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

A Phase I Trial Assessing Several Schedules of Oral S-1 in Combination With a Fixed Dose of Oxaliplatin and Irinotecan in Patients With Advanced or Metastatic Digestive Adenocarcinoma as First- or Second-line Treatment

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).

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