EZH2 inhibitors for treating cancer

Patent metadata

Field	Value
Publication number	US-11147819-B2
Application number	US-201716310597-A
Country	US
Kind code	B2
Filing date	Jun 16, 2017
Priority date	Jun 17, 2016
Publication date	Oct 19, 2021
Grant date	Oct 19, 2021

Abstract

The present disclosure relates to compositions comprising inhibitors of human histone methyltransferase EZH2 and one or more other therapeutic agents, for example, modulators of CD40 pathway activity, such as CD40 agonists, and methods of combination therapy for administering to subjects in need thereof for the treatment of cancer.

First claim

What is claimed is:

1. A method for treating a germinal center-derived lymphoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an EZH2 inhibitor and a CD40 agonist.

2. The method of claim 1 , wherein the germinal center-derived lymphoma is an EZH2 wild type germinal center B-cell lymphoma.

3. The method of claim 1 , wherein the CD40 agonist comprises CD40L, a CD40-binding fragment of CD40L, an agonistic CD40 antibody, an agonistic CD40 antibody fragment, CP870,893, SGN-40, a CD40 agonist peptide, or a small molecule.

4. The method of claim 1 , wherein the EZH2 inhibitor is administered orally.

5. The method of claim 1 , wherein the subject is a human being.

6. The method of claim 1 , wherein the EZH2 inhibitor is of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein
R 701 is H, F, OR 707 , NHR 707 , —(C≡C)—(CH 2 ) n7 —R 708 , phenyl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C 1-3 alkyl, OH, O—C 1-6 alkyl, NH—C 1-6 alkyl, and, C 1-3 alkyl substituted with C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O—C 1-6 alkyl and NH—C 1-6 alkyl is optionally substituted with hydroxyl, O—C 1-3 alkyl or NH—C 1-3 alkyl, each of the O—C 1-3 alkyl and NH—C 1-3 alkyl being optionally further substituted with O—C 1-3 alkyl or NH—C 1-3 alkyl;
each of R 702 and R 703 , independently is H, halo, C 1-4 alkyl, C 1-6 alkoxyl or C 6-10 aryloxy, each optionally substituted with one or more halo;
each of R 704 and R 705 , independently is C 1-4 alkyl;
R 706 is cyclohexyl substituted by N(C 1-4 alkyl) 2 wherein one or both of the C 1-4 alkyl is optionally substituted with C 1-6 alkoxy; or R 706 is tetrahydropyranyl;
R 707 is C 1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C 1-4 alkoxy, amino, mono- or di-C 1-4 alkylamino, C 3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C 3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C 1-3 alkyl;
R 708 is C 1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C 1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O—C 1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C 1-6 alkyl; and
n 7 is 0, 1 or 2.

7. The method of claim 1 , wherein the EZH2 inhibitor is EPZ-6438 having the following formula:

(EPZ-6438) or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 , wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg to about 3,200 mg daily.

9. The method of claim 7 , wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg BID to about 1,600 mg BID.

10. The method of claim 7 , wherein the EZH2 inhibitor is administered to the subject at a dose of about 100 mg BID, 200 mg BID, 400 mg BID, 800 mg BID, or about 1,600 mg BID.

11. The method of claim 1 , wherein the EZH2 inhibitor is:

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein the EZH2 inhibitor

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the CD40 agonist is CD40L.

14. The method of claim 1 , wherein the CD40 agonist comprises an anti-CD40 antibody or an anti-CD40 antibody fragment.

15. The method of claim 1 , wherein the EZH2 inhibitor and the CD40 agonist are administered simultaneously or sequentially.

16. The method of claim 1 , wherein the EZH2 inhibitor is administered prior to administration of the CD40 agonist.

17. The method of claim 1 , wherein the CD40 agonist is administered prior to administration of the EZH2 inhibitor.

18. The method of claim 1 , wherein the germinal center-derived lymphoma is diffuse large B-cell lymphoma, follicular lymphoma, Burkitt's lymphoma or Non-Hodgkin's Lymphoma of germinal center B-cell subtype.

19. The method of claim 6 , wherein the CD40 agonist comprises CD40L, a CD40-binding fragment of CD40L, an agonistic CD40 antibody, an agonistic CD40 antibody fragment, CP870,893, SGN-40, a CD40 agonist peptide, or a small molecule.

20. The method of claim 6 , wherein the CD40 agonist comprises an anti-CD40 antibody or an anti-CD40 antibody fragment.

21. The method of claim 6 , wherein the CD40 agonist is CD40L.

22. The method of claim 21 , wherein the germinal center-derived lymphoma is diffuse large B-cell lymphoma, follicular lymphoma, Burkitt's lymphoma or Non-Hodgkin's Lymphoma of germinal center B-cell subtype.

23. The method of claim 6 , wherein the germinal center-derived lymphoma is diffuse large B-cell lymphoma, follicular lymphoma, Burkitt's lymphoma or Non-Hodgkin's Lymphoma of germinal center B-cell subtype.

24. The method of claim 7 , wherein the CD40 agonist comprises CD40L, a CD40-binding fragment of CD40L, an agonistic CD40 antibody, an agonistic CD40 antibody fragment, CP870,893, SGN-40, a CD40 agonist peptide, or a small molecule.

25. The method of claim 7 , wherein the CD40 agonist comprises an anti-CD40 antibody or an anti-CD40 antibody fragment.

26. The method of claim 7 , wherein the CD40 agonist is CD40L.

27. The method of claim 26 , wherein the germinal center-derived lymphoma is diffuse large B-cell lymphoma, follicular lymphoma, Burkitt's lymphoma or Non-Hodgkin's Lymphoma of germinal center B-cell subtype.

28. The method of claim 7 , wherein the germinal center-derived lymphoma is diffuse large B-cell lymphoma, follicular lymphoma, Burkitt's lymphoma or Non-Hodgkin's Lymphoma of germinal center B-cell subtype.

29. The method of claim 7 , wherein the germinal center-derived lymphoma is diffuse large B-cell lymphoma.

Assignees

• Epizyme Inc

Inventors

• Ribich Scott
• Thomenius Michael

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K39/395

  Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title