Methods for treating pancreatic cancer using combination therapies

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 a solid tumor in a patient, the method comprising administering to the patient in need thereof once every two weeks a single dose of 50-150 mg/m 2  irinotecan (free base) in an intravenous pharmaceutical formulation comprising liposomal irinotecan having a total irinotecan half life of 25.8 hours, wherein the Cmax in the plasma and the Area Under the plasma concentration Curve (AUC) linearly increase with the dose of the liposomal irinotecan. 
     
     
         2 . The method of  claim 1 , wherein the liposomal irinotecan administered to the patient is converted to the metabolite SN-38 with a Cmax in plasma that increases proportionally with the dose of total irinotecan administered to the patient in the liposomal irinotecan. 
     
     
         3 . The method of  claim 2 , wherein the liposomal irinotecan administered to the patient is converted to the metabolite SN-38 and the total AUC of SN-38 in the plasma increases less than proportionally with the dose of total irinotecan administered to the patient in the liposomal irinotecan. 
     
     
         4 . The method of  claim 1 , wherein the liposomal irinotecan administered to the patient is converted to the metabolite SN-38 and the total AUC of SN-38 in the plasma increases less than proportionally with the dose of total irinotecan administered to the patient in the liposomal irinotecan. 
     
     
         5 . The method of  claim 1 , wherein the total irinotecan Cmax in plasma is 37.2 μg/mL. 
     
     
         6 . The method of  claim 1 , wherein the total irinotecan AUC in plasma is 1364 h·μg/mL. 
     
     
         7 . The method of  claim 1 , wherein the total irinotecan Volume of Distribution in plasma is 4.1 L. 
     
     
         8 . The method of  claim 1 , wherein the liposomal irinotecan administered to the patient is converted to the metabolite SN-38, and wherein the total SN-38 AUC in plasma is 620 h·ng/mL 
     
     
         9 . The method of  claim 1 , wherein the liposomal irinotecan administered to the patient is converted to the metabolite SN-38, wherein the total SN-38 Cmax in plasma is 5.4 ng/mL. 
     
     
         10 . The method of  claim 1 , wherein a total of 60-100 mg/m 2  irinotecan (free base) dose of the liposomal irinotecan is administered once every two weeks. 
     
     
         11 . The method of  claim 10 , wherein at least 95% of the total irinotecan remains liposome encapsulated and the ratio between total and encapsulated irinotecan does not change with time from administration to 169.5 hours post administration. 
     
     
         12 . A method of treating a solid tumor in a patient, the method comprising administering to the patient in need thereof once every two weeks a single dose of 50-150 mg/m 2  irinotecan (free base) in an intravenous pharmaceutical formulation comprising liposomal irinotecan to treat the solid tumor in the patient, wherein
 a. the Cmax in the plasma and the Area under the plasma concentration curve (AUC) linearly increase with the dose of the liposomal irinotecan; and   b. the liposomal irinotecan administered to the patient is converted to the metabolite SN-38 with a Cmax in plasma that increases proportionally with the dose of total irinotecan administered to the patient in the liposomal irinotecan.   
     
     
         13 . The method of  claim 12 , wherein a total of 60-100 mg/m 2  irinotecan (free base) dose of the liposomal irinotecan is administered once every two weeks. 
     
     
         14 . The method of  claim 12 , wherein at least 95% of the total irinotecan remains liposome encapsulated and the ratio between total and encapsulated irinotecan does not change with time from administration to 169.5 hours post administration. 
     
     
         15 . The method of  claim 12 , wherein the total irinotecan Cmax in plasma is 29.8-46.5 μg/mL, the total irinotecan AUC in plasma is 1091-1705 hug/mL. 
     
     
         16 . The method of  claim 12 , wherein the ratio of the total SN-38 AUC in plasma to the total SN-38 Cmax in plasma is (620 h·ng/mL)/(5.4 ng/mL). 
     
     
         17 . A method of treating a solid tumor in a patient, the method comprising administering to the patient in need thereof once every two weeks a single dose of 50-150 mg/m 2  irinotecan (free base) in an intravenous pharmaceutical formulation comprising liposomal irinotecan to treat the solid tumor in the patient, wherein the liposomal irinotecan administered to the patient is converted to the irinotecan metabolite SN-38 within the patient, and wherein
 a. the total irinotecan Cmax in plasma is 29.8-46.5 μg/mL, the total irinotecan AUC in plasma is 1091-1705 h·μg/mL; and   b. the ratio of the total SN-38 AUC in plasma to the total SN-38 Cmax in plasma is (620 h·ng/mL)/(5.4 ng/mL).   
     
     
         18 . The method of  claim 17 , wherein the Cmax in the plasma and the Area Under the plasma Concentration curve (AUC) linearly increase with the dose of the liposomal irinotecan, or the total SN-38 Cmax in plasma increases proportionally with the dose of total irinotecan administered to the patient in the liposomal irinotecan. 
     
     
         19 . The method of  claim 18 , wherein at least 95% of the total irinotecan remains liposome encapsulated and the ratio between total and encapsulated irinotecan does not change with time from administration to 169.5 hours post administration. 
     
     
         20 . The method of  claim 19 , wherein a total of 60-100 mg/m 2  irinotecan (free base) dose of the liposomal irinotecan is administered once every two weeks.