4064 Background: Combinations of irinotecan (CPT11) with continuous folinic acid (FA) and 5-fluorouracil (5-FU) have shown promising activity in advanced or metastatic gastric cancer (AGC). We prospectively evaluated toxicity, efficacy and survival of CPT11/FA/5-FU (arm A) versus Etoposide/FA/5-FU (ELF; arm B) in AGC. As ELF was not inferior to FAMTX or Cisplatin/5-FU in a recent EORTC trial, ELF served as control arm. Methods: Metastatic or locally advanced adenocarcinoma of the stomach or gastroesophageal junction; performance status (PS) 0–2; no prior chemotherapy. Patients (pts) were eligible and randomized to arm A with CPT11 80 mg/m2, FA 500 mg/m2, 24h-5-FU 2000 mg/m2, d 1,8,15,22,29,36, q7w or to arm B with E 120 mg/m2, FA 300 mg/m2, 5-FU 500 mg/m2, d1–3+22–24, q6w. Results: From Nov 2000 to Apr 2003, (A/B) 56/58 pts were randomized. Median age (61/63 y), gender, distribution of tumors of gastric origin and esophageal junction, rate of surgical pretreatment (52/53%), PS, localization and numbers of metastatic sites were comparable for both arms. Median treatment duration were 14.1 (0.1–90) and 6.4 (0.3–61) weeks. All pts were eligible and evaluable for toxicity, 48/52 pts for response in A/B, respectively. Grade 3/4 toxicity per pt for A/B (%): neutropenia 7/47, neutropenic fever 7/7, diarrhoea 20/0, nausea 16/7, emesis 7/5, asthenia 2/7, 1 death occurred in A due to pt incompliance after 5 days diarrhoea, 2 deaths due to cerebrovascular events in B. Best overall response (% of pts) for A/B: CR 4/0, PR 40/17, NC 14/12, tumor control rate (CR+PR+NC) 58/29. Median progression-free time for A/B: 129 (CI95% 8–693) and 63 (0–545) days. Overall survival has not yet been reached. Conclusions: CPT11/FA/5-FU is highly effective in advanced or metastatic gastric cancer. CPT11/FA/5-FU can safely be given on an outpatient basis with proper management of adverse events. Cardiovascular deaths occurred only with ELF. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Germany