Method for treating cancer using camptothecin derivatives and 5-fluorouracil

Abstract

A combination therapy for treating cancer including administering at least one camptothecin derivative in conjunction with another anticancer agent. The combination therapy is preferably used as a first-line therapy for treating metastatic colorectal cancer and preferably involves administration of a combination of CPT-11, 5-fluorouracil and folinic acid, according to specific infusional treatment schedules which show therapeutic synergy in the treatment of cancer.

What is claimed is:  
     
         1 . A method for treating a cancer in a patient comprising administration of a combination of at least one camptothecin derivative, 5-fluorouracil (5-FU) and folinic acid (FA) to said patient in an amount and in a schedule of administration that is therapeutically synergistic in the treatment of said cancer and wherein said cancer is colon, rectal or colorectal cancer.  
     
     
         2 . The method as set forth in  claim 1  wherein said cancer is colorectal cancer.  
     
     
         3 . The method as set forth in  claim 1  wherein said cancer is colon cancer.  
     
     
         4 . The method as set forth in  claim 1  wherein said cancer is rectal cancer.  
     
     
         5 . The method as set forth in  claim 1  wherein said patient is having at least about twenty percent metastatic cancer.  
     
     
         6 . The method as set forth in  claim 1  wherein the administration of the combination is by infusion.  
     
     
         7 . The method as set forth in  claim 1  wherein the administration of the combination is by injection.  
     
     
         8 . The method as set forth in  claim 1  wherein the combination is administered intravenously.  
     
     
         9 . The method as set forth in  claim 1  wherein the combination is administered orally.  
     
     
         10 . The method as set forth in  claim 1  wherein said camptothecin derivative is of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is selected from hydrogen, halogen and alkyl;  
 X is selected from chlorine and NR 2 R 3 , wherein R 2  and R 3 , which may be identical or different, are selected independently from hydrogen, optionally substituted alkyl, carbocycle and heterocycle which are optionally substituted, and optionally substituted alkyl forms with the nitrogen atom to which it is attached a heterocycle optionally containing another heteroatom selected from O, S or NR 4 , R 4  being selected from hydrogen and alkyl.  
 
     
     
         11 . The method as set forth in  claim 10  wherein the group X—CO—O— is located at position 9, 10 or 11 on ring A.  
     
     
         12 . The method as set forth in  claim 10  wherein X—CO—O— is [4-(1-piperidino)-1-piperidino]carbonyloxy.  
     
     
         13 . The method as set forth in  claim 1  wherein said camptothecin derivative is CPT-11.  
     
     
         14 . The method as set forth in  claim 13 , wherein said schedule comprises a cycle of: administering FA 500 mg/m 2  i.v. over 2 hours followed by the administration of 5-FU (from 2300 to 2600 mg/m 2 ) i.v. and 80 mg/m 2  of CPT-11 over 24 hours, once a week for 6 weeks, followed by a one week rest; and repeating said cycle until a progression or an unacceptable toxicity is observed.  
     
     
         15 . The method as set forth in  claim 14 , wherein said method is a first-line therapy for metastatic colorectal cancer.  
     
     
         16 . The method as set forth in  claim 14 , wherein said method is a first-line therapy for metastatic colon cancer.  
     
     
         17 . The method as set forth in  claim 14 , wherein said method is a first-line therapy for metastatic rectal cancer.  
     
     
         18 . The method as set forth in  claim 13 , wherein said schedule comprises administering a two-week cycle wherein: 200 mg/m 2  of folinic acid is administered i.v. over two hours on days one and two of said two-week cycle, 400 mg/m 2  of 5-FU is administered by i.v. bolus on day one of said two-week cycle and 600 mg/m 2  of said 5-FU is administered i.v. over 22 hours on day one of said two-week cycle, and 180 mg/m 2  of CPT-11 is administered i.v. on day one of said two week cycle; and said two-week cycle is repeated until a progression or an unacceptable toxicity is observed.  
     
     
         19 . The method as set forth in  claim 18 , wherein said method is a first-line therapy for metastatic colorectal cancer.  
     
     
         20 . The method as set forth in  claim 1 , wherein said at least one camptothecin derivative is CPT-11 and is administered orally at the dose of from about 60 to 70 mg/m 2  daily for five consecutive days, said schedule of CPT-11 administration being reproduced every three weeks.