Treatment of cancers using pi3 kinase isoform modulators

Abstract

Provided herein are methods, kits, and pharmaceutical compositions that include a PI3 kinase inhibitor for treating cancers or hematologic disorders.

1 - 38 . (canceled) 
     
     
         39 . A method for treating a hematologic malignancy selected from B-cell lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), CLL/SLL,), indolent non-Hodgkin lymphoma (iNHL), follicular lymphoma, mantle cell lymphoma (MCL), T-cell lymphoma, peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) in a human subject comprising orally administering to the subject twice daily 25mg to 75 mg of a compound having the following structure or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof: 
       
         
           
           
               
               
           
         
       
     
     
         40 . The method of  claim 39 , wherein the hematologic malignancy has a high expression level of PI3K-δ, or PI3K-γ, or both PI3K-δ and PI3K-γ. 
     
     
         41 . The method of  claim 39 , wherein the compound or pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof is administered in an amount sufficient to provide a plasma concentration of the compound at steady state at a level higher than the IC 90  for PI3K-δ and at a level higher than the IC 50  for PI3K-γ. 
     
     
         42 . The method of  claim 39 , wherein the compound or pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof is administered in an amount sufficient to provide a plasma concentration of the compound at steady state of 350 ng/ml to 450 ng/ml. 
     
     
         43 . The method of  claim 39 , wherein the hematologic malignancy is chronic lymphocytic leukemia (CLL), indolent non-Hodgkin lymphoma (iNHL), small lymphocytic lymphoma (SLL), CLL/SLL, or follicular lymphoma. 
     
     
         44 . The method of  claim 39 , wherein the hematologic malignancy is relapsed or refractory. 
     
     
         45 . The method of  claim 43 , wherein the hematologic malignancy is relapsed or refractory. 
     
     
         46 . The method of  claim 39 , wherein the hematologic malignancy is refractory to rituximab therapy, chemotherapy, and/or radioimmunotherapy. 
     
     
         47 . The method of  claim 39 , wherein the PI3K inhibitor is administered in combination with a second active agent selected from the group consisting of a BCL-2 inhibitor, an HDAC inhibitor, a MEK inhibitor, an EZH2 inhibitor, a BTK inhibitor and a PLK-1 inhibitor. 
     
     
         48 . The method of  claim 47 , wherein the second active agent is selected from the group consisting of:
 (i) an HDAC inhibitor selected from the group consisting of belinostat, vorinostat, panobinostat, ACY-1215, and romidepsin;   (ii) a MEK inhibitor selected from the group consisting of tametinib/GSK1120212, selumetinob, pimasertib/AS703026/MSC1935369, XL-518/GDC-0973, refametinib/BAY869766/RDEA119, PD-0325901, TAK733, MEK162/ARRY438162, RO5126766, WX-554, R04987655/CH4987655, and AZD8330;   (iii) an EZH2 inhibitor selected from the group consisting of EPZ-6438, GSK-126, GSK-343, E11, and 3-deazaneplanocin A (DNNep);   (iv) a PLK-1 inhibitor selected from the group consisting of volasertib (BI6727), BI2536, ZK-Thiazolidone, TAK-960, MLN0905, GSK461364, rigosertib (ON-01910), and HMN-214;   (v) a BCL-2 inhibitor selected from the group consisting of ABT-199, ABT-737, ABT-263, GX15-070 (obatoclax mesylate), or G3139 (Oblimersen); and   (vi) a BTK inhibitor selected from the group consisting of ibrutinib, GDC-0834, CGI-560, CGI-1746, HM-71224, AVL-292, ONO-4059, CNX-774, or LFM-A13.   
     
     
         49 . The method of  claim 48 , wherein the BCL-2 inhibitor is ABT-199. 
     
     
         50 . The method of  claim 48  wherein the BTK inhibitor is ibrutinib. 
     
     
         51 . The method of  claim 39 , wherein the PI3K inhibitor is administered in combination with a second active agent selected from the group consisting of:
 (i) an anti-CD37 antibody;   (ii) an anti-CD20 antibody selected from the group consisting of from  131 I tositumomab,  90 Y ibritumomab,  111 I ibritumomab, obinutuzumab and ofatumumab; and   (iii) an anti-CD52 antibody.   
     
     
         52 . The method of  claim 51 , wherein the PI3K inhibitor is administered in combination with an anti-CD20 antibody. 
     
     
         53 . The method of  claim 52 , wherein the anti-CD20 antibody is obinutuzumab. 
     
     
         54 . The method of  claim 39 , wherein the PI3K inhibitor is administered in combination with a second active agent selected from the group consisting of:
 (i) if the hematologic malignancy is iNHL, the second active agent is rituximab, bendamustine, or lenalidomide, or a combination thereof;   (ii) if the hematologic malignancy is CLL, the second active agent is rituximab, bendamustine, or lenalidomide, or a combination thereof;   (iii) if the hematologic malignancy is T-cell lymphoma, the second active agent is rituximab, bendamustine, or romidepsin, or a combination thereof; and   (iv) if the hematologic malignancy is mantle cell lymphoma, the second active agent is rituximab, bendamustine, or ibrutinib, or a combination thereof.   
     
     
         55 . The method of  claim 39 , further comprising a step of determining a change in the level of a biomarker over a period of time. 
     
     
         56 . The method of  claim 55 , wherein the biomarker is chosen from CXCL13, CCL4, CCL17, CCL22, TNF-α, or MMP-9, or a combination thereof; and wherein the subject is responsive to the treatment if the level of the biomarker decreases over the period of time. 
     
     
         57 . The method of  claim 55 , wherein the period of time is 180 days, 90 days, 50 days, 40 days, 35 days, 30 days, 28 days, 24 days, 20 days, 16 days, 14 days, 12 days, 8 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 6 hours, 3 hours, or 1 hour, after administration of the compound or pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof to the subject. 
     
     
         58 . The method of  claim 55 , further comprising a step of adjusting the dose of the compound or pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof based on the change in the level of a biomarker over a period of time. 
     
     
         59 . The method of  claim 55 , wherein the subject is evaluated prior to treatment, during treatment, or after treatment, with the compound or pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. 
     
     
         60 . The method of  claim 55 , further comprising monitoring the subject for a change in level of one or more of:
 (i) a mutation of one or more of: IGH7, KRAS, NRAS, A20, CD79B, TP53, CARD11, MYD88, EZH2, JAK1/2, PTEN, and PIK3CA;   (ii) a reduction of PTEN expression, DNA modification of PTEN, PTEN deletion, PTEN mutation, or a combination thereof;   (iii) expression level of one or more PI3K isoform(s); and/or   (iv) activation of RAS pathway, activation of PI3K pathway, or both.   
     
     
         61 . The method of  claim 55 , wherein:
 (i) the hematologic malignancy is CLL or SLL, and the biomarker is CCL1, IL-10, CXCL13, CCL3, CCL4, CCL17, CCL22, TNFα, IL-12 (p40), CXCL10, or MMP-9, or a combination thereof;   (ii) the hematologic malignancy is iNHL, and the biomarker is CCL1, CCL17, CCL22, CXCL13, IL-12 (p40), MMP-12, MMP-9, TNFα, or IL-16, or a combination thereof;   (iii) the hematologic malignancy is MCL, and the biomarker is CCL17, CCL22, CXCL10, CXCL13, or MMP-9, or a combination thereof;   (iv) the hematologic malignancy is T-cell lymphoma, and the biomarker is CCL17, CCL22, CXCL10, CXCL13, MMP-9, GM-CSF, IL-12 (p40), TNF-α, TGF-α, an ERK (extracellular signal regulated kinase), PRAS40, or pS6, or a combination thereof; and   (v) the hematologic malignancy is CLL and wherein the subject has CD38 positive, CD69 positive, CD38/CD69 double positive, Ki67 positive, pAKT positive, or Ki67/pAKT double positive cancer cells.