Pharmaceutical combination for the treatment of melanoma

Abstract

The present invention relates to a pharmaceutical combination comprising a cyclin dependent kinase (CDK) inhibitor represented by a compound of formula I (as described herein) or a pharmaceutically acceptable salt thereof; and at least one anticancer agent selected from a BRAF inhibitor or a MEK inhibitor, for use in the treatment of melanoma. The present invention also relates to a method for the treatment of melanoma comprising administering to a subject in need thereof, a therapeutically effective amount of a CDK inhibitor and a therapeutically effective amount of at least one anticancer agent selected from a BRAF inhibitor or a MEK inhibitor.

1 . A method of treating melanoma comprising administering to a subject in need thereof a therapeutically effective amount of a CDK (cyclin dependent kinase) inhibitor selected from the compound of formula I or a pharmaceutically acceptable salt thereof; 
       
         
           
           
               
               
           
         
       
       wherein Ar is phenyl, which is substituted by 2 different substituents selected from chlorine and trifluoromethyl; and a therapeutically effective amount of at least one anticancer agent selected from a BRAF (serine-threonine protein kinase B-raf) inhibitor or a MEK (mitogen activated protein kinase) inhibitor. 
     
     
         2 . (canceled) 
     
     
         3 . The method according to  claim 1 , wherein the CDK inhibitor is (+)-trans-2-(2-chloro-4-trifluoromethylphenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one hydrochloride. 
     
     
         4 . The method according to  claim 1 , wherein the BRAF inhibitor or the MEK inhibitor is an inhibitor of V600 mutated form of BRAF. 
     
     
         5 . The method according to  claim 4 , wherein the BRAF inhibitor is an inhibitor of V600E mutated form of BRAF. 
     
     
         6 . The method according to  claim 1 , wherein the BRAF inhibitor is selected from sorafenib, vemurafenib, GDC-0879, dabrafenib, PLX4720, BMS-908662, LGX818, PLX3603, ARQ-736, DP-4978 and RAF265. 
     
     
         7 . The method according to  claim 1 , wherein the BRAF inhibitor is vemurafenib. 
     
     
         8 . The method according to  claim 1 , wherein the BRAF inhibitor is dabrafenib. 
     
     
         9 . The method according to  claim 1 , wherein the MEK inhibitor is an inhibitor of V600E or V600K mutated form of BRAF. 
     
     
         10 . The method according to  claim 1 , wherein the MEK inhibitor is selected from selumetinib, binimetinib, PD-0325901, trametinib, cobimetinib, refametinib, pimasertib, TAK-733 and WX-554. 
     
     
         11 . The method according to  claim 1 , wherein the MEK inhibitor is trametinib. 
     
     
         12 . The method according to  claim 1 , wherein the said CDK inhibitor; and the said at least one anticancer agent selected from a BRAF inhibitor or a MEK inhibitor; are administered simultaneously to a subject in need thereof. 
     
     
         13 . The method according to  claim 1 , wherein the said CDK inhibitor and the said at least one anticancer agent selected from a BRAF inhibitor or a MEK inhibitor; are administered sequentially to a subject in need thereof. 
     
     
         14 . The method according to  claim 1 , wherein the melanoma is non-refractory melanoma. 
     
     
         15 . The method according to  claim 14 , wherein the melanoma is non-refractory BRAF mutant melanoma. 
     
     
         16 . The method according to  claim 15 , wherein the melanoma is non-refractory BRAFV600 mutant melanoma. 
     
     
         17 . The method according to  claim 16 , wherein the melanoma is non-refractory BRAFV600E or BRAFV600K mutant melanoma. 
     
     
         18 . The method according to  claim 1 , wherein the melanoma is recurrent or refractory melanoma. 
     
     
         19 . The method according to  claim 18 , wherein the melanoma is recurrent or refractory BRAF mutant melanoma. 
     
     
         20 . The method according to  claim 19 , wherein the melanoma is recurrent or refractory BRAFV600 mutant melanoma. 
     
     
         21 . The method according to  claim 20 , wherein the melanoma is recurrent or refractory BRAFV600E melanoma or BRAFV600K mutant melanoma. 
     
     
         22 . The method according to  claim 1 , wherein the melanoma is metastatic melanoma. 
     
     
         23 . The method according to  claim 22 , wherein the melanoma is metastatic BRAF mutant melanoma. 
     
     
         24 . The method according to  claim 23 , wherein the melanoma is metastatic BRAFV600 mutant melanoma. 
     
     
         25 . The method according to  claim 24 , wherein the melanoma is metastatic BRAFV600E melanoma or BRAFV600K mutant melanoma.