Treatment of indolent or aggressive b-cell lymphomas using a combination comprising btk inhibitors

Abstract

Disclosed herein is a method for the prevention, delay of progression or treatment of indolent or aggressive B-cell lymphomas in an individual in need thereof, comprising administering a Btk inhibitor (in particularly (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof) in combination with an anti-PD-1 antibody. The potent and selective BTK inhibitor in combination with the anti-PD-1 antibody have a manageable toxicity profile in patients with indolent and aggressive lymphomas.

What is claimed is: 
     
         1 . A method for the prevention, delay of progression or treatment of indolent or aggressive B-cell lymphomas in an individual in need thereof, comprising administering a therapeutically effective amount of a Btk inhibitor, in combination with a therapeutically effective amount of an anti-PD-1 antibody,
 wherein the Btk inhibitor is a compound of Formula (I),   
       
         
           
           
               
               
           
         
         or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: 
         A is a 5- or 6-membered aromatic ring comprising 0-3 heteroatoms of N, S or O; 
         each W is independently —(CH 2 )— or —C(O)—; 
         L is a bond, CH 2 , NR 12 , O, or S; 
         S/D is a single or double bond, and when a double bond, R 5  and R 7  are absent; 
         m is 0, or an integer of 1-4; 
         n is 0, or an integer of 1-4, wherein when n is more than 1, each R 2  may be different; 
         p is 0, or an integer of 1-2, wherein when p is 0, m is non-zero, and when p is more than 1, each R 6  and each R 7  may be different; 
         R 1 , R 4 , R 5 , R 6 , and R 7  are each independently H, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 14 , —NR 13 CONR 14 R 15 , —NR 13 CO 2 R 14 , —SO 2 R 13 , —NR 13 SO 2 NR 14 R 15 , or —NR 13 SO 2 R 14 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R 16 , wherein (R 4  and R 5 ), or (R 4  and R 6 ), or (R 6  and R 7 ), or (R 6  and R 6  when p is 2), together with the atoms to which they are attached, can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings optionally substituted with at least one substituent R 16 ; 
         R 2  is halogen, alkyl, —S-alkyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 14 , —NR 13 CONR 14 R 15 , —NR 13 CO 2 R 14 , —SO 2 R 13 , —NR 13 SO 2 NR 14 R 15 , or —NR 13 SO 2 R 4 ; 
         R 12  is H or lower alkyl; 
         R 13 , R 14  and R 15  are each independently H, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heteroaryl; wherein (R 13  and R 14 ), and/or (R 14  and R 15 ) together with the atom(s) to which they are attached, each can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings optionally substituted with at least one substituent R 16 ; 
         R 16  is halogen, subsituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, subsituted or unsubstituted alkynyl, subsituted or unsubstituted cycloalkyl, subsituted or unsubstituted aryl, subsituted or unsubstituted heteroaryl, subsituted or unsubstituted heterocyclyl, oxo, —CN, —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —C(═NR a )NR b R c , —NR a COR b , —NR a CONR a R b , —NR a CO 2 R b , —SO 2 R a , —SO 2 aryl, —NR a SO 2 NR b R c , or —NR a SO 2 R b , wherein R a , R b , and R 0  are independently hydrogen, halogen, subsituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, subsituted or unsubstituted alkynyl, subsituted or unsubstituted cycloalkyl, subsituted or unsubstituted aryl, subsituted or unsubstituted heteroaryl, subsituted or unsubstituted heterocyclyl, wherein (R a  and R b ), and/or (R b  and R c ) together with the atoms to which they are attached, can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings. 
       
     
     
         2 . The method of  claim 1 , wherein the anti-PD-1 antibody is a monoclonal antibody. 
     
     
         3 . The method of  claim 2 , wherein the anti-PD-1 antibody is a monoclonal antibody or a fragment thereof, comprising a heavy chain variable region (Vh) amino acid sequence of SEQ ID No 24, a light chain variable region (Vl) amino acid sequence of SEQ ID No 26, and an IgG4 constant domain amino acid sequence of SEQ ID NO 88. 
     
     
         4 . The method of  claim 1 , wherein the indolent or aggressive B-cell lymphoma is indolent or aggressive Hodgkin's B-cell lymphoma, or indolent or aggressive non-Hodgkin's B-cell lymphoma. 
     
     
         5 . The method of  claim 4 , wherein the B-cell lymphoma is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), non-germinal center B-cell diffuse large B-cell lymphoma (non-GCB DLBCL), germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL) or DLBCL with undetermined subtype, follicular lymphoma (FL) or transformed FL, marginal zone lymphoma (MZL), Hairy cell leukemia (HCL), Richter's transformation, primary central nervous system lymphoma (PCNSL), secondary central nervous system lymphoma (SCNSL) of breast or testicular origin, transformed lymphoma, or a combination of two or more thereof. 
     
     
         6 . The method of  claim 4 , wherein the B-cell lymphoma is CLL, SLL, MCL, non-GCB DLBCL, GCB DLBCL, FL, transformed FL, MZL, HCL, or Richter's transformation. 
     
     
         7 . The method of  claim 1 , wherein the BTK inhibitor is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of  claim 7 , wherein the BTK inhibitor is administrated at a dose of 320 mg QD or 160 mg BID. 
     
     
         9 . The method of  claim 8 , wherein the BTK inhibitor is administrated with or without food. 
     
     
         10 . The method of  claim 3 , wherein the anti-PD-1 antibody is administrated at a dose of 2 mg/kg Q3W to 200 mg/kg Q3W. 
     
     
         11 . The method of  claim 10 , wherein the anti-PD-1 antibody is administrated at a dose of 2 mg/kg Q3W, 5 mg/kg Q3W, or 200 mg flat Q3W. 
     
     
         12 . The method of  claim 11 , wherein the anti-PD-1 antibody is administered at a dose of 200 mg flat dose every 21 days. 
     
     
         13 . The method of  claim 3 , wherein the anti-PD-1 antibody is administered intravenously. 
     
     
         14 . The method of  claim 3 , wherein the BTK inhibitor is administered at least 30 minutes before the anti-PD-1 antibody if administered on the same day.