-1 Days 1-14, Days 1-7, Days 1-7, Days 8, 15 Days 1, 8 Days 1, 8 22-28 15-21 15-21 200 mg 200 mg 200 mg 100 mg/m2 100 mg/m2 100 mg/m2 DL1 Days 1-14, Days 1-7, Days 1-7, Days 8, 15 Days 1, 8 Days 1, 8 22-28 15-21 15-21 300 mg 300 mg 300 mg 100 mg/m2 100 mg/m2 100 mg/m2 DL2 Days 1-14, Days 1-7, Days 1-7, Days 8, 15 Days 1, 8 Days 1, 8 22-28 15-21 15-21 Table 3: Oral Azacitidine Dose Levels for Arm C -Ccle121das Ccle2 21das Ccles3+ 21das Oral Azacitidine 200m, Da s 144 200m, Da s 144 200m, Da s 144 300m, Da s 144 300m, Da s 144 300m, Da s 144 200m, Da s 1—21 200m, Da s 1—21 200 m. Da s 1—21 300m, Da s 1—21 300m, Da s 1—21 300 m. Da s 1—21 ] Efficacy Assessments: Subjects are evaluated for tumor response after Cycle 2 and every other Cycle thereafter. The primary efficacy variables are tumor response at the end of ent, and the proportion of ts alive and progression-free (progression-free survival; PFS) at the end of Cycle 6. Tumor response is based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for e states which require at least one measurable target lesion at baseline for study eligibility. Progression-free survival rates are computed using the Kaplan-Meier estimates. on of response is reported in subjects who have a complete or l response. Ninety percent confidence intervals (90% Cls) of the response rate at the end of treatment, and of the PPS rate at time of each scheduled response assessment (i.e., Cycles 2, 4, 6, etc.) are provided by tumor type. Other endpoints that are explored include time-to-tumor-progression and overall survival.

The influence of major disease characteristics and prognostic indications are considered in relationship to efficacy, with special ion given to subjects in Arm A who were previously d with a platin and to ts in Arm B who were previously treated with a taxane. Full details on the efficacy is are given in the tical Analysis Plan (SAP).

] Safety Assessments: Safety assessments include adverse events (AEs), physical examinations (PEs), ding height and body weight); vital signs (including systolic/diastolic blood pressure [BP], pulse rate, respiratory rate, and oral temperature); Eastern Cooperative Oncology Group (ECOG) performance status; 12-lead electrocardiogram (ECG [including rhythm, heart rate, PR, QRS, and QT intervals]); complete blood count (CBC) (including hemoglobin, hematocrit, red blood cell count with indices [mean corpuscular volume {MCV}, mean corpuscular hemoglobin {MCH}, and mean corpuscular hemoglobin concentration {MCHC}, white blood cell [WBC] count with absolute differential [neutrophils, lymphocytes, monocytes, eosinophils, and basophils], and platelet count); coagulation (international normalized ratio [INR], prothrombin time [PT], and partial thromboplastin time [PTT]); serum chemistry (non-fasting) (including albumin, alkaline phosphatase, bicarbonate, blood urea nitrogen [BUN], calcium, chloride, creatinine, glucose, lactic dehydrogenase [LDH], phosphorus, potassium, ate aminotransferase [AST], alanine aminotransferase [ALT], sodium, total bilirubin, total protein, and uric acid); screening serum pregnancy test required for all females of child-bearing potential (FCBP) prior to Cycle 1 Day 1 dosing (test result must be obtained and read prior to dosing on Day 1.); tumor biopsy (optional); and tumor assessment.

Study Endpoints: The nature, incidence and severity ofABS are evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) criteria, Version 4.0. For oral azacitidine, CBDCA, and ABX (administered alone and in ation), the ing plasma PK parameters are assessed: (1) maximum observed tration in plasma ; (2) area under the concentration-time curve (AUC); (3) time to maximum concentration (tmax); (4) terminal half-life (tl/z); (5) apparent total body clearance (CL/F); and (6) apparent volume of distribution (Vz/F). To evaluate the PD effects of oral azacitidine in blood, plasma, and tumor tissue, the following endpoints are collected: (1) change from baseline (Cycle 1 Day 1 pre-dose) in DNA methylation (global and gene- specif1c assays) in whole blood and tumor tissue (as available in Part 1); (2) reduction from baseline (Cycle 1 Day 1 predose) in DNMTl protein levels in tumor tissue (as available in Part 1). Anti-tumor activity endpoints using tumor-specific response criteria for each tumor type e: (1) response rate and duration of se; and (2) ssion-free survival (PFS). lar characteristics of the blood and tumor, including, but not limited to, DNA/RNA methylation, gene sequence and mRNA/miRNA expression, may be evaluated at baseline and post-therapy for examination in relation to tumor responses.

Part l/Arm A: ts in Arm A receive their first dose of oral azacitidine at their assigned DL in the clinic on Cycle 1 Day 1 along with PK se through 8 hours post-dose oral azacitidine) and predose PD blood tory) and tumor (optional) sampling.

On Days 2 through 7, subjects self-administer oral idine daily according to their assigned DL. Subjects return to the clinic for CBDCA dosing on Day 8 along with predose PD sampling (blood). CBDCA is administered at AUC = 4 using the Glomerular Filtration Rate (GFR) calculation from the Modification of Diet in Renal Disease (MDRD) formula below as an iv. lI‘lfiISlOIl over 1 hour.

Modification of Diet in Renal Disease (MDRD) Equation for GFR: This IDMS- traceable MDRD study equation calculator is for use with Scr reported in mg/dL: GFR (mL/min/1.73 m2) = 175 x (sag-L154 x (Age)'0'203 x (0.742 if ) x (1.212 if African American) (conventional units) The equation does not require weight because the s are ed normalized to 1.73 m2 body surface area (BSA), which is an accepted average adult surface area.

CBDCA dose (mg) = 4 (GFR + 25) An e calculator can be found at the following link: /www.nkdep.nih.gov/professionals/gfr_calculators/idms_con.htm In some embodiments, oral azacitidine is not administered on Day 8 so that the PK profile of CBDCA alone can be established. On Day 9, subjects return to the clinic for CBDCA PK sampling approximately 24 hours after the end of the initial infilsion and before administration of oral azacitidine. On Day 9, subjects receive their dose of oral azacitidine at their ed DL in the clinic. On Days 10 through 14, subjects self-administer oral azacitidine. Subjects return to the clinic on Cycle 1 Day 15 for blood PD sampling (mandatory) and tumor biopsy (optional). On Days 15 through 21 no study medication is administered (except for subjects in DL-2, who self-administer oral azacitidine daily). On Day 22, subjects return to clinic for administration of oral azacitidine with predose blood collection tory) for PD analysis. On Days 23 h 28 of Cycle 1, subjects self- administer oral azacitidine daily according to their assigned DL (Figure 1).

Subjects who complete Cycle 1 meet the following hematologic criteria at the beginning of each subsequent Cycle: (1) ANC > 1.5 X 109 L; and (2) ets > 75 X 109/L.

If the hematologic criteria are not met, the start of Cycle 2 may be delayed for up to 7 days to allow the counts to recover. If ry has not occurred after 7 days, this is considered a DLT.

In Cycle 2, Arm A subjects receive oral azacitidine in the clinic on Day 1 followed by CBDCA AUC = 4 as an iv. infilsion over 1 hour, along with PK (predose through 8 hours following the end of the CBDCA infiasion). On Day 2, subjects return to the clinic for PK sampling approximately 24 hours following the end of the CBDCA infilsion.

On Days 2 through 7, subjects self-administer oral idine daily according to their ed DL. On Days 8 through 14 of Cycle 2, no study medication is administered (except for subjects in DL-2 who self-administer oral azacitidine at their assigned DL). On Days 15 through 21, subjects self-administer oral azacitidine at their assigned DL.

In Cycles 3 and beyond, Arm A subjects receive oral azacitidine at their assigned DL in the clinic on Day 1 followed by CBDCA AUC = 4 as an iv. infusion over 1 hour. On Days 2 through 7, subjects self-administer oral azacitidine daily according to their assigned DL. On Days 8 through 14, no study medication is administered t for subjects in DL-2 who self-administer oral azacitidine at their assigned DL). On Days 15 through 21, subjects self-administer oral azacitidine at their assigned DL. Subjects may continue to receive their assigned combination ent if they have no unacceptable ty and if there is no clinical or radiographic ce of disease progression or they are deriving potential benefit as assessed by the investigator. If combination treatment is suspended for ptable toxicity that is believed to be related to CBDCA, ts may continue to take single agent oral azacitidine at their assigned DL once the toxicity resolves.

Part 1/Arm B: Subjects in Arm B receive their first dose of oral azacitidine at their assigned DL in the clinic on Cycle 1 Day 1 along with PK (predose through 8 hours post- dose oral azacitidine) and PD blood sampling. Tumor biopsy (optional) is obtained prior to the first dose of oral azacitidine on Day 1. On Days 2 through 7, subjects self-administer oral azacitidine daily according to their assigned DL. Subjects return to the clinic on Day 8 for oral azacitidine followed by ABX 100 mg/m2 i.v., along with PK (predose through imately 8 hours post end ofABX infusion) and predose PD blood sampling. Subjects return to the clinic on Days 9, 10 and 11 for ABX PK sampling approximately 24, 48 and 72 hours from the end of the ABX infusion. On Days 9 through 14, subjects dminister oral azacitidine at their assigned DL. On Cycle 1 Day 15, subjects report to the clinic for blood PD sampling (mandatory) and tumor biopsy (optional). ne® 100 mg/m2 i.v is administered on Cycle 1 Day 15 ed by PK sampling (predose through approximately 8 hours after the end of the ABX infilsion). Subjects return to the clinic on Days 16, 17, and 18 for ABX PK sampling approximately 24, 48 and 72 hours from the end of the ABX infusion.

On Days 15 through 21, no oral azacitidine is administered (except for subjects assigned to DL-2 who self-administer oral azacitidine daily according to their assigned DL on Days 19 through 21). In some ments, oral azacitidine is not administered on Days 15 through 18 of Cycle 1 for subjects in DL-2 so that the PK profile ofABX alone can be established.

On Day 22, subjects return to the clinic for oral azacitidine followed by ABX 100 mg/m2 iv. in the clinic after obtaining predose blood (mandatory) PD sampling. On Days 23 through 28, subjects self-administer oral idine daily according to their assigned DL (Figure 2).

Subjects who complete Cycle 1 meet the ing hematologic criteria at the beginning of each subsequent Cycle: (1) Absolute phil Count (ANC) > 1.5 X 109/L; and (2) Platelets > 75 x 10%.

WO 67043 If the hematologic criteria are not met, the start of Cycle 2 may be delayed for up to 7 days to allow the hematologic counts to recover. If recovery has not occurred after 7 days, this is considered a DLT.

In Cycle 2, Arm B subjects receive oral azacitidine ed by ABX 100 mg/m2 i.v on Day 1. On Days 2 through 7, subjects self-administer oral azacitidine at their assigned DL. Subjects return to the clinic on Day 8 for ABX 100 mg/m2 i.v. In some ments, oral azacitidine is not stered on Days 8 through 14 t for subjects in DL-2 who self-administer oral azacitidine at their assigned DL). Oral azacitidine followed by ABX 100 mg/m2 i.v. is administered on Day 15. On Days 16 through 21, subjects self-administer oral azacitidine at their assigned DL. Subjects who complete Cycle 2 without unacceptable toxicity and without objective evidence of disease progression as per a tumor assessment may proceed to Cycle 3.

In Cycle 3 and beyond, Arm B subjects receive oral azacitidine at their assigned DL in the clinic on Day 1, followed by ABX 100 mg/m2 i.v. On Days 2 through 7, subjects self-administer oral azacitidine at their assigned DL. Subjects return to the clinic on Day 8 for ABX 100 mg/m2 i.v. In some ments, oral azacitidine is not stered on Days 8 through 14 (except for subjects in DL-2 who self-administer oral azacitidine at their assigned DL). Oral azacitidine followed by ABX 100 mg/m2 i.v. is administered on Day 15 in the clinic. On Days 16 through 21, subjects self-administer oral azacitidine at their ed DL.

Subjects may continue to receive their assigned combination treatment if they have no unacceptable toxicity and if there is no al or radiographic evidence of disease progression. If combination treatment is suspended for unacceptable toxicity that is believed to be d to ABX, subjects may continue to take single agent oral azacitidine at their assigned DL once the toxicity resolves.

Part 1/Arm C: Subjects in Arm C e their first dose of oral azacitidine at their assigned DL in the clinic on Cycle 1 Day 1. Predose tumor collection (optional) accompanies oral azacitidine on Cycle 1 Days 1 and 15. Pre-dose PD blood tion (mandatory) accompanies oral azacitidine dosing on Cycle 1 Days 1, 8, and 15 and Cycle 2 Day 1. On Days 2 through 7, 9 through 14 and 16 through 21 of each Cycle, subjects self-administer oral azacitidine at their assigned DL; subjects in DL-1 and DL-2 only self-administer oral azacitidine Days 2 through 7 and 9 through 14 (Figure 3).

In Cycle 2 and beyond, Arm C subjects self-administer oral azacitidine on Days 2 through 21; subjects in DL-1 and DL-2 only self-administer oral azacitidine on Days 2 through 14. Subjects who complete Cycle 2 without ptable ty and without objective evidence of disease progression on a tumor assessment may proceed to Cycle 3.

Subjects may continue to receive oral azacitidine at their assigned DL as long as they have no ptable toxicity and no clinical or radiographic evidence of disease progression.

DLT Definitions: Any non-hematologic toxicity ofNCI CTCAE v 4.0 Grade = 3 that is believed to be related to oral azacitidine or to the combination of oral azacitidine with CBDCA or ABX with the following ions: (1) Grade 3 emesis that responds to optimal antiemetic therapy within 72 hours; (2) Grade 3 diarrhea that responds to optimal l management within 72 hours; (3) Alopecia of any grade; (4) Grade 3 fatigue in a subject who had Grade 2 fatigue at study entry and that recovers to baseline grade or less within 72 hours; and (5) Grade 3 or 4 laboratory abnormalities that are not accompanied by clinical signs or symptoms and are not believed by the investigator to be medically significant.

The following hematologic ties are considered DLT: (1) Grade 4 neutropenia lasting > 7 days or accompanied by fever; (2) Grade 3 thrombocytopenia with clinically significant ng; and (3) Failure to meet hematologic criteria for starting Cycle 2 within 7 days of Cycle 1 Day 28.

Definition of DLT-evaluable Subjects: To be evaluable for DLT for the purpose of dose escalation decisions, a subject must meet one of the following conditions: (1) Experienced a DLT during Cycle 1; or (2) Did not receive Cycle 2 Day 1 treatment due solely to not meeting hematologic criteria within 7 days of Cycle 1 Day 28 (for Arm C subjects, Cycle 1 Day 21); or (3) Completed dosing for Cycle 1 Day 28 (for Arm C subjects, Cycle 1 Day 2l)without DLT and (i) missed no more than 4 total planned doses of oral azacitidine within Cycle 1; (ii) Arm A subjects: received scheduled dose of CBDCA during Cycle 1; and (iii) Arm B subjects: received all scheduled doses ofABX during Cycle 1.

Subjects who do not meet any of the ia for being DLT evaluable (e.g., who withdraw from study prior to the end of Cycle 1 for reasons other than DLT) are replaced so that dose escalation decisions can be based on a minimum of 6 DLT-evaluable subjects.

] Part 2: Once the RP2D and schedule have been determined for oral azacitidine as a single agent and in combination with CBDCA and/or ABX in Part 1, enrollment of Part 2 of the study begins. One objective of Part 2 is to further define the , PK, and PD of oral azacitidine combinations with CBDCA and/or ABX and as a single agent in subjects with particular tumor types and to explore candidate predictive biomarkers of anti-tumor ty.

Up to 2 tumor types are ed for each Arm of the study. The tive selection of tumor types evaluated in Part 2 are determined by any antitumor signal observed in Part 1.

For each tumor type, enrollment proceeds in a 2-stage fashion. For each Arm, if at least 2 objective responses are seen by Cycle 6 in the first 14 subjects, an additional 6 subjects are enrolled for a total of 20 subjects. If none of the first 14 subjects has an objective response, no fiarther subject is enrolled.

PD and Predictive Biomarkers: One objective of this study is to identify a dose and le of oral azacitidine that is not only safe but that exhibits pharmacologic activity. ation changes in nucleated blood cells can provide confirmation that a dose is pharmacologically active and can help distinguish which dose and le shows the most compelling cologic activity.

Predictive biomarkers can allow prospective identification of patients who are likely to benefit clinically from the combination of oral azacitidine as a single agent or ed with CBDCA or ABX. The PD and tive biomarkers analyzed in this study (e.g., Part 1 or Part 2 of the study) are shown in Table 4.

Table 4: PD and Predictive Biomarker Studies Pred" Genomic DNA Global Meth lation Anal sis x5» ““1016 93“) Global Meth 1mm Anal sis >< Free DNA Candidate Gene Meth lation Anal sis Global Meth lation Anal SlS ><>< Genomic DNA Tumor (Fresh Candidate Gene Meth lation Anal sis >< Frozen) Global Meth lation Anal sis >< Candidate Gene Meth lation Anal sis DNMT 1 Tumor (FFPE) n (IHC) Candidate Short Half-Life Proteins, DNA ><>< Damage, Apoptosis Markers a Change from pre-treatment to Cycle 1 Day 7 b Baseline profile and change from pre-treatment to Cycle 1 Day 7 Dosage Forms and Study Treatments: Oral azacitidine is provided as 100 mg tablets for oral administration, for example, supplied by Celgene Corporation. See, e.g., US.

Patent Publication No. 2009/0286752 (App. No. ,213), which is incorporated herein in its entirety.

Abraxane® is provided in single-use vials, for example, supplied by Celgene Corporation. Each single-use 50 mL vial contains 100 mg paclitaxel and human albumin (HA) as a izer. Unreconstituted ABX is stored at controlled room temperature (25 °C or 77 oF; excursions ted to 15-30 0C). Reconstituted ABX is refrigerated at 2 0C to 8 0C (36 CF to 46 CF) and used within 8 hours. Both forms are stored in an area free of environmental extremes.

WO 67043 CBCDA may be obtained as a commercially available product through a hospital cy or licensed distributor.

Each dose of oral azacitidine is taken with 8 ounces (240 mL) of room temperature water. Oral azacitidine may be taken on an empty stomach or with food. If the dose is taken in the morning, subjects may consume their usual ast before or after administration.

No adjustment of the oral azacitidine dose is allowed during Cycle 1. Oral azacitidine may be held for up to 7 days between the end of Cycle 1 and the start of Cycle 2 (to allow hematologic criteria) for Cycle 2 to begin. For subjects who experience unacceptable toxicity after the start of Cycle 2, oral azacitidine may be held for up to 7 days or until the ty recovers to grade 1 or less. If recovery has not occurred after 7 days, dosing is permanently discontinued. Subjects who recover within the 7 day period may resume dosing at a reduced dose on the planned Cycle day (226., missed doses are not made up). For the first e of unacceptable toxicity in Cycle 2 or a later Cycle, if the subject recovers within 7 days of ion of dosing with oral azacitidine and had previously been receiving 300 mg of oral azacitidine, the subject may resume dosing at a dose of 200 mg. If the t had previously been receiving 200 mg of oral azacitidine, the subject may resume at a dose of 100 mg. Subjects who experience unacceptable ty after Cycle 2 at a dose of 100 mg may resume dosing at the same dose ifthey recover within 7 days of dosing cessation.

For the second episode of unacceptable toxicity after Cycle 2, if the subject recovers within 7 days of cessation of dosing and had previously been receiving 200 mg of oral azacitidine, the subject may resume dosing at a dose of 100 mg. For subjects on reduced doses of oral azacitidine, the dose may be re-escalated (one dose level at a time) to their originally ed DL provided they have not experienced unacceptable toxicity in 2 consecutive Cycles.

] If, prior to the second e of unacceptable toxicity, the subject had been receiving 100 mg of oral azacitidine, dosing is permanently discontinued. Any t who experiences a third episode of unacceptable toxicity on a reduced dose of oral azacitidine discontinues dosing permanently. No intra-subject dose escalation beyond the dose originally prescribed is allowed.

For the purposes of dose adjustment, unacceptable toxicity is defined as any AE that is deemed by the investigator to be related to oral azacitidine and/or to the combination of oral azacitidine with CBDCA or ABX and that poses a medical risk or substantial discomfort to the subject including but not d to Grade 3 or 4 hematologic or non- hematologic toxicity. If the unacceptable toxicity is believed by the investigator to be more likely to be associated with the backbone agent (e.g., neuropathy with ABX), the subject may continue on single agent oral azacitidine.

] Administration of Oral Azacitidine: ts are advised not to consume any grapefruit/grapefruit juice during the study, beginning 3 days prior to Cycle 1 Day 1.

Subjects drink 8 ounces (240 mL) of room temperature water with each dose. Oral azacitidine may be taken on an empty stomach or with food. If the dose is taken in the morning, subjects may consume their usual breakfast before or after administration. The breakfast meal is not to exceed 600 calories; however, the actual calorie count need not be measured or recorded. If a meal other than breakfast is ed, a light meal (not more than 25% of a subject’s usual daily calories) may be eaten before or after dose administration.

] On days when subjects are not in the clinic, subjects take oral azacitidine at home.

Subjects are given ient quantity of oral azacitidine for the dosing days at home.

Subjects are instructed to inspect each oral azacitidine tablet and only take tablets that are totally intact. Subjects are instructed to return any tablet found to not be intact. Subjects are instructed to record the date and time of oral azacitidine administration in a Diary Card. On days when oral azacitidine is taken at home or on days when PK samples are not collected during the clinic visit, subjects are encouraged to ingest oral idine on an empty h or with food, with 8 ounces (240 mL) of room ature water.

Study Results: In one embodiment, in Part 1, Arm A of the study, 5-azacytidine was dosed from Day 1 to Day 14 and CBDCA was dosed on Day 8 at AUC 4, in a 21-day cycle. Safety and PD were analyzed. In one embodiment, certain patients were dosed with 5-azacytidine at a dose of 200 mg from Day 1 to Day 14 and CBDCA at a dose ofAUC 4 on Day 8, in a 21-day cycle, to treat cancers, such as, NSCLC (non-small cell lung cancer), sarcoma, CRC (colorectal ), melanoma, ovarian cancer, or al cancer. In one embodiment, certain patients were dosed with 5-azacytidine at a dose of 300 mg from Day 1 to Day 14 and CBDCA at a dose ofAUC 4 on Day 8, in a 21-day cycle, to treat cancers, such as, mesothelioma, endometrial cancer, merkel cell cancer, melanoma, chodrosarcoma, NSCLC, or HNSCC (head and neck squamous cell carcinoma).

In one embodiment, in Part 1, Arm B of the study, ytidine was dosed from Day 1 to Day 14 and ABX was dosed on Days 8 and 15 at 100 mg/mz, in a 21-day cycle.

Safety and PD were analyzed. In one embodiment, certain patients were dosed with 5- azacytidine at a dose of 200 mg from Day 1 to Day 14 and ABX at a dose of 100 mg/m2 on Days 8 and weekly thereafter, in a 21-day cycle, to treat cancers, such as, endometrial cancer, pancreatic cancer, ovarian cancer, or breast cancer. Partial responses were observed in endometrial cancer and pancreatic cancer (6.g. metastatic atic cancer). For example, in one patient with atic pancreatic cancer, after Cycle 2, CA19-9 level was decreased from 1867 to 15, and partial response was observed for seven months or more. One patient with endometrial cancer progressed 8 months on the study after 5 cycles of Carbo/Taxol, with no evidence of e at primary site. In one embodiment, certain patients were dosed with -azacytidine at a dose of 200 mg from Day 1 to Day 14 and ABX at a dose of 100 mg/m2 on Days 8 and 15, in a 21-day cycle, to treat cancers, such as, pancreatic cancer, cholangio cancer, HNSCC, CRC, or n cancer. In one embodiment, certain patients were dosed with 5-azacytidine at a dose of 300 mg from Day 1 to Day 14 and ABX at a dose of 100 mg/m2 on Days 8 and 15, in a 21-day cycle, to treat cancers, such as, cholangio cancer, pancreatic cancer, or cervical cancer. Partial responses were observed in cervical cancer.

In one embodiment, in Part 1, Arm C of the study, 5-azacytidine was dosed from Day 1 to Day 21, in a 21-day cycle (continuous). Safety and PD were analyzed. In one embodiment, certain ts were dosed with 5-azacytidine at a dose of 200 mg from Day 1 to Day 21, in a 21-day cycle, to treat cancers, such as, CRC, head and neck cancer, or GIST (gastrointestinal l . In one embodiment, n patients were dosed with 5- azacytidine at a dose of 300 mg from Day 1 to Day 21, in a 21-day cycle, to treat cancers, such as, CRC, NSCLC, or NP (nasopharyngeal) cancer. Partial responses were observed in aryngeal cancer.

Additional clinical efficacy observed in Part 1 of the study are summarized below: Time AZA Prior Regimens (best. .

ARM Tumor Response on Dose response, months on Rx) Stud 200 mg NSCLC SD > 7 mo Erlotinib + bevacizumab SD 16 mo 200 mg Sarcoma SD > 7 mo os (SD 3 mo) Gem/Taxotere PD 2 mo 300 mg Endometrial CA-125 ] > 4 mo Carbo/Taxol (SD 5 mo) > 100% Arm B 200 mg Pancreatic Mixed > 3 mo Gem/Reolysin (SD 8 mo) (AZA + res oonse CC-122 PD 1 mo - > 50% Tivantinib/erlotinib PD 1 mo --200 mg Colorectal > SFU/Leuc/bev (2 mo) taret refracto to orior treatment > 50% PR > 3 mo SFU/cisplat (PR 5 mo) (AZA) Erbitux (PD 3 mo) In one embodiment, in Part 2, Arm A of the study, 5-azacytidine was dosed orally, e. g., at 300 mg (on Days 1 to 14 of a 21-day cycle), and CBDCA was dosed, e.g., at AUC 4, to treat patients with solid tumor, such as relapsed and refractory bladder cancer (e.g., bladder carcinoma, or lial malignancies) or relapsed and refractory ovarian cancer (e.g., epithelial n carcinoma). Tissue samples are analyzed to evaluate activity and efficacy.

In one embodiment, in Part 2, Arm B of the study, ytidine was dosed orally, e.g., at 200 mg (on Days 1 to 14 of a 21-day cycle), in combination with ABX (e.g., at a dose of 100 , to treat patients with solid tumor, such as relapsed and refractory NSCLC (non-small cell lung cancer) or relapsed and refractory atic cancer. Tissue samples are analyzed to evaluate activity and efficacy.

In one embodiment, in Part 2, Arm C of the study, 5-azacytidine was dosed alone (e.g., orally at a dose of 200 mg or 300 mg on Days 1 to 14 of a 21-day cycle) to treat patients with solid tumor, such as relapsed and refractory colorectal cancer. Tissue samples are analyzed to evaluate activity and efficacy. 2012/062845 B. Example 2 DNA methylation is employed as a ker to monitor responses in ts treated with azacitidine in the clinical studies described herein. Analysis is performed with an Inf1nium Assay (commercially ble from Illumina, Inc., San Diego, California). The Infinium Assay combined with BeadChips allows large-scale interrogation of ions in the human genome. For example, the Inf1nium HumanMethylation27 BeadChip enables interrogation of 27,578 CpG loci, covering over 14,000 genes. The DNA Methylation Assay protocol includes the following steps: (l)bisulf1te conversion; (2) DNA amplification; (3) DNA fragmentation; (4) DNA precipitation; (5) DNA ization to BeadChip; (6) extension and staining on BeadChip; and (7) imaging of BeadChip. In other embodiments, DNA methylation assay with 450K array (instead of 27K array) is used.

The assay for methylation is used to detect methylation status at individual CpG loci by typing bisulfite-converted DNA. Methylation protected C from conversion, whereas unmethylated C is converted to T. A pair of bead-bound probes is used to detect the presence of T or C by hybridization followed by single-base ion with a labeled nucleotide. Up to twelve samples are profiled in parallel. Blood samples were collected and DNA methylation was ed in parallel. In other embodiments, bone marrow samples are collected and DNA methylation analyzed in parallel.

Methylation of plasma DNA and PBMC DNA of patients from Part I of the clinical study exemplified in Example 1 was analyzed.

C. Example 3 Clinical studies are conducted to assess the ability of an oral formulation comprising a ne analog, such as ytidine, to treat patients having lung cancer, e.g., all-cell lung cancer (NSCLC). Such studies may include, e.g., an assessment of the y to stop or reverse the growth of particular NSCLC cell types in patients having NSCLC). In certain clinical studies, patients are tested for particular NSCLC cell types, prior to administration of the oral formulation. In certain clinical studies, patients with cell types known or believed to benefit preferentially from cytidine analog (6.g. , 5-azacytidine) administration may be enrolled. In n clinical studies, patients having NSCLC are enrolled without analysis of particular NSCLC cell type. In certain clinical studies, patients having any type ofNSCLC cells are candidates for treatment with an oral formulation ed herein.

In certain clinical s, patients from any of the three main NSCLC groups may be enrolled, z'.e. with tumors that are surgically resectable; (2) ts with either , (1) ts locally or regionally advanced lung cancer; or (3) patients with distant metastases at the time of diagnosis. In certain clinical studies, patients may be currently undergoing additional treatment for NSCLC, including, 6.g. or radiation therapy. , surgery, chemotherapy, ] In certain clinical studies, patients who are administered an oral formulation comprising a cytidine analog (6.g. , 5-azacytidine) may also be administered one or more additional therapeutic agents, examples of which are disclosed herein. The additional therapeutic agent(s) may be administered in the same oral formulation as the cytidine analog, or may be co-administered (e.g., via PO, SC or IV administration) in combination with an oral ation comprising the cytidine analog. The appropriate amount and dosing schedule for an additional therapeutic agent may be determined for a particular patient using methods known in the art.

In particular embodiments, the co-administered agent is carboplatin. In particular ments, the co-administered agent is paclitaxel (e.g. , Abraxane®).

An association n gene methylation and recurrence ofNSCLC tumors is known in the art. See, e.g., M.V. Brock et al., N. Engl. J. Med, 2008, ):lll8-28.

Accordingly, in certain al studies provided herein, patients are screened prior to enrollment and/or monitored during the trial for DNA or RNA methylation levels, which indicate a potential se to treatment with an oral formulation comprising a cytidine analog (e.g., 5-azacytidine). In n clinical studies, patients with high levels ofDNA methylation (e.g., CpG island methylation) and/or an increased potential for transcriptional silencing of tumor-suppressor genes may be administered a cytidine analog (e.g., 5- azacytidine) known or believed to t or reverse hypermethylation (e.g., by reducing the activity of one or more DNA methyltransferase enzymes). In certain clinical s, patients with high levels ofDNA methylation (e.g. island methylation) of n genes may be , CpG administered a cytidine analog (e.g., 5-azacytidine). In certain clinical studies, patients with low levels ofDNA methylation (e.g., CpG island methylation) of certain genes may be administered a cytidine analog (e.g., 5-azacytidine). In certain clinical studies, patients with a particular DNA methylation signature (6.g. , CpG island ation) of certain genes may be administered a cytidine analog (e.g., 5-azacytidine). In such studies, patients may also be co- administered one or more additional eutic agents known or believed to reduce epigenetic silencing, such as, e.g., compounds that inhibit histone deacetylase enzymes (HDACs), which regulate the acetylation and ylation of histone residues that increase or decrease gene expression. See, e.g., J.G. Herman & S.B. Baylin, N. Engl. J. Med, 2003, 349:2042-54; P.A. Jones & S.B. Baylin, Nature Rev. Gen, 2002, 3:415-28. le HDAC inhibitors for co-administration in the clinical studies disclosed herein are known in the art and/or bed herein (e.g., entinostat or vorinostat).

The amount of cytidine analog (e.g., 5-azacytidine) in the oral formulations administered during the clinical studies depends, e.g. on the individual characteristics of the patient, including, inter alia, the stage and progression of the patient’s NSCLC, the patient’s age and weight, the patient’s prior treatment regimens, and other variables, as known in the art. In certain clinical studies, ial starting doses may be, e.g., about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 600 mg, about 660 mg, about 720 mg, about 780 mg, about 840 mg, about 900 mg, about 960 mg, about 1020 mg, or greater than about 1020 mg of the ne analog (e.g., ytidine) daily for a specified time period, e.g., about 1 week, about 1.5 weeks, about 2 weeks, about 2.5 weeks, about 3 weeks, about 3.5 weeks, about 1 month, about 1.5 , about 2 months, or a longer time period. Other potential starting doses and time periods are sed herein. Cycles may be repeated as desired, e.g., over a period of one or more months, as disclosed herein. After a certain number of cycles, the dosage may be increased to increase the beneficial effect, provided such an increase does not cause undesirable toxicity effects.

Patients may be treated for a minimum number of cycles, as disclosed herein. Complete or partial response may require additional treatment cycles. Treatment may be continued as long as the patient continues to benefit.

D. Example 4 ] Clinical s are conducted to assess the ability of an oral formulation sing a cytidine analog, such as 5-azacytidine, to treat patients having an ovarian cancer (including, e.g., the ability to stop or reverse the growth of cancer cells in patients having an ovarian cancer). Particular ovarian cancers include, but are not d to, ovarian epithelial cancer, ovarian germ cell tumors, and ovarian low malignant ial tumors. In certain clinical studies, patients are screened for the presence of a particular type of ovarian cancer prior to administration of the oral formulation. In certain clinical studies, patients with a type of ovarian cancer known or believed to benefit preferentially from cytidine analog (6.g. 5- idine) administration may be enrolled. In certain clinical studies, patients having ovarian cancer are enrolled without screening for particular ovarian cancer types. In n clinical s, ts having any type of ovarian cancer are candidates for treatment with an oral formulation provided herein. In certain clinical studies, patients may be currently undergoing additional treatment for ovarian cancer, including, e.g., surgery, chemotherapy, or radiation therapy.

In certain clinical studies, patients who are administered an oral ation comprising a cytidine analog (6.g. , 5-azacytidine) may also be administered one or more additional therapeutic agents, examples of which are disclosed herein (e.g., carboplatin). The additional therapeutic s) may be stered in the same oral formulation as the cytidine analog, or may be co-administered (e.g., via PO, SC or IV administration) in combination with an oral formulation comprising a cytidine analog. The appropriate amount and dosing schedule for an additional therapeutic agent may be determined for a particular patient using methods known in the art.

In particular embodiments, the co-administered agent is carboplatin. In particular embodiments, the inistered agent is paclitaxel (e.g. , ne®).

An association between gene methylation and ovarian cancer is known in the art.

See, e.g., G. Gifford et (1]., Clin. Cancer Res, 2004, 10:4420-26. Accordingly, in certain clinical studies provided herein, patients are screened prior to enrollment and/or monitored during the trial for DNA or RNA methylation levels, which indicate a potential response to treatment with an oral formulation comprising a cytidine analog (e.g., 5-azacytidine). In certain clinical studies, patients with high levels ofDNA methylation (e.g., CpG island methylation) and/or an increased potential for riptional silencing of suppressor genes may be administered a cytidine analog (e.g., 5-azacytidine) known or believed to prevent or reverse hypermethylation (e.g, by reducing the activity of one or more DNA methyltransferase enzymes). In certain clinical studies, patients with high levels ofDNA methylation (e.g., CpG island methylation) of certain genes may be administered a cytidine analog (e.g., 5-azacytidine). In certain clinical studies, patients with low levels ofDNA methylation (e.g., CpG island methylation) of n genes may be administered a ne analog (e.g., 5-azacytidine). In certain clinical s, patients with a ular DNA methylation signature (6.g. , CpG island methylation) of certain genes may be administered a ne analog (e.g, 5-azacytidine). In such studies, patients may also be co-administered one or more additional therapeutic agents known or believed to reduce epigenetic silencing, such as, e.g., compounds that inhibit histone deacetylase enzymes (HDACs), which te the acetylation and deacetylation of histone residues that increase or decrease gene expression. See, e.g., J.G. Herman & SB. Baylin, N. Engl. J. Med, 2003, 349:2042-54; P.A.

Jones & SB. Baylin, Nature Rev. Gen, 2002, 28. Suitable HDAC inhibitors for co- administration in the clinical studies disclosed herein are known in the art and/or described herein (6.g. entinostat or stat).

The amount of cytidine analog (e.g., 5-azacytidine) in the oral formulations administered during the clinical studies depends, e.g. on the individual characteristics of the patient, including, inter alia, the type, stage, and progression of the patient’s ovarian cancer, the patient’s age and weight, the patient’s prior treatment regimens, and other variables, as known in the art. 11 n clinical studies, potential starting doses may be, e.g., about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 600 mg, about 660 mg, about 720 mg, about 780 mg, about 840 mg, about 900 mg, about 960 mg, about 1020 mg, or greater than about 1020 mg of the cytidine analog (e.g., 5-azacytidine) daily for a specified time period, e.g., about 1 week, about 1.5 weeks, about 2 weeks, about 2.5 weeks, about 3 weeks, about 3.5 weeks, about 1 month, about 1.5 months, about 2 months, or a longer time period. Other potential starting doses and time periods are disclosed herein. Cycles may be repeated as desired, e.g., over a period of one or more months, as disclosed herein. After a n number of cycles, the dosage may be increased to increase the beneficial effect, provided such an increase does not cause rable toxicity effects.

Patients may be treated for a m number of cycles, as disclosed herein. te or l se may require additional treatment cycles. Treatment may be continued as long as the patient continues to benefit.

E. Example 5 Clinical studies are conducted to assess the ability of an oral formulation comprising a cytidine analog, such as 5-azacytidine, to treat patients having a pancreatic cancer (including, e.g., the ability to stop or reverse the growth of cancer cells in patients having pancreatic cancer). In certain clinical studies, patients are screened prior to enrollment for a particular type of atic cancer prior to administration of the oral formulation. Cellular fications of pancreatic cancers are known in the art and include, e.g., duct cell carcinoma; acinar cell carcinoma; papillary mucinous oma; signet ring carcinoma; adenosquamous carcinoma; undifferentiated carcinoma; mucinous carcinoma; giant cell oma; mixed type (ductal-endocrine or -endocrine); small cell carcinoma; cystadenocarcinoma (serous and us types); unclassified; pancreatoblastoma; papillary-cystic neoplasm (Frantz tumor); invasive adenocarcinoma associated with cystic mucinous neoplasm or intraductal papillary mucinous neoplasm; mucinous cystic tumor with dysplasia; intraductal papillary mucinous tumor with dysplasia; and pseudopapillary solid tumor. In certain clinical studies, patients are screened prior to enrollment for a particular stage of pancreatic cancer (6.g. the size of the tumor in the pancreas, whether the cancer has spread, and if so, to what parts of the body) prior to administration of the oral formulation. In certain clinical studies, pancreatic cancer patients believed to benefit preferentially from cytidine analog (e.g., 5-azacytidine) administration may be ed. In certain clinical studies, patients having pancreatic cancer are enrolled without screening for ular pancreatic cancer types. In certain clinical studies, patients having any type of atic cancer are candidates for treatment with an oral formulation provided herein. In certain clinical studies, patients may be currently undergoing additional ent for pancreatic cancer, including, e.g., surgery, chemotherapy, or radiation therapy.

In certain clinical s, patients who are administered an oral formulation comprising a cytidine analog (6.g. , 5-azacytidine) may also be administered one or more additional therapeutic agents, es of which are disclosed herein (e.g., gemcitabine).

The additional therapeutic agent(s) may be stered in the same oral formulation as the cytidine analog, or may be co-administered (e.g., via PO, SC or IV administration) in ation with an oral formulation comprising a cytidine analog. The appropriate amount and dosing schedule for an additional therapeutic agent may be determined for a ular patient using methods known in the art.

In particular ments, the co-administered agent is carboplatin. In particular embodiments, the co-administered agent is paclitaxel (e.g. , Abraxane®).

In n al studies provided herein, patients are screened prior to enrollment and/or monitored during the trial for DNA or RNA methylation levels, which indicate a ial response to treatment with an oral formulation comprising a cytidine analog (e.g., 5-azacytidine). In certain clinical studies, patients with high levels ofDNA methylation (e.g., CpG island methylation) and/or an increased potential for transcriptional silencing of suppressor genes may be administered a cytidine analog (e.g., 5- azacytidine) known or believed to prevent or reverse hypermethylation (e.g., by reducing the activity of one or more DNA transferase enzymes). In certain clinical studies, patients with high levels ofDNA methylation (e.g. island methylation) of certain genes may be , CpG administered a cytidine analog (e.g., 5-azacytidine). In certain clinical studies, patients with low levels ofDNA methylation (e.g., CpG island methylation) of certain genes may be administered a cytidine analog (e.g., 5-azacytidine). In certain clinical studies, patients with a particular DNA ation signature (e.g. , CpG island methylation) of certain genes may be administered a cytidine analog (e.g, 5-azacytidine). In such studies, patients may also be co- administered one or more additional therapeutic agents known or believed to reduce epigenetic silencing, such as, e.g., compounds that inhibit histone deacetylase enzymes (HDACs), which regulate the acetylation and deacetylation of histone es that increase or decrease gene expression. See, e.g., J.G. Herman & S.B. Baylin, N. Engl. J. Med, 2003, 349:2042-54; P.A. Jones & S.B. Baylin, Nature Rev. Gen., 2002, 3:4l5-28. Suitable HDAC tors for inistration in the clinical s disclosed herein are known in the art and/or described herein (e.g., entinostat or vorinostat).

The amount of cytidine analog (e.g., 5-azacytidine) in the oral formulations administered during the clinical studies depends, e.g. on the individual characteristics of the patient, including, inter alia, the type, stage, and progression of the t’s pancreatic , the patient’s age and weight, the patient’s prior treatment regimens, and other variables, as known in the art. In certain clinical studies, potential starting doses may be, e.g, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 600 mg, about 660 mg, about 720 mg, about 780 mg, about 840 mg, about 900 mg, about 960 mg, about 1020 mg, or greater than about 1020 mg of the cytidine analog (e.g, 5- idine) daily for a ed time period, e.g., about 1 week, about 1.5 weeks, about 2 weeks, about 2.5 weeks, about 3 weeks, about 3.5 weeks, about 1 month, about 1.5 months, about 2 months, or a longer time period. Other potential starting doses and time periods are disclosed herein. Cycles may be repeated as desired, e.g., over a period of one or more months, as disclosed herein. After a certain number of cycles, the dosage may be increased to increase the beneficial effect, provided such an increase does not cause rable toxicity effects. Patients may be treated for a minimum number of , as disclosed herein.

Complete or l se may e additional treatment cycles. Treatment may be continued as long as the patient ues to benefit.

F. Example 6 Clinical studies are conducted to assess the ability of an oral formulation comprising a cytidine analog, such as 5-azacytidine, to treat patients haVing a colorectal cancer (including, e.g., the ability to stop or reverse the growth of cancer cells in patients haVing a colorectal cancer). In certain clinical s, patients are ed prior to enrollment for a particular type of colorectal cancer prior to administration of the oral formulation. Histologic types of colon s are known in the art and include, 6.g. , adenocarcinoma; mucinous (colloid) adenocarcinoma; signet ring adenocarcinoma; scirrhous tumors; and neuroendocrine tumors. The World Health Organization classification of tumors of the colon and rectum include (1) Epithelial Tumors, which include: Adenoma (e.g. tubular, Villous, tubulovillous, and serrated); Intraepithelial neoplasia (dysplasia) associated with chronic atory diseases (e.g., low-grade glandular intraepithelial sia and high-grade glandular intraepithelial neoplasia); Carcinoma (e.g., adenocarcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma, small cell carcinoma, adenosquamous oma, medullary carcinoma, and undifferentiated carcinoma); oid (well- differentiated neuroendocrine neoplasm) (e.g. enterochromaff1n (EC)—cell, serotonin- producing neoplasm, L-cell, on-like peptide and pancreatic polypeptide/peptide YY (PYY)-producing tumor, and others); and Mixed carcinoma-adenocarcinoma; and (2) Nonepithelial Tumors, which include: Lipoma; Leiomyoma; Gastrointestinal stromal tumor; Leiomyosarcoma; arcoma; Kaposi sarcoma; Melanoma; and others; as well as ant lymphomas (e.g., marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, mantle cell lymphoma, diffilse large B-cell lymphoma, Burkitt lymphoma, and Burkitt-like/atypical Burkitt lymphoma. In certain clinical studies, patients are screened prior to enrollment for a particular stage of colorectal cancer (6.g. the size of the tumor in the colon or rectum, whether the cancer has spread, and if so, to what parts of the body) prior to administration of the oral formulation. In certain clinical studies, ctal cancer patients believed to benefit preferentially from cytidine analog (e.g., 5-azacytidine) administration may be enrolled. In certain clinical studies, patients haVing a colorectal cancer are enrolled without screening for particular colorectal cancer types. In n clinical studies, patients haVing any type of colorectal cancer are candidates for ent with an oral formulation provided herein. In certain clinical s, patients may be currently undergoing additional treatment for colorectal cancer, including, 6.g. or ion therapy. , surgery, chemotherapy, In certain clinical studies, patients who are administered an oral formulation comprising a cytidine analog (6.g. , 5-azacytidine) may also be administered one or more additional therapeutic agents, examples of which are disclosed herein. The additional therapeutic agent(s) may be administered in the same oral formulation as the ne analog, or may be co-administered (e.g., via PO, SC or IV administration) in combination with an oral formulation comprising a cytidine analog. The appropriate amount and dosing schedule for an additional therapeutic agent may be determined for a particular t using methods known in the art.

In particular embodiments, the inistered agent is carboplatin. In particular embodiments, the co-administered agent is paclitaxel (e.g. , Abraxane®).

An association between gene ation and colorectal cancer is known in the art. See, e.g., A.M. Jubb et al., J. Path01., 2001, l95:lll-l34. Accordingly, in certain clinical studies provided herein, patients are screened prior to enrollment and/or monitored during the trial for DNA or RNA ation levels, which indicate a potential se to treatment with an oral ation comprising a cytidine analog (e.g., 5-azacytidine). In certain clinical studies, patients with high levels ofDNA methylation (e.g., CpG island methylation) and/or an sed potential for transcriptional silencing of tumor-suppressor genes may be administered a cytidine analog (e.g., 5-azacytidine) known or believed to prevent or reverse hypermethylation (e.g., by reducing the activity of one or more DNA methyltransferase enzymes). In certain clinical studies, patients with high levels ofDNA ation (e.g., CpG island methylation) of certain genes may be administered a cytidine analog (e.g., 5-azacytidine). In certain clinical studies, patients with low levels ofDNA methylation (e.g., CpG island methylation) of certain genes may be administered a ne analog (e.g., 5-azacytidine). In certain clinical studies, patients with a particular DNA methylation signature (6.g. , CpG island methylation) of certain genes may be administered a cytidine analog (e.g., 5-azacytidine). In such studies, patients may also be co-administered one or more additional therapeutic agents known or believed to reduce etic silencing, such as, e.g., compounds that inhibit e deacetylase enzymes (HDACs), which regulate the acetylation and deacetylation of histone residues that se or decrease gene expression. See, e.g., J.G. Herman & S.B. , N. Engl. J. Med, 2003, 42-54; P.A.

Jones & SB. Baylin, Nature Rev. Gen, 2002, 3:415-28. Suitable HDAC inhibitors for co- administration in the clinical studies disclosed herein are known in the art and/or described herein (6.g. entinostat or vorinostat).

The amount of cytidine analog (e.g., ytidine) in the oral ations administered during the clinical studies depends, e.g. on the individual characteristics of the patient, including, inter alia, the type, stage, and progression of the patient’s colorectal cancer, the patient’s age and weight, the t’s prior treatment regimens, and other variables, as known in the art. In certain clinical studies, potential starting doses may be, e.g., about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 600 mg, about 660 mg, about 720 mg, about 780 mg, about 840 mg, about 900 mg, about 960 mg, about 1020 mg, or greater than about 1020 mg of the cytidine analog (e.g., 5- azacytidine) daily for a specified time period, e.g., about 1 week, about 1.5 weeks, about 2 weeks, about 2.5 weeks, about 3 weeks, about 3.5 weeks, about 1 month, about 1.5 months, about 2 , or a longer time . Other ial starting doses and time periods are disclosed herein. After a n number of cycles, the dosage may be increased to increase the beneficial effect, ed such an increase does not cause undesirable toxicity s.

Patients may be d for a minimum number of cycles, as disclosed herein. Complete or partial response may require onal treatment cycles. Treatment may be continued as long as the patient continues to benefit.

G. Example 7 Clinical studies are conducted to assess the ability of an oral formulation comprising a ne analog, such as 5-azacytidine, to treat patients having a bladder cancer (including, e.g., the ability to stop or e the growth of cancer cells in patients having a bladder cancer). In certain clinical studies, patients are screened prior to ment for a particular type of bladder cancer prior to administration of the oral formulation. In certain clinical studies, patients are screened prior to enrollment for a particular stage of bladder cancer (e.g., the size of the tumor, whether the cancer has spread, and if so, to what parts of the body) prior to administration of the oral formulation. In certain clinical studies, patients are screened prior to enrollment for a particular type of bladder cancer prior to administration of the oral formulation. In certain clinical studies, bladder cancer patients believed to benefit preferentially from cytidine analog (e.g., 5-azacytidine) administration may be enrolled. In certain clinical studies, patients having a bladder cancer are enrolled t screening for particular bladder cancer types. In certain al studies, patients having any type of r cancer are candidates for treatment with an oral ation provided herein. In certain clinical studies, patients may be currently undergoing additional treatment for bladder cancer, including, e.g., y, chemotherapy, or radiation therapy.

In certain clinical studies, patients who are stered an oral formulation comprising a cytidine analog (6.g. , 5-azacytidine) may also be administered one or more additional therapeutic agents, examples of which are disclosed herein. The additional therapeutic agent(s) may be administered in the same oral formulation as the cytidine analog, or may be co-administered (e.g., via PO, SC or IV administration) in combination with an oral formulation comprising a cytidine analog. The appropriate amount and dosing schedule for an additional therapeutic agent may be determined for a particular patient using methods known in the art.

In particular embodiments, the co-administered agent is carboplatin. In particular embodiments, the co-administered agent is axel (e.g. , ne®).

In certain clinical studies provided herein, ts are screened prior to ment and/or monitored during the trial for DNA or RNA methylation levels, which indicate a ial response to treatment with an oral formulation comprising a cytidine analog (e.g., 5-azacytidine). In certain clinical studies, patients with high levels ofDNA methylation (e.g., CpG island methylation) and/or an increased potential for transcriptional silencing of tumor-suppressor genes may be stered a cytidine analog (e.g., 5- azacytidine) known or believed to prevent or reverse hypermethylation (e.g., by reducing the activity of one or more DNA methyltransferase enzymes). In n clinical studies, patients with high levels ofDNA methylation (e.g. island methylation) of certain genes may be , CpG administered a ne analog (e.g., 5-azacytidine). In certain clinical studies, patients with low levels ofDNA methylation (e.g., CpG island methylation) of certain genes may be administered a cytidine analog (e.g., 5-azacytidine). In certain clinical s, patients with a ular DNA methylation signature (6.g. , CpG island methylation) of certain genes may be administered a cytidine analog (e.g., 5-azacytidine). In such studies, patients may also be co- administered one or more onal therapeutic agents known or believed to reduce epigenetic silencing, such as, e.g., compounds that inhibit histone deacetylase enzymes (HDACs), which regulate the acetylation and deacetylation of histone residues that increase or decrease gene expression. See, e.g., J.G. Herman & S.B. Baylin, N. Engl. J. Med, 2003, 349:2042-54; P.A. Jones & S.B. Baylin, Nature Rev. Gen, 2002, 3:415-28. Suitable HDAC inhibitors for co-administration in the clinical studies disclosed herein are known in the art and/or described herein (e.g., entinostat or vorinostat).

] The amount of cytidine analog (e.g., 5-azacytidine) in the oral formulations administered during the clinical studies s, e.g. on the individual characteristics of the patient, including, inter alia, the type, stage, and progression of the t’s bladder cancer, the patient’s age and weight, the patient’s prior ent ns, and other variables, as known in the art. In certain clinical studies, potential starting doses may be, e.g., about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 600 mg, about 660 mg, about 720 mg, about 780 mg, about 840 mg, about 900 mg, about 960 mg, about 1020 mg, or greater than about 1020 mg of the cytidine analog (e.g., 5-azacytidine) daily for a specified time , e.g., about 1 week, about 1.5 weeks, about 2 weeks, about 2.5 weeks, about 3 weeks, about 3.5 weeks, about 1 month, about 1.5 months, about 2 months, or a longer time period. Other potential starting doses and time periods are disclosed herein. After a certain number of , the dosage may be increased to increase the beneficial effect, provided such an increase does not cause undesirable toxicity effects.

Patients may be treated for a minimum number of cycles, as disclosed herein. Complete or partial response may require additional treatment . Treatment may be continued as long as the patient continues to benefit.

H. e 8 ] Clinical studies are conducted to assess the ability of an oral formulation comprising a cytidine analog, such as 5-azacytidine, to treat patients having a breast cancer (including, e.g., the ability to stop or reverse the growth of cancer cells in patients having a breast cancer). In certain clinical studies, patients are screened prior to enrollment for a ular type of breast cancer prior to administration of the oral formulation. In n clinical studies, patients are screened prior to enrollment for a particular stage of breast cancer (6.g. the size of the tumor in the breast, whether the cancer has spread, and if so, to what parts of the body) prior to administration of the oral formulation. In certain clinical studies, patients are screened prior to enrollment for a particular type of breast cancer prior to administration of the oral formulation. In certain clinical studies, breast cancer patients believed to benefit preferentially from cytidine analog (e.g., 5-azacytidine) administration may be enrolled. In certain clinical studies, patients having a breast cancer are ed t screening for particular breast cancer types. In certain clinical studies, patients having any type of breast cancer are candidates for treatment with an oral formulation provided herein. In certain clinical studies, patients may be currently undergoing additional treatment for breast cancer, including, 6.g. or radiation y. , surgery, chemotherapy, In certain clinical studies, patients who are administered an oral formulation comprising a cytidine analog (6.g. , 5-azacytidine) may also be stered one or more additional therapeutic agents, examples of which are disclosed herein. The additional therapeutic agent(s) may be administered in the same oral formulation as the cytidine analog, or may be co-administered (e.g, Via PO, SC or IV administration) in ation with an oral formulation comprising a cytidine analog. The appropriate amount and dosing schedule for an additional therapeutic agent may be determined for a particular patient using methods known in the art. In some embodiments, the co-administered agent is latin. In particular embodiments, the co-administered agent is paclitaxel (e.g., ne®).

In certain clinical studies provided herein, ts are screened prior to enrollment and/or monitored during the trial for DNA or RNA methylation levels, which indicate a potential response to ent with an oral formulation comprising a cytidine analog (e.g., 5-azacytidine). In n clinical s, patients with high levels ofDNA ation (e.g., CpG island methylation) and/or an increased potential for transcriptional silencing of tumor-suppressor genes may be administered a cytidine analog (e.g., 5- azacytidine) known or believed to prevent or reverse hypermethylation (e.g., by reducing the activity of one or more DNA methyltransferase enzymes). In certain clinical studies, patients with high levels ofDNA methylation (e.g. island methylation) of certain genes may be , CpG stered a cytidine analog (e.g., ytidine). In certain clinical studies, patients with low levels ofDNA methylation (e.g., CpG island methylation) of certain genes may be administered a cytidine analog (e.g., 5-azacytidine). In certain clinical s, patients with a ular DNA methylation signature (6.g. , CpG island methylation) of certain genes may be administered a cytidine analog (e.g, 5-azacytidine). In such studies, patients may also be co- administered one or more additional therapeutic agents known or believed to reduce epigenetic silencing, such as, e.g., compounds that inhibit histone deacetylase s (HDACs), which regulate the acetylation and deacetylation of histone residues that increase or se gene expression. See, e.g., J.G. Herman & S.B. Baylin, N. Engl. J. Med, 2003, WO 67043 42-54; P.A. Jones & S.B. Baylin, Nature Rev. Gen, 2002, 3:415-28. Suitable HDAC inhibitors for co-administration in the clinical studies disclosed herein are known in the art and/or described herein (e.g., entinostat or vorinostat).

The amount of cytidine analog (e.g., 5-azacytidine) in the oral formulations administered during the clinical s depends, e.g. on the individual characteristics of the patient, including, inter alia, the type, stage, and progression of the patient’s breast cancer, the patient’s age and weight, the patient’s prior treatment regimens, and other les, as known in the art. In certain clinical studies, potential starting doses may be, e.g., about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 600 mg, about 660 mg, about 720 mg, about 780 mg, about 840 mg, about 900 mg, about 960 mg, about 1020 mg, or r than about 1020 mg of the cytidine analog (e.g., 5-azacytidine) daily for a specified time period, e.g., about 1 week, about 1.5 weeks, about 2 weeks, about 2.5 weeks, about 3 weeks, about 3.5 weeks, about 1 month, about 1.5 months, about 2 , or a longer time period. Other potential starting doses and time periods are disclosed herein. After a certain number of cycles, the dosage may be increased to increase the beneficial effect, ed such an increase does not cause undesirable ty effects.

Patients may be treated for a minimum number of , as disclosed herein. Complete or partial response may require additional treatment cycles. Treatment may be continued as long as the patient continues to benefit. 1. Example 9 The effects ofAZA dose and schedule (short-term vs. extended) on pharmacodynamic markers such as DNMTl depletion, DNA methylation, and DNA damage were evaluated in MDA-MB-23l breast cancer cells in vitro and in viva. For in vitro experiments, MDA-MB-23l cells were treated daily with 0.1 or 0.3 uM AZA for up to 12 days, and harvested at various times during treatment, as well as up to 12 days ing treatment. For in vivo studies, MDA-MB-23l tumor-bearing mice were dosed (ip) with l or 3 mg/kg AZA daily for 3, 7, 14, 21, or 28 days and tumors were harvested during and at several time points after the dosing period. DNA and cell lysates were prepared (from cell pellets or xenograft tumors) for DNA methylation analysis (LINE-l or EpiTech Methyl qPCR assay) and DNMTl/yH2AX western blotting, respectively.

In both in vitro and in vivo studies, AZA caused a rapid (by 8 hours post in viva dose), dose-dependent depletion of DNMTl protein; when AZA treatment was , DNMTl protein levels returned to basal levels within 3-4 days. Consistent with these results, AZA in vitro and in viva caused a dose-dependent decrease in DNA methylation (LINE-l and gene-specific) and further reduction in DNA methylation with additional days ofAZA dosing. In vitro, DNA ation returned to basal levels upon AZA removal (within 8 days); the kinetics ofDNA re-methylation was slower in more hypomethylated DNA. Lastly, DNA damage was not observed in tumors from mice until 14 or 21 days of dosing with 3 mg/kg or 1 mg/kg AZA, respectively.

Thus, extended AZA dosing maintained low DNMTl levels and DNA methylation, and induced DNA damage. These results provide a strong rationale for extended AZA dosing for the ent of cancer ts.

J. Example 10 In patients treated with 5-azacytidine alone or in combination with an additional therapeutic agent such as CDBCA or ABX, the pharmacodynamic effects are determined using one or more methods provided in the table below. In addition, the methods below can be used as predictive biomarkers to predict clinical response to treatments.

Tissue Whole Blood Genomic DNA Infinium® Methylation27 Array PBMCS Plasma Free DNA Infinium® Meth lation450 Arra “'- Tumor Genomic DNA Infinium® Meth lation450 Arra “'- (Fresh Frozen) Candidate ene ex ression anal sis “'- Tumor Protein (IHC) DNMT1,DNMT3A, .HZAX, cPARP “'- (FFPE) ate short half-life oroteins “H. 1 PD: Change at Day 15 from baseline. 2 tive Biomarker: Baseline in relation to al response.

In one embodiment, PBMC DNA was used for assessing changes in DNA methylation, using assays such as LINE-l methylation, %5de mass spec, Infinium® Methylation27 Array, and Infinium® Methylation450 Array. In one study, DNA methylation (LINE-l) in PBMC DNAs from ts in clinical studies described in Example 1, dosed with 200 mg oral AZA alone or in combination with CDBCA or ABX, was measured on Days 1, 8, and 15 of 21-day cycle. Decreases in LINE-l methylation were observed for two patients in Arm C. In one study, %5de in PBMC DNAs from patients in al studies bed in Example 1, dosed with 200 mg oral AZA alone or in combination with CDBCA or ABX, was measured on Days 1, 8, and 15 of 2l-day cycle. In one study, methylation levels were measured on Days 1, 8, and 15 of 21-day cycle using m® Methylation27 Array (patients dosed with 200 mg oral AZA alone or in combination with CDBCA or ABX) and density profiles of average methylation levels were ed. Upon treatment, decreases in hypermethylated loci (beta >0.7) were ed in PBMCs ofArm C ts; no change in DNA methylation was observed in PBMCs ofArm A patients, and minor decrease in DNA methylation was observed in PBMCs ofArm B patients. In another study, methylation levels were measured using Infinium® Methylation450 Array (patients dosed with 300 mg oral AZA alone or in combination with CDBCA or ABX) and density s of average methylation levels were analyzed, as well as % change of hypermethylated loci (beta >0.7) upon treatment. The data suggested that the decreases in DNA methylation ated with the PK exposure ofAZA in the patients.

In summary, DNA hypomethylation in PBMCs was observed in patients dosed with 200 mg oral AZA alone or in combination with an additional eutic agent (5/6 Arm C patients; 2/6 Arm B patients; and 0/6 Arm A patients). DNA thylation in PBMCs was ed in patients dosed with 300 mg oral AZA alone or in combination with an additional therapeutic agent (3/3 Arm C patients; and 2/4 Arm A patients). Decreases in DNA methylation appeared to correlate with PK exposure ofAZA in the patients, for example, were observed in patients with AUCinf > 350 mL.

K. Example 1 1 ] Figure 6 shows in vitro modeling of the dosing schema of the clinical study described in Example 1. DNA hypomethylation (e.g., LINE-l, p16) was measured 72 hours after AZA treatment alone or in combination with CBDCA or ABX. p16 (mRNA) re- expression was determined 72 hours after AZA treatment alone or in combination with CBDCA or ABX. Ninety-two cancer cell lines were tested in order to identify specific tumor types that become sensitized to CBDCA or ABX after treatment with AZA (bladder cancer n=8; head and neck cancer n=8, breast cancer n=2l; lung cancer n=35; pancreatic cancer n=7; ovarian cancer n=7; and melanoma n=6). The result from this study can also be used to identify predictive biomarkers for enhanced sensitivity to the combination treatment of CBDCA or ABX with AZA.

Interaction ofAZA treatment with ABX treatment was evaluated, in the following cancer cell lines: (1) bladder cancer cell lines, including 5637, J82, HT-l376, SCaBER, TCCSUP, and UM-UC-3, which showed ve effects; (2) head and neck cancer cell lines, 2012/062845 including A253, BHY, CAL-27, , and HN, which showed additive effects; (3) breast cancer cell lines, including ZR—75-1, , MDA-MB-231, , Hs578t, HCC1500, 87, and ZR—75-3 0, which showed additive effects; (4) pancreatic cancer cell lines, including MiaPaca-2, which showed synergistic effects; (5) NSCLC cell lines, including H1792, which showed synergistic effects; and H460, H1299, H23, H1975, H2122, H838, H28, H1838, CALU-3, H2030, H1437, H596, H647, and H1650, which showed additive effects; (6) ovarian cancer cell lines, including OVCAR-3, OVCAR-5, OVCAR-8, SKOV3, and IGR-OVl, which showed ve effects; and (7) melanoma cell lines, including Malme 3M and SKMEL5, which showed additive effects. However, antagonism was observed for combination ofAZA with ABX in 1/4 of the cell lines tested, including breast (1/3), NSCLC (1/4), and melanoma (2/3) cell lines. In other experiments, antagonism was also observed in some cell lines with DAC (decitabine) priming.

Interaction ofAZA treatment with CBDCA treatment was evaluated, in the following cancer cell lines: (1) r cancer cell lines, including UM-UC-3, which showed synergistic effects; and 5637, J82, HT-1376, SCaBER, and TCCSUP, which showed additive effects; (2) head and neck cancer cell lines, including Detroit562 and FADU, which showed synergistic effects; and A253, BHY, , CAL-33, HN, and RPMI-2650, which showed additive effects; (3) breast cancer cell lines, ing BT-549, Hs578t, MDA-MB-157, SUM-149, and HCC-38, which showed synergistic effects; and T47D, ZR—75-1, CAL-51, CAL-120, MCF7, HCC1500, AU565, HCC-1187, MDA-MB-436, and ZR30, which showed additive effects; (4) atic cancer cell lines, including BXPC3, MiaPaca-2, and Hs766t, which showed synergistic effects; (5) NSCLC cell lines, including H460, H1299, A549, H838, HOP62, H1792, H1838, H1755, H2030, H1437, HOP92, and H2110, which showed synergistic effects; and H23, H1975, H226, H2122, H28, H2228, H727, SK-LU-l, H520, H596, H647, H1568, H1944, and H1650, which showed additive effects; (6) ovarian cancer cell lines, including OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, SKOV3, and IGR-OVl, which showed additive effects; and (7) melanoma cell lines, including SKMEL5, which showed synergistic effects; and M14, Malme 3M, MeWO, SKMEL2, and SKMEL28, which showed ve effects. Additivity or synergy was observed for combination ofAZA with CBDCA in the majority of cell lines tested (e.g., about 1/3 NSCLC cell lines showed synergy). In other experiments, additivity or synergy was also ed in some cell lines with DAC (decitabine) priming.

Moreover, for the combination ofAZA with CBDCA, selected panels of cell lines which showed synergistic or additive effects were further studied in order to fy predictive kers to predict synergy of the combination. The selected cell lines included (1) UM-UC-3 (bladder), FADU (head and neck), MiaPaca-2 (pancreatic), H838 (NSCLC), H2110 (NSCLC), and HOP62 ), which showed synergistic effects, and (2) CAL-120 (breast), AU565 (breast), Detroit562 (head and neck), H520 (NSCLC), H1838 (NSCLC), H1568 (NSCLC), and CALU-6 (NSCLC). Basal gene expression and DNA methylation were compared. In addition, AZA-induced s in gene expression and DNA methylation were compared. The extent of synergy was calculated using AAUC values. Strong synergy was observed in 18 hours to 72 hours or more ofAZA priming, for example, in HOP62, UM- UC-3, and FADU.

Similar results were ed in the kinetics of AZA-induced DNMTl depletion when comparing synergistic cell lines with additive cell lines (e.g., HOP62 vs. H1568; H838 vs. H520, FADU vs. Detroit5 62), and similar extent of DNMTl ion at 48 hours were observed when ing istic cell lines with additive cell lines. Similar effects of DNA hypomethylation (LINE-1) was observed in when comparing synergistic cell lines with additive cell lines upon AZA treatment alone or in combination with CBDCA (e.g. in FADU, Detroit562, HOP62, and H520). Dramatic increase in PARP cleavage in the synergistic cell line H838 was observed upon treatment with combination ofAZA and CBDCA, suggesting synergistic effect of the combination on PARP cleavage in H838 cells. rmore, to identify tive biomarkers for enhanced sensitivity, basal gene expression, promoter methylation, and mutation status are analyzed in ed cancer cell lines. Moreover, gene expression and promoter methylation changes upon AZA treatment are analyzed in selected cancer cell lines.

The present disclosure has been described in connection with certain embodiments and es; however, unless otherwise indicated, the claimed invention should not be unduly limited to such specific embodiments and examples.

Claims (25)

WHAT IS CLAIMED IS:

1. The use of 5-azacytidine, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the manufacture of a composition for oral administration for the treatment of non-small cell lung cancer in a subject, wherein the treatment further comprises administering at least one additional therapeutic agent comprising a platinum agent.

2. The use of claim 1, wherein the all cell lung cancer is a relapsed or tory non-small cell lung .

3. The use of claim 1 or 2, n the additional therapeutic agent is carboplatin.

4. The use of any one of claims 1 to 3, wherein the treatment comprises the sequential steps of: (i) administering 5-azacytidine to the subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days; and (ii) administering the additional therapeutic agent to the subject for one or more days.

5. The use of claim 4, n the additional therapeutic agent is administered parenterally.

6. The use of claim 4, wherein the additional therapeutic agent is administered orally.

7. The use of any one of claims 4 to 6, wherein step (ii) further comprises administering 5-azacytidine orally for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

8. The use of any one of claims 4 to 6, n the treatment comprises the sequential steps of: (i) administering 5-azacytidine to the subject for 7 days; (ii) administering the additional therapeutic agent to the subject for 1 day; (iii) administering 5-azacytidine to the subject for 6 days; and (iv) repeating steps (i) to (iii) after 7 days of resting period.

9. The use of any one of claims 4 to 6, wherein the treatment comprises the sequential steps of: (i) administering 5-azacytidine to the subject for 7 days; (ii) administering 5-azacytidine and the additional eutic agent to the subject for 1 day; (iii) administering 5-azacytidine to the subject for 6 days; and (iv) repeating steps (i) to (iii) after 7 days of resting period.

10. The use of any one of claims 4 to 6, n the treatment comprises the sequential steps of: (i) administering ytidine to the subject for 7 days; (ii) administering 5-azacytidine and the additional therapeutic agent to the subject for 1 day; (iii) administering 5-azacytidine to the subject for 6 days; (iv) administering the additional therapeutic agent to the subject for 1 day; and (v) repeating steps (i) to (iv) after 6 days of resting .

11. The use of any one of claims 4 to 6, wherein the treatment ses the tial steps of: (i) administering 5-azacytidine to the subject for 7 days; (ii) administering 5-azacytidine and the additional therapeutic agent to the subject for 1 day; (iii) administering ytidine to the subject for 6 days; (iv) administering the additional therapeutic agent to the subject for 1 day; (v) after 6 days of resting period, administering 5-azacytidine and the additional therapeutic agent to the subject for 1 day; (vi) administering 5-azacytidine to the subject for 6 days; and (vii) repeating steps (ii) to (vi).

12. The use of any one of claims 1 to 3, wherein the treatment ses administering 5-azacytidine to the subject for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 days, before administering the additional therapeutic agent to the subject.

13. The use of claim 12, wherein the additional therapeutic agent is administered erally for one or more days.

14. The use of claim 12, n the additional therapeutic agent is administered orally for one or more days.

15. The use of any one of claims 1 to 14, wherein the composition is a tablet.

16. The use of any one of claims 1 to 14, wherein the composition is a capsule.

17. The use of any one of claims 1 to 16, wherein the composition comprises about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg of 5-azacytidine.

18. The use of claim 17 wherein the composition comprises about 200 mg of 5- azacytidine.

19. The use of claim 17, wherein the composition comprises about 300 mg of 5- azacytidine.

20. The use of any one of claims 1 to 19, wherein the t is a human.

21. The use according to claim 1, substantially as herein described or exemplified.

22. The use of any one of claims 4 to 6, wherein the treatment comprises the tial steps of: (i) administering 5-azacytidine and the additional therapeutic agent to the t for 1 day; (ii) administering 5-azacytidine to the subject for 13 days; and (iii) repeating steps (i) and (ii) after 7 days of resting period.

23. The use of any one of claims 4 to 6, wherein the treatment comprises the sequential steps of: (i) administering 5-azacytidine and the additional therapeutic agent to the subject for 1 day; (ii) administering 5-azacytidine to the subject for 20 days; and (iii) repeating steps (i) and (ii).

24. The use of any one of claims 4 to 6, wherein the treatment comprises the sequential steps of: (i) administering 5-azacytidine and the additional therapeutic agent to the subject for 1 day; (ii) administering 5-azacytidine to the t for 6 days; (iii) stering ytidine and the additional therapeutic agent to the subject for 1 day; (iv) administering 5-azacytidine to the subject for 6 days; (v) repeating steps (i) to (iv) after 7 days of resting period.

25. The use of any one of claims 4 to 6, wherein the treatment comprises the sequential steps of: (i) administering 5-azacytidine and the additional therapeutic agent to the subject for 1 day; (ii) administering 5-azacytidine to the subject for 6 days; (iii) stering 5-azacytidine and the additional therapeutic agent to the subject for 1 day; (iv) administering 5-azacytidine to the subject for 13 days; (v) repeating steps (i) to (iv).