Claims for Patent: 10,335,388

Summary for Patent: 10,335,388

Title:	Combination therapy of a HIF-2-alpha inhibitor and an immunotherapeutic agent and uses thereof
Abstract:	The present invention provides methods and pharmaceutical compositions for treating proliferative disorders. The method involves step of administering to said subject a HIF-2alpha inhibitor and an immunotherapeutic agent.
Inventor(s):	Josey; John A. (Dallas, TX), Wallace; Eli M. (Richardson, TX), Han; Guangzhou (Plano, TX)
Assignee:	PELOTON THERAPEUTICS, INC. (Dallas, TX)
Application Number:	15/564,348
Patent Claims:	1. A method of treating cancer in a subject in need thereof, comprising administering to said subject an effective amount of a HIF-2.alpha. inhibitor in combination B with an immunotherapeutic agent, wherein the cancer is selected from the group consisting of melanoma, renal cell carcinoma, and colorectal cancer, wherein the immunotherapeutic agent is a PD-1 inhibitor or a CTLA-4 inhibitor, and wherein the HIF-2.alpha. inhibitor is a compound of Formula I-C: ##STR00977## or a pharmaceutically acceptable salt thereof, wherein: X is CR.sup.5 or N; Y is CR.sup.6 or N; Z is --O--, --S--, --C(HR.sup.7)--, --N(R.sup.8)-- or absent; R.sup.1 is alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl or cyano; R.sup.4 is nitro, halo, cyano, alkyl, cycloalkyl, heteroaryl, carboxyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are independently hydrogen, halo, hydroxy, cyano, alkyl or alkoxy; R.sup.11 is hydrogen, halo, hydroxy, alkoxy or amino; R.sup.12 is hydrogen, alkyl, alkenyl or alkynyl; or R.sup.11 and R.sup.12 in combination form oxo or oxime; each of R.sup.13 is independently selected from the group consisting of hydrogen, fluoro, chloro, hydroxy, alkyl and heteroalkyl; or two R.sup.13s and the carbon atom(s) to which they are attached form a 3- to 8-membered cycloalkyl or heterocycloalkyl moiety; and n is 0, 1, 2, 3 or 4. 2. The method of claim 1, wherein the HIF-2.alpha. inhibitor and the immunotherapeutic agent yield a synergistic effect in treating the cancer. 3. The method of claim 1, wherein the HIF-2.alpha. inhibitor is administered before, simultaneously with, or after the immunotherapeutic agent. 4. The method of claim 1, wherein the HIF-2.alpha. inhibitor inhibits one or more biological effects selected from the group consisting of heterodimerization of HIF-2.alpha. to HIF1.beta., HIF-2.alpha. target gene expression, VEGF gene expression, and VEGF protein secretion. 5. The method of claim 4, wherein the HIF-2.alpha. inhibitor inhibits heterodimerization of HIF-2.alpha. to HIF1.beta. but not heterodimerization of HIF1.alpha. to HIF1.beta.. 6. The method of claim 1, wherein the HIF-2.alpha. inhibitor binds the PAS-B domain cavity of HIF2.alpha.. 7. The method of claim 1, wherein R.sup.12 is hydrogen. 8. The method of claim 1, wherein: R.sup.4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl; R.sup.11 is hydroxy or amino; and R.sup.12 is hydrogen. 9. The method of claim 1, wherein R.sup.13 is fluoro and n is 1, 2 or 3. 10. The method of claim 1, wherein the HIF-2.alpha. inhibitor is a compound of Formula I-H, I-I, I-J or I-K: ##STR00978## or a pharmaceutically acceptable salt thereof. 11. The method of claim 1, wherein R.sup.11 is hydroxy or amino. 12. The method of claim 1, wherein R.sup.1 is phenyl, monocyclic heteroaryl or bicyclic heteroaryl. 13. The method of claim 12, wherein R.sup.1 is phenyl or pyridyl. 14. The method of claim 1, wherein R.sup.1 is substituted with at least one substituent selected from the group consisting of halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy and cyano. 15. The method of claim 1, wherein R.sup.4 is cyano, fluoroalkyl, sulfinyl, sulfonamidyl, sulfonyl or sulfoximinyl. 16. The method of claim 1, wherein Z is --O--. 17. The method of claim 1, wherein: R.sup.4 is fluoroalkyl or sulfonyl; n is 0, 1, 2 or 3; Z is --O--; R.sup.11 is hydroxy; and R.sup.12 is hydrogen. 18. The method of claim 17, wherein R.sup.1 is phenyl, pyridyl, cycloalkyl or heterocycloalkyl. 19. The method of claim 1, wherein X is CR.sup.5 and Y is CR.sup.6. 20. The method of claim 1, wherein the HIF-2.alpha. inhibitor is selected from the group consisting of: ##STR00979## ##STR00980## or a pharmaceutically acceptable salt thereof. 21. The method of claim 1, wherein the immunotherapeutic agent is selected from nivolumab, pembrolizumab, tremelimumab and ipilimumab.

Details for Patent 10,335,388

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bristol-myers Squibb Company	YERVOY	ipilimumab	Injection	125377	03/25/2011		2035-04-17
Merck Sharp & Dohme Corp.	KEYTRUDA	pembrolizumab	For Injection	125514	09/04/2014		2035-04-17
Merck Sharp & Dohme Corp.	KEYTRUDA	pembrolizumab	Injection	125514	01/15/2015		2035-04-17