Methods for treating pancreatic cancer using combination therapies comprising liposomal irinotecan

1. A method of treating metastatic adenocarcinoma of the pancreas in a human patient in need thereof, the patient being homozygous for the UGT1A1*28 allele, the method comprising intravenously administering to the patient once in a two week treatment cycle 60 mg/m 2 of the antineoplastic agent MM-398 liposomal irinotecan 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 2400 mg/m 2 of the antineoplastic agent 5-fluorouracil to treat the metastatic adenocarcinoma of the pancreas in the patient, wherein the patient has previously been treated with gemcitabine and no other antineoplastic agent is administered to the human patient in the two week treatment cycle for the treatment of the metastatic adenocarcinoma of the pancreas.

2. The method of claim 1 , wherein beginning on day 1 of the two week treatment cycle, the MM-398 liposomal irinotecan, leucovorin and 5-fluorouracil are administered sequentially to the patient.

3. The method of claim 2 , wherein 400 mg/m 2 of the (l+d) racemic form of leucovorin is administered.

4. The method of claim 3 , wherein leucovorin is administered to the patient prior to the 5-fluorouracil.

5. The method of claim 3 , wherein MM-398 liposomal irinotecan is administered to the patient prior to the leucovorin.

6. The method of claim 1 , wherein MM-398 liposomal irinotecan is administered to the patient over 90 minutes.

7. The method of 6 , wherein leucovorin is administered over 30 minutes and 5 fluorouracil is administered over 46 hours.

8. The method of claim 1 , wherein the patient has metastatic adenocarcinoma of the pancreas that has progressed on gemcitabine-based therapy prior to the administration of the MM-398 liposomal irinotecan.

9. The method of claim 1 , wherein beginning on day 1 of the two week treatment cycle, the MM-398 liposomal irinotecan, 200 mg/m 2 of the (1) form of the leucovorin and the 5-fluorouracil are administered sequentially to the patient.

10. The method of claim 9 , wherein leucovorin is administered to the patient prior to the 5-flurouracil.

11. The method of claim 10 , wherein MM-398 liposomal irinotecan is administered to the patient prior to leucovorin.

12. The method of claim 11 , wherein leucovorin is administered over 30 minutes and 5 fluorouracil is administered over 46 hours.

13. The method of claim 3 , wherein the patient has metastatic adenocarcinoma of the pancreas that has progressed on gemcitabine-based therapy prior to the administration of the MM-398 liposomal irinotecan.

14. A method of treating metastatic adenocarcinoma of the pancreas in a human patient in need thereof who has previously been treated with gemcitabine, the patient being homozygous for the UGT1A1*28 allele, the method comprising: intravenously administering to the patient an antineoplastic therapy once every two weeks, the antineoplastic therapy consisting of intravenously administering either 50 mg/m 2 or 60 mg/m 2 of MM-398 liposomal irinotecan over 90 minutes, followed by 200 mg/m 2 of the (1) form of leucovorin over 30 minutes, followed by 2400 mg/m 2 of 5-fluorouracil over 46 hours beginning on day 1 of a two week treatment cycle.

15. The method of claim 14 , wherein the patient has metastatic adenocarcinoma of the pancreas that has progressed on gemcitabine-based therapy prior to administration of MM-398 liposomal irinotecan.

16. The method of claim 14 , further comprising premedicating the patient with an anti-emetic prior to initiating each antineoplastic therapy.

17. A method of treating metastatic adenocarcinoma of the pancreas with disease progression after prior gemcitabine or gemcitabine containing therapy in a human patient in need thereof who is homozygous for the UGT1A1*28 allele, the method consisting of once every two weeks: premedicating with an anti-emetic followed by intravenously administering to the patient a single infusion of 60 mg/m 2 of MM-398 liposomal irinotecan in combination with a single infusion of 200 mg/m 2 of the (l)-form of leucovorin, and a single infusion of 2400 mg/m 2 of 5-fluorouracil to treat the metastatic adenocarcinoma of the pancreas in the human patient.

18. The method of claim 17 , wherein the irinotecan is administered over 90 minutes, followed by administering the leucovorin over 30 minutes, followed by administration of the 5-fluorouracil over 46 hours over a total of about 48 hours.

19. The method of claim 1 , further comprising one or more subsequent treatment cycles that include decreasing the dose of the MM-398 liposomal irinotecan, wherein the dose of the MM-398 liposomal irinotecan is reduced from 60 mg/m 2 to 50 mg/m 2 in a subsequent two week treatment cycle to a patient who experienced a Grade 3 or Grade 4 adverse event after administration of the MM-398 liposomal irinotecan in a previous two week treatment cycle.

20. The method of claim 1 , further comprising administering an anti-emetic to the patient prior to initiating the two week treatment cycle.

21. The method of claim 1 , further comprising administering to the patient at least three consecutive two week treatment cycles.

22. The method of claim 21 , further comprising increasing the dose of the MM-398 liposomal irinotecan from 60 mg/m 2 up to 80 mg/m 2 in at least one of the second or third consecutive two week treatment cycles.

23. The method of claim 14 , wherein the 200 mg/m 2 of the (l) form of leucovorin is administered as 400 mg/m 2 of the (l+d) racemic form of leucovorin.

24. The method of claim 14 , further comprising administering one or more subsequent antineoplastic therapies once every two weeks, wherein at least one of the one or more subsequent antineoplastic therapies comprises decreasing the dose of MM-398 liposomal irinotecan from 60 mg/m 2 to 50 mg/m 2 in a subsequent antineoplastic therapy to a patient who experienced a Grade 3 or Grade 4 adverse event after administration of MM-398 liposomal irinotecan in a previous two-week antineoplastic therapy.

25. The method of claim 24 , further comprising administering to the patient at least three consecutive antineoplastic therapies once every two weeks to the patient.

26. The method of claim 15 , further comprising

a. administering an anti-emetic to the patient prior to initiating each antineoplastic therapy;

b. administering a first antineoplastic therapy to the patient, wherein the antineoplastic therapy consists of intravenously administering 50 mg/m 2 of MM-398 liposomal irinotecan;

c. administering the 200 mg/m 2 of the (l) form of leucovorin as 400 mg/m 2 of the (l+d) racemic form of leucovorin during each antineoplastic therapy; and

d. administering at least two subsequent antineoplastic therapies to the patient once every two weeks, wherein each subsequent antineoplastic therapy optionally includes decreasing the dose of MM-398 liposomal irinotecan from 60 mg/m 2 to 50 mg/m 2 in a subsequent antineoplastic therapy.

27. The method of claim 17 , wherein the 200 mg/m 2 of the (l) form of leucovorin is administered as 400 mg/m 2 of the (l+d) racemic form of leucovorin.

28. A method of treating metastatic adenocarcinoma of the pancreas in a human patient in need thereof who has previously been treated with gemcitabine, the patient being homozygous for the UGT1A1*28 allele, the method comprising intravenously administering to the patient a treatment cycle of an antineoplastic therapy once every two weeks, the antineoplastic therapy comprising:

a. a first two-week treatment cycle consisting of intravenously administering to the patient: 60 mg/m 2 of MM-398 liposomal irinotecan over a 90 minute infusion, followed by 200 mg/m 2 of the (l)-form of leucovorin over 30 minutes, followed by 2400 mg/m 2 of 5-fluorouracil over 46 hours, the antineoplastic therapy being administered over a total of about 48 hours beginning on day one of the first two-week treatment cycle;

b. a second two-week treatment cycle consisting of intravenously administering to the patient starting after the first two-week treatment cycle:

i. either 60 mg/m 2 or 80 mg/m 2 of MM-398 liposomal irinotecan over a 90 minute infusion if the patient has not experienced a Grade 3 or Grade 4 adverse event after administration of the MM-398 liposomal irinotecan in the first two-week treatment cycle, or 50 mg/m 2 of MM-398 liposomal irinotecan over a 90 minute infusion if the patient has experienced a Grade 3 or Grade 4 adverse event after administration of the MM-398 liposomal irinotecan in the first two-week treatment cycle; followed by

ii. 200 mg/m 2 of the (l)-form of leucovorin over 30 minutes, followed by 2400 mg/m 2 of 5-fluorouracil over 46 hours, the antineoplastic therapy being administered over a total of about 48 hours beginning on day one of the second two-week treatment cycle; and

c. a third two-week treatment cycle consisting of intravenously administering to the patient starting after the second two-week treatment cycle: 50 mg/m 2 , 60 mg/m 2 or 80 mg/m 2 of MM-398 liposomal irinotecan over a 90 minute infusion, followed by 200 mg/m 2 of the (l)-form of leucovorin over 30 minutes, followed by 2400 mg/m 2 of 5-fluorouracil over 46 hours, the antineoplastic therapy being administered over a total of about 48 hours beginning on day one of the third two-week treatment cycle,

to treat the metastatic adenocarcinoma of the pancreas in the patient.

29. The method of claim 28 , wherein the 200 mg/m 2 of the (l) form of leucovorin is administered as 400 mg/m 2 of the (l+d) racemic form of leucovorin, and the method further comprises administering an anti-emetic to the patient prior to each two-week treatment cycle; and the third two-week treatment cycle consists of intravenously administering to the patient starting after the second two-week treatment cycle, either 60 mg/m 2 or 80 mg/m 2 of MM-398 liposomal irinotecan over a 90 minute infusion if the patient has not experienced a Grade 3 or Grade 4 adverse event after administration of the MM-398 liposomal irinotecan in the first two-week treatment cycle, or 50 mg/m 2 of MM-398 liposomal irinotecan over a 90 minute infusion if the patient has experienced a Grade 3 or Grade 4 adverse event after administration of the MM-398 liposomal irinotecan in the first two-week treatment cycle.