Claims for Patent: 10,456,407

Summary for Patent: 10,456,407

Title:	Combination therapy for treating cancer
Abstract:	The present disclosure relates to compositions comprising inhibitors of human histone methyltransferase EZH2 and one or more other therapeutic agents (such as tyrosine kinase inhibitors or VEGF/VEGFR inhibitors), particularly anticancer agents such as sunitinib, and methods of combination therapy for administering to subjects in need thereof for the treatment of cancer.
Inventor(s):	Keilhack; Heike (Belmont, MA), Pili; Roberto (Indianapolis, IN)
Assignee:	Epizyme, Inc. (Cambridge, MA) Health Research, Inc. (Buffalo, NY)
Application Number:	15/567,838
Patent Claims:	1. A method for treating renal cancer in a patient in need thereof comprising administering a therapeutically effective amount of an EZH2 inhibitor and one or more tyrosine kinase inhibitors; wherein the EZH2 inhibitor is GSK-126 having the following formula: ##STR00115## or a pharmaceutically acceptable salt thereof; or a compound of Formula (I): ##STR00116## or a pharmaceutically acceptable salt thereof; wherein: R.sup.701 is H, F, OR.sup.707, NHR.sup.707, --(C.ident.C)--(CH.sub.2).sub.n7--R.sup.708, phenyl, 5- or 6-membered heteroaryl, C.sub.3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C.sub.3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C.sub.1-3 alkyl, OH, O--C.sub.1-6 alkyl, NH--C.sub.1-6 alkyl, and, C.sub.1-3 alkyl substituted with C.sub.3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O--C.sub.1-6 alkyl and NH--C.sub.1-6 alkyl is optionally substituted with hydroxyl, O--C.sub.1-3 alkyl or NH--C.sub.1-3 alkyl, each of the O--C.sub.1-3 alkyl and NH--C.sub.1-3 alkyl being optionally further substituted with O--C.sub.1-3 alkyl or NH--C.sub.1-3 alkyl; each of R.sup.702 and R.sup.703, independently is H, halo, C.sub.1-4 alkyl, C.sub.1-6 alkoxyl or C.sub.6-C.sub.10 aryloxy, each optionally substituted with one or more halo; each of R.sup.704 and R.sup.705, independently is C.sub.1-4 alkyl; R.sup.706 is cyclohexyl substituted by N(C.sub.1-4 alkyl).sub.2 wherein one or both of the C.sub.1-4 alkyl is substituted with C.sub.1-6 alkoxy; or R.sup.706 is tetrahydropyranyl; R.sup.707 is C.sub.1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C.sub.1-4 alkoxy, amino, mono- or di-C.sub.1-4 alkylamino, C.sub.3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C.sub.3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C.sub.1-3 alkyl; R.sup.708 is C.sub.1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C.sub.1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O--C.sub.1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C.sub.1-6 alkyl; and n.sub.7 is 0, 1 or 2. 2. The method of claim 1, wherein the EZH2 inhibitor is of Formula (I). 3. The method of claim 1, wherein the one or more tyrosine kinase inhibitors are VEGF/VEGFR inhibitors. 4. A method for treating renal cancer in a patient in need thereof comprising administering a therapeutically effective amount of an EZH2 inhibitor and one or more VEGF/VEGFR inhibitors; wherein the EZH2 inhibitor is GSK-126 having the following formula: ##STR00117## or a pharmaceutically acceptable salt thereof; or a compound of Formula (I): ##STR00118## or a pharmaceutically acceptable salt thereof; wherein: R.sup.701 is H, F, OR.sup.707, NHR.sup.707, --(C.ident.C)--(CH.sub.2).sub.n7--R.sup.708, phenyl, 5- or 6-membered heteroaryl, C.sub.3-8 cycloalkyl, or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the phenyl, 5- or 6-membered heteroaryl, C.sub.3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is optionally substituted with one or more groups selected from halo, C.sub.1-3 alkyl, OH, O--C.sub.1-6 alkyl, NH--C.sub.1-6 alkyl, and, C.sub.1-3 alkyl substituted with C.sub.3-8 cycloalkyl or 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein each of the O--C.sub.1-6 alkyl and NH--C.sub.1-6 alkyl is optionally substituted with hydroxyl, O--C.sub.1-3 alkyl or NH--C.sub.1-3 alkyl, each of the O--C.sub.1-3 alkyl and NH--C.sub.1-3 alkyl being optionally further substituted with O--C.sub.1-3 alkyl or NH--C.sub.1-3 alkyl; each of R.sup.702 and R.sup.703, independently is H, halo, C.sub.1-4 alkyl, C.sub.1-6 alkoxyl or C.sub.6-C.sub.10 aryloxy, each optionally substituted with one or more halo; each of R.sup.704 and R.sup.705, independently is C.sub.1-4 alkyl; R.sup.706 is cyclohexyl substituted by N(C.sub.1-4 alkyl).sub.2 wherein one or both of the C.sub.1-4 alkyl is substituted with C.sub.1-6 alkoxy; or R.sup.706 is tetrahydropyranyl; R.sup.707 is C.sub.1-4 alkyl optionally substituted with one or more groups selected from hydroxyl, C.sub.1-4 alkoxy, amino, mono- or di-C.sub.1-4 alkylamino, C.sub.3-8 cycloalkyl, and 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, wherein the C.sub.3-8 cycloalkyl or 4-7 membered heterocycloalkyl each independently is further optionally substituted with C.sub.1-3 alkyl; R.sup.708 is C.sub.1-4 alkyl optionally substituted with one or more groups selected from OH, halo, and C.sub.1-4 alkoxy, 4-7 membered heterocycloalkyl containing 1-3 heteroatoms, or O--C.sub.1-6 alkyl, wherein the 4-7 membered heterocycloalkyl can be optionally further substituted with OH or C.sub.1-6 alkyl; and n.sub.7 is 0, 1 or 2. 5. The method of claim 1, wherein the cancer is resistant to VEGF/VEGFR inhibitor treatment. 6. The method of claim 1, wherein the EZH2 inhibitor is compound 44 having the following formula: ##STR00119## or pharmaceutically acceptable salt thereof. 7. The method of claim 1, wherein the EZH2 inhibitor is: ##STR00120## or pharmaceutically acceptable salt thereof. 8. The method of claim 1, wherein the EZH2 inhibitor is GSK-126. 9. The method of claim 1, wherein the one or more tyrosine kinase inhibitors are selected from erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib (Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab (Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux); panitumumab (Vectibix); everolimus (Afinitor); alemtuzumab (Campath); gemtuzumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient); dasatinib (Sprycel); nilotinib (Tasigna); and vatalanib (Ptk787; ZK222584). 10. The method of claim 1, wherein the one or more tyrosine kinase inhibitors includes sunitinib. 11. The method of claim 4, wherein the one or more VEGF/VEGFR inhibitors are selected from bevacizumab (Avastin); sorafenib (Nexavar); sunitinib (Sutent); ranibizumab; pegaptanib; vandetinib; Vatalanib (Ptk787 or ZK222584); and motesanib diphosphate. 12. The method of claim 4, wherein the one or more VEGF/VEGFR inhibitors include sunitinib. 13. The method of claim 1, wherein the EZH2 inhibitor and the one or more tyrosine kinase inhibitors are administered simultaneously or sequentially. 14. The method of claim 1, wherein the EZH2 inhibitor is administered prior to administration of the one or more tyrosine kinase inhibitors. 15. The method of claim 4, wherein the EZH2 inhibitor and the one or more VEGF/VEGFR inhibitors are administered simultaneously or sequentially. 16. The method of claim 4, wherein the EZH2 inhibitor is administered prior to administration of the one or more VEGF/VEGFR inhibitors. 17. The method of claim 1, wherein the cancer is renal cell carcinoma. 18. The method of claim 4, wherein the cancer is resistant to VEGF/VEGFR inhibitor treatment. 19. The method of claim 4, wherein the EZH2 inhibitor is Compound 44 having the following formula: ##STR00121## or pharmaceutically acceptable salt thereof. 20. The method of claim 4, wherein the cancer is renal cell carcinoma.

Details for Patent 10,456,407

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2035-04-20
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2035-04-20
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2035-04-20