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Background: Treatment options for patients with unresectable locally advanced pancreatic cancer are scarce. Results from a subanalysis of the phase 3 MPACT trial in metastatic pancreatic cancer suggested potential activity of nab-paclitaxel plus gemcitabine against locally advanced pancreatic cancer. The objective of this phase 2 trial was to evaluate safety and efficacy of nab-paclitaxel plus gemcitabine in previously untreated locally advanced pancreatic cancer., Methods: This international, open-label, multicentre, phase 2 trial (LAPACT) took place at 35 sites in five countries (USA, France, Spain, Canada, and Italy). Patients with Eastern Cooperative Oncology Group performance status of up to 1 underwent six cycles of induction with nab-paclitaxel 125 mg/m 2 plus gemcitabine 1000 mg/m 2 (days 1, 8, and 15 of each 28-day cycle). After induction, patients without progressive disease or unacceptable adverse events were eligible to receive continued therapy per investigator's choice: continued nab-paclitaxel plus gemcitabine, chemoradiation, or surgery. The primary endpoint was time to treatment failure; secondary endpoints were disease control rate, overall response rate, progression-free survival, overall survival, safety, and quality of life. The reported efficacy outcomes were analysed in the intention-to-treat population, and safety outcomes were analysed in the treated population. This trial is registered with ClinicalTrials.gov, NCT02301143, and EudraCT, 2014-001408-23 and is complete., Findings: Between April 21, 2015, and April 26, 2018, 107 patients were enrolled in the study. 106 received the study treatment; one patient enrolled but did not receive treatment. 44 (41%) of 107 enrolled patients discontinued induction; the most common reason for discontinuing induction was adverse events (22 [21%] patients). 62 (58%) of 107 enrolled patients completed induction treatment and 47 (44%) patients subsequently received continued treatment per investigator's choice: 12 (11%) continued nab-paclitaxel plus gemcitabine, 18 (17%) received chemoradiation, and 17 (16%) underwent surgery (seven had R0 resection status, nine had R1). 15 (14%) patients completed induction treatment but did not receive continued treatment. Median time to treatment failure was 9·0 months (90% CI 7·3-10·1); median progression-free survival was 10·9 months (90% CI 9·3-11·6), and median overall survival was 18·8 months (90% CI 15·0-24·0). During induction, 83 patients achieved disease control and the disease control rate was 77·6% (90% CI 70·3-83·5). 36 patients had a best response of partial response; the overall response rate during induction was 33·6% (90% CI 26·6-41·5). The most common treatment-emergent adverse events that were grade 3 or higher in the treated population during induction were neutropenia (35 [33%] of 106 patients), anaemia (12 [11%]), and fatigue (11 [10%]). The most common treatment-emergent serious adverse events during induction were pneumonia (five [5%] patients), pyrexia (five [5%]), and febrile neutropenia (three [3%]). No deaths were caused by treatment-related adverse events during the induction phase, and global quality of life was maintained in most patients., Interpretation: The data from this trial support the tolerability and activity of nab-paclitaxel plus gemcitabine for locally advanced pancreatic cancer, and a potential to convert unresectable, locally advanced disease to surgically resectable disease. The safety profile was generally consistent with previous findings., Funding: Celgene., (Copyright © 2020 Elsevier Ltd. All rights reserved.)