We designed a phase I/II trial of S-1 combined with weekly docetaxel to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and toxicity in metastatic gastric carcinoma ( docetaxel. Dose-limiting toxicities included grade 3 elevated liver enzymes, gastric perforation, grade 3 diarrhoea/fatigue, febrile neutropenia with grade 3 anorexia/fatigue, and neutropenic infection with grade 3 stomatitis/anorexia. In phase II (n ¼ 52), the overall response rate was 66.7% (95% confidence interval (CI): 53.8 -79.6%) and the median time to progression and overall survival were 6.5 months (95% CI: 4.9 -8.1) and 13.7 months (95% CI: 9.9 -17.5), respectively. The most common grade 3/4 toxicity was neutropenia (29.4%), and febrile neutropenia/neutropenic infection occurred in 19.6% of patients. Non-haematological toxicities were generally mild. There was one treatment-related death due to pneumonitis. S-1 combined with weekly docetaxel is active in MGC with moderate toxicities.

14005 Background: We conducted a study to define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of S-1 plus weekly docetaxel in pts with metastatic gastric cancer (MGC), and to recommend a dose for phase II study Methods: Pts with MGC, age ≥ 18 yrs, ECOG PS 0–2, adequate organ function, and no or 1–2 prior chemotherapy were eligible. S-1 was given twice daily, p.o. on D1–14 and docetaxel i.v. on D1, 8, q 3 wks. Each cohort of 3 pts was treated with escalating doses of S-1/docetaxel at 60/25 (level I), 70/25 (level II), 70/30 (level III), 80/30 (level IV), 80/35 (level V), 90/35 (level VI), and 90/40 mg/m2 (level VII). The DLT pertaining to 1st cycle only was obtained. Results: Thirty pts with median age of 50 yrs (range: 27–71) with MGC received a median of 8 cycles (range: 1–12). A total of 222 cycles were administered. DLTs were; G3 elevated liver enzyme at level I (1/6 pts), gastric perforation at level V (1/6), G3 diarrhea and febrile neutropenia (FN) with G3 nausea/anorexia/fatigue at level VI (2/6), and FN and neutropenic infection (NI) with G3 stomatitis at level VII (2/3). After DLT occurred in 2 of 3 pts in level VII, 2 of additional 3 pts enrolled at level VI had DLT. Then, 1 pt developed DLT among additional 3 pts enrolled at level V. Therefore, MTD and recommended dose (RD) were level VI and V, respectively. There were 2 CRs, 17 PRs with response rate of 65.5% (95% CI 48.2–82.8%), 8 SDs and 2 PDs among 29 efficacy-evaluable pts. Conclusions: MTD for this regimen was S-1 90 mg/m2/d + docetaxel 35 mg/m2 and RD was S-1 80 mg/m2/d (D1–14) + docetaxel 35 mg/m2 (D1, 8). (Supported by National Cancer Center Grant; Docetaxel and S-1 were provided by Sanofi-Aventis Korea and Jeil Pharm. Co., respectively) [Table: see text] No significant financial relationships to disclose.

4633 CYP2A6 genetic polymorphism as a predictive marker for clinical outcomes in patients (pts) with metastastic gastric carcinoma (MGC) treated with S-1 plus docetaxel Background: Tegafur, a component of S-1, a novel oral fluoropyrimidine, is converted to 5-fluorouracil via CYP2A6. An allelic variant of CYP2A6, -48T>G (CYP26A*9) encodes an enzyme with reduced activity. We investigated the association between the polymorphism of CYP2A6*9 and treatment outcomes in Korean pts with MGC who received S-1 plus docetaxel. Methods: From Oct 2005 to July 2006, 50 pts with MGC were enrolled for a phase II study of first line chemotherapy with S-1 and docetaxel. Treatment consisted of oral S-1 40 mg/m2 bid on days 1–14, and i.v. docetaxel 35 mg/m2 on days 1, 8, every 3 weeks. Genotypes were determined with single base extension method for CYP26A*9 from genomic DNA extracted from the peripheral blood samples. Results: The median age was 53 years (range, 23–70) with the median PS of 1 (range, 0–2). The frequency of wild type allele (w/w) was 34 (68%), heterozygous (*9/w), 12 (24%), and homozygous (*9/*9), 4 (8%). The response rate was 25.0% in homozygous pts, 50.0% in heterozygous and 76.5% in wild type (p=0.03, Fisher’s exact test). The median time to progression at a median follow-up of 9.8 months (mo) was shorter in homozygous pts (3.9 mo; 95% CI, 0.4–7.4) as compared to heterozygous and wild types (6.9 mo; 95% CI, 6.0–7.8) (p=0.11). Although the median overall survival did not reach in 4 homozygous pts, it was 13.5 mo (95% CI, 8.3–18.7) in heterozygous and wild type. The frequencies of grade (G) 3/4 toxicities were lower in homozygous pts than the others without statistical significance. Conclusions: The data suggest that CYP2A6*9 polymorphism might be a predictive marker for efficacy and toxicity of S-1 based chemotherapy in MGC pts. Further studies involving more pts are needed to confirm the results. (Supported by NCC Grant 0610520) [Table: see text] No significant financial relationships to disclose.

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