Use of a combination comprising a btk inhibitor for treating cancers

Abstract

A method for the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject in need thereof a Btk inhibitor, particularly, (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazo-lo[1,5-a]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor or a targeted therapy agent. A pharmaceutical combination comprising a Btk inhibitor, particularly, (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, in combination with an immune checkpoint inhibitor or a targeted therapy agent.

1 - 58 . (canceled) 
     
     
         59 . A method for the prevention, delay of progression or treatment of cancer in a subject, wherein the cancer is a carcinoma, comprising administering to the subject in need thereof a therapeutically effective amount of a Btk inhibitor, in combination with a therapeutically effective amount of an anti-PD-1 antibody or a fragment thereof;
 wherein the anti-PD-1 antibody comprises (i) a heavy chain variable region comprising complement determinant region (CDR)-H1 comprising SEQ ID NO:31, CDR-H2 comprising SEQ ID NO:32, and CDR-H3 comprising SEQ ID NO:33, and (ii) a light chain variable region comprising CDR-L1 comprising SEQ ID NO:34, CDR-L2 comprising SEQ ID NO:35, and CDR-L3 comprising SEQ ID NO:36; and   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 3 , —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 14 ; 
 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 unsubstitued alkyl, substituted or unsubstituted alkenyl, subsituted or unsubstitued alkynyl, subsituted or unsubstitued cycloalkyl, subsituted or unsubstitued aryl, subsituted or unsubstitued heteroaryl, subsituted or unsubstitued 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 c  are independently hydrogen, halogen, subsituted or unsubstitued alkyl, substituted or unsubstituted alkenyl, subsituted or unsubstitued alkynyl, subsituted or unsubstitued cycloalkyl, subsituted or unsubstitued aryl, subsituted or unsubstitued heteroaryl, subsituted or unsubstitued 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. 
   
     
     
         60 . The method of  claim 59 , 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. 
     
     
         61 . The method of  claim 59 , wherein the Btk inhibitor is administered orally at a dose of 320 mg once a day (QD) or 160 mg twice a day (BID). 
     
     
         62 . The method of  claim 59 , wherein the anti-PD-1 antibody is a monoclonal antibody comprising: the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:24, and the light chain variable region comprising the amino acid sequence of SEQ ID NO:26. 
     
     
         63 . The method of  claim 62 , wherein the anti-PD-1 antibody comprises an IgG4 constant domain comprising the amino acid sequence of SEQ ID NO:88. 
     
     
         64 . The method of  claim 59 , wherein the anti-PD-1 antibody is administered parenterally at a dose of 2 mg/kg once every three weeks (Q3W) to 200 mg/kg Q3W. 
     
     
         65 . The method of  claim 59 , wherein the anti-PD-1 antibody is administered parenterally at a dose of 2 mg/kg once every three weeks (Q3W) to 10 mg/kg Q3W. 
     
     
         66 . The method of  claim 59 , wherein:
 (i) 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; and   (ii) the anti-PD-1 antibody comprises the heavy chain variable region comprising the amino acid sequence of SEQ ID NO:24, the light chain variable region comprising the amino acid sequence of SEQ ID NO:26, and an IgG4 constant domain comprising the amino acid sequence of SEQ ID NO:88.   
     
     
         67 . The method of  claim 66 , wherein the Btk inhibitor is administered orally at a dose of 320 mg QD or 160 mg BID, and wherein the anti-PD-1 antibody is administered intravenously at a dose of 2 mg/kg Q3W to 10 mg/kg Q3W. 
     
     
         68 . The method of  claim 59 , wherein the carcinoma is a squamous cell carcinoma. 
     
     
         69 . The method of  claim 59 , wherein the carcinoma is an epidermoid carcinoma. 
     
     
         70 . The method of  claim 59 , wherein the cancer is selected from the group consisting of: bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma. 
     
     
         71 . The method of  claim 59 , wherein the cancer is a relapsed or refractory cancer. 
     
     
         72 . The method of  claim 71 , wherein the relapsed or refractory cancer is selected from the group consisting of: bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma. 
     
     
         73 . The method of  claim 59 , wherein the cancer is a metastasized cancer. 
     
     
         74 . The method of  claim 73 , wherein the metastasized cancer is selected from the group consisting of: bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma. 
     
     
         75 . The method of  claim 59 , wherein the subject is human. 
     
     
         76 . The method of  claim 59 , wherein the method is for the delay of progression or treatment of cancer. 
     
     
         77 . The method of  claim 67 , wherein the method is for the delay of progression or treatment of cancer and the subject is human. 
     
     
         78 . The method of  claim 77 , wherein the carcinoma is a squamous cell carcinoma or an epidermoid carcinoma.