Background: FOLFIRINOX, consisting of leucovorin (LV), fluorouracil (FU), irinotecan (IRI) and oxaliplatin (L-OHP), and GnP, consisting of gemcitabine (GEM) plus nab-paclitaxel (nPTX), have shown superior efficacy over GEM in patients (pts) with metastatic pancreatic cancer. Although several studies have reported the efficacy of FOLFIRINOX or GnP for pts with locally advanced pancreatic cancer (LAPC), no randomized controlled trial to compare the two regimens has been conducted in those pts. To select the most promising chemotherapy for LAPC, a randomized phase II selection design trial (JCOG1407) was conducted to compare between modified FOLFIRINOX (FOLFIRINOX with dose reduction of IRI and without bolus FU; Arm A) and GnP (Arm B) for pts with LAPC. Methods: In Arm A, 85 mg/m² of L-OHP, 200 mg/m² of l-LV, 150 mg/m² of IRI, followed by 2,400 mg/m² of continuous FU over 46 hours are infused every 2 weeks. In Arm B, 125 mg/m² of nPTX followed by 1,000 mg/m² of GEM are infused on days 1, 8, and 15 every 4 weeks. The primary endpoint was overall survival (the proportion of 1-year OS), and secondary endpoints included progression-free survival (PFS), distant metastasis-free survival (MFS) and response rate in pts with target lesions. The planned sample size was 124 pts to select more effective regimen in 1-year OS with a probability of at least 0.85 and to test the null hypothesis of 53% in 1-year OS with a one-sided alpha of 5% and 80% Results: From 2015 to 2019, a total of 126 pts was enrolled from 29 Japanese institutions, and were allocated to Arm A (n = 62) or Arm B (n = 64). The median (range) age was 66 (44-75) years and 58.7% were male. At the analysis, after a median (range) follow-up of 1.52 (0.55-3.99) years, 75 (59.5%) pts died. The proportion of 1-year OS was better in Arm B, 77.4% [95% CI 64.9–86.0] vs. 82.5% [95% CI 70.7–89.9], but 2-year OS was better in Arm A, 48.2% [95% CI 33.3–61.7] vs. 39.7% [95% CI 28.6–52.5]. Median OS was 2.0 years [95% CI 1.6-2.7] in Arm A and 1.8 years [95% CI 1.5-2.0] in Arm B. 1-year PFS for Arm A/B was 47.5 % [95% CI 34.5-59.4]/40.2% [95% CI 27.8-52.3], and 1-year MFS was 64.2 % [95% CI 50.9-74.8]/57.3% [95% CI 43.9-68.6]. Arm A was better OS in pts with CA19-9 <1000 U/mL and the opposite trend was observed in pts with CA19-9>1000 U/mL. Response rate was 30.9% [95% CI 19.1-44.8] in Arm A, and 41.4% [95% CI 28.6-55.1]) in Arm B. Incidences of grade 3-4 non-hematological toxicities for Arm A and Arm B were 66.1% and 67.2%, respectively. There was no treatment-related death. Conclusions: This study was the first randomized trial comparing the two regimens. The 1-year OS of the primary endpoint in GnP was better than mFOLFIRINOX, but mFOLFIRINOX achieved longer survival in 2-year OS. It is required to confirm longer OS and safety profiles which regimen should be selected as a standard regimen in LAPC. Clinical trial information: jRCTs031180085.