Methods for treating pancreatic cancer using combination therapies
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 metastatic adenocarcinoma of the pancreas in a human patient who has previously been treated with the antineoplastic agent gemcitabine, comprising intravenously administering to the patient once every two weeks, an antineoplastic therapy consisting of:
a) irinotecan sucrose octasulfate salt liposome injection in an amount providing the equivalent of 70 mg/m 2 of irinotecan free base, the irinotecan sucrose octasulfate salt liposome injection comprising irinotecan sucrose octasulfate encapsulated in liposomes, wherein, following administration in patients, the irinotecan sucrose octasulfate salt liposome injection has a mean total SN-38 terminal elimination half-life in the plasma of 67.8±44.5 hours;
b) 200 mg/m 2 of the (l) form of leucovorin or 400 mg/m 2 of the (l+d) racemic form of leucovorin; and
c) 2,400 mg/m 2 of the antineoplastic agent 5-fluorouracil.
2. The method of claim 1 , wherein the irinotecan sucrose octasulfate salt liposome injection is administered intravenously over 90 minutes, followed by intravenous administration of the leucovorin over 30 minutes, followed by intravenous administration of the 5-fluorouracil over 46 hours.
3. The method of claim 2 , wherein the patient has metastatic adenocarcinoma of the pancreas that has progressed on gemcitabine-based therapy prior to the administration of the irinotecan sucrose octasulfate salt liposome injection.
4. The method of claim 3 , wherein, following administration in patients, the irinotecan sucrose octasulfate salt liposome injection has an area under the plasma concentration curve extrapolated to time infinity (AUC 0-∞ ) of the mean total SN-38 that increases less than proportionally with the dose of irinotecan sucrose octasulfate salt liposome injection.
5. The method of claim 3 , wherein, following administration in patients, the irinotecan sucrose octasulfate salt liposome injection has a mean total SN-38 area under the plasma concentration curve extrapolated to time infinity (AUC 0-∞ ) of 620±329 h·ng/mL.
6. The method of claim 3 , wherein, following administration in patients, the irinotecan sucrose octasulfate salt liposome injection has a mean total SN-38 maximum plasma concentration of 5.4±3.4 nanograms/mL.
7. The method of claim 3 , wherein the leucovorin is provided by administering 400 mg/m 2 of the (l+d) form of leucovorin.
8. The method of claim 2 , further comprising premediating the human patient with an anti-emetic prior to administering the antineoplastic therapy.
9. The method of claim 1 , wherein the irinotecan sucrose octasulfate salt liposome injection contains N-(methoxy-poly(ethyleneglycol) (M.W. 2000)-oxycarbonyl)-distearoylphosphatidylethanolamine.
10. The method of claim 1 , wherein the sucrose octasulfate salt liposome injection comprises phosphatidylcholine, cholesterol, and N-(methoxy-poly(ethyleneglycol) (M.W. 2000)-oxycarbonyl)-distearoylphosphatidylethanolamine in a molar ratio of 3:2:0.015.
11. The method of claim 1 , wherein the liposomes have an average size of from about 80 to about 140 nm as determined by volume-averaged mean of the liposome size distribution by quasi-elastic light scattering (QELS) using Gaussian model.
12. The method of claim 11 , wherein the liposomes have an average size of about 110 nm as determined by volume-averaged mean of the liposome size distribution by quasi-elastic light scattering (QELS) using Gaussian model.
13. The method of claim 1 , wherein the liposomes have been filtered through a 0.2 micron filter.