title: Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial.
abstract: 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/m(2) every 3 weeks, equivalent to 100 mg/m(2) of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m(2), equivalent to 70 mg/m(2) 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.
  
  
  RESULTS
  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%]).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Merrimack Pharmaceuticals.
authors.affiliation: Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Wang-Gillam
authors.affiliation: Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Chung-Pin
authors.initials: CP
authors.lastname: Li
authors.affiliation: St László Teaching Hospital, Budapest, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Bodoky
authors.affiliation: St John of God Hospital, Subiaco, WA, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dean
authors.affiliation: National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yan-Shen
authors.initials: YS
authors.lastname: Shan
authors.affiliation: TGen, Phoenix, and HonorHealth, Scottsdale, AZ, USA.
authors.forename: Gayle
authors.initials: G
authors.lastname: Jameson
authors.affiliation: Vall d'Hebron University Hospital (HUVH) and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Macarulla
authors.affiliation: Seoul National University Hospital, Seoul, South Korea.
authors.forename: Kyung-Hun
authors.initials: KH
authors.lastname: Lee
authors.affiliation: The Royal Marsden Hospital, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: Hôpital Saint-André, Bordeaux, France.
authors.forename: Jean F
authors.initials: JF
authors.lastname: Blanc
authors.affiliation: The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hubner
authors.affiliation: China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chang-Fang
authors.initials: CF
authors.lastname: Chiu
authors.affiliation: Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Schwartsmann
authors.affiliation: Klinikum rechts der Isar der T U München, Munich, Germany.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
authors.affiliation: Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.
authors.forename: Fadi
authors.initials: F
authors.lastname: Braiteh
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Moyo
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Belanger
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Navreet
authors.initials: N
authors.lastname: Dhindsa
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Eliel
authors.initials: E
authors.lastname: Bayever
authors.affiliation: TGen, Phoenix, and HonorHealth, Scottsdale, AZ, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, and Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan. Electronic address: leochen@nhri.org.tw.
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000401:mortality; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D003967:Diarrhea / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced; D000093542:Gemcitabine
chemical_list: D008081:Liposomes; D003841:Deoxycytidine; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin; D000093542:Gemcitabine