Combination therapies for cancer

Abstract

A novel combination comprising a B-Raf inhibitor, particularly N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof, the MEK inhibitor N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)6,8-dimethyl;-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate thereof, and a PD-1 antagonist; pharmaceutical compositions comprising the same and methods of using such combinations and compositions in the treatment of conditions in which the inhibition of MEK and/or B-Raf and/or immune modulation through PD-1 is beneficial, eg. cancer.

1 . A combination comprising a PD-1 antagonist and one or both of a Compound A and a Compound B, wherein:
 the Compound B is a compound of structure (II)   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof; and 
         
         the Compound A is a compound of structure (I): 
       
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt or solvate thereof. 
         
       
     
     
         2 . A combination comprising a PD-1 antagonist and one or both of a Compound A and a Compound B, wherein the Compound B is N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate; and the Compound A is N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethyl sulfoxide (solvate). 
     
     
         3 . (canceled) 
     
     
         4 . The combination of  claim 1 , wherein the Compound A is trametinib, the Compound B is dabrafenib and the PD-1 antagonist is an anti-human PD-1 antibody. 
     
     
         5 . The combination of  claim 4 , wherein the anti-human PD-1 antibody comprises a heavy chain comprising the sequence of amino acids set forth in SEQ ID NO: 21 and a light chain comprising the sequence of amino acids set forth in SEQ ID NO: 22. 
     
     
         6 . A pharmaceutical composition comprising a PD-1 antagonist wherein the pharmaceutical composition comprises one or both of a Compound A and a Compound B together with a pharmaceutically acceptable diluent or carrier, and wherein:
 the Compound A is a compound of structure (I):   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt or solvate thereof; and 
         
         the compound B is a compound of structure (11): 
       
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof. 
         
       
     
     
         7 . The composition of  claim 6 , wherein:
 the composition comprises each of Compound A and Compound B; and   the PD-1 antagonist is an anti-human PD-1 antibody or an antigen binding fragment thereof.   
     
     
         8 . The composition of  claim 6 , wherein:
 the composition does not comprise Compound B; and   the PD-1 antagonist is an anti-human PD-1 antibody or an antigen binding fragment thereof.   
     
     
         9 . The composition of  claim 6 , wherein:
 the composition does not comprise Compound A; and   the PD-1 antagonist is an anti-human PD-1 antibody or an antigen binding fragment thereof.   
     
     
         10 . (canceled) 
     
     
         11 . The composition of  claim 7 , wherein the anti-human PD-1 antibody comprises a heavy chain comprising the sequence of amino acids set forth in SEQ ID NO: 21 and a light chain comprising the sequence of amino acids set forth in SEQ ID NO: 22. 
     
     
         12 . The composition of  claim 8 , wherein the anti-human PD-1 antibody comprises a heavy chain comprising the sequence of amino acids set forth in SEQ ID NO: 21 and a light chain comprising the sequence of amino acids set forth in SEQ ID NO: 22. 
     
     
         13 . The composition of  claim 9 , wherein the anti-human PD-1 antibody comprises a heavy chain comprising the sequence of amino acids set forth in SEQ ID NO: 21 and a light chain comprising the sequence of amino acids set forth in SEQ ID NO: 22. 
     
     
         14 . The composition of  claim 10 , wherein the Compound A is trametinib, the Compound B is dabrafenib, the anti-human PD-1 antibody comprises a heavy chain comprising the sequence of amino acids set forth in SEQ ID NO: 21 and a light chain comprising the sequence of amino acids set forth in SEQ ID NO: 22 and the cancer tests positive for human PD-L1 expression. 
     
     
         15 . (canceled) 
     
     
         16 . A method of treating cancer in a mammal comprising administering to said mammal a combination therapy, wherein the combination therapy comprises a therapeutically effective amount of a PD-1 antagonist and one or both of a therapeutically effective amount of a Compound A and a therapeutically effective amount of a Compound B, wherein:
 the Compound B is a compound of structure (II):   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof; and 
         
         the Compound A is a compound of structure (I): 
       
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt or solvate thereof. 
         
       
     
     
         17 . The method of  claim 16 , wherein the mammal is a human, the PD-1 antagonist is an anti-human PD-1 antibody or an antigen binding fragment thereof, the Compound B is N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide or a pharmaceutically acceptable salt thereof and the Compound A is N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         18 . The method of  claim 16 , wherein the mammal is a human, the PD-1 antagonist is MK-3475, the Compound B is N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide methanesulfonate, and the Compound A is N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethyl sulfoxide solvate. 
     
     
         19 . (canceled) 
     
     
         20 . The method of any one of  claim 17 , the combination therapy comprises trametinib, dabrafenib and an anti-human PD-1 antibody comprising a heavy chain comprising the sequence of amino acids set forth in SEQ ID NO: 21 and a light chain comprising the sequence of amino acids set forth in SEQ ID NO: 22. 
     
     
         21 . The method of  claim 20 , wherein the therapeutically effective amount of the anti-human PD-1 antibody is 2 mg/kg once every 3 weeks or 10 mg/kg once every 2 weeks, the therapeutically effective amount of trametinib is 2 mg once daily and the therapeutically effective amount of dabrafenib is 150 mg twice daily. 
     
     
         22 . The method of  claim 17 , wherein the combination therapy does not comprise the Compound B. 
     
     
         23 . The method of  claim 22 , wherein the therapeutically effective amount of the anti-human PD-1 antibody is 2 mg/kg once every 3 weeks or 10 mg/kg once every 2 weeks and the therapeutically effective amount of trametinib is 2 mg once daily. 
     
     
         24 . The method of  claim 17 , wherein the combination therapy does not comprise Compound A. 
     
     
         25 . The method of  claim 24 , wherein the therapeutically effective amount of the anti-human PD-1 antibody is 2 mg/kg once every 3 weeks or 10 mg/kg once every 2 weeks and the therapeutically effective amount of dabrafenib is 150 mg twice daily.