Combination

Abstract

The present invention relates to a method of treating cancer in a human and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering a proteasome inhibiting compound, and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, and optional additional antineoplastic agents, to a human in need thereof.

1 . A combination comprising:
 (i) a compound of Structure (I):   
       
         
           
           
               
               
           
         
       
       and
 (ii) a compound of Structure (II): 
 
       
         
           
           
               
               
           
         
         optionally in the form of a monohydrochloride salt, and 
         (iii) optional additional antineoplastic agents; 
         where the amount of the compound of Structure (I) is an amount selected from 1.35 to 2.0 mg/m 2 , and that amount is administered intravenously or subcutaneously once per week. 
       
     
     
         2 . A combination kit comprising a combination according to  claim 1  together with a pharmaceutically acceptable carrier or carriers. 
     
     
         3 . A combination according to  claim 1  where the amount of the compound of Structure (I) is 1.5 mg/m 2 , and that amount is administered intravenously or subcutaneously once per week. 
     
     
         4 . A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of  claim 1 , to such human,
 wherein the amount of bortezomib is selected from 1.35 to 2.0 mg/m 2  and that amount is administered intravenously or subcutaneously once per week,   wherein the combination is administered within a specified period, and   wherein the combination is administered for a duration of time.   
     
     
         5 . A method according to  claim 4  wherein the amount of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 50 mg to about 300 mg, and that amount is administered once per day, and the amount of bortezomib is selected from 1.35 to 2.0 mg/m 2 , and that amount is administered intravenously or subcutaneously once per week. 
     
     
         6 . A method according to  claim 5  wherein the amount of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 60 mg to about 300 mg, and that amount is administered once per day, and bortezomib is administered intravenously or subcutaneously once a week in an amount of 1.5 mg/m 2 . 
     
     
         7 . A method according to  claim 6  wherein bortezomib and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride are administered within 12 hours of each other for 1 day during a seven day period and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride is administered alone for the remaining days of the 7 day period, optionally followed by one or more cycles of repeat dosing. 
     
     
         8 . A method according to  claim 7  wherein the cancer is selected from: brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,
 Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia, 
 malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, 
 neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer. 
 
     
     
         9 . A method according to  claim 4  wherein the cancer is multiple myeloma. 
     
     
         10 . A method according to  claim 5  wherein the cancer is multiple myeloma. 
     
     
         11 . A method treating a cancer selected from: brain (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,
 Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, Chronic neutrophilic leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma Megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia,   malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma,   neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer;   in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of bortezomib, and N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, to such human,   wherein the compounds of the combination are administered sequentially, and   wherein the amount of bortezomib is selected from 1.35 to 2.0 mg/m 2  and that amount is administered intravenously or subcutaneously once or twice per week.   
     
     
         12 . A method according to  claim 11  wherein the amount of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 50 mg to about 300 mg, and that amount is administered once per day, and the amount of bortezomib is selected from 1.35 to 2.0 mg/m 2 , and that amount is administered intravenously or subcutaneously once per week. 
     
     
         13 . A method according to  claim 12  wherein the amount of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide, or a pharmaceutically acceptable salt thereof, is selected from about 60 mg to about 300 mg, and that amount is administered once per day, and bortezomib is administered intravenously or subcutaneously once a week in an amount of 1.5 mg/m 2 . 
     
     
         14 . A method according to  claim 13  wherein bortezomib is administered, followed by an optional drug holiday of from 1 to 14 days, followed by administration of N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide hydrochloride for from 1 to 30 days. 
     
     
         15 . A method according to  claim 14  wherein the cancer is multiple myeloma. 
     
     
         16 . A method according to  claim 15  wherein the cancer is multiple myeloma. 
     
     
         17 . A combination comprising:
 (i) a compound of Structure (I):   
       
         
           
           
               
               
           
         
       
       and
 (ii) a compound of Structure (II): 
 
       
         
           
           
               
               
           
         
         optionally in the form of a monohydrochloride salt, and 
         (iii) optional additional antineoplastic agents; 
         where the amount of the compound of Structure (I) is an amount selected from 0.5 to 1.3 mg/m 2 , and that amount is administered subcutaneously once or twice per week. 
       
     
     
         18 . A combination kit comprising a combination according to  claim 17  together with a pharmaceutically acceptable carrier or carriers. 
     
     
         19 . A combination according to  claim 17  where the amount of the compound of Structure (I) is 1.3 mg/m 2 , and that amount is administered subcutaneously once or twice per week. 
     
     
         20 . A method of treating cancer in a human in need thereof which comprises the in vivo administration of a therapeutically effective amount of a combination of  claim 17 , to such human,
 wherein the amount of bortezomib is selected from 0.5 to 1.3 mg/m 2  and that amount is administered subcutaneously once or twice per week,   wherein the combination is administered within a specified period, and   wherein the combination is administered for a duration of time.