Combination Therapies Using Hdac Inhibitors

Abstract

The present invention pertains to a method for treating cancer, such as lung cancer, multiple myeloma, lymphoma, and epithelial ovarian cancer, comprising the administration to a patient in need thereof a first amount or dose of a histone deacetylase (HDAC) inhibitor, such as PXD-101, and a second amount or dose of another chemotherapeutic agent, such as dexamethasone or 5-fluorouracil, or an epidermal growth factor receptor (EGFR) inhibitor, such as TarcevaÚ, wherein the first and second amounts or doses together comprise a therapeutically effective amount.

1 . A method for treating cancer comprising administering to a patient in need thereof,
 a first amount or dose of a histone deacetylase inhibitor, and   a second amount or dose of another chemotherapeutic agent or an epidermal growth factor receptor inhibitor,   wherein the first and second amounts or doses together comprise a therapeutically effective amount.   
     
     
         2 . A method according to  claim 1 , wherein the histone deacetylase inhibitor is selected from compounds represented by the following formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is an unsubstituted phenyl group; 
 Q 1  is a covalent bond or a C 1-7 alkylene group; 
 J is: 
 
       
         
           
           
               
               
           
         
         R 1  is hydrogen, C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl; and 
         Q 2  is: 
       
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts and solvates thereof. 
     
     
         3 . A method according to  claim 1 , wherein the histone deacetylase inhibitor is selected from PXD-101 and pharmaceutically acceptable salts and solvates thereof. 
     
     
         4 . A method according to  claim 1 , wherein the histone deacetylase inhibitor is PXD-101. 
     
     
         5 . A method according to  claim 1 , wherein the second amount or dose is a second amount or dose of another chemotherapeutic agent. 
     
     
         6 . A method according to  claim 1 , wherein the second amount or dose is a second amount or dose of an epidermal growth factor receptor inhibitor. 
     
     
         7 . A method according to  claim 1 , wherein the second amount or dose is a second amount or dose of a compound selected from: Cisplatin, 5-Fluorouracil, Oxaliplatin, Topotecan, Gemcitabine, Docetaxel, Doxorubicin, Tamoxifen, Dexamethasone, 5-Azacytidine, Chlorambucil, Fludarabine, Tarceva®, Alimta®, Melphalan, and pharmaceutically acceptable salts and solvates thereof. 
     
     
         8 . A method according to  claim 1 , wherein the second amount or dose is a second amount or dose of Tarceva®. 
     
     
         9 . A method according to  claim 1 , wherein the second amount or dose is a second amount or dose of dexamethasone. 
     
     
         10 . A method according to  claim 1 , wherein the second amount or dose is a second amount or dose of 5-fluorouracil. 
     
     
         11 . A method according to  claim 1 , wherein the second amount or dose is a second amount or dose of carboplatin/paclitaxel 
     
     
         12 . A method according to  claim 1 , wherein the cancer is lung cancer. 
     
     
         13 . A method according to  claim 1 , wherein the cancer is multiple myeloma. 
     
     
         14 . A method according to  claim 1 , wherein the cancer is lymphoma. 
     
     
         15 . A method according to  claim 1 , wherein the cancer is epithelial ovarian cancer. 
     
     
         16 . A method according to  claim 1 , wherein a synergistic effect is achieved as a result of the combination. 
     
     
         17 . Use of a histone deacetylase inhibitor in the manufacture of a medicament for the treatment of cancer, wherein said treatment comprises treatment with (i) said histone deacetylase inhibitor and (ii) another chemotherapeutic agent or an epidermal growth factor receptor inhibitor. 
     
     
         18 . Use according to  claim 17 , wherein the histone deacetylase inhibitor is selected from compounds represented by the following formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is an unsubstituted phenyl group; 
 Q 1  is a covalent bond or a C 1-7 alkylene group; 
 J is: 
 
       
         
           
           
               
               
           
         
         R 1  is hydrogen, C 1-7 alkyl, C 3-20 heterocyclyl, or C 5-20 aryl; and 
         Q 2  is: 
       
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts and solvates thereof. 
     
     
         19 . Use according to  claim 17 , wherein the histone deacetylase inhibitor is selected from PXD-101 and pharmaceutically acceptable salts and solvates thereof. 
     
     
         20 . Use according to  claim 17 , wherein the histone deacetylase inhibitor is PXD-101. 
     
     
         21 . Use according to any  claim 17 , wherein said treatment comprises treatment with (i) said histone deacetylase inhibitor and (ii) another chemotherapeutic agent. 
     
     
         22 . Use according to  claim 17 , wherein said treatment comprises treatment with (i) said histone deacetylase inhibitor and (ii) an epidermal growth factor receptor inhibitor. 
     
     
         23 . Use according to  claim 17 , wherein said treatment comprises treatment with (i) said histone deacetylase inhibitor and (ii) a compound selected from: Cisplatin, 5-Fluorouracil, Oxaliplatin, Topotecan, Gemcitabine, Docetaxel, Doxorubicin, Tamoxifen, Dexamethasone, 5-Azacytidine, Chlorambucil, Fludarabine, Tarceva®, Alimta®, Melphalan, and pharmaceutically acceptable salts and solvates thereof. 
     
     
         24 . Use according to  claim 17 , wherein said treatment comprises treatment with (i) said histone deacetylase inhibitor and (ii) Tarceva®. 
     
     
         25 . Use according to  claim 17 , wherein said treatment comprises treatment with (i) said histone deacetylase inhibitor and (ii) dexamethasone. 
     
     
         26 . Use according to  claim 17 , wherein said treatment comprises treatment with (i) said histone deacetylase inhibitor and (ii) 5-fluorouracil. 
     
     
         27 . Use according to  claim 17 , wherein said treatment comprises treatment with (i) said histone deacetylase inhibitor and (ii) carboplatin/paclitaxel 
     
     
         28 . Use according to  claim 17 , wherein the cancer is lung cancer. 
     
     
         29 . Use according to  claim 17 , wherein the cancer is multiple myeloma. 
     
     
         30 . Use according to  claim 17 , wherein the cancer is lymphoma. 
     
     
         31 . Use according to  claim 17 , wherein the cancer is epithelial ovarian cancer. 
     
     
         32 . A kit or kit-of-parts comprising:
 (a) a histone deacetylase inhibitor, such as PXD-101, preferably as a component of a pharmaceutically acceptable formulation, and preferably provided in a suitable container and/or with suitable packaging; and   (b) another chemotherapeutic agent, such as dexamethasone or 5-fluorouracil, or an epidermal growth factor receptor (EGFR) inhibitor, such as Tarceva®, preferably as a component of a pharmaceutically acceptable formulation, and preferably provided in a suitable container and/or with suitable packaging;   wherein said kit or kit-of-parts is suitable for use in a method for treating cancer.