Therapeutic Combinations of a MEK Inhibitor and a BTK Inhibitor

Abstract

Therapeutic combinations of a MEK inhibitor and a Bruton's tyrosine kinase (BTK) inhibitor are described. In some embodiments, the invention provides pharmaceutical compositions comprising combinations of a MEK inhibitor and a BTK inhibitor and methods of using the pharmaceutical compositions for treating a disease, in particular a cancer.

1 . A method of treating a hyperproliferative disease, comprising co-administering, to a human in need thereof, therapeutically effective amounts of (1) a MEK inhibitor or a pharmaceutically acceptable salt thereof, and (2) a Bruton's tyrosine kinase (BTK) inhibitor or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the MEK inhibitor is administered to the human before administration of the BTK inhibitor. 
     
     
         3 . The method of  claim 1 , wherein the MEK inhibitor is administered to the human simultaneously with the administration of the BTK inhibitor. 
     
     
         4 . The method of  claim 1 , wherein the MEK inhibitor is administered to the human after administration of the BTK inhibitor. 
     
     
         5 . The method of  claim 1 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts thereof. 
       
     
     
         6 . The method of  claim 1 , wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts thereof. 
       
     
     
         7 . The method of  claim 1 , wherein the MEK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts thereof. 
       
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the hyperproliferative disease is a cancer. 
     
     
         14 . The method of  claim 13 , wherein the cancer is a B cell hematological malignancy. 
     
     
         15 . The method of  claim 14 , wherein the B cell hematological malignancy is 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, and myelofibrosis. 
     
     
         16 . The method of  claim 13 , wherein the cancer is a solid tumor cancer. 
     
     
         17 . The method of  claim 16 , wherein the solid tumor cancer is selected from the group consisting of bladder cancer, non-small cell lung cancer, cervical cancer, anal cancer, pancreatic cancer, squamous cell carcinoma including head and neck cancer, renal cell carcinoma, melanoma, ovarian cancer, small cell lung cancer, glioblastoma, gastrointestinal stromal tumor, breast cancer, lung cancer, colorectal cancer, thyroid cancer, bone sarcoma, stomach cancer, oral cavity cancer, oropharyngeal cancer, gastric cancer, kidney cancer, liver cancer, prostate cancer, esophageal cancer, testicular cancer, gynecological cancer, colon cancer, and brain cancer. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . A method of treating a cancer in a human intolerant to a bleeding event comprising the step of administering (1) a therapeutically effective amount of a MEK inhibitor or a pharmaceutically acceptable salt thereof, and (2) a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor or a pharmaceutically acceptable salt thereof, wherein the BTK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salt thereof. 
       
     
     
         21 . The method of  claim 20 , wherein the bleeding event is selected from the group consisting of subdural hematoma, gastrointestinal bleeding, hematuria, post-procedural hemorrhage, bruising, petechiae, and combinations thereof. 
     
     
         22 . The method of  claim 20 , wherein the MEK inhibitor is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically-acceptable salts thereof. 
       
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 20 , further comprising the step of administering a therapeutically effective amount of an anticoagulant or antiplatelet active pharmaceutical ingredient. 
     
     
         27 . The method of  claim 26 , wherein the anticoagulant or antiplatelet active pharmaceutical ingredient is selected from the group consisting of acenocoumarol, anagrelide, anagrelide hydrochloride, abciximab, aloxiprin, antithrombin, apixaban, argatroban, aspirin, aspirin with extended-release dipyridamole, beraprost, betrixaban, bivalirudin, carbasalate calcium, cilostazol, clopidogrel, clopidogrel bisulfate, cloricromen, dabigatran etexilate, darexaban, dalteparin, dalteparin sodium, defibrotide, dicumarol, diphenadione, dipyridamole, ditazole, desirudin, edoxaban, enoxaparin, enoxaparin sodium, eptifibatide, fondaparinux, fondaparinux sodium, heparin, heparin sodium, heparin calcium, idraparinux, idraparinux sodium, iloprost, indobufen, lepirudin, low molecular weight heparin, melagatran, nadroparin, otamixaban, parnaparin, phenindione, phenprocoumon, prasugrel, picotamide, prostacyclin, ramatroban, reviparin, rivaroxaban, sulodexide, terutroban, terutroban sodium, ticagrelor, ticlopidine, ticlopidine hydrochloride, tinzaparin, tinzaparin sodium, tirofiban, tirofiban hydrochloride, treprostinil, treprostinil sodium, triflusal, vorapaxar, warfarin, warfarin sodium, ximelagatran, salts thereof, solvates thereof, hydrates thereof, and combinations thereof. 
     
     
         28 . The method of  claim 20 , wherein the cancer is selected from the group consisting of bladder cancer, squamous cell carcinoma including pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, head and neck cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immune deficiency syndrome (AIDS)-related cancers (e.g., lymphoma and Kaposi's sarcoma), viral-induced cancer, glioblastoma, esophogeal tumors, hematological neoplasms, non-small-cell lung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus infection, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma, indolent non-Hogkin's lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular lymphoma, mantle cell lymphoma, Burkitt's lymphoma, and myelofibrosis. 
     
     
         29 - 71 . (canceled)