Background: The addition of trastuzumab to cisplatin and 5-fluorouracil or capecitabine has been shown to have superior survival benefit. In this study, the addition of trastuzumab to chemotherapy combination, S-1 (tegafur, gimeracil, oteracil potassium; TS-ONE^R) and cisplatin, a standard first line therapy for advanced gastric cancer in Japan, was evaluated for efficacy and safety. Methods: This was a single-arm, phase II trial recruiting patients with advanced HER-2 positive (IHC 3+ or FISH +) gastric adenocarcinoma who had not had prior systemic therapy. Patients included had measurable disease, ECOG 0-2, creatinine clearance >60ml/min, LVEF at least 50%. Patients accrued received cisplatin at 60mg/m2 on day 1 of each cycle, trastuzumab at 8mg/kg as loading dose followed by 6mg/kg on day 1 of each cycle and oral S-1 for 14 days ( dosing based on BSA), every 3 weeks. Treatment continued till progressive disease or unbearable toxicity. Primary endpoint was response rate (ORR) and secondary endpoints were PFS, OS, CBR and safety. The study was designed to distinguish a favorable ORR of 55% from a null rate of 30% at 5% significance level and 80% power. Results: A total of 30 patients were recruited. Median age was 61.9 years, 73% were males and 90% had no prior resection of primary tumor. 56.7% were Chinese, 23.3% Japanese and 20% Korean. One patient achieved complete response, 16 had partial response and 2 had stable disease >24 weeks (ORR 63%; CBR 70.4%). Three patients did not have evaluable disease. With a median follow-up of 7.2 months, the median PFS was 7.4 months with 67.7% free of disease progression at the 6-month mark. Median OS was 14.6 months. The most common AEs were anorexia (50%), fatigue (47%), diarrhea ( 47%), nausea (37%), neutropenia (33%), anemia (27%) and mucositis ( 27%). LVEF decreased <50% in 14 patients and none led to treatment discontinuation nor death. Two patients had fatal SAEs that were deemed related to study drug ( neutropenic sepsis and hypotensive shock). Correlative studies will be reported later. Conclusions: The combination of trastuzumab with S-1 and cisplatin in advanced gastric cancer is active and tolerable. Clinical trial information: NCT01736410.