Combination therapy of a type ii anti-cd20 antibody with a selective bcl-2 inhibitor

Abstract

The present invention is directed to a combination therapy involving a type II anti-CD20 antibody and a selective Bcl-2 inhibitor for the treatment of a patient suffering from cancer, particularly, a CD20-expressing cancer.

What is claimed is: 
     
         1 . A method for the treatment of a cancer in a human in need thereof comprising administering to said human an effective amount of a GA101 antibody or 241H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide or a pharmaceutically acceptable salt thereof for one or more dosing periods, followed by co-administering an effective amount of said GA101antibody and 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide or a pharmaceutically acceptable salt thereof for one or more dosing periods. 
     
     
         2 . A method for the treatment of a cancer in a human in need thereof comprising administering to said human an effective amount of a GA101antibody or 241H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide or a pharmaceutically acceptable salt thereof for 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days, followed by co-administering an effective amount of said GA101antibody and 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide or a pharmaceutically acceptable salt thereof for one or more dosing periods. 
     
     
         3 . The method of  claim 1 , wherein an effective amount of said GA101 antibody is administered once every dosing period for 1, 2, 3, 4, 5 or 6 cycles, followed by co-administrating the effective amount of said GA101antibody once every dosing period and 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide or a pharmaceutically acceptable salt thereof one, two or three times a day for one or more dosing periods. 
     
     
         4 . The method of  claim 1 , wherein an effective amount of 2-(1 I-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide or a pharmaceutically acceptable salt thereof is administered one, two or three times a day for 1, 2, 3, 4, 5 or 6 dosing periods, followed by co-administering an effective amount of said GA101 antibody once every dosing period and 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide or a pharmaceutically acceptable salt thereof one, two or three times a day for one or more dosing periods. 
     
     
         5 . The method of  claim 4 , wherein the effective amount of said GA101 antibody is from about 500 mg to about 3000 mg and the effective amount of 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide or a pharmaceutically acceptable salt thereof is from about 20 mg to about 500 mg. 
     
     
         6 . The method of  claim 4 , wherein the effective amount of said GA101antibody is 800, 900, 1000, 1100, 1200, 1300, 1400, or 1500 mg, and the effective amount of 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide or a pharmaceutically acceptable salt thereof is 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg. 
     
     
         7 . The method of  claim 1 , wherein said GA101antibody and 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide or a pharmaceutically acceptable salt thereof are co-administered sequentially during each dosing period, and each dosing period is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days. 
     
     
         8 . The method of  claim 1 , wherein said GA101antibody is an anti-human CD20 antibody comprising an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, an HVR-H2 comprising the amino acid sequence of SEQ ID NO:2, an HVR-113 comprising the amino acid sequence of SEQ ID NO:3, an HVR-LI comprising the amino acid sequence of SEQ ID NO:4, an HVR-L2 comprising the amino acid sequence of SEQ ID NO:5, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO:6. 
     
     
         9 . The method of  claim 8 , wherein said GA101 antibody further comprises a V H domain comprising the amino acid sequence of SEQ ID NO:7 and a VL domain comprising the amino acid sequence of SEQ ID NO:8. 
     
     
         10 . The method of  claim 1 , wherein said GA101 antibody comprises an amino acid sequence of SEQ ID NO:9 and an amino acid sequence of SEQ ID NO: 10. 
     
     
         11 . The method of  claim 1 , wherein in the GA101 antibody is known as obinutuzumab. 
     
     
         12 . The method of  claim 1 , wherein the GA101 antibody comprises an amino acid sequence that has at least 95% sequence identity with amino acid sequence of SEQ ID NO:9 and at least 95% sequence identity with an amino acid sequence of SEQ ID NO: 10. 
     
     
         13 . The method of  claim 1 , wherein the cancer is a CD20-expressing cancer. 
     
     
         14 . The method of  claim 13 , wherein the cancer is a non-solid tumor. 
     
     
         15 . The method of  claim 13 , wherein the cancer is a lymphoma or a leukemia. 
     
     
         16 . The method of  claim 13 , wherein the leukemia is chronic lymphocytic leukemia (CLL). 
     
     
         17 . The method of  claim 16 , wherein the patient is suffering from relapsed or refractory or previously untreated chronic lymphocytic leukemia. 
     
     
         18 . A method for the treatment of a cancer in a human in need thereof comprising co-administering to said human an effective amount of a GA101 antibody and 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide in a dosing period, wherein the GA101 antibody is administered at 500-3000 mg weekly and 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-211-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide is administered at 50-300 mg 1-3 times per day in the dosing period. 
     
     
         19 . A method for the treatment of a cancer in a human in need thereof comprising administering to said human a GA101 antibody and 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-21H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide in multiple dosing cycles, wherein each dosing cycle is for at least 2, 3, 4, 5 or 6 weeks, and 500 mg to 3000 mg of the GA101 antibody is administered once per dosing cycle for one or more dosing cycles of the multiple dosing cycles, and 10 mg to 300 mg of 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide is administered each day per dosing cycle for one or more dosing cycles of the multiple dosing cycles. 
     
     
         20 . The method of  claim 19 , wherein both the GA101 antibody and 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide are administered to the patient in at least 2, 3, 4, 5, 6, 7, 8, or more than 8, dosing cycles of the multiple dosing cycles. 
     
     
         21 . The method of  claim 19 , wherein following the last dosing cycle of the multiple dosing cycles, doses of 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide are administered to the patient in the absence of the GA101 antibody being administered to the patient. 
     
     
         22 . The method of  claim 21 , wherein the doses of 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide administered to the patient in the absence of the GA101 antibody are between about 10 mg to about 300 mg 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide. 
     
     
         23 . The method of  claim 22 , wherein the doses of 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl) benzamide administered to the patient in the absence of the GA101 antibody are administered to the patient for at least 3, 4, 5, 6, 7, 8 days, or for 10 or more days, 20 or more days, or 30 or more days. 
     
     
         24 . The method of  claim 19 , wherein the multiple dosing cycles comprise an escalating dosing cycle in which 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenylsulfonyl)benzamide is administered to the patient in escalating daily dose amounts during the escalating dosing cycle. 
     
     
         25 . The method of  claim 24 , wherein the escalating daily dose amounts comprise an initial daily dose amount of 10 mg and a final daily dose amount of 300 mg. 
     
     
         26 . The method of  claim 19 , wherein the cancer is a non-solid tumor. 
     
     
         27 . The method of  claim 19 , wherein the cancer is chronic lymphocytic leukemia (CLL). 
     
     
         28 . The method of  claim 13 , wherein the cancer is non-Hodgkin's lymphoma (NHL). 
     
     
         29 . The method of  claim 13 , wherein the cancer is acute myeloid leukemia (AML).