Pharmaceutical combinations comprising a histone deacetylase inhibitor and a programmed death-ligand 1 (pd-l1) inhibitor and methods of use thereof

Abstract

The present disclosure relates to a pharmaceutical combination comprising (a) a histone deacetylase 6 inhibitor and (b) a programmed death ligand 1 (PD-L1) inhibitor, including combined preparations and pharmaceutical compositions thereof; uses of such combination in the treatment or prevention of cancer; and methods of treating or preventing cancer in a subject comprising administering a therapeutically effective amount of such combination.

1 . A pharmaceutical combination comprising:
 a) a histone deacetylase 6 (HDAC6) inhibitor of Formula I:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein, 
         ring B is aryl or heteroaryl; 
         R 1  is aryl or heteroaryl, each of which may be optionally substituted by OH, halo, or C 1-6 -alkyl; and 
         R is H or C 1-6 -alkyl; and 
         b) a programmed death ligand 1 (PD-L1) inhibitor, or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The pharmaceutical combination of  claim 1 , wherein the combination further comprises:
 c) a compound selected from the group consisting of thalidomide, pomalidomide, and lenalidomide or an analog thereof, or a pharmaceutically acceptable salt thereof.   
     
     
         3 . The pharmaceutical combination of  claim 1 , wherein the compound of Formula I is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The pharmaceutical combination of  claim 1 , wherein the compound of Formula I is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The pharmaceutical combination of  claim 1 , wherein the PD-L1 inhibitor is a PD-L1 inhibitory antibody. 
     
     
         6 . The pharmaceutical combination of  claim 1 , wherein the PD-L1 inhibitor is selected from atezolizumab (MPDL3280), avelumab (MSB0010718C), durvalumab (MEDI-4736), and MDX-1105 (BMS-936559), or pharmaceutically acceptable salts thereof. 
     
     
         7 . The pharmaceutical combination of  claim 5 , wherein:
 the PD-L1 inhibitory antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a variable region comprising three CDRs comprising amino acid sequences within the amino acid sequence of SEQ ID NO.: 1, and wherein the light chain comprises a variable region comprising three CDRs comprising amino acid sequences within the amino acid sequence of SEQ ID NO.: 2.   
     
     
         8 . The pharmaceutical combination of  claim 5 , wherein:
 the PD-L1 inhibitory antibody comprises a heavy chain variable region comprising an amino acid sequence within the amino acid sequence of SEQ ID NO.: 1, and a light chain variable region comprising an amino acid sequence within the amino acid sequence of SEQ ID NO.: 2.   
     
     
         9 . The pharmaceutical combination of  claim 5 , wherein:
 the PD-L1 inhibitory antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO.: 1, and a light chain comprising the amino acid sequence of SEQ ID NO.: 2.   
     
     
         10 . The pharmaceutical combination of  claim 1 , wherein the HDAC inhibitor and the PD-L1 inhibitor are in the same formulation. 
     
     
         11 . The pharmaceutical combination of  claim 10 , wherein the combination further comprises one or more pharmaceutically acceptable carriers. 
     
     
         12 . The pharmaceutical combination of  claim 1 , wherein the HDAC inhibitor and the PD-L1 inhibitor are in separate formulations. 
     
     
         13 . The pharmaceutical combination of  claim 1 , wherein the combination further comprises dexamethasone. 
     
     
         14 - 20 . (canceled)