Phase I study of two schedules of oral S-1 in combination with fixed doses of oxaliplatin and bevacizumab in patients with advanced solid tumors.

Background: S-1 is a novel oral agent combining the 5-fluorouracil (FU) prodrug tegafur with gimeracil and oteracil, which inhibit 5-FU degradation by dihydropyrimidine dehydrogenase and phosphorylation within the gastrointestinal tract, respectively. The study was designed to identify the maximum tolerable dose and the dose-limiting toxicities of two schedules of S-1 combined with oxaliplatin and bevacizumab, in advanced solid tumor patients.

Methods: Schedule A: S-1 was administered orally at 20 mg/m(2) twice daily for 14 consecutive days, escalated by 5 mg/m(2), with fixed-dose intravenous bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m(2) on day 1 of each 3-week cycle. Schedule B: S-1 was administered at 25 mg/m(2) twice daily for 7 consecutive days, escalated by 5 mg/m(2), with fixed-dose intravenous bevacizumab 5 mg/kg and oxaliplatin 85 mg/m(2) on day 1 of each 2-week cycle.

Results: The maximum tolerated dose and recommended phase II dose of S-1 was 25 mg/m(2) twice daily for 14 days for schedule A and 35 mg/m(2) twice daily for 7 days for schedule B. The most common dose-limiting toxicities were grade 3 diarrhea. Both regimens were well tolerated. No pharmacokinetic interactions between oxaliplatin and S-1 components were observed.

Conclusions: S-1, oxaliplatin and bevacizumab can be administered with acceptable safety and tolerability and without evidence of pharmacokinetic interactions.