Combination therapies

Abstract

Provided herein are pharmaceutical compositions comprising a phosphatidylinositol 3-kinase inhibitor or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor or a pharmaceutically acceptable form thereof. Also provided herein are methods for treating cancer comprising administration the compositions, and uses of the compositions, e.g., for the treatment of cancer.

1 . (canceled) 
     
     
         2 . A method of treating a cancer in a subject comprising administering to the subject a synergistic combination of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, wherein the PI3K inhibitor is (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one or (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof. 
     
     
         3 . A composition comprising a synergistic combination of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, wherein the PI3K inhibitor is (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one or (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof. 
     
     
         4 . The method of  claim 2 , wherein the combination is synergistic as indicated by a combination index value that is less than 1, less than 0.7, or less than 0.5 for the combination of the PI3K inhibitor and the Bcl-2 inhibitor. 
     
     
         5 - 6 . (canceled) 
     
     
         7 . The method of  claim 2 , wherein the combination index value is assessed at 50% or more inhibition. 
     
     
         8 . The method of  claim 2 , wherein the combination index value is assessed at 50% or more growth inhibition. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The method of  claim 2 , wherein PI3K inhibitor is at an amount sufficient to reach maximum plasma concentration at steady state (Cmaxss) at about 1000 ng/mL to about 5000 ng/mL; and the Bcl-2 inhibitor is administered at an amount to reach Cmaxss at about 0.1 μg/mL to about 1000 μg/mL. 
     
     
         12 . The method of  claim 2 , wherein PI3K inhibitor is at an amount sufficient to reach an area under the plasma concentration-time curve at steady-state (AUCss) at about 5000 ng/mL*hr to about 10000 ng/mL*hr; and the Bcl-2 inhibitor is administered at an amount to reach an AUCss at about 0.1 ng/mL*hr to about 10000 ng/mL*hr. 
     
     
         13 . The method of  claim 2 , wherein the PI3K inhibitor is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable form thereof. 
     
     
         14 . The method of  claim 2 , wherein the PI3K inhibitor is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable form thereof. 
     
     
         15 . The method of  claim 2 , wherein the Bcl-2 inhibitor is ABT-199, ABT-263, ABT-737, G3139 (genasense or oblimersen), GX15-070 (obatoclax mesylate), HA14-1, TW-37, sabutoclax, Gossypol (AT-101), antimycin A, apogossypol, S44563, or a combination thereof. 
     
     
         16 . The method of  claim 15 , wherein the Bcl-2 inhibitor is ABT-199. 
     
     
         17 . The method of  claim 16 , wherein the composition comprises 50 to 350 mg of ABT-199. 
     
     
         18 . The method of  claim 16 , wherein the composition comprises about 400 mg, about 325 mg, about 150 mg, or about 75 mg of ABT-199. 
     
     
         19 - 21 . (canceled) 
     
     
         22 . The method of  claim 2 , wherein the PI3K inhibitor is Compound 1 or a pharmaceutically acceptable form thereof and the molar ratio of Compound 1, or the pharmaceutically acceptable form thereof, to the Bcl-2 inhibitor, or pharmaceutically acceptable form thereof, is in the range of from about 50:1 to about 1:50, from about 10:1 to about 1:10, or from about 1:3 to about 1:7. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 2 , wherein the PI3K inhibitor is Compound 1, or a pharmaceutically acceptable form thereof, at an amount in the range of from about 0.01 mg to about 75 mg and the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, at an amount of in the range of from about 0.01 mg to about 1100 mg. 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 2 , wherein the PI3K inhibitor, or a pharmaceutically acceptable form thereof, and the Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, are in a single dosage form or in separate dosage forms. 
     
     
         27 - 28 . (canceled) 
     
     
         29 . The method of  claim 2 , wherein the concentration of the PI3K inhibitor that is required to achieve inhibition is at least 20% lower when the PI3K inhibitor is administered in combination with the Bcl-2 inhibitor than when the PI3K inhibitor is administered alone. 
     
     
         30 . The method of  claim 2 , wherein the concentration of the Bcl-2 inhibitor that is required to achieve inhibition is at least 20% lower when the Bcl-2 inhibitor is administered in combination with PI3K inhibitor than when the Bcl-2 inhibitor is administered alone. 
     
     
         31 .- 36 . (canceled) 
     
     
         37 . The method of  claim 2 , wherein the anti-cancer effect provided by the composition is greater than the anti-cancer effect provided by a monotherapy with the same dose of the PI3K inhibitor or pharmaceutically acceptable form thereof as is included in the composition. 
     
     
         38 . The method of  claim 2 , wherein the anti-cancer effect provided by the composition is at least 2 fold greater, at least 3 fold greater, at least 5 fold greater, or at least 10 fold greater than the anti-cancer effect provided by the monotherapy with the PI3K inhibitor or pharmaceutically acceptable form thereof. 
     
     
         39 - 41 . (canceled) 
     
     
         42 . The method of  claim 3 , wherein the PI3K inhibitor, or a pharmaceutically acceptable form, is administered concurrently with, subsequent to, or prior to the Bcl-2 inhibitor. 
     
     
         43 - 44 . (canceled) 
     
     
         45 . The method of  claim 2 , which delays resistance of the cancer to the PI3K inhibitor or reduces the risk that the cancer becomes resistant to the PI3K inhibitor. 
     
     
         46 . (canceled) 
     
     
         47 . The method of  claim 45 , wherein the cancer does not become resistant to the PI3K inhibitor for at least 12, 18, or 24 months. 
     
     
         48 . The method of  claim 2 , which prolongs remission in the subject. 
     
     
         49 . The method of  claim 48 , wherein the subject experiences remission for at least 12 months. 
     
     
         50 . (canceled) 
     
     
         51 . The method of  claim 2 , wherein the subject experiences complete remission. 
     
     
         52 . The method of  claim 2 , which results in a reduction in the level of minimal residual disease (MRD). 
     
     
         53 . The method of  claim 2 , wherein the subject has substantially no detectable MRD. 
     
     
         54 - 58 . (canceled) 
     
     
         59 . A method of delaying or decreasing resistance of a subject having a cancer, comprising administering to the subject a synergistic amount of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, thereby delaying or decreasing resistance. 
     
     
         60 - 61 . (canceled) 
     
     
         62 . A method of reducing the level of minimal residual disease (MRD) compared to a reference value in a subject having a cancer, comprising administering to the subject a synergistic amount of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, and a Bcl-2 inhibitor, or a pharmaceutically acceptable form thereof, thereby reducing the level of MRD in the subject. 
     
     
         63 . A method of treating a cancer or tumor in a subject, comprising:
 acquiring a value for one or more of: the presence, absence, amount or level of an alteration or biomarker chosen from one, two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14, 15, or all of: an STK11 copy number, TSC1 copy number, TSC2 copy number, TP53 copy number, PTEN copy number, CBFA2T3 copy number, YWHAE copy number, PER1 copy number, GAS7 copy number, FSTL3 copy number, USP6 copy number, MAP2K4 copy number, EGFR copy number, a BCR pathway mutation a p53 pathway mutation, or a MAPK pathway mutation, or any combination thereof, and   responsive to said value, administering to the subject a composition according to  claim 3 .   
     
     
         64 - 67 . (canceled) 
     
     
         68 . The method of  claim 63 , wherein one, two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, or all of the following is indicative of decreased responsiveness of the cancer or tumor, or the subject, to the treatment:
 (i) a copy number loss of STK11;   (ii) a copy number loss of TSC1 or TSC2, or both;   (iii) a copy number loss of TP53;   (iv) a copy number loss of PTEN;   (v) a copy number loss of CBFAT2T3;   (vi) a copy number loss of YWHAE;   (vii) a copy number loss of PER1;   (viii) a copy number loss of GAS7;   (ix) a copy number loss of FSTL3;   (x) a copy number loss of USP6;   (xi) a copy number loss of MAP2K4;   (xii) a BCR pathway mutation   (xiii) a p53 pathway mutation; or   (xiv) a MAPK pathway mutation.   
     
     
         69 . The method of  claim 2 , wherein the cancer is of hematopoietic origin. 
     
     
         70 . The method of  claim 69 , wherein the cancer is a lymphoma or leukemia. 
     
     
         71 . The method of  claim 70 , wherein the cancer is acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL), B-cell ALL (B-ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), blast phase CML, small lymphocytic lymphoma (SLL), CLL/SLL, blast phase CLL, Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), B-cell NHL, T-cell NHL, indolent NHL (iNHL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), aggressive B-cell NHL, B-cell lymphoma (BCL), Richter's syndrome (RS), T-cell lymphoma (TCL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), transformed mycosis fungoides, Sézary syndrome, anaplastic large-cell lymphoma (ALCL), follicular lymphoma (FL), Waldenström macroglobulinemia (WM), lymphoplasmacytic lymphoma, Burkitt lymphoma, multiple myeloma (MM), myeloproliferative disorder (MPD), myelofibrosis (MF), chronic myelomonocytic leukemia (CMML), angioimmunoblastic lymphoma, cutaneous lymphoma, myeloma, plasmacytoma, diffuse large B-cell lymphoma activated B-cell like, or diffuse large B-cell lymphoma germinal center B-cell-like. 
     
     
         72 - 87 . (canceled)