Claims for Patent: 12,168,014

Summary for Patent: 12,168,014

Title:	Method for treating cancer
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).
Inventor(s):	Heike Keilhack, Brett TRUITT, Yuta Suzuki, Tsukasa Murase, Futoshi SHIKATA
Assignee:	Eisai R&D Management Co Ltd , Epizyme Inc
Application Number:	US16/998,144
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 12,168,014
Patent Claims:	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 Compound 1 is present in an amount equivalent to about 40-60 wt. % of Compound 1, in each case relative to the total weight of each tablet; 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. 26. The method of claim 25, wherein the active ingredient is the monohydrobromide salt of Compound 1. 27. The method of claim 25, 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. 28. The method of claim 26, 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. 29. The method of claim 25, wherein each tablet comprises about 10-20 wt. % diluent, about 15-25 wt. % disintegrant, about 1-10 wt. % binder, about 0.5-5 wt. % lubricant, and about 1-10 wt. % coating composition. 30. The method of claim 26, wherein each tablet comprises about 10-20 wt. % diluent, about 15-25 wt. % disintegrant, about 1-10 wt. % binder, about 0.5-5 wt. % lubricant, and about 1-10 wt. % coating composition. 31. The method of claim 29, wherein the diluent comprises lactose monohydrate. 32. The method of claim 30, wherein the diluent comprises lactose monohydrate. 33. The method of claim 31, wherein the disintegrant comprises low-substituted hydroxypropyl cellulose, sodium starch glycolate, or a combination thereof. 34. The method of claim 32, wherein the disintegrant comprises low-substituted hydroxypropyl cellulose, sodium starch glycolate, or a combination thereof. 35. The method of claim 33, wherein the binder comprises hydroxypropyl cellulose. 36. The method of claim 34, wherein the binder comprises hydroxypropyl cellulose. 37. The method of claim 35, wherein the lubricant comprises magnesium stearate. 38. The method of claim 36, wherein the lubricant comprises magnesium stearate. 39. The method of claim 37, wherein the coating composition comprises hypromellose, talc, macrogol, and optionally further comprises titanium dioxide and/or iron (III) oxide. 40. The method of claim 38, wherein the coating composition comprises hypromellose, talc, macrogol, and optionally further comprises titanium dioxide and/or iron (III) oxide. 41. A method of treating follicular lymphoma 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,l′-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 Compound 1 is present in an amount equivalent to about 40-60 wt. % of Compound 1, in each case relative to the total weight of each tablet; 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. 42. The method of claim 41, wherein the active ingredient is the monohydrobromide salt of Compound 1. 43. The method of claim 41, 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. 44. The method of claim 42, 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. 45. The method of claim 41, wherein the follicular lymphoma is refractory. 46. The method of claim 42, wherein the follicular lymphoma is refractory. 47. The method of claim 41, wherein the human subject has a tumor with an EZH2 mutation at amino acid Y646. 48. The method of claim 42, wherein the human subject has a tumor with an EZH2 mutation at amino acid Y646. 49. The method of claim 41, wherein the human subject has a tumor with an EZH2 SET-domain mutation. 50. The method of claim 42, wherein the human subject has a tumor with an EZH2 SET-domain mutation. 51. The method of claim 41, wherein each tablet comprises about 10-20 wt. % diluent, about 15-25 wt. % disintegrant, about 1-10 wt. % binder, about 0.5-5 wt. % lubricant, and about 1-10 wt. % coating composition. 52. The method of claim 42, wherein each tablet comprises about 10-20 wt. % diluent, about 15-25 wt. % disintegrant, about 1-10 wt. % binder, about 0.5-5 wt. % lubricant, and about 1-10 wt. % coating composition. 53. The method of claim 51, wherein the diluent comprises lactose monohydrate. 54. The method of claim 52, wherein the diluent comprises lactose monohydrate. 55. The method of claim 53, wherein the disintegrant comprises low-substituted hydroxypropyl cellulose, sodium starch glycolate, or a combination thereof. 56. The method of claim 54, wherein the disintegrant comprises low-substituted hydroxypropyl cellulose, sodium starch glycolate, or a combination thereof. 57. The method of claim 55, wherein the binder comprises hydroxypropyl cellulose. 58. The method of claim 56, wherein the binder comprises hydroxypropyl cellulose. 59. The method of claim 57, wherein the lubricant comprises magnesium stearate. 60. The method of claim 58, wherein the lubricant comprises magnesium stearate. 61. The method of claim 59, wherein the coating composition comprises hypromellose, talc, macrogol, and optionally further comprises titanium dioxide and/or iron (III) oxide. 62. The method of claim 60, wherein the coating composition comprises hypromellose, talc, macrogol, and optionally further comprises titanium dioxide and/or iron (III) oxide.