Induction Chemoterapy With Folfoxiri Plus Cetuxumab in Unresectable Colorectal Cancer Patient

This is a phase II randomized study of 4-months induction first-line chemotherapy with FOLFOXIRI + cetuximab followed by maintenance with cetuximab or bevacizumab in patients affected by KRAS wild type (wt) mCRC.

The aim of the study is to obtain a rapid disease control with the therapy and the maximum tumoral shrinkage, and than to treat patient with less intensive maintenance to inhibit tumoral regrowth.

Eligibility Criteria:
Inclusion Criteria:

* Histologically confirmed colorectal adenocarcinoma;
* Availability of formalin-fixed paraffin embedded tumor block from primary and/or metastasis;
* KRAS wild-type status of primary colorectal cancer or related metastasis;
* Unresectable and measurable metastatic disease according to RECIST criteria;
* Male or female, aged \> 18 years and \< 75 years;
* ECOG PS \< 2 if aged \< 71 years, ECOG PS = 0 if aged 71-75 years;
* Life expectancy of more than 3 months;
* Adequate haematological function: ANC ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L, Hb ≥ 9 g/dL;
* Adequate liver and renal function: serum bilirubin ≤ 1.5 x ULN; alkaline phosphatase and transaminases ≤ 2.5 x ULN (in case of liver metastases \< 5 x ULN); serum creatinine ≤ 1.5 x ULN;
* Previous adjuvant chemotherapy containing oxaliplatin is allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse;
* Previous adjuvant chemotherapy with fluoropyrimidine monotherapy is allowed if more than 6 months have elapsed between the end of adjuvant and first relapse;
* At least 6 weeks from prior extended radiotherapy and 4 weeks from surgery;
* Written informed consent to experimental treatment and KRAS analysis.

Exclusion Criteria:

* Prior palliative chemotherapy;
* Prior treatment with EGFR or VEGF inhibitors;
* Symptomatic peripheral neuropathy \> 2 grade NCIC-CTG criteria;
* Presence or history of CNS metastasis;
* Active uncontrolled infections; active disseminated intravascular coagulation;
* Past or current history of malignancies other than colorectal carcinoma, except for curatively treated basal and squamous cell carcinoma of the skin cancer or in situ carcinoma of the cervix;
* Clinically significant cardiovascular disease: cerebrovascular accidents or myocardial infarction ≤ 12 months before treatment start, unstable angina, NYHA ≥ grade 2 chronic heart failure, uncontrolled arrhythmia, uncontrolled hypertension;
* Serious, non-healing wound, ulcer, or bone fracture;
* Evidence of bleeding diathesis or coagulopathy;
* Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start;
* Current or recent (within 10 days prior to study treatment start) ongoing treatment with anticoagulants for therapeutic purposes or chronic, daily treatment with high-dose aspirin (\>325 mg/day);
* Subtotal colectomy, malabsorption syndrome and chronic inflammatory bowel disease (i.e. ulcerative colitis, Chron syndrome);
* Fertile women (\<2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception.
* Psychiatric disorder precluding understanding of information on trial related topics,
* Serious underlying medical condition (judged by the investigator) which could impair the ability of the patient to participate in the trial (e.g. uncontrolled diabetes mellitus, active autoimmune disease)
* Concurrent treatment with other experimental drugs or other anti-cancer therapy; treatment in a clinical trial within 30 days prior to trial entry
* Definite contraindications for the use of corticosteroids and antihistamines as premedication
* Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs
* Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies
* Pregnancy
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
* Medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent