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KR-102964530-B1 - METHOD FOR TREATING CANCER

KR102964530B1KR 102964530 B1KR102964530 B1KR 102964530B1KR-102964530-B1

Abstract

The present invention relates to a pharmaceutical composition comprising inhibitor(s) of human histone methyltransferase EZH2 and a method for treating cancer using the EZH2 inhibitor(s).

Inventors

  • 케일해크, 헤이케
  • 트루잇, 브렛
  • 스즈키, 유타
  • 무라세, 츠카사
  • 시카타, 후토시

Assignees

  • 에피자임, 인코포레이티드
  • 에자이 알앤드디 매니지먼트 가부시키가이샤

Dates

Publication Date
20260513
Application Date
20151117
Priority Date
20141117

Claims (20)

  1. As a solid pharmaceutical formulation for treating solid tumors or B-cell lymphoma, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide present in an amount of about 40 to 60 wt.% with respect to the total weight of the solid pharmaceutical formulation: ("Compound 1") or a pharmaceutically acceptable salt of Compound 1 present in an amount corresponding to about 40 to 60 wt.% of Compound 1, or a combination of Compound 1 and a pharmaceutically acceptable salt of Compound 1 present in an amount corresponding to about 40 to 60 wt.% of Compound 1; A diluent containing lactose monohydrate; About 15 to 25 wt.% of a disintegrant comprising low-substituted hydroxypropyl cellulose, sodium starch glycolate, or a combination thereof; About 1 to 10 wt.% of a binder comprising hydroxypropyl cellulose; and It comprises about 0.5 to 5 wt.% of a lubricant containing magnesium stearate, and Here, "medicine" refers to a solid pharmaceutical formulation meaning ±10% of the specified value.
  2. A solid pharmaceutical formulation according to claim 1, wherein (i) the cancer is advanced cancer, refractory cancer, or resistant cancer, or (ii) the cancer is an INI1-deficient tumor.
  3. A solid pharmaceutical formulation according to claim 1, wherein the solid pharmaceutical formulation provides a maximum plasma concentration of compound 1 at a median Tmax of about 1 hour to about 2 hours after repeated administration for 15 days, wherein "about" means ±10% of the specified value.
  4. The solid pharmaceutical formulation of claim 1, wherein four tablets comprising the solid pharmaceutical formulation are administered orally to a human subject twice daily; compound 1 is present in each tablet in an amount of about 200 mg; and after oral administration of the four tablets twice daily for 15 days, the human subject exhibits an average Cmax that is biologically equivalent to the average Cmax of compound 1 of about 957 ± 396 ng/ml, wherein "medium" means ±10% of the specified value.
  5. In claim 1, four tablets comprising a solid pharmaceutical formulation are administered orally to a human subject twice daily; compound 1 is present in an amount of about 200 mg in each tablet; and the human subject further exhibits one or more of the following, wherein "about" means ±10% of the specified value, the solid pharmaceutical formulation: Mean AUC (0-12) of Compound 1 at approximately 4553±1636 ng*hr/ml after oral administration of 4 tablets twice daily for 15 days and a mean AUC (0-12) that is biologically equivalent; or Maximum plasma concentration of Compound 1 at the median Tmax of about 1 to 2 hours after oral administration of 4 tablets twice daily for 15 days.
  6. A solid pharmaceutical formulation according to claim 1, wherein the formulation comprises compound 1 as a monobromide hydrochloride of compound 1 in an amount corresponding to about 40 to 60 wt.% of compound 1, wherein "about" means ±10% of the specified value.
  7. A solid pharmaceutical formulation according to claim 4, wherein the formulation comprises compound 1 as a monobromide hydrochloride of compound 1 in an amount corresponding to about 40 to 60 wt.% of compound 1, wherein "about" means ±10% of the specified value.
  8. A solid pharmaceutical formulation according to claim 5, wherein the formulation comprises compound 1 as a monobromide hydrochloride of compound 1 in an amount corresponding to about 40 to 60 wt.% of compound 1, wherein "about" means ±10% of the specified value.
  9. A solid pharmaceutical formulation according to claim 1, wherein the diluent comprises lactose monohydrate in an amount of about 10 to 20 wt.%, wherein "about" means ±10% of the specified value.
  10. A solid pharmaceutical formulation according to claim 1, wherein the formulation comprises low-substituted hydroxypropyl cellulose in an amount of about 11 to 19 wt.%, wherein "about" means ±10% of the specified value.
  11. A solid pharmaceutical formulation according to claim 1, wherein the formulation contains sodium starch glycolate in an amount of about 3 to 7 wt.%, wherein "about" means ±10% of the specified value.
  12. A solid pharmaceutical formulation according to claim 6, wherein the formulation comprises low-substituted hydroxypropyl cellulose in an amount of about 11 to 19 wt.% and sodium starch glycolate in an amount of about 3 to 7 wt.%, wherein "about" means ±10% of the specified value.
  13. A solid pharmaceutical formulation according to claim 1, wherein the formulation comprises about 4 wt.% hydroxypropyl cellulose, wherein "about" means ±10% of the specified value.
  14. A solid pharmaceutical formulation according to paragraph 12, wherein the formulation comprises about 4 wt.% hydroxypropyl cellulose and about 2 wt.% magnesium stearate, wherein "about" means ±10% of the specified value.
  15. A solid pharmaceutical formulation according to claim 14, wherein the formulation further comprises a coating composition in an amount of about 1 to 10 wt.%, wherein "about" means ±10% of the specified value.
  16. A solid pharmaceutical formulation according to claim 15, wherein the coating composition comprises hypromellose, talc, macrogol, titanium dioxide, and iron oxide (III).
  17. In paragraph 1, a solid pharmaceutical formulation comprising the following, wherein "medicine" means ±10% of the specified value: A pharmaceutically acceptable salt of compound 1 present in an amount of 40 to 60 wt.% or an amount corresponding to 40 to 60 wt.% of compound 1, or a combination of compound 1 and a pharmaceutically acceptable salt of compound 1 present in an amount corresponding to 40 to 60 wt.% of compound 1; Lactose monohydrate; Low-substituted hydroxypropyl cellulose in an amount of about 11 to 19 wt.%; Sodium starch glycolate in an amount of about 3 to 7 wt.%; Hydroxypropyl cellulose in an amount of about 1 to 10 wt.%; Magnesium stearate in an amount of about 0.5 to 5 wt.%; and A coating composition containing hypromellose, talc, macrogol, titanium dioxide, and iron oxide (III) in an amount of about 1 to 10 wt.%.
  18. A solid pharmaceutical formulation according to claim 17, comprising a hydrobromide of compound 1 present in an amount of about 50 wt.% or 55 wt.%, wherein "about" means ±10% of the specified value.
  19. In paragraph 18, a solid pharmaceutical formulation in the form of a tablet consisting of an inner phase and an outer phase.
  20. In paragraph 19, a solid pharmaceutical formulation in which the tablet corresponds to 100 mg, 200 mg, or 400 mg of compound 1.

Description

Method for treating cancer [Related Applications] The present application claims the benefit of and priority to U.S. patent application 62/080,985 filed November 17, 2014; U.S. patent application 62/166,572 filed May 26, 2015; and U.S. patent application 62/251,903 filed November 6, 2015; the contents of each of these applications are incorporated herein by reference in their entirety. [Technology Field] The present invention relates to a pharmaceutical composition comprising inhibitor(s) of human histone methyltransferase EZH2 and a method for treating cancer using the EZH2 inhibitor(s). EZH2, or histone methyltransferase, has been associated with various types of cancer. In particular, mutations and/or hyperreactions of EZH2 are found in various cancers such as lymphoma, leukemia, and breast cancer. Novel agents are still needed as EZH2 inhibitors for use in anticancer therapy. Figures 1a and 1b are plots of the average EPZ-6438 plasma concentration versus time profile when EPZ-6438 was administered twice daily: Figure 1a; Day 1 and Figure 1b; Day 15. Figure 2 is a plot of the average molar ratio of metabolite to parent compound (ER-897387/EPZ-6438) exposure when administered once (Day 1) and twice daily (Day 15). Figure 3a is a plot of maximum tumor change rate versus dose, and Figure 3b is a plot of maximum tumor change rate versus steady-state (day 15) exposure. Figure 4 is a graph showing the average percentage of cells stained positive for H3K27Me3 in skin biopsy samples (C1D1 = baseline before administration of cycle 1, day 1; C2D1 = cycle 2, day 1). Figure 5 is a plot of the percentage change from baseline versus the dose of EPZ-6438 among cells stained positive for H3K27Me3 in skin biopsy samples. Figure 6 is a plot of the percentage of maximum tumor change versus the percentage of change from baseline among cells stained positive for H3K27Me3 in skin biopsy samples. Figure 7 is a plot showing the correlation between the percentage change from baseline among cells stained positive for H3K27Me3 in skin biopsy samples and EPZ-6438 exposure (the line indicates conformity to the inhibition PK/PD model). FIG. 8 is a flowchart of an embodiment of a method for manufacturing film-coated EPZ-6438 tablets. Figure 9 is a plot showing the dissolution profiles of EPZ-6438 50 mg, 100 mg, and 200 mg tablets (n = 6, mean) (Paddle method (Paddle method) (Apparatus 2 of USP<711>), pH 4.5 acetate buffer, 900 ml, 50 rpm). Figure 10 is a plot showing the dissolution profiles of EPZ-6438 50 mg, 100 mg, and 200 mg tablets (n = 6, mean) (Paddle method (device 2 of USP<711>), 0.1N HCl, 900 mL, 50 rpm). Figure 11 is a plot showing the solubility profiles of different formulations (n = 2, mean) of EPZ-6438 (Paddle method (device 2 of USP<711>), 0.1N HCl, 900 mL, 50 rpm). Figure 12 is a plot showing the solubility profiles of different formulations (n = 2, mean) of EPZ-6438 (Paddle method (device 2 of USP<711>), 0.1N HCl, 900 mL, 50 rpm). Figure 13 is a plot showing the solubility profiles of different formulations of EPZ-6438 (n = 2, mean) (Paddle method (device 2 of USP<711>), pH 4.5 acetate buffer, 900 ml, 50 rpm). Figure 14 is a plot showing the solubility profiles of different formulations of EPZ-6438 (n = 2, mean) (Paddle method (device 2 of USP<711>), pH 4.5 acetate buffer, 900 ml, 50 rpm). Figure 15a is a series of plots of the average EPZ-6438 plasma concentration versus time profile when EPZ-6438 was administered twice daily at the time of day 1 and day 15. Figure 15b is a series of photographs showing the pharmacodynamics of EPZ-6438 in the skin. Figure 15c is a plot showing the correlation between histone methylation inhibition and EPZ-6438 exposure. Figures 16a to 16f are a series of plots or images obtained from an advanced imaging analysis of H3K27 trimethylation in the skin obtained from subjects administered the EZH2 inhibitor tazemetostat. Examples Example 1: PK/PD Study A Phase 1 study, the first of its kind in humans, was conducted using an enhancer of the zest-homologous 2 (EZH2) histone methyltransferase inhibitor EPZ-6438 as a single agent in patients with advanced solid tumors ("ST") or B-cell lymphoma. Phase 1 dose escalation was performed to measure maximum tolerated dose (MTD) safety, PK, PD, and preliminary antitumor activity in patients ("pts") with B-cell lymphoma or advanced solid tumors. Methods: EPZ-6438 was administered sequentially PO BID to a cohort of 3 to 6 patients at a maximum feasible dose of 1600 mg BID or less. Blood samples were collected for PK analysis and skin biopsies for PD analysis. PD samples were stained with H3K27me3-specific antibodies, and the percentage change from baseline in H3K27Me3-positive cells was measured. The PK/PD relationship was analyzed. Tumor evaluations were performed every 8 weeks. Twenty-one patients were enrolled as of August 14, 2014, and treated at five dose levels: 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, and 1600 mg BID. Diagnoses of B-cell