Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a BCL-2 Inhibitor

Abstract

Therapeutic combinations of a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms (PI3K-γ,δ, PI3K-γ, and PI3K-δ), a Janus kinase-2 (JAK-2) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, and/or a B-cell lymphoma-2 (BCL-2) inhibitor are described. In some embodiments, the invention provides therapeutic combinations of a PI3K-δ inhibitor and a BTK inhibitor, a JAK-2 and a BTK inhibitor, and a BCL-2 and BTK inhibitor.

1 - 86 . (canceled) 
     
     
         87 . A method of treating a cancer, comprising co-administering, to a human in need thereof, one or more compositions comprising therapeutically effective amounts of (1) B-cell lymphoma 2 (BCL-2) inhibitor or a pharmaceutically acceptable salt thereof, and (2) a Bruton's tyrosine kinase (BTK) inhibitor or a pharmaceutically acceptable salt thereof. 
     
     
         88 . The method of  claim 87 , wherein the BCL-2 inhibitor is administered before administration of the BTK inhibitor. 
     
     
         89 . The method of  claim 87 , wherein the BCL-2 inhibitor is administered concurrently with the administration of the BTK inhibitor. 
     
     
         90 . The method of  claim 87 , wherein the BCL-2 inhibitor is administered to the subject after administration of the BTK inhibitor. 
     
     
         91 . The method of  claim 87 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically-acceptable salts thereof. 
     
     
         92 . The method of  claim 87 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically-acceptable salts thereof. 
     
     
         93 . The method of  claim 87 , wherein the BCL-2 inhibitor is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof. 
     
     
         94 . The method of  claim 87 , wherein the method further comprises the step of administering to the human a therapeutically effective amount of an anti-CD20 antibody selected from the group consisting of rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, ibritumomab, and fragments, derivatives, conjugates, variants, radioisotope-labeled complexes, and biosimilars thereof. 
     
     
         95 . The method of  claim 87 , wherein the cancer is a hematological malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenström's macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, or myelofibrosis. 
     
     
         96 . A composition comprising a BTK inhibitor, wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and a pharmaceutically-acceptable salt thereof, and a BCL-2 inhibitor, wherein the BCL-2 inhibitor is venetoclax: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof. 
     
     
         97 . The composition of  claim 96 , comprising an amount of the BTK inhibitor selected from the group consisting of 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, or 550 mg. 
     
     
         98 . The composition of  claim 96 , comprising an amount of the BCL-2 inhibitor selected from the group consisting of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg.