Therapies for hematologic malignancies

Abstract

The invention provides methods that relate to a novel therapeutic strategy for the treatment of hematological malignancies and inflammatory diseases. In particular, the method comprises administration of a compound of formula A, wherein R is H, halo, or C1-C6 alkyl; R′ is C1-C6 alkyl; or a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable excipient.

1 . A method to treat a condition, wherein the condition is cancer or an autoimmune condition, comprising administering to a subject in need of such treatment, an effective amount of a compound having a formula A, 
       
         
           
           
               
               
           
         
         wherein R is H, halo, or C1-C6 alkyl; 
         R′ is C1-C6 alkyl; or 
         a pharmaceutically acceptable salt thereof; and 
         optionally a pharmaceutically acceptable excipient. 
       
     
     
         2 . The method according to  claim 1 , wherein the compound is predominantly the S-enantiomer. 
     
     
         3 . The method according to  claim 1 , wherein R is fluoro (F) and is attached to position 5 or 6 of the quinazolinyl ring. 
     
     
         4 . The method according to  claim 1 , wherein R is H or F; and R′ is methyl, ethyl or propyl. 
     
     
         5 . The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method according to  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method according to  claim 1 , wherein the autoimmune condition is allergic rhinitis, asthma, COPD, or rheumatoid arthritis. 
     
     
         8 . The method according to  claim 1 , wherein the condition is cancer. 
     
     
         9 . The method according to  claim 8 , wherein the cancer is a hematological malignancy. 
     
     
         10 . The method according to  claim 9 , wherein said hematological malignancy is leukemia. 
     
     
         11 . The method according to  claim 9 , wherein said hematological malignancy is lymphoma. 
     
     
         12 . The method according to  claim 9 , wherein the hematological malignancy is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenstrom's macroglobulinemia (WM), B-cell lymphoma and diffuse large B-cell lymphoma (DLBCL). 
     
     
         13 . The method according to  claim 8 , wherein the cancer is acute lymphocytic leukemia (ALL). 
     
     
         14 . The method according to  claim 8 , wherein the cancer is acute myeloid leukemia (AML). 
     
     
         15 . The method according to  claim 8 , wherein the cancer is chronic lymphocytic leukemia (CLL). 
     
     
         16 . The method according to  claim 8 , wherein the cancer is multiple myeloma (MM). 
     
     
         17 . The method according to  claim 8 , wherein the cancer is B-cell lymphoma. 
     
     
         18 . The method according to  claim 8 , wherein the cancer is diffuse large B-cell lymphoma (DLBCL). 
     
     
         19 . The method according to  claim 8 , wherein the cancer is B-cell or T-cell ALL. 
     
     
         20 . The method according to  claim 8 , wherein the cancer is Hodgkin's lymphoma. 
     
     
         21 . The method according to  claim 8 , wherein the cancer is breast or ovarian cancer. 
     
     
         22 . The method according to  claim 8 , wherein the subject is refractory to chemotherapy treatment, or in relapse after treatment with chemotherapy. 
     
     
         23 . The method according to  claim 8 , further comprising administering at least one additional therapeutic agent. 
     
     
         24 . The method according to  claim 23 , wherein said additional therapeutic agent is a proteasome inhibitor. 
     
     
         25 . The method according to  claim 23 , wherein the additional therapeutic agent is combined with the compound of Formula A. 
     
     
         26 . The method according to  claim 23 , wherein the additional therapeutic agent is selected from the group consisting of Bortezomib (Velcade®), Carfilzomib (PR-171), PR-047, disulfiram, lactacystin, PS-519, eponemycin, epoxomycin, aclacinomycin, CEP-1612, MG-132, CVT-63417, PS-341, vinyl sulfone tripeptide inhibitors, ritonavir, PI-083, (+/−)-7-methylomuralide, and (−)-7-methylomuralide. 
     
     
         27 . The method according to  claim 23 , wherein the additional therapeutic agent is bortezomib. 
     
     
         28 . The method according to  claim 23 , wherein the compound is administered in combination with at least a group of at least two agents, wherein said group of agents is selected from the groups consisting of a-q,
 a) CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone);   b) R-CHOP (rituximab-CHOP);   c) hyperCV AD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine);   d) R-hyperCV AD (rituximab-hyperCV AD);   e) FCM (fludarabine, cyclophosphamide, mitoxantrone);   f) R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone);   g) bortezomib and rituximab;   h) temsirolimus and rituximab;   i) temsirolimus and Velcade®;   j) Iodine-131 tositumomab (Bexxar®) and CHOP;   k) CVP (cyclophosphamide, vincristine, prednisone);   l) R-CVP (rituximab-CVP);   m) ICE (iphosphamide, carboplatin, etoposide);   n) R-ICE (rituximab-ICE);   o) FCR (fludarabine, cyclophosphamide, rituximab);   p) FR (fludarabine, rituximab); and   q) D.T. PACE (Dexamethasone, Thalidomide, Cisplatin, Adriamycin, Cyclophosphamide, Etoposide).   
     
     
         29 . The method according to  claims 1 , wherein the compound of formula A is present in a pharmaceutical composition comprising the compound of formula A and at least one pharmaceutically acceptable excipient. 
     
     
         30 . A method to treat a condition, wherein the condition is selected from the group consisting of multiple myeloma, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), B cell ALL, T cell ALL, Hodgkin's lymphoma, breast, and ovarian cancer, comprising administering to a subject in need of such treatment, an effective amount of a compound having a formula I″ or formula II″ or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The method according to  claim 30 , wherein the subject is refractory to chemotherapy treatment or in relapse after treatment with chemotherapy. 
     
     
         32 . The method according to  claim 30 , wherein the subject has a cancer that constitutively expresses Akt phosphorylation activity. 
     
     
         33 . The method according to  claim 30 , wherein the subject has a cancer with high p110δ activity and low p110α activity. 
     
     
         34 . The method according to  claims 30 , wherein the compound is used in combination with Bortezomib. 
     
     
         35 . A method to treat a hematological cancer comprising administering to a subject in need of such treatment, an effective amount of a compound having formula I″ or formula II″ and bortezomib or carfilzomib. 
     
     
         36 . The method according to  claim 8 , wherein the compound maintains an average blood concentration above the EC 50  level for PI3Kδ activation and below the level for EC 50  PI3Kγ activation in basophils over a period of at least 12 hours from compound administration. 
     
     
         37 . The method according to  claim 8 , wherein the compound maintains an average blood plasma concentration between 100 nM and 1100 nM over a period of at least 12 hours from compound administration. 
     
     
         38 . The method according to  claim 8 , wherein the subject is resistant to standard chemotherapeutic treatments. 
     
     
         39 . The method according to  claim 8 , wherein the subject has at least one enlarged lymph node. 
     
     
         40 . The method according to  claim 22 , wherein the subject is refractory to at least two standard or experimental chemotherapy treatments. 
     
     
         41 . The method according to  claim 40 , wherein each chemotherapy treatment is selected from the group consisting of fludarabine, alkylating agents, rituximab, alemtuzumab, and the treatments a-q listed in  claim 28 .