Combination therapy for treating cancer

• US 10,463,671 B2
• Filed: 11/10/2017
• Issued: 11/05/2019
• Est. Priority Date: 12/06/2013
• Status: Active Grant

• Current Assignee: Epizyme, Inc. (Ipsen Sa)
• Original Assignee: Epizyme, Inc. (Ipsen Sa)
• Inventors: Keilhack, Heike, Knutson, Sarah K., Kuntz, Kevin W.
• Primary Examiner(s): Chu, Yong L
• Application Number:
  US15/809,445
• Publication Number:
  US 20180280402A1
• Time in Patent Office: 725 Days
• Field of Search: 5142288
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/635 having a heterocyclic ring, e.g. sulfadiazine
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2887 against CD20

Abstract

The present invention relates to compositions comprising inhibitors of human histone methyltransferase EZH2 and one or more other therapeutic agents, particularly anticancer agents such as prednisone, and methods of combination therapy for administering to subjects in need thereof for the treatment of cancer.

Claims

1. A method for treating cancer in a patient in need thereof comprising administering:

(i) a therapeutically effective amount of an EZH2 inhibitor and a therapeutically effective amount of a standard of care agent;

(ii) a therapeutically effective amount of a combination comprising an EZH2 inhibitor and a standard of care agent;

or

(iii) a therapeutically effective amount of a composition comprising an EZH2 inhibitor and a standard of care agent;

wherein the EZH2 inhibitor is Compound 44 having the following formula;

2. The method of claim 1, wherein the cancer is a Non-Hodgkin'"'"'s lymphoma.

3. The method of claim 2, wherein the Non-Hodgkin lymphoma is DLBCL (diffuse large B-cell lymphoma) or GCB (germinal center B-cell-like) lymphoma.

4. The method of claim 1, wherein (i) the cancer is an EZH2 wild type cancer, or (ii) the cancer is characterized by increased trimethylation at H3K27, or (iii) the cancer is an EZH2 inhibitor resistant or refractory cancer.

5. The method of claim 3, wherein the lymphoma is an EZH2 mutant lymphoma.

6. The method of claim 5, wherein the EZH2 mutant lymphoma has an Y646, A682 or A692 mutation.

7. The method of claim 1, wherein the standard of care agent is a PI3K/Akt/mTOR signaling cascade inhibitor.

8. The method of claim 1, wherein the EZH2 inhibitor and the standard of care agent are administered simultaneously or sequentially.

9. The method of claim 1, wherein the EZH2 inhibitor is administered prior to administration of the standard of care agent.

10. The method of claim 1, wherein the patient has upregulated expression of at least one gene selected from the group consisting of Sestrin, TNF, GILZ, and glucocorticoid target genes.

11. The method of claim 10, wherein the upregulation of the at least one gene is used to determine or adjust the therapeutically effective amount of the EZH2 inhibitor, or the upregulation of a gene is used to determine or adjust the therapeutically effective amount of the standard of care agent.

12. The method of claim 10, wherein the patient has upregulated expression of Sestrin, TNF or GILZ.

13. The method of claim 1, wherein the patient is further administered an R-CHOP component.

14. The method of claim 1, wherein the patient is further administered prednisolone or dexamethasone.

15. The method of claim 1, wherein the standard of care agent is two or more compounds selected from the group consisting of navitoclax, obatoclax, ABT-199, MK-2206, idelalisib, trametinib, tamatinib, and ibrutinib.

16. The method of claim 15, wherein the standard of care agent comprises navitoclax, obatoclax, or ABT-199.

17. The method of claim 15, wherein the standard of care agent is a PI3K/Akt/mTOR signaling cascade inhibitor.

18. The method of claim 15, wherein the standard of care agent comprises MK-2206, idelalisib, trametinib, tamatinib, or ibrutinib.

19. The method of claim 1, wherein the standard of care agent is navitoclax.

20. The method of claim 1, wherein the standard of care agent is obatoclax.

21. The method of claim 1, wherein the standard of care agent is ABT-199.

22. The method of claim 1, wherein the standard of care agent is MK-2206.

23. The method of claim 1, wherein the standard of care agent is idelalisib.

24. The method of claim 1, wherein the standard of care agent is trametinib.

25. The method of claim 1, wherein the standard of care agent is ibrutinib.