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

Study Overview
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Brief Summary
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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).

Detailed Description
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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).

Official Title
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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

Conditions
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Digestive Cancer

Intervention / Treatment
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* Drug: S-1
* Drug: Irinotecan
* Drug: Oxaliplatin
* Other: G-csf


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SIRINOX<br>S-1: Administered orally twice daily from day 1 for 7 consecutive days followed by a 7-day recovery period in a 14-day cycle. The starting dose of S-1 will be two levels below the recommended dose defined in SIRI (20 mg/m² BID minimum) with a cohort dose escalation by 5 mg/m² increments (5 dose levels). Irinotecan : fixed dose of 180 mg/m² IV over 90 minutes on d1 of every cycle Oxaliplatin : fixed dose of 85 mg/m² over 120 minutes on d1 of every cycle G-csf : d8 to d13 systematically | Drug: S-1<br>* S-1: Administered orally twice daily from day 1 for 7 consecutive days followed by a 7-day recovery period in a 14-day cycle. The starting dose of S-1 will be two levels below the recommended dose defined in SIRI (20 mg/m² BID minimum) with a cohort dose escalation by 5 mg/m² increments (5 dose levels).<br>Drug: Irinotecan<br>* Irinotecan : fixed dose of 180 mg/m² IV over 90 minutes on d1 of every cycle<br>Drug: Oxaliplatin<br>* Oxaliplatin : fixed dose of 85 mg/m² over 120 minutes on d1 of every cycle<br>Other: G-csf<br>* G-csf : d8 to d13 systematically<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicities | Dose limiting toxicities occurring during the first two administered cycles. | up to 5 years |