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