First-line FOLFOXIRI In Combination With Bevacizumab For Metastatic Colorectal Cancer

Inclusion Criteria: * Histologically confirmed colorectal adenocarcinoma * Unresectable and measurable metastatic disease (RECIST criteria) * Male or female, aged \> 18 years and ≤ 75 years * ECOG Performance Status (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 * INR ≤ 1.5 and aPTT ≤ 1.5 x ULN within 7 days prior to starting study treatment * Adequate liver 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 * Urine dipstick for proteinuria \< 2+. If urine dipstick is ≥ 2+, 24- hour urine must demonstrate ≤ 1 g of protein in 24 hours * Previous adjuvant chemotherapy is allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse * At least 6 weeks from prior radiotherapy and 4 weeks from surgery Exclusion Criteria: * Prior palliative chemotherapy * Prior treatment with bevacizumab * Bowel obstruction (or subobstruction) * History of inflammatory enteropathy or extensive intestinal resection (\> hemicolectomy or extensive small intestine resection with chronic diarrhea) * Symptomatic peripheral neuropathy \> 2 grade NCIC-CTG criteria * Presence or history of CNS metastasis * Active uncontrolled infections * Active disseminated intravascular coagulation * Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to treatment, or anticipation of the need for major surgery during the course of the study * Central Venous Access Device (CVAD) for chemotherapy administration inserted within 2 days prior to study treatment start * 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, for example cerebrovascular accidents (CVA) (≤ 6 months before treatment start), myocardial infarction (≤ 6 months before treatment start), unstable angina, NYHA ≥ grade 2 chronic heart failure (CHF), uncontrolled arrhythmia * Uncontrolled hypertension * 24-hour urine protein \> 1 g if dipstick \> 2+ * History of thromboembolic or hemorrhagic events within 6 months prior to treatment * Evidence of bleeding diathesis or coagulopathy * Serious, non healing wound/ulcer or serious bone fracture * No therapeutic anticoagulation or antiplatelet agents or NSAID with anti-platelet activity (aspirin ≤ 325 mg/day allowed) * Pregnancy or lactation * Fertile women (\< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception