Background: Advanced gastroesophageal cancers (AGEC) harbour a dismal prognosis (overall survival [OS] < 1 year). EGFR inhibitors showed promising activity in patients (pts) with AGEC. Dysregulation of the HGF/c-Met pathway is a rational therapeutic target in AGEC. This randomised phase II study aims to assess the efficacy and safety of fluorouracil (FU), folinic acid (FA) and oxaliplatin-based chemotherapy (modified FOLFOX6 regimen) alone or combined to either panitumumab, an anti-EGFR monoclonal antibody, or to AMG 102, an anti-HGF monoclonal antibody, as first-line treatment for pts with AGEC. Methods: This multicentre, open-label, randomised phase II trial is ongoing in 30 centres in France. Main eligibility criteria include: histologically proven adenocarcinoma of the stomach, esophagus or gastroesophageal junction; locally advanced or metastatic disease; measurable disease (RECIST 1.1); no known HER2 overexpression; no prior palliative chemotherapy; age > 18 years; ECOG performance status 0 or 1; adequate bone marrow, liver and renal function. Patients are randomised to modified FOLFOX6 (oxaliplatin 85 mg/m^², FA 400 mg/m², FU 400 mg/m² bolus then 2400 mg/m² over 46 hr) alone or combined to either panitumumab (6 mg/kg) or AMG 102 (10 mg/kg) every two weeks until unacceptable toxicity or disease progression. Judgment criteria include 4-month progression-free survival rate (primary endpoint), OS, objective response rate, and safety. Ancillary studies aim to identify candidate predictive and prognostic biomarkers among functional of molecular alterations of the EGFR/RAS/RAF and HGF/c-Met pathways, and to monitor circulating tumour cells and circulating immune cells (myeloid derived suppressor cells, NK cells) in sequential blood samples taken at baseline and through the study treatment. A total of 165 pts will be enrolled (Fleming’s one-step design). The first patient enrolled in January 2011.