Combination therapy for treating cancer

Abstract

The present invention relates to compositions comprising inhibitors of human histone methyltransferase EZH2 and one or more other therapeutic agents, particularly anticancer agents such as prednisone, and methods of combination therapy for administering to subjects in need thereof for the treatment of cancer.

1 . A method for treating cancer in a patient in need thereof comprising administering (i) a therapeutically effective amount of an EZH2 inhibitor and a therapeutically effective amount of a standard of care agent, (ii) a therapeutically effective amount of a combination comprising an EZH2 inhibitor and a standard of care agent, or (iii) a therapeutically effective amount of a composition comprising an EZH2 inhibitor and a standard of care agent. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the cancer is a Non-Hodgkin's lymphoma. 
     
     
         5 . The method of  claim 4 , wherein the Non-Hodgkin lymphoma is DLBCL (diffuse large B-cell lymphoma) or GCB (germinal center B-cell-like) lymphoma. 
     
     
         6 . The method of  claim 1 , wherein (i) the cancer is an EZH2 wild type cancer, or (ii) the cancer is characterized by increased trimethylation at H3K27, or (iii) the cancer is an EZH2 inhibitor resistant or refractory cancer. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 5 , wherein the lymphoma is an EZH2 mutant lymphoma. 
     
     
         9 . The method of  claim 8 , wherein the EZH2 mutant lymphoma has an Y646, A682 or A692 mutation. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the standard of care agent is one or more compounds selected from the group consisting of an R-CHOP component, a BCL inhibitor, or a BCR inhibitor. 
     
     
         12 . The method of  claim 11 , wherein the R-CHOP is a glucocorticosteroid receptor agonist. 
     
     
         13 . The method of  claim 12 , wherein the glucocorticosteroid receptor agonist is prednisolone or dexamethasone. 
     
     
         14 . The method of  claim 11 , wherein doxorubicin is omitted from R-CHOP. 
     
     
         15 . The method of  claim 11 , wherein the BCL inhibitor is navitoclax, obatoclax or ABT-199. 
     
     
         16 . The method of  claim 11 , wherein the BCR inhibitor is a PI3K/Akt/mTOR signaling cascade inhibitor. 
     
     
         17 . The method of  claim 11 , wherein the BCR inhibitor is rituximab, MK-2206, idelalisib, trametinib, tamatanib, everolimus, VELCADE, or ibrutinib. 
     
     
         18 . The method of  claim 1 , wherein the EZH2 inhibitor is Compound 44 having the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 18 , wherein the EZH2 inhibitor and the standard of care agent are administered simultaneously or sequentially. 
     
     
         20 . The method of  claim 18 , wherein the EZH2 inhibitor is administered prior to administration of the standard of care agent. 
     
     
         21 . The method of  claim 18 , wherein at least one gene is upregulated in the patient. 
     
     
         22 . The method of  claim 21 , wherein the gene is selected from the group consisting of Sestrin, TNF, and GILZ, or the gene is a glucocorticoid target gene. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 21 , wherein the upregulation of a gene is used to determine or adjust the therapeutically effective amount of the EZH2 inhibitor of  claim 1 , or the upregulation of a gene is used to determine or adjust the therapeutically effective amount of the standard of care agent of  claim 1 . 
     
     
         25 . (canceled) 
     
     
         26 . A method of selecting a patient for a method of treatment according to  claim 1 , wherein the patient is selected based on the expression profile of one or more genes selected from the group consisting of Sestrin, TNF and GILZ. 
     
     
         27 . A method of treatment according to  claim 1  wherein the patient has upregulated expression of Sestrin, TNF or GILZ.