a trial assessing several schedules of oral s-1 in combination with a fixed dose of oxaliplatin and irinotecan

Conditions: Digestive Cancer

Summary: this study is to determine the maximal tolerated dose (mtd), the dose limitant toxicities (dlts) and the safety profile of s-1 combined with fixed doses of irinotecan (siri schedule) and fixed doses of irinotecan and oxaliplatin (sirinox schedule).

given the therapeutic potential and reduced toxicity advantages of s-1 compared with other fluoropyrimidines, this trial assessing s-1 with oxaliplatin plus irinotecan is warranted for future investigations (phase ii-iii). the primary objectives are to determine the maximal tolerated dose (mtd), the dose limitant toxicities (dlts) and the safety profile of s-1 combined with fixed doses of irinotecan (siri schedule) and fixed doses of irinotecan and oxaliplatin (sirinox schedule).

Eligibility criteria:
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