Claims for Patent: 9,492,442

Summary for Patent: 9,492,442

Title:	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.
Inventor(s):	Bayever; Eliel (Cambridge, MA), Dhindsa; Navreet (Boston, MA), Fitzgerald; Jonathan Basil (Arlington, MA), Laivins; Peter (Scituate, MA), Moyo; Victor (Ringoes, NJ), Niyikiza; Clet (Gulph Mills, PA), Kim; Jaeyeon (Lexington, MA)
Assignee:	Merrimack Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	14/851,111
Patent Claims:	1. A method of treating an exocrine pancreatic cancer, the method comprising intravenously administering an antineoplastic therapy once every two weeks to a human patient having the exocrine pancreatic cancer, the antineoplastic therapy consisting of: a. administering a 60-80 mg/m.sup.2 dose of a liposomal irinotecan composition in a diluted irinotecan injection formulation to the human patient in a single infusion over about 90 minutes, the diluted irinotecan injection formulation comprising irinotecan liposomes in 500 mL of an injectable liquid and a volume of a 5 mg/mL liposomal irinotecan composition effective to deliver the dose of liposomal irinotecan, in combination with b. administering a therapeutically effective amount of leucovorin and 5-fluorouracil, to treat the exocrine pancreatic cancer in the patient, wherein the irinotecan liposome composition comprises phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine, and the irinotecan liposomes in the liposomal irinotecan composition have 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 every 200 phospholipid molecules in the irinotecan liposomes. 3. The method of claim 1, wherein the liposomal irinotecan composition comprises liposomes that are unilamellar lipid bilayer vesicles 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, wherein the therapeutically effective amount of leucovorin is 200 mg/m.sup.2 of the (1) form of leucovorin optionally administered as 400 mg/m.sup.2 of the (l+d) racemic form of leucovorin, and the therapeutically effective amount of 5-fluorouracil is a 2,400 mg/m.sup.2 dose. 6. The method of claim 5, wherein the diluted irinotecan injection formulation, leucovorin and 5-fluorouracil are administered sequentially to the patient beginning on day 1 of a 2-week cycle, resulting in the irinotecan liposomes, leucovorin and 5-fluorouracil being simultaneously present in the blood of the patient. 7. The method of claim 6, wherein the diluted irinotecan injection formulation is administered to the patient prior to the 5-fluorouracil. 8. The method of claim 7, wherein: a. the patient has previously been treated with gemcitabine; b. the leucovorin is administered as 400 mg/m.sup.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 diluted irinotecan injection formulation; d. the irinotecan liposome composition comprises liposomes that are unilamellar lipid bilayer vesicles comprising phosphatidylcholine and cholesterol, encapsulating irinotecan sucrose octasulfate; and e. the irinotecan liposome composition comprises a polyethyleneglycol-derivatized phosphatidyl-ethanolamine in the amount of approximately one polyethyleneglycol molecule for every 200 phospholipid molecules in the irinotecan liposome composition. 9. The method of claim 1, further comprising storing the diluted irinotecan injection formulation at a temperature of about 2-8.degree. C. for no more than 24 hours prior to administration. 10. 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 an antineoplastic therapy consisting of: a. a 60-80 mg/m.sup.2 dose of liposomal irinotecan composition comprising irinotecan liposomes in a diluted irinotecan injection formulation, the diluted irinotecan injection formulation obtained by diluting a volume of the liposomal irinotecan composition containing 5 mg/mL of liposomal irinotecan into 500 mL of an injectable liquid, in combination with b. a 200 mg/m.sup.2 dose of the (1) form of leucovorin and a 2,400 mg/m.sup.2 dose of 5-fluorouracil, to treat the exocrine pancreatic cancer in the patient, the irinotecan liposome composition comprising irinotecan sucrose octasulfate encapsulated within the irinotecan composition liposomes comprising phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine, and having a diameter of approximately 80-140 nm, wherein the diluted irinotecan injection formulation, leucovorin and 5-fluorouracil are administered sequentially to the patient beginning on day 1 of a 2-week cycle. 11. The method of claim 10, further comprising storing the diluted irinotecan injection formulation at a temperature of about 2-8.degree. C. for no more than 24 hours prior to administration. 12. The method of claim 11, wherein the irinotecan liposome composition comprises approximately one polyethyleneglycol (PEG) molecule for every 200 phospholipid molecules. 13. The method of claim 12, wherein the patient has failed prior treatment with gemcitabine or become resistant to gemcitabine prior to administration of the diluted irinotecan injection formulation. 14. The method of claim 13, wherein the 200 mg/m.sup.2 dose of the (1) form of leucovorin is provided by administering a 400 mg/m.sup.2 dose of the (l+d) form of leucovorin. 15. The method of claim 14, wherein the dose of liposomal irinotecan dose is 60 mg/m.sup.2, 70 mg/m.sup.2 or 80 mg/m.sup.2. 16. The method of claim 15, wherein the dose of liposomal irinotecan dose is 80 mg/m.sup.2 and the human patient is not homozygous for the UGT1A1*28 allele. 17. The method of claim 16, wherein the liposomal irinotecan is administered as the diluted irinotecan injection as a 90-minute infusion, the leucovorin is administered after the irinotecan over 30 minutes and the 5-fluorouracil is administered after the leucovorin over 46 hours. 18. The method of claim 17, wherein the irinotecan liposomes are a unilamellar lipid bilayer vesicle that encapsulates an aqueous space which contains irinotecan in a gelated or precipitated state with sucrose octasulfate salt of irinotecan. 19. A method of treating pancreatic cancer in a human patient, whose cancer has progressed following gemcitabine based therapy, the method comprising administering an antineoplastic therapy to the human patient once every two weeks, the antineoplastic therapy consisting of intravenously administering to the human patient: a diluted irinotecan injection formulation providing a 60, 70 or 80 mg/m.sup.2 dose of liposomal irinotecan, in combination with a 200 mg/m.sup.2 dose of the (1) form of leucovorin and a 2,400 mg/m.sup.2 dose of 5-fluorouracil to treat the pancreatic cancer in the human patient, wherein a. the liposomes in the diluted irinotecan injection formulation have a diameter of approximately 80-140 nm, and comprise phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine; and b. the diluted irinotecan injection formulation comprises the liposomal irinotecan in 500 mL of an injectable liquid stored at a temperature of about 2-8.degree. C. for no more than 24 hours prior to each administration. 20. The method of claim 19, wherein the diluted irinotecan injection formulation comprises 500 mL of the injectable liquid and a volume of a 5 mg/mL liposomal irinotecan composition, wherein the volume is calculated to deliver the dose of liposomal irinotecan. 21. The method of claim 19, wherein a 80 mg/m.sup.2 dose of liposomal irinotecan is administered to a human patient who is not homozygous for the UGT1A1*28 allele; and the 200 mg/m.sup.2 dose of the (1) form of leucovorin is provided by administering a 400 mg/m.sup.2 dose of the (l+d) form of leucovorin. 22. The method of claim 21, wherein the method further comprises administering an anti-emetic to the patient prior to administering the antineoplastic therapy; and the liposomal irinotecan is administered as the diluted irinotecan injection formulation as a single 90-minute infusion, the leucovorin dose is administered after the liposomal irinotecan over 30minutes and the 5-fluorouracil dose is administered after the leucovorin over 46 hours. 23. The method of claim 1, wherein the irinotecan liposomes are a unilamellar lipid bilayer vesicle that encapsulates an aqueous space which contains irinotecan in a gelated or precipitated state with sucrose octasulfate salt of irinotecan. 24. The method of claim 23, wherein the injectable liquid is 5% dextrose injection. 25. The method of claim 10, wherein the irinotecan liposomes are a unilamellar lipid bilayer vesicle that encapsulates an aqueous space which contains irinotecan in a gelated or precipitated state with sucrose octasulfate salt of irinotecan. 26. The method of claim 25, wherein the injectable liquid is 5% dextrose injection. 27. The method of claim 19, wherein the irinotecan liposomes are a unilamellar lipid bilayer vesicle that encapsulates an aqueous space which contains irinotecan in a gelated or precipitated state with sucrose octasulfate salt of irinotecan. 28. The method of claim 27, wherein the injectable liquid is 5% dextrose injection. 29. A method of treating metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy in a human patient who is not homozygous for the UGT1A1*28 allele, the method comprising the following steps performed once every two weeks: a. diluting a volume of a 5 mg/mL liposomal irinotecan composition in 500 mL of an injectable liquid, to obtain a diluted irinotecan injection formulation, then b. optionally storing the diluted irinotecan injection formulation at a temperature of about 2-8.degree. C. for no more than 24 hours prior to administration; then c. administering an antineoplastic therapy to the human patient, the antineoplastic therapy consisting of intravenously administering to the human patient: the diluted irinotecan injection formulation providing a 80 mg/m.sup.2 dose of liposomal irinotecan to the human patient, in combination with a 200 mg/m.sup.2 dose of the (1) form of leucovorin and a 2,400 mg/m.sup.2 dose of 5-fluorouracil, to treat the pancreatic cancer in the human patient; the liposomes in the liposomal irinotecan composition having a diameter of approximately 80-140 nm, and comprising a unilamellar lipid bilayer vesicle that encapsulates an aqueous space which contains irinotecan in a gelated or precipitated state with sucrose octasulfate salt of irinotecan, the unilamellar lipid bilayer comprising phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine. 30. The method of claim 29, wherein the injectable liquid is 5% dextrose injection.