Combination therapy for cancer

Abstract

This invention relates to a combination of gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate (chemical name: 2′-Deoxy-2′,2′-difluoro-D-cytidine-5′-O-[phenyl (benzoxy-L-alaninyl)] phosphate)(NUC-1031) and a platinum-based anticancer agent selected from carboplatin, oxaliplatin, satraplatin and nedaplatin. The combinations are useful in the treatment of cancer and particularly ovarian cancer.

1 - 27 . (canceled) 
     
     
         28 . A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula 2: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, in combination with carboplatin. 
     
     
         29 . The method of  claim 28 , wherein the compound of Formula 2 comprises greater than about 90% of the diastereomer represented by Formula 3: 
       
         
           
           
               
               
           
         
       
     
     
         30 . The method of  claim 28 , wherein the compound of Formula 2 is a mixture of phosphate diastereoisomers. 
     
     
         31 . The method of  claim 28 , wherein the compound of Formula 2 is not in the form of a salt. 
     
     
         32 . The method of  claim 28 , wherein the compound of Formula 2 is administered intravenously. 
     
     
         33 . The method of  claim 28 , wherein the cancer is selected from the group consisting of pancreatic cancer, breast cancer, ovarian cancer, bladder cancer, colorectal cancer, lung cancer, billiary cancer, prostate cancer, cholangiocarcinoma, renal cancer, lymphoma, leukemia, cervical cancer, thymic cancer, a cancer of an unknown primary origin, esophageal cancer, mesothelioma, adrenal cancer, cancer of the uterus, cancer of the fallopian tube, endometrial cancer, testicular cancer, head and neck cancer, cancer of the central nervous system, and germ cell tumors. 
     
     
         34 . The method of  claim 28 , wherein the cancer is selected from the group consisting of lung cancer, bladder cancer, breast cancer, and ovarian cancer. 
     
     
         35 . The method of  claim 28 , wherein the cancer is relapsed. 
     
     
         36 . The method of  claim 28 , wherein the cancer is refractory, resistant or partially resistant to carboplatin. 
     
     
         37 . The method of  claim 28 , wherein the cancer is sensitive to carboplatin. 
     
     
         38 . The method of  claim 28 , wherein the dose of the compound of Formula 2, or a pharmaceutically acceptable salt thereof administered at each administration event is between 250 mg/m 2  and 1250 mg/m 2 . 
     
     
         39 . The method of  claim 28 , wherein at each administration event the compound of Formula 2, or a pharmaceutically acceptable salt thereof, is administered in a dosage between 300 mg/m 2  and 1000 mg/m 2 . 
     
     
         40 . The method of  claim 28 , wherein at each administration event the compound of Formula 2, or a pharmaceutically acceptable salt thereof, is administered in a dosage between 400 mg/m 2  and 800 mg/m 2 . 
     
     
         41 . The method of  claim 28 , wherein at each administration event carboplatin is administered in a dosage selected to provide an AUC of between 2 and 5.5 mgmL −1  min −1 . 
     
     
         42 . The method of  claim 28 , wherein at each administration event carboplatin is administered in a dosage selected to provide an AUC of between 2.5 and 4.5 mgmL −1  min −1 . 
     
     
         43 . The method of  claim 28 , wherein the compound of Formula 2, or a pharmaceutically acceptable salt thereof, and carboplatin are administered simultaneously. 
     
     
         44 . The method of  claim 28 , wherein the compound of Formula 2, or a pharmaceutically acceptable salt thereof, are administered sequentially. 
     
     
         45 . A pharmaceutical formulation comprising:
 a compound of Formula 2:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 carboplatin, and 
 at least one pharmaceutically acceptable excipient. 
 
     
     
         46 . A kit comprising:
 a first formulation comprising a compound of Formula 2:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient; 
         a second formulation comprising carboplatin, and at least one pharmaceutically acceptable excipient; and 
         instructions for administering the first formulation and the second formulation in combination to a subject having cancer.