NZ768247B2

NZ768247B2 - Method for treating cancer

Info

Publication number: NZ768247B2
Application number: NZ768247A
Authority: NZ
Inventors: Heike Keilhack; Tsukasa Murase; Futoshi Shikata; Yuta Suzuki; Brett Truitt
Original assignee: Eisai R&D Management Co Ltd; Epizyme Inc
Filing date: 2015-11-17
Publication date: 2024-09-03

Abstract

The present invention relates to pharmaceutical compositions comprising inhibitor(s) of human histone methyltransferase EZH2, such as EPZ-6438, and methods of cancer therapy using the EZH2 inhibitor(s).

Claims

What is claimed is:

1. Use of Compound 1 in the manufacture of a medicament for ng a cancer selected from a solid tumor, B cell lymphoma, and a cancer with aberrant H3-K27 ation, the medicament comprising a solid pharmaceutical formulation comprising: N- dimethyloxo-1,2-dihydropyridinyl)methyl)(ethyl(tetrahydro-2H-pyran yl)amino)methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]carboxamide: (“Compound 1”), wherein the formulation comprises: an amount of 40-60 wt.% of Compound 1, or a pharmaceutically acceptable salt of Compound 1 in an amount equivalent to 40-60 wt.% of Compound 1, or a combination of Compound 1 and a ceutically acceptable salt of Compound 1 wherein the combination is present in an amount equivalent to 40-60 wt.% of Compound 1; lactose monohydrate; low-substituted hydroxypropyl cellulose in an amount of about 11-19 wt.%; sodium starch glycolate in an amount of about 3-7 wt.%; hydroxypropyl cellulose in an amount of about 1-10 wt.%; magnesium stearate in an amount of about 0.5-5 wt.%; and a coating composition in an amount of about 1-10 wt.%.

2. The use of claim 1, wherein the formulation comprises: a hydrobromide salt of Compound 1 in an amount lent to 50 wt.% ± 2.5 wt.% of Compound 1; lactose monohydrate in an amount of 16 wt.% ± 0.8 wt.%; a disintegrant sing bstituted hydroxypropyl cellulose in an amount of 15 wt.% ± 0.75 wt.%, and sodium starch glycolate; hydroxypropyl cellulose in an amount of 4 wt.% ± 0.2 wt.%; magnesium stearate in an amount of 2 wt.% ± 0.2 wt.%; and a coating composition in an amount of 3 wt.% ± 0.06 wt.%.

3. The use of claim 2, wherein the disintegrant comprising low-substituted hydroxypropyl ose and sodium starch glycolate is in an amount of 20 wt.% ± 1.0 wt.%.

4. The use of claim 1, n the formulation comprises: a hydrobromide salt of Compound 1 in an amount of 55 wt.% ± 0.55 wt.%; lactose monohydrate in an amount of 16 wt.% ± 0.8 wt.%; a disintegrant comprising low-substituted hydroxypropyl cellulose in an amount of 15 wt.% ± 0.75 wt.%, and sodium starch glycolate; hydroxypropyl cellulose in an amount of 4 wt.% ± 0.2 wt.%; magnesium stearate in an amount of 2 wt.% ± 0.2 wt.%; and a coating composition in an amount of 3 wt.% ± 0.06 wt.%.

5. The use of claim 4, wherein the disintegrant comprising low-substituted hydroxypropyl cellulose and sodium starch glycolate is in an amount of 20 wt.% ± 1.0 wt.%.

6. The use of claim 1, wherein the formulation ses lactose monohydrate in an amount of about 10-20 wt.%.

7. The use of claim 1, wherein the formulation comprises lactose monohydrate in an amount of 20 wt.% ± 5.0 wt.%.

8. The use of any one of claims 1, 6, and 7, wherein the formulation comprises Compound 1 as a hydrobromide salt of Compound 1 in an amount equivalent to about 40-60 wt.% of Compound 1.

9. The use of claim 1, wherein the formulation comprises: a hydrobromide salt of Compound 1 in an amount of 50 wt.% ± 2.5 wt.%; lactose monohydrate; low-substituted ypropyl cellulose in an amount of 15 wt.% ± 0.75 wt.%; sodium starch glycolate in an amount of 5 wt.% ± 0.5 wt.%; hydroxypropyl cellulose in an amount of 4 wt.% ± 0.2 wt.%; magnesium stearate in an amount of 2 wt.% ± 0.2 wt.%; and a coating composition in an amount of 3 wt.% ± 0.06 wt.%.

10. The use of claim 9, n the formulation comprises lactose monohydrate in an amount of about 20 wt.%.

11. The use of claim 10, wherein the ation comprises lactose monohydrate in an amount of 20 wt.% ± 5.0 wt.%.

12. The use of claim 1, wherein the formulation comprises: a hydrobromide salt of Compound 1 in an amount of 55 wt.% ± 0.55 wt.%; lactose monohydrate in an amount of 16 wt.% ± 0.8 wt.%; low-substituted hydroxypropyl cellulose in an amount of 15 wt.% ± 0.75 wt.%; sodium starch glycolate in an amount of 5 wt.% ± 0.5 wt.%; hydroxypropyl cellulose in an amount of 4 wt.% ± 0.2 wt.%; magnesium stearate in an amount of 2 wt.% ± 0.2 wt.%; and a coating composition in an amount of 3 wt.% ± 0.06 wt.%.

13. The use of any one of claims 1-12, n the coating composition comprises hypromellose, talc, macrogol, titanium dioxide, and iron (III) oxide.

14. The use of claim 13, wherein the coating composition further ses a colorant.

15. The use of claim 14, wherein the pharmaceutical ation is in the form of a tablet.

16. The use of claim 15, wherein the tablet consists of an internal phase and an external phase.

17. The use of claim 15 or 16, wherein the tablet comprises the equivalent of 100 mg, 200 mg, or 400 mg of Compound 1.

18. The use of any one of claims 1-17, wherein (i) the cancer is ed, refractory or resistant cancer; or (ii) the cancer is an INI1-deficient tumor.

19. The use of any one of claims 1-18, wherein the cancer is a solid tumor or a cancer with aberrant H3-K27 methylation.

20. The use of claim 19, wherein the cancer is ctal adenocarcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, Ewing’s sarcoma, al sarcoma, alveolar sarcoma, alveolar soft part sarcoma, prostatic adenocarcinoma, rhabdoid sarcoma, malignant id tumor, or urothelial carcinoma.

21. The use of any one of claims 1-17, wherein the cancer is a B cell ma.

22. The use of claim 21, wherein the lymphoma comprises follicular lymphoma (FL), germinal center B-cell like diffuse large B-cell lymphoma (GCB DLBCL), Burkitt’s lymphoma, Primary Mediastinal Large B-Cell Lymphoma (PMBCL), or marginal zone lymphoma (MZL).

23. Use of nd 1 in the manufacture of a medicament for treating a cancer selected from a solid tumor, B cell lymphoma, and a cancer with aberrant H3-K27 methylation by inhibiting histone transferase activity of EZH2 or a mutant thereof, the medicament comprising a solid pharmaceutical formulation comprising: N-((4,6-dimethyloxo-1,2-dihydropyridinyl)methyl)(ethyl(tetrahydro-2H-pyran yl)amino)methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]carboxamide: (“Compound 1”), wherein the formulation comprises: in an amount of 40-60 wt.% of nd 1, or a pharmaceutically acceptable salt of Compound 1 in an amount equivalent to 40-60 wt.% of Compound 1, or a combination of nd 1 and a pharmaceutically acceptable salt of Compound 1 wherein the combination is present in an amount equivalent to 40-60 wt.% of Compound 1; lactose monohydrate; low-substituted hydroxypropyl cellulose in an amount of about 11-19 wt.%; sodium starch glycolate in an amount of about 3-7 wt.%; hydroxypropyl ose in an amount of about 1-10 wt.%; magnesium stearate in an amount of about 0.5-5 wt.%; and a coating composition in an amount of about 1-10 wt.%.

24. The use of claim 23, wherein Compound 1 is present as a hydrobromide salt of nd 1 in an amount equivalent to about 40-60 wt.% of Compound 1.

25. The use of claim 23 or 24, wherein lactose monohydrate is present in an amount of about 10-20 wt.%.

26. The use of claim 23 or 24, wherein lactose monohydrate is present in an amount of 20 wt.% ± 5.0 wt.%.

27. The use of any one of claims 1-26, wherein the solid pharmaceutical formulation is for administration to a subject in need thereof in combination with one or more components of R-CHOP, a BCL inhibitor, or a BCR inhibitor.

28. The use of any one of claims 1-27, wherein a single dose of the solid pharmaceutical formulation to a subject provides a mean 12) bioequivalent to a mean AUC(0-12) of from about 1720 ng*hr/ml to about 18882 ng*hr/ml to the t.

29. The use of any one of claims 1-27, wherein a single dose of the solid pharmaceutical formulation administered to a subject provides a mean AUC(0-12) bioequivalent to a mean AUC(0-12) of from about 4 ng*hr/ml to about 12 ng*hr/ml for each 1 mg of Compound 1 to the subject.

30. The use of any one of claims 1-27, wherein a single dose of the solid pharmaceutical formulation administered to a subject provides a mean AUC(0-12) ivalent to a mean AUC(0-12) of at least about 1170 ng*hr/ml to the subject.

31. The use of any one of claims 1-27, wherein a single dose of the solid ceutical formulation administered to a t provides a mean Cmax bioequivalent to a mean Cmax of from about 102 ng/ml to about 4125 ng/ml to the subject.

32. The use of any one of claims 1-27, wherein a single 800 mg dose of the solid pharmaceutical formulation administered to a subject provides a mean Cmax bioequivalent to a mean Cmax of from about 1730 ng/ml to about 2063 ng/ml to the subject.

33. The use of any one of claims 1-27, n Compound 1 or a pharmaceutically acceptable salt f is to be administered to the subject at a dose of approximately 100 mg BID to approximately 1600 mg BID.

34. The use of any one of claims 1-27, wherein Compound 1 or a pharmaceutically acceptable salt thereof is to be administered to the subject at a dose of approximately 200 mg BID, approximately 400 mg BID, or approximately 800 mg BID.

35. The use of any one of claims 1-27, n Compound 1 or a pharmaceutically acceptable salt thereof is to be administered to the subject at a dose of approximately 800 mg gaging 3E?“ Emma mEmmE wm?m wm?w 3221A! 05656 09900 HUGQAUHU Time (hr)