Phase I clinical trial of oral administration of S-1 in combination with intravenous gemcitabine and cisplatin in patients with advanced biliary tract cancer

Objective: This study aimed to determine the maximum tolerated dose and the recommended dose of combining S-1 with gemcitabine and cisplatin for advanced biliary tract adenocarcinoma first-line therapy. Methods: Chemotherapy-naive patients with histologically or cytologically proven unresectable or metastatic biliary tract adenocarcinomawere enrolled. Patients with advanced biliary tract adenocarcinoma received gemcitabine and cisplatin intravenously on Days 1 and 8 and S-1 orally twice daily from Days 1 to 14. Cycles were repeated every 21 days until disease progression. Patients were scheduled to receive gemcitabine (mg/m²/week), cisplatin (mg/m²/week) and S-1 (mg/m²/day) at four dose levels: 800/25/40 (level 0), 1000/25/40 (level 1), 1000/25/60 (level 2) and 1000/25/80 (level 3). Level 1was chosen as the starting dose. For caseswhere recommended dose could not be determined within the triweekly schedule, we prepared a biweekly schedule to find recommended dose. Results: Seventeen patients with advanced biliary tract adenocarcinoma were treated across three dose levels. Maximum tolerated dose and recommended dosewere defined as level 0. Dose-limiting toxicities included a Grade 3 maculopapular rash, Grade 4 thrombocytopenia and consecutive administration skips of gemcitabine and cisplatin on Day 8. Five partial responses were observed. Conclusions: This triweekly triplet regimen was well tolerated and showed promising antitumor activity in patients with advanced biliary tract adenocarcinoma.We recommend level 0, gemcitabine at 800 mg/m²/week, cisplatin at 25 mg/m²/week and S-1 at 40 mg/m²/day during a 21-day cycle, in further studies with this schedule.