Methods for treating pancreatic cancer using combination therapies comprising liposomal irinotecan

Abstract

Provided are methods for treating pancreatic cancer in a patient by administering liposomal irinotecan (MM-398) alone or in combination with additional therapeutic agents. In one embodiment, the liposomal irinotecan (MM-398) is co-administered with 5-fluorouracil and leucovorin.

What is claimed is: 
     
         1 . A method of treating an exocrine pancreatic cancer, the method comprising intravenously administering to a human patient having an exocrine pancreatic cancer 60-80 mg/m 2  of irinotecan in an irinotecan liposome injection formulation having a total volume of 500 mL over about 90 minutes, in combination with a therapeutically effective amount of leucovorin and 5-fluorouracil, to treat the exocrine pancreatic cancer in the patient, the irinotecan liposome injection formulation comprising an irinotecan liposome having irinotecan encapsulated within a liposome comprising phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine, and the irinotecan liposome having a diameter of approximately 80-140 nm. 
     
     
         2 . The method of  claim 1 , wherein the polyethyleneglycol-derivatized phosphatidyl-ethanolamine is in the amount of approximately one polyethyleneglycol molecule for 200 phospholipid molecules in the irinotecan liposome. 
     
     
         3 . The method of  claim 1 , wherein the irinotecan liposome is a unilamellar lipid bilayer vesicle comprising the phosphatidylcholine and cholesterol, encapsulating irinotecan sucrose octasulfate. 
     
     
         4 . The method of  claim 1 , wherein the exocrine pancreatic cancer has progressed on gemcitabine based therapy prior to the administration of the irinotecan liposome. 
     
     
         5 . The method of  claim 1 , further comprising obtaining the irinotecan liposome injection formulation by diluting a solution comprising about 5 mg irinotecan/mL to obtain a dose equivalent of 60-80 mg/m 2  of irinotecan in a volume of 500 mL prior to administration of the irinotecan liposome injection formulation. 
     
     
         6 . The method of  claim 1 , wherein the therapeutically effective amount of leucovorin is 200 mg/m 2  of the (l) form of leucovorin optionally administered as 400 mg/m 2  of the (l+d) racemic form of leucovorin, and the therapeutically effective amount of 5-fluorouracil is 2,400 mg/m 2 . 
     
     
         7 . The method of  claim 6 , wherein the irinotecan liposome, leucovorin and 5-fluorouracil are administered sequentially to the patient beginning on day 1 of a 2-week cycle, resulting in the irinotecan liposome, leucovorin and 5-fluorouracil being simultaneously present in the blood of the patient. 
     
     
         8 . The method of  claim 7 , wherein the irinotecan liposome is administered followed by the leucovorin, followed by the 5-fluorouracil. 
     
     
         9 . The method of  claim 8 , wherein:
 a. the patient has previously been treated with gemcitabine;   b. the leucovorin is administered as 400 mg/m 2  of the (l+d) racemic form of leucovorin;   c. the exocrine pancreatic cancer has progressed on gemcitabine based therapy prior to the administration of the irinotecan liposome;   d. the irinotecan liposome is a unilamellar lipid bilayer vesicle comprising phosphatidylcholine and cholesterol, encapsulating irinotecan sucrose octasulfate; and   e. the irinotecan liposome comprises a polyethyleneglycol-derivatized phosphatidyl-ethanolamine in the amount of approximately one polyethyleneglycol molecule for 200 phospholipid molecules in the irinotecan liposome.   
     
     
         10 . A method of treating an exocrine pancreatic cancer, the method comprising intravenously administering to a patient having an exocrine pancreatic cancer 60-80 mg/m 2  of irinotecan in an irinotecan liposome injection formulation in a total volume of 500 mL over about 90 minutes, in combination with 200 mg/m 2  of the (l)-form of leucovorin or 400 mg/m 2  of the (l+d) racemic form of leucovorin, and 1,800-2,400 mg/m 2  5-fluorouracil to treat the exocrine pancreatic cancer in the human patient. 
     
     
         11 . The method of  claim 10 , wherein the irinotecan liposome encapsulates irinotecan sucrose octasulfate. 
     
     
         12 . The method of  claim 10 , wherein the irinotecan liposome comprises vesicles having a diameter of approximately 80-140 nm encapsulating irinotecan sucrose octasulfate. 
     
     
         13 . The method of  claim 10 , wherein the irinotecan liposome comprises a vesicle enclosing an aqueous space which contains irinotecan complexed in a gelated or precipitated state as a salt with the sucrose octasulfate. 
     
     
         14 . The method of  claim 10 , wherein the irinotecan liposome comprises phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine in the amount of approximately one polyethyleneglycol molecule for 200 phospholipid molecules in the irinotecan liposome. 
     
     
         15 . The method of  claim 10 , wherein the irinotecan liposome is a unilamellar lipid bilayer vesicle comprising the phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine in the amount of approximately one polyethyleneglycol for 200 phospholipid molecules in the irinotecan liposome. 
     
     
         16 . The method of  claim 10 , wherein the patient has previously been treated with gemcitabine. 
     
     
         17 . The method of  claim 10 , wherein the exocrine pancreatic cancer has progressed on gemcitabine based therapy prior to the administration of the irinotecan liposome. 
     
     
         18 . The method of  claim 10 , further comprising obtaining the irinotecan liposome injection formulation by diluting a solution comprising about 5 mg irinotecan/mL to obtain a dose equivalent of 60-80 mg/m 2  in a volume of 500 mL prior to administration of the irinotecan liposome injection formulation. 
     
     
         19 . The method of  claim 18 , further comprising storing the irinotecan liposome injection formulation at a temperature of about 2-8° C. for no more than 24 hours prior to administration. 
     
     
         20 . A method of treating an exocrine pancreatic cancer in a human patient who has previously been treated with gemcitabine, the method comprising intravenously administering to the patient 60-80 mg/m 2  of irinotecan in an irinotecan liposome injection formulation in a total volume of 500 mL, in combination with 400 mg/m 2  of the (l+d) racemic form of leucovorin and 2,400 mg/m 2  5-fluorouracil to treat the exocrine pancreatic cancer in the patient, the irinotecan liposome injection formulation comprising irinotecan sucrose octasulfate encapsulated within a liposome comprising phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine, and having a diameter of approximately 80-140 nm, wherein the irinotecan liposome, leucovorin and 5-fluorouracil are administered sequentially to the patient beginning on day 1 of a 2-week cycle.