Claims for Patent: 9,717,724

Summary for Patent: 9,717,724

Title:	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.
Inventor(s):	Bayever; Eliel (New York, NY), 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:	Ipsen Biopharm Ltd. (Wrexham, GB)
Application Number:	15/241,128
Patent Claims:	1. A method of treating patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy who are not homozygous for the UTG1A1*28 allele, the method comprising intravenously administering to the patient in need thereof an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of: a. administering liposomal irinotecan as an intravenous infusion in an amount providing 70 mg/m.sup.2 of irinotecan free base, the liposomal irinotecan composition comprising irinotecan encapsulated in irinotecan liposomes having a diameter of approximately 110 nm and an irinotecan terminal elimination half-life in the patient of 25.8 hours; 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 liposomal irinotecan has an area under the plasma concentration curve extrapolated to time infinity (AUC.sub.0-.infin.) of 1091-1705 [h.mu.g/mL]. 3. The method of claim 1, wherein liposomal irinotecan has an area under the plasma concentration curve extrapolated to time infinity (AUC.sub.0-.infin.) of 1364 [h.mu.g/mL]. 4. The method of claim 1, wherein liposomal irinotecan has a maximum plasma concentration of 29-47 micrograms/mL. 5. The method of claim 1, wherein liposomal irinotecan has a maximum plasma concentration of 37 micrograms/mL. 6. The method of claim 1, wherein the irinotecan liposomes are unilamellar lipid bilayer vesicles comprising phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine. 7. The method of claim 1, wherein the irinotecan liposomes are approximately 110 nm in diameter. 8. The method of claim 1, wherein the irinotecan liposomes encapsulate an aqueous space containing irinotecan in a gelated or precipitated state as the sucrose octasulfate salt. 9. The method of claim 1, wherein the liposomal irinotecan comprises 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and methoxy-terminated polyethylene glycol (MW 2000)-distearoylphosphatidyl ethanolamine (MPEG-2000-DSPE). 10. 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. 11. A method of treating patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy who are not homozygous for the UTG1A1*28 allele, the method comprising intravenously administering to the patient in need thereof an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of: a. administering liposomal irinotecan as an intravenous infusion over 90 minutes in an amount providing 70 mg/m.sup.2 of irinotecan free base, the liposomal irinotecan composition comprising irinotecan encapsulated in irinotecan liposomes having an area under the plasma concentration curve extrapolated to time infinity (AUC.sub.0-.infin.) of about 1091-1705 [h.mu.g/mL]; followed by b. 200 mg/m.sup.2 of the (l) form of leucovorin; and c. 2,400 mg/m.sup.2 of 5-fluorouracil. 12. The method of claim 11, wherein the irinotecan liposomes have a diameter of approximately 110 nm and comprise phosphatidylcholine, cholesterol, and a polyethyleneglycol-derivatized phosphatidyl-ethanolamine. 13. The method of claim 11, 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 11, wherein liposomal irinotecan has a maximum plasma concentration of about 29-47 micrograms/mL. 15. The method of claim 11, wherein the irinotecan liposomes encapsulate an aqueous space containing irinotecan in a gelated or precipitated state as the sucrose octasulfate salt. 16. 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 70 mg/m.sup.2 of irinotecan free base in an irinotecan nanoparticle composition comprising irinotecan nanoparticles having a diameter of 80-140 nm, 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, wherein the irinotecan nanoparticle composition has one or more characteristics selected from the group consisting of: a. an area under the plasma concentration curve extrapolated to time infinity (AUC.sub.0-28) of about 1091-1705[h.mu.h/mL]; and b. a maximum plasma concentration of about 29-47 micrograms/mL. 17. The method of claim 16, wherein the irinotecan liposome has 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. 18. The method of claim 16, wherein the irinotecan nanoparticles 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. 19. The method of claim 16, wherein the irinotecan nanoparticle composition has an irinotecan terminal elimination half-life in the patient of about 25.8 hours. 20. The method of claim 16, 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. 21. A method of treating patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy, the method comprising intravenously administering to the patient in need thereof an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of: an intravenous infusion of liposomal irinotecan in an amount providing a total of 70 mg/m.sup.2 of irinotecan free base, in combination with therapeutically effective amounts of 5-fluorouracil and leucovorin. 22. The method of claim 21, wherein the patient is not homozygous for the UTG1A1*28 allele and the liposomal irinotecan comprises irinotecan encapsulated in irinotecan liposomes having a diameter of approximately 110 nm and an irinotecan terminal elimination half life in the patient of 25.8 hours. 23. The method of claim 22, wherein each intravenous infusion of liposomal irinotecan is administered over 90 minutes. 24. The method of claim 23, wherein a. the irinotecan liposomes encapsulate an aqueous space containing irinotecan in a gelated or precipitated state as the sucrose octasulfate salt; and b. the liposomal irinotecan comprises 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and methoxy-terminated polyethylene glycol (MW 2000)-distearoylphosphatidyl ethanolamine (MPEG-2000-DSPE).