IRinotecan and Oxaliplatin for Colon Cancer in Adjuvant Setting

A Phase III, Randomised, International Trial Comparing mFOLFIRINOX Triplet Chemotherapy to mFOLFOX for High-risk Stage III Colon Cancer in Adjuvant Setting

The trial is a phase III, multicenter, open-labeled randomized trial comparing the association of 5-fluorouracil (5-FU), folinic acid, irinotecan, and oxaliplatin (mFOLFIRINOX) versus oxaliplatin, folinic acid, and 5-FU (mFOLFOX 6) chemotherapy protocols in patients with high-risk stage III colon cancer in the adjuvant setting.

After inclusion and non-inclusion criteria have been fulfilled and the patient consent has been obtained, the patient will be included and randomized in the trial. The maximum delay allowed between the signature of the consent form by the patient and the randomization in the study is 28 days.

The randomization procedure using minimization method will allocate the treatments mFOLFIRINOX or mFOLFOX 6 with a 1:1 ratio, and will be stratified by the following criteria:

• Perforation or urgent surgery versus no perforation and no urgent surgery.
• T1-T3N2 vs T4aN1 versus T4bN1 versus T4N2.
• Right colon (right of splenic flexure) vs left colon.
• Country (France vs Canada vs Italy). Patient eligible and who have signed the informed consent will be randomized in one of the two treatments arms and will receive every 14 days their treatment for a duration of 12 cycles.

Arm A: mFOLFIRINOX Arm B: mFOLFOX 6

DIAGNOSIS AND INCLUSION CRITERIA:

1. Patient ≥18 years and < 75 years

2. Patient ≥18 years and <71 years must have an ECOG ≤1 - Patients ≥71 years and < 75 years must have an ECOG = 0

3. Pathologically confirmed high-risk stage III colon adenocarcinoma, restricted to pT4N1 or pT1-4N2 tumor.

4. Curative R0 surgical resection.

5. Patients who have undergone surgery for colon cancer, defined as a tumor location >12 cm from the anal verge by endoscopy and/or above the peritoneal reflection at surgery (high rectum), without gross or microscopic evidence of residual disease after surgery with curative intent

6. Start of study drug treatment has to be performed less than 56 days after surgery.

7. No prior chemotherapy.

8. No prior abdominal or pelvic irradiation.

9. Patient with adequate organ function:

   • Absolute neutrophil count (ANC) ≥ 2 x 109/L
   • Haemoglobin ≥9 g/dL
   • Platelets (PTL) ≥100 x 109/L
   • AST/ALT ≤2.5 x ULN
   • Alkaline phosphatase ≤2.5 x ULN
   • Total Bilirubin ≤1.5 x ULN (Upper Limit of Normal)
   • Creatinine clearance ≥50 mL/min (Cockcroft and Gault formula)
   • Kalemia, magnesemia, calcemia ≥ 1 LLN (Lower Limit of Normal)
   • Carcinoembryonic antigen (CEA) ≤10ng/mL after surgery (during screening period)

10. Adequate contraception if applicable.

11. Patient able and willing to comply with study procedures as per protocol

12. Patient able to understand and willing to sign and date the written voluntary informed consent form at screening visit prior to any protocol-specific procedures

13. Public or private health insurance coverage

14. Life expectancy of > or = at 5 years

15. Uracilemia < 16 ng/ml (only for french centers)

Exclusion Criteria:

1. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to study treatment start. Incompletely healed wounds or anticipation of the need for major surgical procedure during the course of the study
2. Metastatic disease
3. Presence of inflammatory bowel disease and/or ileus
4. Known hypersensitivity reaction to any of the components of study treatments.
5. Pregnancy (absence to be confirmed by β-hCG test) or breast-feeding period
6. Clinically relevant coronary artery disease or history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia (for men: QTc ≥450 msec, for women: QTc ≥470 msec)
7. Previous malignancy in the last 5 years except curative treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix
8. Medical, geographical, sociological, psychological or legal conditions that would not permit the patient to complete the study or sign informed consent
9. History or current evidence on physical examination of central nervous system disease or peripheral neuropathy ≥ grade 1 Common Toxicity Criteria for Adverse Events (CTCAE) v4.03.
10. Any significant disease which, in the investigator's opinion, would exclude the patient from the study.
11. Patient with a DPD deficiency or UGT1A1 homozygous 7/7; the test should be done for all patients before 5-FU administration, according to ANSM communication regarding recommendation about high risk of no testing DPD in patient before 5-FU administration; (Appendices 8 to 11).
12. Patients already included in another therapeutic trial involving an experimental drug