Background: S-1 (Teysuno), an oral fluoropyrimidine registered in Europe since 2011, provides a good efficacy and safety profile for the treatment (trt) of AEGC in combination with cisplatin. (FLAGS Study; J.A. Ajani. EJC2013). Because triplets with platinum compounds and anthracyclines are commonly used in AEGC, a phase I evaluating S-1 with fixed doses of oxaliplatin (130 mg/m² D1) and epirubicin (50 mg/m² D1) q3w in AGIC pts [cohorts 1 (C1) and 2 (C2)] and in chemonaïve AEGC pts [cohort 3 (C3)] was performed. Methods: Pts >18 years, ECOG/PS 0/1 were enrolled. Standard dose-limiting toxicity (DLT) evaluation was used. The maximum tolerate dose (MTD) was defined as the highest dose level at which less than <2/6 of pts experienced a DLT during Cycle 1. Once MTD was established, the cohort was expanded up to 12 pts. C1 and C2: S-1 dose was defined in cohort of pts (3+3 design): C1 20mg/m² BID (40 mg/m²/day); C2 25 mg/m² BID (50 mg/m²/d). Escalation to dose level (DL) 2 occurred only after DL1 (20mg/m²/BID) was safe according to DLT criteria. In C3 pts received S-1 25mg/m² BID. Results: 23 pts were evaluated. C1 and C2 included AGIC pts at all lines of trt. As in C1: 3 pts had no DLT, dose was increased and 3 pts were included in C2: after 1 DLT (≥Gr3 non-hematological toxicity), 2 more pts were included in C2 with a second DLT (febrile neutropenia). These 2 DLTs occurred in heavily pre-treated pts (3rd line) and led to closing of C2 and 3 additional pts were enrolled in expanded C1. MTD of S-1 was established 20 mg/m² BID. No DLT reported for chemo-naïve pts treated. Since EOS is used to treat AEGC in first line, a new C3 cohort with chemo-naïve pts was opened to again determine MTD of S-1: 6 pts in C3 were included. Here no DLT occurred and additional 6 pts confirmed dose of 25 mg/m² as the MTD. Conclusions: Based on these results, the recommended doses of S-1 in EOS regimen are 20 mg/m²/BID in heavily pre-treated AGIC pts and 25 mg/m²/BID in chemo-naïve AEGC pts. The triplets EOS could represent a well-tolerated alternative first line trt for AEGC pts. Clinical trial information: 2011-003471-11.