Background: The HH pathway is overexpressed in gastroesophageal (GE) tumors. Pre-clinically, HH inhibitors have demonstrated a reduction in GE tumor growth, cell motility and invasiveness. V, an oral small-molecule antagonist of the Hh pathway, has previously been safely combined with FOLFOX chemotherapy. Methods: Pts with untreated metastatic or locally advanced gastric or GEJ adenocarcinoma were randomized 1:1, stratified by institution and disease status (with or w/o distant mets) to FOLFOX (ox 85 mg/m², LV 200 mg/m², 5-FU bolus 400 mg/m², 5-FU infusion 2400 mg/ m² over 48 hrs) q14d plus V or placebo (P) (150mg PO daily). Cycle defined as 2 weeks and no crossover allowed at progression. FFPET and blood were collected for biomarker analyses. Response assessed every 8 weeks (RECIST 1.1). Primary endpoint was progression-free survival (PFS), secondary objectives were overall survival (OS), response rate (RR), and toxicity. Results: 124 pts enrolled at 20 sites between 10/09-2/12. 123 pts eligible for analysis (V/P 60/63). Pt characteristics (V/P): median age 58/62; ECOG PS 0: 24 (40%) / 30 (48%); male 39 (65%) / 52 (83%); GEJ 37 (62%) / 39 (61%); diffuse or mixed histology 19 (32%) / 10 (16%), recurrent disease 10(17%) / 16 (25%). Median number of FOLFOX cycles 10/11. Most common Grade ≥3 toxicities: (% pts V/P) neutropenia 50/32 (p=0.07), neuropathy 19/13 (p=0.49), fatigue 15/10 (p=0.50), thrombosis 14/11 (p=0.92), anemia 10/10 (p=0.99), hemorrhage-GI 8/11 (p=0.77), hypokalemia 10/5 (p=0.76), nausea 8/8 (p=0.99). Death on or within 30 days of treatment 6.7%/15.6% (p=0.20). Median PFS in intent to treat population 7.3/8.0 mo (95% CI 4.6-10.1/5.1-11.0; p=0.64) and median OS 11.5/14.9 mo (95% CI 9.6-13.4/11.3-18.4; p=0.23). Overall RR (%) 35/35 (p=0.99). Conclusions: Addition of V to FOLFOX did not improve PFS in an unselected advanced GE carcinoma population. Blood and tissue biomarker analyses are ongoing to determine if there is a subset of patients who may derive benefit from V. Supported by: N01-CM-62204, -62201, -62207, -62206, -62209, -62208 and 2UL1 TR000457-06. Clinical trial information: NCT00982592.