Combination therapy for treating cancer

Patent metadata

Field	Value
Publication number	US-10787440-B2
Application number	US-201916372657-A
Country	US
Kind code	B2
Filing date	Apr 2, 2019
Priority date	Apr 13, 2012
Publication date	Sep 29, 2020
Grant date	Sep 29, 2020

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.

First claim

What is claimed is:

1. A method of treating follicular lymphoma comprising administering to a subject in need thereof a therapeutically effective dose of a compound of Formula (IIa):

or a pharmaceutically acceptable salt thereof and a therapeutically effective dose of rituximab, wherein
each of R a and R b , independently, is H or C 1 -C 6 alkyl; or R a and R b , together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms; wherein the C 1 -C 6 alkyl or the 4 to 7-membered heterocycloalkyl ring are optionally substituted with one or more -Q 3 -T 3 , in which Q 3 is a bond or unsubstituted or substituted C 1 -C 3 alkyl linker, and T 3 is H, halo, 4 to 7-membered heterocycloalkyl, C 1 -C 3 alkyl, OR d , COOR d , —S(O) 2 R d , or —NR d R e , in which each of R d and R e is independently H or C 1 -C 6 alkyl, or -Q 3 T 3 is oxo;
R 7 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or 4 to 12-membered heterocycloalkyl, each optionally substituted with one or more -Q 5 -T 5 , in which Q 5 is a bond, C(O), C(O)NR k , NR k C(O), S(O) 2 , or C 1 -C 3 alkyl linker, R k being H or C 1 -C 6 alkyl, and T 5 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5 - or 6-membered heteroaryl, or S(O) q R q in which q is 0, 1, or 2 and R q is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 5 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 5 is H, halo, hydroxyl, or cyano; or -Q 5 -T 5 is oxo; and
R 8 is H, methyl, or ethyl;

wherein the follicular lymphoma is resistant or refractory to at least one prior therapy; and
wherein the compound of Formula (IIa) and said rituximab are administered simultaneously or sequentially.

2. The method of claim 1 , wherein the compound of Formula (IIa) or a pharmaceutically acceptable salt thereof, is administered prior to administration of said rituximab.

3. The method of claim 1 , wherein said subject has demonstrated resistance to the compound of Formula (IIa) or a pharmaceutically acceptable salt thereof when administered as a single agent.

4. The method of claim 1 , wherein the follicular lymphoma is resistant to at least one prior monotherapy.

5. The method of claim 1 , wherein the follicular lymphoma is resistant to at least one prior combination therapy.

6. The method of claim 1 , wherein said subject has demonstrated resistance to rituximab when administered as a single agent.

7. The method of claim 1 , wherein the compound of Formula (IIa) is Compound 44:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein R 7 is a C 1 -C 6 alkyl, a 4 to 12-membered heterocycloalkyl, or a C 3 -C 8 cycloalkyl, wherein the C 1 -C 6 alkyl is isopropyl, the 4 to 12-membered heterocycloalkyl is selected from piperidinyl, tetrahydropyran, and tetrahydro-2H-thiopyranyl, and the C 3 -C 8 cycloalkyl is selected from cyclopentyl and cyclohexyl.

9. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective dose of a compound of Formula (IIa):

or a pharmaceutically acceptable salt thereof, a therapeutically effective dose of rituximab, and a therapeutically effective dose of lenalidomide, wherein
each of R a and R b , independently, is H or C 1 -C 6 alkyl; or R a and R b , together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms; wherein the C 1 -C 6 alkyl or the 4 to 7-membered heterocycloalkyl ring are optionally substituted with one or more -Q 3 -T 3 , in which Q 3 is a bond or unsubstituted or substituted C 1 -C 3 alkyl linker, and T 3 is H, halo, 4 to 7-membered heterocycloalkyl, C 1 -C 3 alkyl, OR d , COOR d , —S(O) 2 R d , or -NR d R e , in which each of R d and R e is independently H or C 1 -C 6 alkyl, or -Q 3 T 3 is oxo;
R 7 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or 4 to 12-membered heterocycloalkyl, each optionally substituted with one or more -Q 5 -T 5 , in which Q 5 is a bond, C(O), C(O)NR k , NR k C(O), S(O) 2 , or C 1 -C 3 alkyl linker, R k being H or C 1 -C 6 alkyl, and T 5 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5 - or 6-membered heteroaryl, or S(O) q R q in which q is 0, 1, or 2 and R q is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 5 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 5 is H, halo, hydroxyl, or cyano; or -Q 5 -T 5 is oxo; and
R 8 is H, methyl, or ethyl;

wherein the cancer is resistant or refractory to at least one prior therapy; and
wherein the compound of Formula (IIa) and said rituximab and said lenalidomide are administered simultaneously or sequentially.

10. The method of claim 9 , wherein the compound of Formula (IIa) or a pharmaceutically acceptable salt thereof, is administered prior to administration of said rituximab, said lenalidomide, or a combination of said rituximab and said lenalidomide.

11. The method of claim 9 , wherein the cancer is resistant to at least one prior monotherapy.

12. The method of claim 9 , wherein said subject has demonstrated resistance to the compound of Formula (IIa) or a pharmaceutically acceptable salt thereof when administered as a single agent.

13. The method of claim 9 , wherein the cancer is resistant to at least one prior combination therapy.

14. The method of claim 9 , wherein said subject has demonstrated resistance to lenalidomide when administered as a single agent.

15. The method of claim 9 , wherein said subject has demonstrated resistance to rituximab when administered as a single agent.

16. The method of claim 9 , wherein said subject has demonstrated resistance to rituximab and to lenalidomide when administered as single agents or in combination.

17. The method of claim 9 , wherein the cancer is lymphoma, leukemia, or melanoma.

18. The method of claim 17 , wherein the cancer is follicular lymphoma.

19. The method of claim 9 , wherein the compound of Formula (IIa) is Compound 44:

or a pharmaceutically acceptable salt thereof.

Assignees

• Epizyme Inc

Inventors

• Keilhack Heike
• Knutson Sarah Kathleen
• Kuntz Kevin Wayne

Classifications

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61K31/5386

  spiro-condensed or forming part of bridged ring systems · CPC title

• A61K31/4433

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/397

  having four-membered rings, e.g. azetidine · CPC title