Claims for Patent: 9,452,162

Summary for Patent: 9,452,162

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 (New York, NY), Dhindsa; Navreet (Boston, MA), Fitzgerald; Jonathan Basil (Cambridge, MA), Laivins; Peter (Rowayton, CT), Moyo; Victor (Concord, MA), Niyikiza; Clet (Gulph Mills, PA), Kim; Jaeyeon (Lexington, MA)
Assignee:	Merrimack Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	14/406,776
Patent Claims:	1. A method of treating pancreatic cancer in a human patient who has previously been treated with gemcitabine, the method comprising intravenously administering to the patient in need thereof an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of: a. 60-80 mg/m.sup.2 of liposomal irinotecan composition comprising irinotecan liposomes, the irinotecan liposomes in the liposomal irinotecan composition having a diameter of approximately 80-140 nm and an irinotecan terminal elimination half-life in the patient of about 21-48 hours, wherein the irinotecan liposomes comprise phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine; b. 200 mg/m.sup.2 of the (l) form of leucovorin; and c. 2,400 mg/m.sup.2 of 5-fluorouracil. 2. The method of claim 1, wherein the irinotecan liposomes comprise approximately one polyethyleneglycol (PEG) molecule for every 200 phospholipid molecules. 3. The method of claim 1, wherein the irinotecan is converted to SN-38 and the AUC of total SN-38 increases less than proportionally with the dose of the liposomal irinotecan. 4. The method of claim 1, wherein the patient has failed prior treatment with gemcitabine or become resistant to gemcitabine prior to administration of the liposomal irinotecan composition. 5. The method of claim 4, wherein the irinotecan liposomes comprise approximately one polyethyleneglycol (PEG) molecule for every 200 phospholipid molecules. 6. The method of claim 1, wherein the 200 mg/m.sup.2 of the (l) form of leucovorin is provided by administering 400 mg/m.sup.2 of the (l+d) form of leucovorin. 7. A method of treating pancreatic cancer in a human patient who has previously been treated with gemcitabine, the method comprising intravenously administering to the patient in need thereof an antineoplastic therapy comprising one or more two-week treatment cycles, each two-week treatment cycle consisting of the administration, starting on the first day of each two-week treatment cycle of: a. 60-80 mg/m.sup.2 of liposomal irinotecan composition comprising irinotecan liposomes, the irinotecan liposomes in the liposomal irinotecan composition having a diameter of approximately 80-140 nm and an irinotecan terminal elimination half-life in the patient of about 21 to 48 hours, wherein the irinotecan liposomes comprise irinotecan encapsulated in a unilamellar lipid bilayer vesicle composed of phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine; the irinotecan liposomes administered in combination with b. 200 mg/m.sup.2 of the (l) form of leucovorin; and c. 2,400 mg/m.sup.2 of 5-fluorouracil. 8. The method of claim 7, wherein the irinotecan liposomes comprise approximately one polyethyleneglycol (PEG) molecule for every 200 phospholipid molecules. 9. A method of treating pancreatic cancer in a human patient who has previously been treated with gemcitabine, the method comprising intravenously administering to the patient in need thereof an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of: a. 60, 70 or 80 mg/m.sup.2 of liposomal irinotecan composition comprising irinotecan liposomes, the irinotecan liposomes in the liposomal irinotecan composition having a diameter of about 80-140 nm and an irinotecan terminal elimination half-life in the patient of about 21 to 48 hours, wherein the irinotecan liposomes comprise irinotecan encapsulated in a unilamellar lipid bilayer vesicle composed of phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine; and then administering b. 200 mg/m.sup.2 of the (l) form of leucovorin over 30 minutes; and then administering c. 2,400 mg/m.sup.2 of 5-fluorouracil over 46 hours; wherein the irinotecan is converted to SN-38 within the human patient and the AUC of the SN-38 increases less than proportionally with the dose of the liposomal irinotecan. 10. The method of claim 6, wherein administration of liposomal irinotecan is administered as an infusion over 90 minutes. 11. The method of claim 10, wherein after the irinotecan is administered: the leucovorin is administered over 30 minutes and the 5-fluorouracil is administered over 46 hours. 12. The method of claim 11, wherein the dose of liposomal irinotecan is 80 mg/m.sup.2 and the human patient is not homozygous for the UGT1A1*28 allele. 13. The method of claim 7, wherein the 200 mg/m.sup.2 of the (l) form of leucovorin is provided by administering 400 mg/m.sup.2 of the (l+d) form of leucovorin. 14. The method of claim 13, wherein the irinotecan is administered in an infusion over 90 minutes, the leucovorin is administered after the irinotecan over 30 minutes, and the 5-fluorouracil is administered after the leucovorin over 46 hours. 15. The method of claim 14, wherein the dose of liposomal irinotecan is 80 mg/m.sup.2, and the human patient is not homozygous for the UGT1A1*28 allele. 16. The method of claim 9, wherein the 200 mg/m.sup.2 of the (l) form of leucovorin is provided by administering 400 mg/m.sup.2 of the (l+d) form of leucovorin. 17. The method of claim 16, wherein the irinotecan is administered in an infusion over 90 minutes, 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 antineoplastic therapy comprises at least three two-week treatment cycles. 19. A method of treating pancreatic cancer in a human patient who has previously been treated with gemcitabine, the method comprising intravenously administering to the patient in need thereof an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of: a single dose of 60, 70 or 80 mg/m.sup.2 of a liposomal irinotecan composition comprising irinotecan liposomes, administered in combination with 200 mg/m.sup.2 of the (l) form of leucovorin and 2,400 mg/m.sup.2 of 5-fluorouracil, to treat the pancreatic cancer in the human patient. 20. The method of claim 19, wherein the irinotecan liposomes have a diameter of about 80-140 nm and an irinotecan terminal elimination half-life in the patient of at least about 2-fold higher than that of 125 mg/m.sup.2 free irinotecan as CPT-11 irinotecan hydrochloride injection. 21. The method of claim 19, wherein the irinotecan liposomes comprise irinotecan encapsulated in a unilamellar lipid bilayer vesicle composed of phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine, and the 200 mg/m.sup.2 of the (l) form of leucovorin is provided by administering 400 mg/m.sup.2 of the (l+d) form of leucovorin. 22. The method of claim 21, wherein the irinotecan liposomes have an irinotecan terminal elimination half-life in the patient of about 21 to 48 hours. 23. The method of claim 22, wherein the irinotecan is converted to SN-38 within the human patient and the AUC of the SN-38 increases less than proportionally with the dose of the liposomal irinotecan. 24. The method of claim 7, wherein the irinotecan is converted to SN-38 within the human patient and the AUC of the SN-38 increases less than proportionally with the dose of the liposomal irinotecan. 25. The method of claim 1, wherein 80 mg/m.sup.2 of liposomal irinotecan is administered to a human patient who is not homozygous for the UGT1A1*28 allele, and the 5-fluorouracil is administered over 46 hours starting on the first day of each two week treatment cycle. 26. The method of claim 7, wherein 80 mg/m.sup.2 of liposomal irinotecan is administered to a human patient who is not homozygous for the UGT1A1*28 allele. 27. The method of claim 9, wherein 80 mg/m.sup.2 of liposomal irinotecan is administered to a human patient who is not homozygous for the UGT1A1*28 allele. 28. The method of claim 19, wherein 80 mg/m.sup.2 of liposomal irinotecan is administered to a human patient who is not homozygous for the UGT1A1*28 allele. 29. The method of claim 23, wherein 80 mg/m.sup.2 of liposomal irinotecan is administered to a human patient who is not homozygous for the UGT1A1*28 allele, and the method comprises administering the liposomal irinotecan over a 90 minute infusion, followed by administering 400 mg/m.sup.2 of the (l+d) form of leucovorin over 30 minutes, followed by administering the 5-fluorouracil over 46 hours. 30. The method of claim 7, wherein the patient has failed prior treatment with gemcitabine or become resistant to gemcitabine prior to administration of the liposomal irinotecan composition. 31. The method of claim 9, wherein the patient has failed prior treatment with gemcitabine or become resistant to gemcitabine prior to administration of the liposomal irinotecan composition. 32. The method of claim 19, wherein the patient has failed prior treatment with gemcitabine or become resistant to gemcitabine prior to administration of the liposomal irinotecan composition. 33. The method of claim 1, wherein the antineoplastic therapy comprises at least three two-week treatment cycles. 34. The method of claim 7, wherein the antineoplastic therapy comprises at least three two-week treatment cycles. 35. The method of claim 19, wherein the antineoplastic therapy comprises at least three two-week treatment cycles.