Pharmaceutical combinations for treating cancer

Abstract

The present invention is directed to a combination comprising a proteasome inhibitor and a compound of formula I or a pharmaceutically acceptable salt thereof: to a pharmaceutical composition and to a kit both comprising said combination, to the combination, composition or kit for use in the treatment of cancer, and to a method of treatment of cancer in a patient in need thereof comprising administering to said patient an effective amount of said combination, composition or kit.

1 . A combination comprising a proteasome inhibitor and a compound of formula I or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         2 . The combination according to  claim 1 , wherein the pharmaceutically acceptable salt of the compound of formula I is a hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate or acetate salt. 
     
     
         3 . The combination according to  claim 1 , wherein the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, marizomib, delanzomib (CEP-18770), oprozomib (ONX 0912), ixazomib (MLN-9708), LU-102, and a pharmaceutically acceptable salt thereof. 
     
     
         4 . The combination according to  claim 1 , wherein the proteasome inhibitor is selected from bortezomib, carfilzomib and LU-102. 
     
     
         5 . The combination according to  claim 1 , further comprising a glucocorticoid. 
     
     
         6 . The combination according to  claim 1 , further comprising a glucocorticoid selected from the group consisting of dexamethasone, fluocinolone acetonide and prednisone. 
     
     
         7 . The combination according to  claim 1 , further comprising the glucocorticoid dexamethasone. 
     
     
         8 . The combination according to  claim 1 , further comprising one or more additional pharmaceutically active agents. 
     
     
         9 . The combination according to  claim 1 , wherein the proteasome inhibitor, the compound of formula I or pharmaceutically acceptable salt thereof and, an optional glucocorticoid, are adapted for administration concurrently, sequentially or separately. 
     
     
         10 . The combination according to  claim 1 , wherein the proteasome inhibitor, the compound of formula I or pharmaceutically acceptable salt thereof and, an optional glucocorticoid, are adapted for administration concurrently. 
     
     
         11 . The combination according to  claim 1 , wherein the molar ratio of the proteasome inhibitor to the compound of formula I or pharmaceutically acceptable salt thereof in said combination is from 1:1000 to 1000:1. 
     
     
         12 . The combination according to  claim 1 , wherein the molar ratio of the proteasome inhibitor to the compound of formula I or pharmaceutically acceptable salt thereof in said combination is from 1:1000 to 10:1. 
     
     
         13 . The combination according to  claim 1 , wherein the molar ratio of the proteasome inhibitor to the compound of formula I or pharmaceutically acceptable salt thereof in said combination is from 1:800 to 1:200. 
     
     
         14 . The combination according to  claim 1 , wherein the molar ratio of the proteasome inhibitor to the compound of formula I or pharmaceutically acceptable salt thereof in said combination is from 1:700 to 1:400. 
     
     
         15 . The combination according to  claim 1 , wherein the molar ratio of the proteasome inhibitor to the compound of formula I or pharmaceutically acceptable salt thereof in said combination is from 1:3 to 1:0.5. 
     
     
         16 . The combination according to  claim 1 , comprising the compound of formula I or the acetate salt thereof, and wherein the proteasome inhibitor is selected from bortezomib and carfilzomib, wherein the molar ratio of the proteasome inhibitor selected from bortezomib and carfilzomib to the compound of formula I or pharmaceutically acceptable salt thereof in said combination is from 1:700 to 1:400. 
     
     
         17 . The combination according to  claim 1 , comprising the compound of formula I or the acetate salt thereof and the proteasome inhibitor LU-102, wherein the molar ratio of LU-102 to the compound of formula I or pharmaceutically acceptable salt thereof in said combination is from 1:3 to 1:0.5. 
     
     
         18 . The combination according to  claim 1 , comprising the proteasome inhibitor and the compound of formula I or pharmaceutically acceptable salt thereof, wherein the proteasome inhibitor and the compound of formula I or the pharmaceutically acceptable salt thereof form a synergistic combination. 
     
     
         19 . The combination according to  claim 1 , further comprising a glucocorticoid wherein the molar ratio of the proteasome inhibitor to the compound of formula I or pharmaceutically acceptable salt thereof to the glucocorticoid in said combination is from 1:1000:10 to 1000:1:20. 
     
     
         20 . The combination according to  claim 1 , further comprising a glucocorticoid wherein the molar ratio of the proteasome inhibitor to the compound of formula I or pharmaceutically acceptable salt thereof to the glucocorticoid used in said combination is from 1:1000:10 to 1:100:2. 
     
     
         21 . The combination according to  claim 1 , further comprising a glucocorticoid wherein the molar ratio of the proteasome inhibitor to the compound of formula I or pharmaceutically acceptable salt thereof to the glucocorticoid used in said combination is from 1:700:4 to 1:400:3. 
     
     
         22 . The combination according to  claim 1 , comprising a proteasome inhibitor selected from bortezomib and carfilzomib, the compound of formula I or the acetate salt thereof and dexamethasone, wherein the molar ratio of the proteasome inhibitor selected from bortezomib and carfilzomib to the compound of formula I or the acetate salt thereof to dexamethasone in said combination is from 1:700:4 to 1:400:3. 
     
     
         23 . The combination according to  claim 1 , comprising the proteasome inhibitor LU-102, the compound of formula I or the acetate salt thereof and dexamethasone, wherein the molar ratio of LU-102 to the compound of formula I or the acetate salt thereof to dexamethasone in said combination is from 1:3:4 to 1:0.5:3. 
     
     
         24 . The combination according to  claim 1 , comprising the proteasome inhibitor, the compound of formula I or pharmaceutically acceptable salt thereof and a glucocorticoid, wherein the proteasome inhibitor, the compound of formula I or the pharmaceutically acceptable salt thereof and the glucocorticoid form a synergistic combination. 
     
     
         25 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a combination according to  claim 1 . 
     
     
         26 . A kit comprising a combination according to  claim 1 , and optionally, instructions for treating a patient. 
     
     
         27 - 42 . (canceled) 
     
     
         43 . A method of treating cancer in a patient in need thereof comprising administering to said patient a combination according to  claim 1 . 
     
     
         44 . The method according to  claim 43 , wherein said cancer is selected from a hematologic cancer and breast cancer. 
     
     
         45 . The method according to  claim 43 , wherein said cancer is a hematologic cancer selected from multiple myeloma, lymphoma and leukemia. 
     
     
         46 . The method according to  claim 43 , wherein said cancer is multiple myeloma selected from active myeloma, plasmacytoma, light chain myeloma and non-secretory myeloma. 
     
     
         47 . The method according to  claim 43 , wherein said cancer is lymphoma selected from Hodgkin lymphoma and non-Hodgkin lymphoma. 
     
     
         48 . The method according to  claim 43 , wherein said cancer is leukemia selected from acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia and T-cell acute lymphoblastic leukemia. 
     
     
         49 . The method according to  claim 43 , wherein said cancer is breast cancer selected from claudin-low tumors, basal-like tumors, human epidermal growth factor receptor 2 (HER2) positive tumors, luminal A tumors and luminal B tumors. 
     
     
         50 . The method according to  claim 43 , wherein said cancer is a triple-negative breast cancer. 
     
     
         51 . The method according to  claim 43 , wherein in said method the proteasome inhibitor, the compound of formula I or pharmaceutically acceptable salt thereof and, an optional glucocorticoid, are administered concurrently, sequentially or separately. 
     
     
         52 . The method according to  claim 43 , wherein in said method the proteasome inhibitor, the compound of formula I or pharmaceutically acceptable salt thereof and, an optional glucocorticoid, are administered concurrently. 
     
     
         53 . The method according to  claim 43 , wherein the compound of formula I or pharmaceutically acceptable salt thereof is administered to the patient in need thereof at a dosage range of 10 to 100 mg/kg body weight patient. 
     
     
         54 . The method according to  claim 43 , wherein the compound of formula I or pharmaceutically acceptable salt thereof is administered to the patient in need thereof at a dosage range of 40 to 80 mg/kg body weight patient. 
     
     
         55 . The method according to  claim 43 , wherein the proteasome inhibitor is administered to the patient at a dosage range of 0.01 to 0.3 mg/kg body weight patient. 
     
     
         56 . The method according to  claim 43 , wherein the proteasome inhibitor is administered to the patient at a dosage range of 0.05 to 0.15 mg/kg body weight patient. 
     
     
         57 . The method according to  claim 43 , wherein the combination further comprises a glucocorticoid, and wherein in the method, the glucocorticoid is administered at a dosage range of from 0.1 to 1.0 mg/kg body weight patient. 
     
     
         58 . The method according to  claim 43 , wherein the combination further comprises a glucocorticoid, and wherein in the method, the glucocorticoid is administered at a dosage range of from 0.3 to 0.5 mg/kg body weight patient.