Treatment of cancer

Abstract

Provided herein are compositions and methods for the treatment of a hematological malignancy. Also disclosed herein are compositions and methods for the treatment of Ewing's Sarcoma. Said compositions comprise isoform selective pyrrolo-pyrazole PKC inhibitors.

1 . A method of treating a hematological malignancy in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising5-{[(2S,5R)-2,5-Dimethyl-4—Rtetrahydro-2H-pyran-4-ylmethyl)piperazin-1-yl]carbonyl-N—R5-fluoro-2-methylpyrimidin-4-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or a pharmaceutically acceptable salt thereof, wherein the hematological malignancy is diffuse large B-cell lymphoma (DLBCL). 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the diffuse large B-cell lymphoma (DLBCL) is activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL), germinal center B-celllike diffuse large B-cell lymphoma (GCB-DLBC), primary mediastinal B-cell lymphoma, or intravascular large B-cell lymphoma. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the use of ibritinub is unsuitable or otherwise contraindicated. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 4 , wherein the DLBCL is ABC-DLBCL. 
     
     
         12 . A method of treating a relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in an individual in need thereof, comprising administering to the individual a pharmaceutical composition comprising5-{[(2S,5R)-2,5-Dimethyl-4—Rtetrahydro-2H-pyran-4-ylmethyl)piperazin-1-yl]carbonylI-N—R5-fluoro-2methylpyrimidin-4-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or a pharmaceutically acceptable salt thereof 
     
     
         13 . The method of  claim 12 , wherein the DLBCL is ABC-DLBCL. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 12 , wherein the relapsed or refractory diffuse large B-cell lymphoma is refractory to a BTK inhibitor. 
     
     
         19 . The method of  claim 18 , wherein the BTK inhibitor is ibrutinib. 
     
     
         20 . A method of treating a diffuse large B-cell lymphoma (DLBCL) in an individual in need thereof, comprising administering to the individual: (a) a composition comprising5-1[(2S,5R)-2,5-Dimethyl-4—Rtetrahydro-2H-pyran-4-ylmethyl)piperazin-1-yl]carbonyl -N—R5-fluoro-2-methylpyrimidin-4-yl)-6, 6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine, or a pharmaceutically acceptable salt thereof and (b) a BTK inhibitor. 
     
     
         21 . The method of  claim 20 , wherein the BTK inhibitor is ibrutinib. 
     
     
         22 . The method of  claim 20 , wherein the DLBCL is ABC-DLBCL. 
     
     
         23 - 40 . (canceled) 
     
     
         41 . The method of  claim 20 , wherein the BTK inhibitor is acalabrutinib. 
     
     
         42 . The method of  claim 20 , wherein the BTK inhibitor is selected from the group consisting of GS-4059, spebrutinib, BGB-3111, M7583, MSC2364447C, BII068, AC0058TA, and DTRMWXHS-12.