US2018071295A1PendingUtilityA1

Bruton's tyrosine kinase inhibitor combinations and uses thereof

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Assignee: PHARMACYCLICS LLCPriority: Aug 8, 2014Filed: Jul 21, 2017Published: Mar 15, 2018
Est. expiryAug 8, 2034(~8.1 yrs left)· nominal 20-yr term from priority
Inventors:Hsu-Ping KuoHsin-Kang HsiehBetty Y. ChangLing XueSriram BalasubramanianLeo Cheung
A61K 31/454A61K 45/06A61K 38/21A61K 31/426A61P 35/02A61K 38/2013A61K 31/69A61P 35/00A61K 38/005A61K 38/191A61K 31/519A61P 43/00A61K 31/4164A61K 31/4196A61K 2300/00A61K 38/31
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Claims

Abstract

Disclosed herein are methods, compositions, and kits for treating a B-cell malignancy comprising administering a combination of a BTK inhibitor (e.g. ibrutinib) and a PIM inhibitor. Also disclosed herein are methods, compositions, and kits for treating a BTK-resistant B-cell malignancy comprising administering a combination of a BTK inhibitor (e.g. ibrutinib) and a PIM inhibitor.

Claims

exact text as granted — not AI-modified
1 . A method of treating a B-cell malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination comprising a BTK inhibitor and an anticancer agent, wherein the anticancer agent inhibits MALT1, MCL-1, or IDH1. 
     
     
         2 . The method of  claim 1 , wherein the B-cell malignancy is a BTK inhibitor-resistant B cell malignancy. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the combination sensitizes a B-cell malignancy to the BTK inhibitor. 
     
     
         5 . The method of  claim 1 , wherein the anticancer agent inhibits MALT1. 
     
     
         6 . The method of  claim 5 , wherein the anticancer agent that inhibits MALT1 comprises MI-2, mepazine, thioridazine, and promazine. 
     
     
         7 . The method of  claim 1 , wherein the anticancer agent inhibits MCL-1. 
     
     
         8 . The method of  claim 7 , wherein the anticancer agent that inhibits MCL-1 comprises BI97C10, BI112D1, gossypol, obatoclax, MG-132, MIM1, sabutoclax, and TW-37. 
     
     
         9 . The method of  claim 1 , wherein the anticancer agent inhibits IDH1. 
     
     
         10 . The method of  claim 9 , wherein the anticancer agent that inhibits IDH1 comprises AGI-5198, AG-120, IDH-C227, and ML309. 
     
     
         11 . The method of  claim 1 , wherein the BTK inhibitor is ibrutinib. 
     
     
         12 . The method  claim 1 , wherein the B-cell malignancy is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CIVIL), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. 
     
     
         13 . The method of  claim 12 , wherein the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL) or activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the method further comprises administering a third therapeutic agent. 
     
     
         16 . The method of  claim 15 , wherein the third therapeutic agent is selected from among a chemotherapeutic agent or radiation therapeutic agent. 
     
     
         17 . (canceled) 
     
     
         18 . A pharmaceutical combination comprising:
 a) a BTK inhibitor;   b) an anticancer agent, wherein the anticancer agent inhibits MALT1, MCL-1, IDH1, or proteasome; and   c) a pharmaceutically-acceptable excipient.   
     
     
         19 . A method of treating a B-cell malignancy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination comprising a BTK inhibitor and a PIM inhibitor. 
     
     
         20 . The method of  claim 19 , wherein the combination provides a synergistic effect compared to administration of the BTK inhibitor or the PIM inhibitor alone. 
     
     
         21 . The method of  claim 20 , wherein the combination sensitizes the B-cell malignancy to the BTK inhibitor. 
     
     
         22 . The method of  claim 19 , wherein the BTK inhibitor is ibrutinib. 
     
     
         23 . The method of  claim 19 , wherein the PIM inhibitor comprises mitoxantrone, SGI-1776, AZD1208, AZD1897, LGH447, JP_11646, Pim1 inhibitor 2, SKI-O-068, CX-6258, AR460770, AR00459339 (Array Biopharma Inc.), miR-33a, Pim-1 inhibitory p27 (Kip1) peptide, LY333′531, K00135, quercetagein (3,3′,4′,5,6,7-hydroxyflavone), or LY294002. 
     
     
         24 . (canceled)

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