EP-4741019-A2 - 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.

Inventors

• BAYEVER, ELIEL
• DHINDSA, Navreet
• FITZGERALD, JONATHAN BASIL
• LAIVINS, Peter
• MOYO, VICTOR
• NIYIKIZA, CLET
• KIM, JAEYEON

Assignees

• Ipsen Biopharm Ltd.

Dates

Publication Date

20260513

Application Date

20130612

Claims (15)

1. Liposomal irinotecan for use in a method of treating pancreatic cancer in a human patient, the method comprising co-administering to the patient an effective amount each of liposomal irinotecan, 5-fluorouracil (5-FU), and leucovorin, wherein the method comprises at least one cycle, wherein the cycle is a period of 2 weeks, and wherein for each cycle: (a) liposomal irinotecan is administered to patients not homozygous for the UGT1A1*28 allele on day 1 of each cycle at a dose of 80 mg/m 2 and to patients homozygous for the UGT1A1*28 allele on day 1 of cycle 1 at a dose of 60 mg/m 2 and on day 1 of each subsequent cycle at a dose of 60 mg/m 2 or 80 mg/m 2 ; (b) 5-FU is administered at a dose of 2400 mg/m 2 ; and (c) leucovorin is administered at a dose of 200 mg/m 2 ( l form) or 400 mg/m 2 ( l + d racemic form).
2. Liposomal irinotecan for use of claim 1, wherein, in each cycle, the liposomal irinotecan is administered prior to the leucovorin and the leucovorin is administered prior to the 5-FU.
3. Liposomal irinotecan for use of claim 1 or claim 2, wherein after cycle 1 the dose of liposomal irinotecan administered to the patient homozygous for the UGT1A1*28 allele is increased to 80 mg/m 2 .
4. Liposomal irinotecan for use of any one of the preceding claims, wherein the liposomal irinotecan is administered intravenously over 90 minutes.
5. Liposomal irinotecan for use of any one of claims 1-4, wherein the 5-FU is administered intravenously over 46 hours.
6. Liposomal irinotecan for use of any one of claims 1-5, wherein the leucovorin is administered intravenously over 30 minutes.
7. Liposomal irinotecan for use of any one of claims 1-6, wherein, prior to each administration of liposomal irinotecan, the patient is pre-medicated with dexamethasone and/or a 5-HT3 antagonist or another anti-emetic.
8. Liposomal irinotecan for use of any one of the preceding claims, wherein the pancreatic cancer is an exocrine pancreatic cancer selected from the group consisting of acinar cell carcinoma, adenocarcinoma, adenosquamous carcinoma, giant cell tumor, intraductal papillary-mucinous neoplasm (IPMN), mucinous cystadenocarcinoma, pancreatoblastoma, serous cystadenocarcinoma, and solid and pseudopapillary tumors.
9. Liposomal irinotecan for use of any one of the preceding claims, wherein the liposomal irinotecan is irinotecan sucrose octasulfate salt liposome injection.
10. Liposomal irinotecan for use of claim 9, wherein the method improves chemotherapy outcomes by increasing tumor vascularity, and wherein the dose of liposomal irinotecan administered is effective to increase tumor vascularity.
11. Liposomal irinotecan for use of any one of claims 9 or 10, wherein the method improves chemotherapy outcomes by decreasing tumor hypoxia and increasing small molecule perfusion.
12. Liposomal irinotecan for use of any one of claims 9-11, wherein the method improves chemotherapy outcomes by making tumors more susceptible to 5-fluorouracil and leucovorin.
13. Liposomal irinotecan for use of any one of the preceding claims, wherein the co-administration results in therapeutic synergy or in a positive outcome in the patient, and wherein the positive outcome is pCR, CR, PR, or SD.
14. Liposomal irinotecan for use of any one of claims 1-10, wherein the patient achieves a response which is at least stable disease.
15. Liposomal irinotecan for use of any one of the preceding claims, wherein the patient has failed prior treatment with gemcitabine or become resistant to gemcitabine.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority of U.S. Provisional Application No. 61/659,211 (filed June 13, 2012) and U.S. Provisional Application No. 61/784,382 (filed March 14, 2013), both of which are incorporated herein by reference. BACKGROTIND Despite improvements in cancer treatments, there remains a critical need to further improve therapies so as to prolong patients' lives while maintaining quality of life, particularly in the case of advanced cancers such as pancreatic cancers that often are, or become, resistant to current therapeutic modalities. Incidence of pancreatic cancer has markedly increased during the past several decades. It now ranks as the fourth leading cause of cancer death in the United States. Pancreatic cancer's high mortality rate is due to a dearth of effective therapies and a complete absence of reliably durable therapies. Because of the location of the pancreas, pancreatic cancer is typically not diagnosed until a tumor has become large enough to produce systemic symptoms. This, coupled with the absence of good screening tools and a limited understanding of risk factors, results in patients usually having advanced disease, often advanced metastatic disease, at the time of diagnosis. Metastatic pancreatic cancer has a dismal prognosis and is almost uniformly fatal, with an overall survival rate of less than 4% at 5 years. Chemotherapy with one or more of 5-fluorouracil (5-FU) and gemcitabine has been shown to prolong survival in pancreatic cancer. Combination therapies including folinic acid (leucovorin or levoleucovorin), 5-fluorouracil, and irinotecan (FOLFIRI), folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX), or, less commonly, a combination of folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) are also used to treat some pancreatic cancers. Irinotecan is 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycampothecin, IUPAC name (S)-4.1 1-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1H-pyrano[3',4':6,7]-indolizino[1,2-blquinolin-9-yl-[1,4'bipiperidine]-1'-carboxylate. Irinotecan is a member of the topoisomerase I inhibitor class of drugs and is a semi-synthetic and water soluble analog of the naturally-occurring alkaloid, camptothecin. Also known as CPT-11, irinotecan is currently marketed formulated as an aqueous solution as Camptosar® (irinotecan hydrochloride injection). Topoisomerase I inhibitors such as irinotecan work to arrest uncontrolled cell growth by inhibiting the unwinding of DNA and thereby preventing DNA replication. The pharrnacology of irinotecan is complex, with extensive metabolic conversions involved in the activation, inactivation, and elimination of the drug. Irinotecan is a prodrug that is converted by nonspecific carboxylesterases into a 100-1000 fold more active metabolite, SN-38. SN-38 is not recognized by P-glycoprotein, a drug transporter that plays an important role in acquired drug resistance by pumping certain drugs out of cells, so irinotecan is likely to be active in tumors resistant to other standard chemotherapies. In the body, SN-38 is cleared via glucuronidation, for which major pharmacogenetic variability has been described, and biliary excretion. These drug properties contribute to the marked heterogeneities in efficacy and toxicity observed clinically with irinotecan. Irinotecan hydrochloride injection is approved in the United States for treatment of metastatic colon or renal cancer and is also used to treat colorectal, gastric, lung, uterine cervical and ovarian cancers. There are few approved treatment options for advanced or metastatic pancreatic cancers, particularly for those of exocrine origin. Single-agent gemcitabine is the current standard of care in first-line treatment of advanced and metastatic pancreatic adenocarcinoma. In clinical trials, single-agent gemcitabine has consistently demonstrated a median prolongation of survival of 5 to 6 months and a 1-year survival rate of about 20%. Single agent gemcitabine was also approved as second line treatment for patients previously treated with but no longer responsive to 5-fluorouracil, with a median overall prolongation of survival of 3.9 months. Based upon what is known of the biology of pancreatic cancer, a variety of targeted agents have been evaluated, but only erlotinib, a protein tyrosine kinase inhibitor targeted to EGFR, has been approved for first-line use in advanced pancreatic cancer, and the approval is only for use in combination with gemcitabine. The co-administration of erlotinib with gemcitabine resulted in a statistically significant benefit in survival, and improvements in median survival (6.4 months vs. 5.9 months), and 1-year survival rate (24% vs. 17%) compared to gemcitabine alone. Clinical trials evaluating other targeted agents, including studies testing the antibodies bevacizumab and cetuximab, have been disappointingly negative. Thus, there is an urgent need for improvements i