Phase I/II and pharmacokinetic study of combination chemotherapy with S-1 and oxaliplatin in patients with previously untreated metastatic or recurrent gastric cancer

Abstract

4557 Background: A novel oral fluoropyrimidine, S-1, and oxaliplatin (OX) have been reported to be highly active in advanced gastric cancer (AGC). The objectives of this study were to define the maximal-tolerated dose (MTD) of S-1 in combination with a fixed dose of OX, and to determine the activity and safety of this combination regimen at the recommended dose (RD) when used as the first line treatment of AGC. Methods: Treatment consisted of intravenous OX at a fixed dose of 130 mg/m2 on D1 followed by twice a day oral S-1 [35 mg/m2; level 1(n=3), 40 mg/m2; level 2(n=6), 45 mg/m2; level 3(n=3), or 50 mg/m2; level 4(n=6)] from D1-D14 of a 21-day cycle. At each level, a cohort of 3 patients (pts), which could be expanded to 6 pts, was studied. Dose-limiting toxicities (DLT) were determined during the first treatment cycle. Pharmacokinetic analysis of tegafur, 5-FU, CDHP, and oxonate was performed in 6 pts treated with RD using an optimized HPLC and UV absorption spectrophotometry. Results: In phase I part of the study(n=18), DLT occurred only one pt at level 2 who experienced unconscioussness due to hyponatremia. DLT was not observed in any other pts even though the level 4 dose cohort was expanded to 6 pts. The RD was determined to be level IV and 47 eligible pts, including 2 pts with measurable disease allocated to dose level 4 in the phase I portion, were enrolled in phase II portion. A total of 250 cycles of chemotherapy were administered. The median age was 55 years (31–70) and ECOG PS was 0/1 in 89% of pts. The objective response was observed in 26 (61%; 95% CI, 53–73%) of 43 evaluable pts. SD was achieved in 13 (30%) pts. With a median FU of 19.1 months (m) (95% CI, 18.5–19.7m), median PFS was 6.6 m (95% CI, 4.0–9.2m) with a median OS of 12.5 m (95% CI, 9.2–15.8m). G3–4 toxicities included thrombocytopenia (39%), neutropenia (28%), anemia (17%), febrile neutropenia (FN, 8%), asthenia (8%), and anorexia (8%). There was one G5 FN during the 1st cycle which appeared to be related with DPD deficiency. The pharmacokinetic profiles of S-1 components or its active metabolite did not differ whether S-1 was administered singly or combined with OX. Conclusions: OX plus S-1 regimen is highly active against AGC with favorable toxicity profiles in patients with AGC. No significant financial relationships to disclose.