EZH2 inhibitors for treating cancer

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.