Therapeutic Combination of a PI3K Inhibitor and a BTK Inhibitor

Abstract

In some embodiments, the invention includes a therapeutic combination of a phosphoinositide 3-kinase (PI3K) inhibitor, including PI3K inhibitors selective for the γ- and δ-isoforms and selective for both γ- and δ-isoforms, and a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, the invention includes therapeutic methods of using a BTK inhibitor and a PI3K-δ inhibitor to treat solid tumor cancers by modulation of the tumor microenvironment, including macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts.

1 . A method of treating a hyperproliferative disorder in a subject, comprising co-administering to a subject in need thereof a therapeutically effective amount of a phosphoinositide 3-kinase (PI3K) inhibitor, or of a pharmaceutically acceptable salt thereof, in combination with a Bruton's tyrosine kinase (BTK) inhibitor, or of a pharmaceutically acceptable salt thereof, wherein the BTK inhibitor is: 
       
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , wherein the PI3K inhibitor is selected from the group consisting of a PI3K-γ inhibitor, a PI3K-δ inhibitor, and a PI3K-γ,δ inhibitor. 
     
     
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         6 . The method of  claim 1 , wherein the combination of the PI3K inhibitor with the BTK inhibitor is administered by oral, intravenous, intramuscular, intraperitoneal, subcutaneous or transdermal means. 
     
     
         7 . The method of  claim 1 , wherein the PI3K inhibitor and/or BTK inhibitor is in the form of a pharmaceutically acceptable salt. 
     
     
         8 . The method of  claim 1 , wherein the PI3K inhibitor is administered to the subject before administration of the BTK inhibitor. 
     
     
         9 . The method of  claim 1 , wherein the PI3K inhibitor is administered concurrently with the administration of the BTK inhibitor. 
     
     
         10 . The method of  claim 1 , wherein the PI3K inhibitor is administered to the subject after administration of the BTK inhibitor. 
     
     
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         25 . The method of  claim 1  wherein the amount is effective to inhibit signaling between the cells of the cancer and at least one microenvironment selected from the group consisting of macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts. 
     
     
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         28 . The method of  claim 25 , wherein the amount is further effective to increase immune system recognition and rejection of the cancer by the human. 
     
     
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         32 . A kit comprising a pharmaceutical composition comprising a PI3K inhibitor and a pharmaceutical composition comprising a BTK inhibitor, for co-administration of the PI3K inhibitor and the BTK inhibitor, either simultaneously or separately. 
     
     
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         39 . The method of  claim 1 , wherein the hyperproliferative disorder is mantle cell lymphoma. 
     
     
         40 . The method of  claim 1 , wherein the hyperproliferative disorder is acute myeloid leukemia. 
     
     
         41 . The method of  claim 1 , wherein the hyperproliferative disorder is indolent non-Hodgkin's Lymphomas. 
     
     
         42 . The method of  claim 1 , wherein the hyperproliferative disorder is activated B Cell-Diffuse Large B Cell Lymphoma. 
     
     
         43 . The method of  claim 1 , wherein the hyperproliferative disorder is germinal center B-cell like diffuse large B-cell lymphoma. 
     
     
         44 . The method of  claim 1 , wherein the hyperproliferative disorder is B cell acute lymphoblastic leukemia