METHODS FOR TREATING PANCREATIC CANCER USING COMBINATION THERAPIES COMPRISING LIPOSOMAL IRINOTECAN
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.
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.