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