Anti-angiogenesis therapy for the treatment of ovarian cancer

Abstract

This invention concerns in general treatment of diseases and pathological conditions with anti-VEGF antibodies. More specifically, the invention concerns the treatment of human patients susceptible to or diagnosed with cancer using an anti-VEGF antibody, preferably in combination with one or more additional anti-tumor therapeutic agents for the treatment of ovarian cancer.

What is claimed is: 
     
         1 . A method of treating a patient diagnosed with ovarian cancer, comprising subjecting the patient to a treatment regimen combining a chemotherapy with the administration of an effective amount of an anti-VEGF antibody followed by anti-VEGF maintenance therapy, wherein the chemotherapy of the treatment regimen comprises administration of at least one chemotherapeutic agent, and wherein the treatment regimen effectively extends the progression free survival of the patient. 
     
     
         2 . The method of  claim 1 , wherein the chemotherapeutic agent is taxane, paclitaxel, docetaxel, paclitaxel protein-bound particles (e.g., Abraxane®), platinum analogue, carboplatin, gemcitabine, or combinations thereof. 
     
     
         3 . The method of  claim 1 , wherein the chemotherapy of the treatment regimen comprises administration of taxane and carboplatin. 
     
     
         4 . The method of  claim 1 , wherein the chemotherapy of the treatment regimen comprises administration of carboplatin and gemcitabine. 
     
     
         5 . The method of  claim 1 , wherein the patient is diagnosed with previously untreated ovarian cancer. 
     
     
         6 . The method of  claim 1 , wherein the patient is diagnosed with recurrent ovarian cancer. 
     
     
         7 . The method of  claim 1 , wherein said anti-VEGF antibody binds the same epitope as the monoclonal anti-VEGF antibody A4.6.1 produced by hybridoma ATCC HB 10709. 
     
     
         8 . The method of  claim 1 , wherein the anti-VEGF antibody is a humanized antibody. 
     
     
         9 . The method of  claim 8 , wherein the anti-VEGF antibody is a humanized A4.6.1 antibody or fragment thereof. 
     
     
         10 . The method of  claim 8 , wherein the anti-VEGF antibody is bevacizumab. 
     
     
         11 . The method of  claim 1 , wherein the anti-VEGF antibody is bevacizumab and the chemotherapy of the treatment regimen comprises administration of capecitabine and paclitaxel or docetaxel. 
     
     
         12 . The method of  claim 1 , wherein the anti-VEGF antibody is bevacizumab and the chemotherapy of the treatment regimen comprises administration of carboplatin and gemcitabine. 
     
     
         13 . The method of  claim 1 , wherein the progression free survival of the patient is extended by at least about 3.8 month or more when compared to another patient not treated with the anti-VEGF maintenance therapy. 
     
     
         14 . The method of  claim 8 , wherein the anti-VEGF antibody has a heavy chain variable region comprising the following amino acid sequence: 
       
         
           
                 
               
                   (SEQ ID NO. 1) 
                 
                   EVQLVESGGG LVQPGGSLRL SCAASGYTFT NYGMNWVRQA  
                 
                     
                 
                   PGKGLEWVGW INTYTGEPTY AADFKRRFTF SLDTSKSTAY   
                 
                     
                 
                   LQMNSLRAED TAVYYCAKYP HYYGSSHWYF DVWGQGTLVT VSS 
                 
             
                
                
                
                
                
                
               
            
           
         
         and a light chain variable region comprising the following amino acid sequence: 
       
       
         
           
                 
                 
               
                     
                   (SEQ ID NO. 2) 
                 
                     
                   DIQMTQSPSS LSASVGDRVT ITCSASQDIS NYLNWYQQKP 
                 
                     
                     
                 
                     
                   GKAPKVLIYF TSSLHSGVPS RFSGSGSGTD FTLTISSLQP 
                 
                     
                     
                 
                     
                   EDFATYYCQQ YSTVPWTFGQ GTKVEIKR. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         15 . The method of  claim 2 , wherein the paclitaxel is administered as in  FIG. 1  or  FIG. 2 . 
     
     
         16 . The method of  claim 2 , wherein the carboplatin is administered as in  FIG. 1  or  FIG. 2  or  FIG. 11 . 
     
     
         17 . The method of  claim 2 , wherein the docetaxel is administered as in  FIG. 1 . 
     
     
         18 . The method of  claim 2 , wherein the gemcitabine is administered as in  FIG. 11 . 
     
     
         19 . The method of  claim 2 , wherein the anti-VEGF is administered as in arm III of  FIG. 1  or  FIG. 2  or as in arm II of Example 3. 
     
     
         20 . A kit for treating previously untreated ovarian cancer in a human patient comprising a package comprising an anti-VEGF antibody composition and instructions for using the anti-VEGF antibody composition in combination with taxane therapy and carboplatin followed by anti-VEGF maintenance therapy, wherein the instructions recite that the progression free survival for patients receiving taxane therapy and carboplatin therapy and bevacizumab is 14.1 months with a hazard ratio of 0.717 (p-value<0.0001). 
     
     
         21 . The kit of any one of  claims 20 , wherein the anti-VEGF antibody has a heavy chain variable region comprising the following amino acid sequence: 
       
         
           
                 
               
                   (SEQ ID No. 1) 
                 
                   EVQLVESGGG LVQPGGSLRL SCAASGYTFT NYGMNWVRQA 
                 
                     
                 
                   PGKGLEWVGW INTYTGEPTY AADFKRRFTF SLDTSKSTAY 
                 
                     
                 
                   LQMNSLRAED TAVYYCAKYP HYYGSSHWYF DVWGQGTLVT VSS 
                 
             
                
                
                
                
                
                
               
            
           
         
         and a light chain variable region comprising the following amino acid sequence: 
       
       
         
           
                 
                 
               
                     
                   (SEQ ID No. 2) 
                 
                     
                   DIQMTQSPSS LSASVGDRVT ITCSASQDIS NYLNWYQQKP 
                 
                     
                     
                 
                     
                   GKAPKVLIYF TSSLHSGVPS RFSGSGSGTD FTLTISSLQP 
                 
                     
                     
                 
                     
                   EDFATYYCQQ YSTVPWTFGQ GTKVEIKR. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         22 . The kit of  claim 20 , wherein the anti-VEGF antibody is bevacizumab. 
     
     
         23 . The kit of  claim 20 , wherein the patient has stage III or IV ovarian cancer. 
     
     
         24 . A method of instructing a human subject with ovarian cancer, the method comprising providing instructions to receive ovarian cancer treatment with an anti-VEGF antibody concurrent with chemotherapy followed by anti-VEGF maintenance therapy so as to increase progression free survival of the subject. 
     
     
         25 . The method of  claim 24 , wherein the instructions further comprise providing instructions to receive treatment with at least two chemotherapeutic agent. 
     
     
         26 . A promotional method, comprising promoting administration of an anti-VEGF antibody concurrent with chemotherapy followed by anti-VEGF maintenance therapy for treatment of ovarian cancer in a human subject so as to increase progression free survival of the subject. 
     
     
         27 . The method of  claim 26 , wherein the method further comprises promoting the administration of at least two chemotherapeutic agents. 
     
     
         28 . The method of  claim 26 , wherein the promotion is by a package insert, wherein the package insert provides instructions to receive cancer treatment with an anti-VEGF antibody. 
     
     
         29 . The method of  claim 26 , wherein the promotion is by a package insert accompanying a commercial formulation of the anti-VEGF antibody. 
     
     
         30 . The method of  claim 26 , wherein the promotion is by a package insert accompanying a commercial formulation of the chemotherapeutic agents. 
     
     
         31 . The method of  claim 26 , wherein the promotion is by written communication to a physician or health care provider. 
     
     
         32 . The method of  claim 26 , wherein the promotion is by oral communication to a physician or health care provider. 
     
     
         33 . The method of  claim 26 , wherein the promotion is followed by the treatment of the subject with the anti-VEGF antibody and the chemotherapeutic agents follow by anti-VEGF maintenance therapy. 
     
     
         34 . A business method, comprising marketing an anti-VEGF antibody therapy concurrent with chemotherapy followed by anti-VEGF maintenance therapy for treatment of ovarian cancer in a human subject so as to increase progression free survival of the subject. 
     
     
         35 . The method of  claim 34 , wherein the marketing is followed by treatment of the subject with the anti-VEGF antibody concurrent with chemotherapy followed by anti-VEGF maintenance therapy. 
     
     
         36 . The method of any one of  claims 24 ,  26  or  34 , wherein the chemotherapeutic agent is taxane, paclitaxel, docetaxel, paclitaxel protein-bound particles (e.g., Abraxane®), platinum analogue, carboplatin, gemcitabine, or combinations thereof. 
     
     
         37 . The method of any one of  claims 24 ,  26  or  36 , wherein the anti-VEGF antibody is bevacizumab. 
     
     
         38 . The method of  claim 1 , wherein the chemotherapy of the treatment regimen comprises administration of paclitaxel and carboplatin. 
     
     
         39 . The method of  claim 1 , wherein the anti-VEGF antibody is bevacizumab and the chemotherapy of the treatment regimen comprises administration of paclitaxel and carboplatin. 
     
     
         40 . The method  claim 1 , wherein the progression free survival of the patient is extended by at least about 2.3 months or more compared to another patient not treated with anti-VEGF antibody. 
     
     
         41 . The method of  claim 2 , wherein the paclitaxel is administered as in  FIG. 8 . 
     
     
         42 . The method of  claim 2 , wherein the carboplatin is administered as in  FIG. 8 . 
     
     
         43 . The method of  claim 2 , wherein the anti-VEGF antibody is administered as in Arm B of  FIG. 8 . 
     
     
         44 . A kit for treating previously untreated ovarian cancer in a human patient comprising a package comprising an anti-VEGF antibody composition and instructions for using the anti-VEGF antibody composition in combination with paclitaxel and carboplatin followed by anti-VEGF maintenance therapy, wherein the instructions recite that the progression free survival for patients receiving paclitaxel, carboplatin and anti-VEGF antibody is 18.3 months with a hazard ratio of 0.79.