Method for treating cancer

Patent metadata

Field	Value
Publication number	US-12168014-B2
Application number	US-202016998144-A
Country	US
Kind code	B2
Filing date	Aug 20, 2020
Priority date	Nov 17, 2014
Publication date	Dec 17, 2024
Grant date	Dec 17, 2024

Abstract

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

First claim

We claim:

1. A method of treating a solid tumor or B cell lymphoma, comprising administering to a human subject in need thereof a solid pharmaceutical formulation comprising, in each case relative to the total weight of the solid pharmaceutical formulation, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3 -yl) methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide:

in an amount of about 40-60 wt. %, or a pharmaceutically acceptable salt of Compound 1 in an amount equivalent to about 40-60 wt. % of Compound 1, or a combination of Compound 1 and a pharmaceutically acceptable salt of Compound 1 wherein the combination is present in an amount equivalent to about 40-60 wt. % of Compound 1;
a diluent comprising lactose monohydrate;
a disintegrant in an amount of about 15-25 wt. % comprising low-substituted hydroxypropyl cellulose, sodium starch glycolate, or a combination thereof;
a binder in an amount of about 1-10 wt. % comprising hydroxypropyl cellulose; and
a lubricant in an amount of about 0.5-5 wt. % comprising magnesium stearate; wherein the solid pharmaceutical formulation provides a maximum plasma concentration of Compound 1 at a median Tmax of from about 1 hour to about 2 hours after multiple dosing for 15 days.

2. The method of claim 1 , wherein (i) said solid tumor or B cell lymphoma is an advanced, refractory or resistant solid tumor or B cell lymphoma; or (ii) said solid tumor or B cell lymphoma is an INI1-deficient tumor.

3. The method of claim 1 , wherein four tablets comprising the solid pharmaceutical formulation are administered orally to the human subject twice daily; Compound 1 is present in each tablet in an amount of about 200 mg; and wherein the human subject exhibits a mean Cmax bioequivalent to a mean Cmax of about 957±396 ng/ml of Compound 1 after oral administration of four tablets, twice daily, for 15 days.

4. The method of claim 1 , wherein four tablets comprising the solid pharmaceutical formulation are administered orally to the human subject twice daily; Compound 1 is present in each tablet in an amount of about 200 mg; and
wherein the human subject further exhibits one or more of the following:
a mean AUC (0-12) bioequivalent to a mean AUC (0-12) of about 4553±1636 ng*hr/ml of Compound 1 after oral administration of four tablets, twice daily, for 15 days; or
a maximum plasma concentration of Compound 1 at a median Tmax of from about 1 hour to about 2 hours after oral administration of four tablets, twice daily, for 15 days.

5. The method of claim 1 , wherein the formulation comprises Compound 1 as a monohydrobromide salt of Compound 1 in an amount equivalent to about 40-60 wt. % of Compound 1.

6. The method of claim 3 , wherein the formulation comprises Compound 1 as a monohydrobromide salt of Compound 1 in an amount equivalent to about 40-60 wt. % of Compound 1.

7. The method of claim 4 , wherein the formulation comprises Compound 1 as a monohydrobromide salt of Compound 1 in an amount equivalent to about 40-60 wt. % of Compound 1.

8. The method of claim 1 , wherein the diluent comprises lactose monohydrate in an amount of about 10-20 wt. %.

9. The method of claim 1 , wherein the formulation comprises low-substituted hydroxypropyl cellulose in an amount of about 11-19 wt. %.

10. The method of claim 1 , wherein the formulation comprises sodium starch glycolate in an amount of about 3-7 wt. %.

11. The method of claim 5 , wherein the formulation comprises low-substituted hydroxypropyl cellulose in an amount of about 11-19 wt. % and sodium starch glycolate in an amount of about 3-7 wt. %.

12. The method of claim 1 , wherein the formulation comprises about 4 wt. % hydroxypropyl cellulose.

13. The method of claim 11 , wherein the formulation comprises about 4 wt. % hydroxypropyl cellulose and about 2 wt. % magnesium stearate.

14. The method of claim 13 , wherein the formulation further comprises a coating composition in an amount of about 1-10 wt. %.

15. The method of claim 14 , wherein the coating composition comprises hypromellose, talc, macrogol, titanium dioxide, and iron (III) oxide.

16. The method of claim 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 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 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. % comprising hypromellose, talc, macrogol, titanium dioxide, and iron (III) oxide.

17. The method of claim 16 , wherein the formulation comprises a hydrobromide salt of Compound 1 in an amount of about 50 wt. % or 55 wt. %.

18. The method of claim 17 , wherein the pharmaceutical formulation is in the form of a tablet consisting of an internal phase and an external phase.

19. The method of claim 18 , wherein the tablet comprises the equivalent of 100 mg, 200 mg, or 400 mg of Compound 1.

20. The method of claim 1 , wherein the method is for treating a solid tumor or B cell lymphoma selected from a colorectal adenocarcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, Ewing's sarcoma, synovial sarcoma, alveolar sarcoma, alveolar soft part sarcoma, prostatic adenocarcinoma, rhabdoid sarcoma, malignant rhabdoid tumor, and urothelial carcinoma.

21. The method of claim 20 , wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 100 mg BID to about 1600 mg BID.

22. The method of claim 1 , wherein the method is for treating a B cell lymphoma.

23. The method of claim 22 , wherein the B cell lymphoma is selected from 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), and marginal zone lymphoma (MZL).

24. The method of claim 22 , wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of about 100 mg BID to about 1600 mg BID.

25. A method of treating an INI1-deficient solid tumor comprising oral administration of four tablets, twice daily, to a human subject in need thereof;
wherein each tablet comprises a single active ingredient;
wherein the active ingredient is N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl) methyl)-5 -(ethyl (tetrahydro-2H-pyran-4-yl) amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3 -carboxamide:

or a pharmaceutically acceptable salt thereof;
wherein Compound 1 is present in each tablet in an amount of about 200 mg;
wherein Compound 1 is present in an amount of about 40-60 wt. %, or a pharmaceutically acceptable salt of Compound 1 is present in an amount equivalent to about 40-60 wt. % of Compound 1, or a combination of Compound 1 and a pharmaceutically acceptable salt of

Assignees

• Epizyme Inc
• Eisai R&D Man Co Ltd

Inventors

• Keilhack Heike
• Truitt Brett
• Suzuki Yuta
• Murase Tsukasa
• Shikata Futoshi

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K9/2004

  Excipients; Inactive ingredients · CPC title

• A61K9/2893

  Tablet coating processes (mechanical aspects A61J3/06) · CPC title

• A61K9/2846

  Poly(meth)acrylates · CPC title

• A61K9/2095

  Tabletting processes · CPC title