TY - JOUR
T1 - Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1)
T2 - A global, randomised, open-label, phase 3 trial
AU - NAPOLI-1 Study Group
AU - Wang-Gillam, Andrea
AU - Li, Chung Pin
AU - Bodoky, György
AU - Dean, Andrew
AU - Shan, Yan Shen
AU - Jameson, Gayle
AU - MacArulla, Teresa
AU - Lee, Kyung Hun
AU - Cunningham, David
AU - Blanc, Jean F.
AU - Hubner, Richard A.
AU - Chiu, Chang Fang
AU - Schwartsmann, Gilberto
AU - Siveke, Jens T.
AU - Braiteh, Fadi
AU - Moyo, Victor
AU - Belanger, Bruce
AU - Dhindsa, Navreet
AU - Bayever, Eliel
AU - Von Hoff, Daniel D.
AU - Chen, Li Tzong
N1 - Funding Information:
This study was funded by Merrimack Pharmaceuticals. The study protocol was designed by the funder and external consultants, and data were analysed by a statistician employed by the funder (BB). All authors gathered data and were assisted in writing of the report by a medical writer employed by the funder. L-TC, AW-G, and DDVH had full access to all data in the study, participated in data interpretation, and had final responsibility for the decision to submit for publication. All authors agreed to submit the report.
Funding Information:
GB, C-FC, JFB, RAH, K-HL, C-PL, GS, TM, and Y-SS declare no competing interests. FB and JTS report personal fees from Merrimack Pharmaceuticals advisory boards, outside the submitted work. L-TC reports other funding from Merrimack Pharmaceuticals, during the conduct of the study; and personal fees from PharmaEngine, outside the submitted work. DC reports grants from AstraZeneca, Amgen, Celgene, Merck Serono, Sanofi, Merrimack Pharmaceuticals, and Medimmune, outside the submitted work. AD reports personal fees from AstraZeneca and Specialized Therapeutics, outside the submitted work; grants and personal fees from Roche, outside the submitted work; and grants from Boehringer Ingelheim, outside the submitted work. GJ reports grants from Merrimack Pharmaceuticals, during the conduct of the study. DDVH reports grants from Merrimack Pharmaceuticals, during the conduct of the study; and personal fees from AlphaMed Consulting, outside the submitted work. AW-G reports grants from Newlink, EMD, Pfizer, AstraZeneca, Precision Biological, BioMed Valley, Halozyme, ChemoCentryx, OncoMEd, ADURO, and Millennium, outside the submitted work; other fees from Pfizer and Merrimack Pharmaceuticals, outside the submitted work; and grants from Merrimack Pharmaceuticals, Prometheus, and CTI, outside the submitted work. EB, ND, and VM are employees of Merrimack Pharmaceuticals and have a patent (Methods for treating pancreatic cancer using combination therapies comprising liposomal irinotecan) issued to Merrimack Pharmaceuticals. BB is employed as statistician at Merrimack Pharmaceuticals.
Publisher Copyright:
© 2016 Elsevier Ltd.
PY - 2016/2/6
Y1 - 2016/2/6
N2 - Background Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population. Methods We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m2 every 3 weeks, equivalent to 100 mg/m2 of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m2, equivalent to 70 mg/m2 of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506. Findings Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6·1 months (95% CI 4·8-8·9) vs 4·2 months (3·3-5·3) with fluorouracil and folinic acid (hazard ratio 0·67, 95% CI 0·49-0·92; p=0·012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4·9 months [4·2-5·6] vs 4·2 months [3·6-4·9]; 0·99, 0·77-1·28; p=0·94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). Interpretation Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population. Funding Merrimack Pharmaceuticals.
AB - Background Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population. Methods We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m2 every 3 weeks, equivalent to 100 mg/m2 of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m2, equivalent to 70 mg/m2 of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506. Findings Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6·1 months (95% CI 4·8-8·9) vs 4·2 months (3·3-5·3) with fluorouracil and folinic acid (hazard ratio 0·67, 95% CI 0·49-0·92; p=0·012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4·9 months [4·2-5·6] vs 4·2 months [3·6-4·9]; 0·99, 0·77-1·28; p=0·94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]). Interpretation Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population. Funding Merrimack Pharmaceuticals.
UR - http://www.scopus.com/inward/record.url?scp=84959459386&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(15)00986-1
DO - 10.1016/S0140-6736(15)00986-1
M3 - Article
C2 - 26615328
AN - SCOPUS:84959459386
VL - 387
SP - 545
EP - 557
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10018
ER -