Phase I and pharmacokinetic study of S-1 administered for 14 days in a 21-day cycle in patients with advanced upper gastrointestinal cancer

Purpose S-1 is a novel oral fluoropyrimidine that combines tegafur with CDHP and oxonic acid. To decrease the incidence of late onset, severe diarrhea observed in a previous study, a phase I study was conducted to determine the maximum tolerated dose (MTD) of S-1 utilizing a 14-day schedule, repeated every 21 days, in patients with chemotherapy-refractory upper gastrointestinal malignancies. Methods S-1 was administered orally, twice-daily, at an initial dose level of 30 mg/m(2)/dose; doses were escalated by 5 mg/m2 at each level. A minimum of three patients were enrolled at each dose level. S-1 toxicity, antitumor activity, and pharmacokinetics were assessed. The MTD was based on the dose limiting toxicity (DLT) during the first treatment cycle. Results At 30 mg/m2 no DLT was observed in the first three evaluable patients. Two of the first three patients at the 35 mg/m(2) dose level developed DLTs (grade 3 rash and dehydration). An additional nine patients were subsequently treated at 30 mg/m(2) without DLT and this dose was established as the MTD. Common toxicities at 30 mg/m2 included diarrhea, nausea, skin rash, anorexia, and fatigue. No grade 4 toxicities were observed. One partial response was seen in a patient with gemcitabine-refractory pancreatic adenocarcinoma and ten patients with pancreatic, gastric, or gallbladder carcinomas achieved stable disease as their best response to therapy. The AUC((0-8)) of 5-FU at the 30 and 35 mg/m(2) dose levels were 875 +/- 212 and 894 +/- 151 h ng/ml, respectively. Conclusions In a 14-day dosing schedule, the MTD of S-1 was 30 mg/m(2) and preliminary evidence of antitumor activity was seen in a North American population with refractory upper gastrointestinal malignancies.