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 (V/P 60/64) enrolled at 20 sites between 10/09-2/12. Pt characteristics (V/P): median age 58/62; ECOG PS 0: 23 (40%) / 30 (47%); male 39 (65%) / 53 (83%); GEJ 37 (62%) / 39 (61%); diffuse histology 20 (43%) / 14 (30%). Median number of FOLFOX cycles 9.5/11. Most common Gr ≥3 toxicities: (% pts V/P) neutropenia 50.0/31.7 (p=0.07), neuropathy 23.1/14.3 (p=0.33), fatigue 15.4/9.5 (p=0.50), thrombosis 13.5/11.1 (p=0.92), anemia 9.6/9.5 (p=0.99), hypokalemia 9.6/4.8 (p=0.52), nausea 7.7/9.5 (p=0.99). Death on or within 30 days of treatment 6.7%/15.6% (p=0.20). Median PFS in ITT population 11.5/9.3 mo (95% CI 8.5-14.4/6.7-11.9; p=0.34) and median OS 12.2/13.9 mo (95% CI 10.2-14.3/11.5-16.3; p=0.48). Non-statistically significant trends toward improved PFS with V were noted in female pts, diffuse histology, and PS 1 (p≤ 0.08). RR (%) 33/27 (p=0.64). 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.