{"entity":{"id":"napoli-3","kind":"trial","name":"NAPOLI 3","aka":[],"tldr":"The first head-to-head trial of the two chemotherapy backbones, won narrowly by the four-drug regimen.","summary":"NAPOLI 3, trial NCT04083235 sponsored by Ipsen and reported in 2023, was the first head-to-head trial of the two chemotherapy backbones for first-line metastatic pancreatic cancer, comparing NALIRIFOX, the four-drug regimen built on liposomal irinotecan, with gemcitabine plus nab-paclitaxel. It randomised 770 patients and met its primary overall survival endpoint, with a narrow but statistically significant advantage and a clearer gain in progression-free survival, leading to FDA approval of NALIRIFOX in February 2024. OnCo links it to pancreatic ductal adenocarcinoma, to NALIRIFOX and gemcitabine plus nab-paclitaxel, to Zev A. Wainberg, and to the bottleneck of cold tumours; the result is consistent in direction with PRODIGE 4 for FOLFIRINOX. Critics note the absence of a modified FOLFIRINOX arm, so whether the new regimen beats the older four-drug standard is the open question.","status":"positive","asOf":"2026-09-06","links":[{"label":"ClinicalTrials.gov NCT04083235","url":"https://clinicaltrials.gov/study/NCT04083235"},{"label":"Wainberg et al., NAPOLI 3 (Lancet 2023)","url":"https://doi.org/10.1016/S0140-6736(23)01366-1"},{"label":"Onivyde label (openFDA): NAPOLI 3 results table","url":"https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22ONIVYDE%22"}],"tags":[],"related":[],"cancers":["pancreatic","metastatic-pdac"],"sections":[],"technologies":["cytotoxic-chemotherapy","platinum","topoisomerase-inhibitors"],"targets":[],"drugs":["nalirifox","gemcitabine-nab-paclitaxel"],"companies":["ipsen"],"institutions":[],"pathways":[],"terms":[],"trials":["prodige-4-accord-11","napoli-1","mpact","canstem111p"],"people":["zev-wainberg"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Design (Lancet 2023): 770 patients at 187 sites in 18 countries randomised between February 2020 and August 2021 to NALIRIFOX (liposomal irinotecan 50 mg/m2, oxaliplatin 60 mg/m2, leucovorin 400 mg/m2, fluorouracil 2,400 mg/m2 over 46 hours, days 1 and 15 of 28) or nab-paclitaxel 125 mg/m2 with gemcitabine 1,000 mg/m2 on days 1, 8 and 15. Median follow-up 16.1 months. Label figures (Onivyde, openFDA): overall survival 11.1 against 9.2 months (hazard ratio 0.84, 0.71 to 0.99; p 0.0403), progression-free survival 7.4 against 5.6 months (hazard ratio 0.70; p 0.0001), response 41.8 against 36.2 percent (not significant). Grade 3 or worse treatment-emergent adverse events 87 against 86 percent; treatment-related deaths 6 (2 percent) against 8 (2 percent). FDA approval of the regimen 13 February 2024; EU indication listed on the Onivyde product page; NICE appraisal TA1052 terminated on 2 April 2025 without a company submission.","UK sites (registry, 6): Guy's and St Thomas' NHS Foundation Trust; Royal Marsden (two entries); Imperial College Healthcare; the Christie; Nottingham City Hospital."],"nct":"NCT04083235","phase":"3","setting":"First-line metastatic PDAC: NALIRIFOX vs gemcitabine + nab-paclitaxel","sponsor":"Ipsen","result":"OS HR 0.84; PFS HR 0.69.","started":"2020-02-11","startedType":"actual","yearReported":2023,"enrolled":770,"enrolledBasis":"registry","outcomes":[{"endpoint":"Overall survival","primary":true,"unit":"months","arms":[{"name":"NALIRIFOX","n":383,"value":11.1},{"name":"Gemcitabine + nab-paclitaxel","n":387,"value":9.2}],"hr":0.83,"ci":[0.7,0.99],"p":"0.036","source":"https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01366-1/fulltext"}],"replication":"Consistent in direction with PRODIGE 4/ACCORD 11 (FOLFIRINOX vs gemcitabine); no direct FOLFIRINOX comparison."},"route":"/trials/napoli-3/","neighbours":{"cancer":[{"id":"metastatic-pdac","kind":"cancer","name":"Metastatic pancreatic ductal adenocarcinoma","route":"/cancers/metastatic-pdac/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"technology":[{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"},{"id":"platinum","kind":"technology","name":"Platinum agents","route":"/technologies/platinum/"},{"id":"topoisomerase-inhibitors","kind":"technology","name":"Topoisomerase-I inhibitors (and ADC payloads)","route":"/technologies/topoisomerase-inhibitors/"}],"drug":[{"id":"folfirinox","kind":"drug","name":"FOLFIRINOX / mFOLFIRINOX","route":"/drugs/folfirinox/"},{"id":"gemcitabine-nab-paclitaxel","kind":"drug","name":"Gemcitabine + nab-paclitaxel","route":"/drugs/gemcitabine-nab-paclitaxel/"},{"id":"liposomal-irinotecan","kind":"drug","name":"Liposomal irinotecan","route":"/drugs/liposomal-irinotecan/"},{"id":"nalirifox","kind":"drug","name":"NALIRIFOX (liposomal irinotecan + oxaliplatin + 5-FU/LV)","route":"/drugs/nalirifox/"}],"company":[{"id":"ipsen","kind":"company","name":"Ipsen","route":"/companies/ipsen/"}],"trial":[{"id":"canstem111p","kind":"trial","name":"CanStem111P","route":"/trials/canstem111p/"},{"id":"mpact","kind":"trial","name":"MPACT","route":"/trials/mpact/"},{"id":"napoli-1","kind":"trial","name":"NAPOLI-1","route":"/trials/napoli-1/"},{"id":"prodige-4-accord-11","kind":"trial","name":"PRODIGE 4 / ACCORD 11","route":"/trials/prodige-4-accord-11/"}],"person":[{"id":"zev-wainberg","kind":"person","name":"Zev A. Wainberg","route":"/people/zev-wainberg/"}],"paper":[{"id":"paper-napoli-1-nanoliposomal-irinotecan-lancet-2016","kind":"paper","name":"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","route":"/key-papers/paper-napoli-1-nanoliposomal-irinotecan-lancet-2016/"},{"id":"paper-esmo-pancreatic-cancer-guideline-ann-oncol-2023","kind":"paper","name":"Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","route":"/key-papers/paper-esmo-pancreatic-cancer-guideline-ann-oncol-2023/"}],"roadmap":[{"id":"chemotherapy-roadmap","kind":"roadmap","name":"Chemotherapy roadmap: mustard gas → curative combinations → the warhead inside smarter drugs","route":"/roadmaps/chemotherapy-roadmap/"},{"id":"pancreatic-roadmap","kind":"roadmap","name":"Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question","route":"/roadmaps/pancreatic-roadmap/"}],"bottleneck":[{"id":"b-tme-immunosuppression","kind":"bottleneck","name":"Cold tumours and the immunosuppressive microenvironment","route":"/bottlenecks/b-tme-immunosuppression/"}]}}