Background: The hedgehog (Hh) pathway is an evolutionally highly conserved signaling cascade important for control of many developmental processes. It is critical in gastroesophageal (GE) embryogenesis and normal cell growth and survival. The Hh pathway is also implicated in GE cancer formation and progression.(Berman, 2003; Rubin, 2006; Ma, 2005; Ohta, 2005) Pathway overexpression has been demonstrated preclinically in GE tumors and the degree of activation correlates with clinical and histologic features. Hh antagonists have demonstrated a dose dependent reduction in GE tumor growth as well as inhibition of cell motility and invasiveness. (Yanai, 2007; Yoo, 2008) GDC-0449 is an oral small-molecule antagonist of the Hh pathway which binds to and inhibits SMO thereby blocking Hh signal transduction. This study will provide data on efficacy and safety of GDC-0449 plus FOLFOX relative to a current standard of care (FOLFOX alone) as 1^st line treatment in pts with advanced GE cancers. Methods: This is an NCI-sponsored multicenter randomized, placebo controlled phase II study of FOLFOX with and w/o GDC-0449 in pts with advanced treatment-naive GE adenocarcinoma. Pts are randomized 1:1, stratified by institution and disease status (with or w/o distant mets) to treatment with FOLFOX(ox 85 mg/m² IV d1, leucovorin 200 mg/m² IV d1, 5-FU 400 mg/m² IV bolus d1, 5-FU 2400 mg/ m² CI over 48 hrs) q14d with GDC-0449/placebo 150mg PO qd continuously. FFPET and blood samples will be collected for biomarker analyses. Primary endpoint is PFS and 116 pts are required to achieve 90% power to detect a 69% increase in median PFS (9.8 vs. 5.8 mo), at the 1- sided 0.10 significance level. Secondary objectives are OS, RR, and toxicity rates. Exploratory objectives include investigation of correlations b/t baseline tumor Hh pathway expression and tumor genetic variation with efficacy, measurement of serum growth factor levels and shed collagen epitopes as a surrogate for response in the microenvironment, and correlation of circulating endothelial progenitor cells with response. 58 patients are currently enrolled and accrual continues. Supported by: N01-CM-62204.