4003 Background: An open-label, multicenter study of 1st-line advanced gastric cancer patients (pts) was designed to compare the effects of CPT-11 + 5FU/FA with CDDP + 5FU. Primary efficacy variable: time to progression (TTP); secondary endpoints: time to treatment failure (TTF), overall survival (OS), and safety. Methods: Male and female pts aged 28–77 years were randomized to receive: CPT-11 80 mg/m2 iv as 30-min infusion, followed by FA 500 mg/m2 iv over 2 h, followed by 5FU 2000 mg/m2 iv over 22 h weekly for 6 wk (IF); or CDDP 100 mg/m2 iv as 1–3 h infusion on Day 1, followed by 5FU 1000 mg/m2/d continuous infusion over 5 d every 4 wk (CF). Treatment was administered up to progression, unacceptable toxicities, or consent withdrawal. Results: Of 337 randomized pts, 333 (170 with IF; 163 with CF) were treated. In the full-analysis population, a trend toward superiority was noted for TTP with IF vs CF (hazard ratio [HR] 1.23; 95% confidence interval [CI] 0.97–1.57; P = .088), corresponding to a 19% progression risk reduction. Median TTP for IF and CF was 5.0 and 4.2 months, respectively. Interval-censored analysis, a method taking into account that the true date of progression is unknown and that the progression occurs between 2 tumor assessments, showed an HR of 1.27 (P = .05). Median TTF was 4.0 (range 3.60–4.80) and 3.4 (2.53–3.78) months with IF and CF, respectively (HR 1.43; 95% CI 1.14–1.78; P = .018). IF did not demonstrate superiority vs CF (HR 1.08; 95% CI 0.86–1.35) for OS. 67 pts (40%) with IF had grade 3/4 drug-related adverse events (AEs) vs 73 (44%) with CF. The main imbalances on grade 3/4 drug-related AEs against IF were diarrhea (21.6% vs 7.2%), and against CF were neutropenia (52% vs 25%), febrile neutropenia or neutropenic infection (10.2% vs 4.8%), stomatitis (16.9% vs 2.4%), and nausea (9.0% vs 4.8%). More pts withdrew from the study due to drug-related AEs with CF than with IF (21.5% vs 10.0%; P = .004), including 5 toxic deaths with CF vs 1 with IF. Conclusions: In advanced gastric cancer patients, IF showed a trend to TTP superiority, compared with CF, as well as a better safety profile. Thus, CPT-11 + 5FU/FA is an alternative 1st-line treatment option without CDDP for these patients.