Randomized multicenter phase II/III study of gemcitabine plus nab-paclitaxel or modified FOLFIRINOX or S-IROX in patients with metastatic or recurrent pancreatic cancer (JCOG1611, GENERATE).
Authors: Ohba Akihiro , Ozaka Masato , Mizusawa Junki , Katayama Hiroshi , Okusaka Takuji , Kobayashi Satoshi , Ikeda Masafumi , Kaneko Shuichi , Sasahira Naoki , Okano Naohiro , Furukawa Masayuki , Miki Ikuya , Mizuno Nobumasa , Yasuda Ichiro , Fujimori Nao , Kataoka Tomoko , Ueno Makoto , Ishii Hiroshi , Fukuda Haruhiko , Furuse Junji 
Published: January 2022

TPS627 Background: Pancreatic cancer is one of the most dismal cancers with few effective drugs. Both FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GnP) showed superiority in overall survival (OS) to gemcitabine in phase III studies and became the standard of care for first-line chemotherapy. However, to date, there is no prospective randomized controlled studies comparing FFX and GnP. In addition, the original FFX has the problems of high toxicity and complicated administration, and we have been developing modified FFX with dose reduction of irinotecan and without bolus fluorouracil and S-IROX, which replaces continuous intravenous fluorouracil with orally administered fluoropyrimidine of S-1. The modified FFX showed median OS of 11.2months [95% confidence interval (CI), 9.0-not calculated] as good as the original FFX in a phase II study, and the S-IROX showed a high objective response rate (ORR) of 57.1% (95% CI, 34.0–78.2%) in a phase I study. This phase II/III study aims to confirm the superiority of modified FFX and S-IROX to GnP in metastatic or recurrent pancreatic cancer. Methods: The main eligibility criteria are metastatic or recurrent pancreatic cancer, histologically diagnosed as adenocarcinoma or adenosquamous carcinoma, no prior chemotherapy for pancreatic cancer, Eastern Cooperative Oncology Group Performance Status 0 or 1, and age 20-75 years old. Enrolled patients are randomized 1:1:1 to GnP, modified FFX, or S-IROX. GnP is consisted of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) on days 1, 8, and 15, every 4 weeks, modified FFX is consisted of oxaliplatin (85 mg/m2), irinotecan (150 mg/m2), l-leucovorin (200 mg/m2), and fluorouracil (2400 mg/m2, 46-hour continuous infusion), every 2 weeks, and S-IROX is consisted of oxaliplatin (85 mg/m2), irinotecan (150 mg/m2) and S-1 (80 mg/m2, days 1-7), every 2 weeks. All regimens are administered until disease progression or unacceptable toxicity. The primary endpoint of the phase II part is the ORR to S-IROX with the null hypothesis of a threshold ORR of less than 20%, which decide whether to proceed to the phase III part in three arms or two arms (GnP and modified FFX). The primary endpoint of the phase III part is OS, and secondary endpoints are progression-free survival, ORR, incidence of adverse events (AEs) and serious AEs, and dose intensity. We calculated a sample of 732 patients to maintain 80% power at a one-sided alpha error of 2.5% in each comparison, and the hazard ratios of modified FFX and S-IROX versus GnP were estimated at 0.73 each. The study started patient accrual in April 2019 and 349 patients have been enrolled as of September 2021. Clinical trial registry: jRCTs031190009. Clinical trial information: jRCTs031190009.