A Trial Assessing Several Schedules of Oral S-1 in Combination With a Fixed Dose of Oxaliplatin and Irinotecan

Inclusion Criteria: * Male or female ≥ 18 years old * Histologically confirmed diagnosis of advanced or metastatic digestive adenocarcinoma (gastroesophageal adenocarcinoma, colorectal adenocarcinoma, pancreatic adenocarcinoma, cholangiocarcinoma, hepatocarcinoma) * Metastatic or advanced disease not eligible for curative surgery * No active biliary obstruction * Previous adjuvant chemotherapy is allowed. It must be completed at least 6 months before the start of the study treatment * First line chemotherapy is allowed (excluding chemotherapy with Capecitabine or 5 FU or Irinotecan or Oxaliplatin). Previous Oxaliplatin is allowed in patients receiving SIRI * A four-week washout period since prior treatment * One or more measurable metastatic lesions * ECOG status ≤ 1 * Total bilirubin ≤ 1.5 Upper limit of normal (ULN), ALT or AST ≤ 2.5 ULN (or \< 5 in case of liver impairment) * Haemoglobin ≥ 10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3 and white blood cells \> 3000 /mm3 * Lipase \< 1.5 ULN, serum creatinine ≤ 1.5 ULN * Negative pregnancy test in women of childbearing potential * Use of an effective contraceptive method during the whole treatment and up to 3 months after the completion of treatment * Life expectancy \> 3 months * Informed consent form (ICF) signed prior to any study specific procedures * Patients must be affiliated to a Social Security System Exclusion Criteria: * History of previous treatment with Oxaliplatin except for SIRI, Irinotecan, 5 FU or Capecitabine as first-line chemotherapy * Peripheral sensory neuropathy ≥ grade 2 at the time of signing the ICF * Known central nervous system metastases * Unique bone metastasis * History or presence of other cancer within the past 5 years (except curatively treated non-melanoma skin cancer) * Patients with a known deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD), as well as patients who, within the previous four weeks, have been treated with a medicine that inhibits this enzyme * Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose or galactose malabsorption * Malabsorption syndrome or disease significantly affecting gastro-intestinal function * Patient with dysphagia or inability to swallow the tablets * Inflammatory bowel disease with chronic diarrhoea (Grade ≥ 2 NCI CTC V4.03) * History of organ transplantation with use of immunosuppression therapy * Concomitant severe infection (\> grade 2 NCI.CTCAE v4.03) or major organ failure * Active cardiac disease, angina pectoris or myocardial infarction in the last 6 months * Renal disease * Unstable diabetes * Creatinine clearance \< 50 ml/min calculated using the MDRD formula * Pregnant or breastfeeding women * Participation in another clinical trial within 30 days prior to study entry * Psychological, social, geographical or any other condition that would preclude study compliance (treatment administration and study follow-up) * Legal incapacity or physical, psychological or mental status interfering with the patient's ability to sign the informed consent or to terminate the study