Comparison FOLFIRINOX Panitumumab vs mFOLFOX6 Panitumumab in RAS/B-RAF Wild-type Metastatic Colorectal Cancer Patients

National trial, multicenter, randomized, phase II assessing FOLFIRINOX + Panitumumab versus mFOLFOX6 + Panitumumab in metastatic colorectal cancer patients selected by RAS and B-RAF status from circulating DNA analysis.

Evaluation of complete response rate on treatment combining FOLFIRINOX and panitumumab.

PRIMARY OBJECTIVE: Evaluation of complete response rate on treatment combining FOLFIRINOX and panitumumab

SECONDARY OBJECTIVE(S):

* Overall Survival
* Progression free survival
* Secondary resection
* Early tumor shrinkage (ETS)
* Depth of response (DpR)
* Safety profile (NCI-CTCAE v4.03 classification)
* Diagnostic performance of ccfDNA analysis compared to the tumor-tissue analysis (current gold standard)

Eligibility Criteria:
Inclusion Criteria:

1. Age between 18 and 75 years
2. ECOG PS between 0 and 1
3. Histologically confirmed adenocarcinoma of the colon or rectum
4. Untreated synchronous or metachronous metastatic disease deemed unresectable with curative intent
5. K-Ras (codons 12, 13, 59, 61, 117, 146), N-Ras (codons 12, 13, 59, 61) and B-Raf (codon 600) wild-type tumor status according to plasma analysis of circulating cell free DNA by Intplex technology
6. Measurable disease according to RECIST version 1.1
7. Adequate hematologic, hepatic and renal functions:

   * Absolute neutrophil count (ANC) ≥2 x 109/L
   * Haemoglobin ≥9 g/dL
   * Platelets (PTL) ≥100 x 109/L
   * AST/ALT ≤5 x ULN
   * Alkaline phosphatase ≤2.5 x ULN
   * Bilirubin ≤1.5 x ULN
   * Creatinine clearance ≥50 mL/min (Cockcroft and Gault formula)
8. Life expectancy of at least 3 months
9. Adequate contraception if applicable
10. Patient affiliated to a social security regimen
11. Patient information and signed written consent form
12. Uracilemia \< 16 ng/ml

Exclusion Criteria:

1. History of other malignancy within the previous 5 years (except for appropriately treated in-situ cervix carcinoma and non-melanoma skin carcinoma)
2. Adjuvant treatment with oxaliplatin
3. Previous treatment for metastatic disease
4. Patients who received any chemo- and/or radiotherapy within 15 days from the date of blood sampling for the RAS and BRAF test
5. Brain metastases
6. Patients with a history of severe or life-threatening hypersensitivity to the active substances or to any of the excipients delivered in this study
7. Patient with history of pulmonary fibrosis or interstitial pneumonitis
8. Previous organ transplantation, HIV or other immunodeficiency syndromes
9. Concomitant medications/comorbidities that may prevent the patient from receiving study treatment as uncontrolled intercurrent illness (for instance: active infection, active inflammatory disorders, inflammatory bowel disease, intestinal obstruction, symptomatic congestive heart failure, uncontrolled hypertension...)
10. Persistent peripheral neuropathy \>grade1 (NCI CT v4.03)
11. Ionic disorders as:

    * Kalemia ≤1 x LLN
    * Magnesemia \<0.5mmol/L
    * Calcemia \<2mmol/L
12. Patient with known dihydropyrimidine dehydrogenase deficiency
13. QT/QTc\>450msec for men and \>470msec for women
14. Patient with contraindication for trial drugs (investigators have to refer to SmPC drugs, see Appendix 7)
15. Concomitant intake of St. John's wort
16. Other concomitant cancer
17. Participation in another therapeutic trial
18. Pregnant woman or lactating woman
19. Patients with psychological, familial, sociological or geographical condition hampering compliance with the study protocol and follow-up schedule
20. Legal incapacity or limited legal capacity