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

Open-label, Multicenter, Phase II Study Of First-line Biweekly Irinotecan, Oxaliplatin And Infusional 5-FU/LV (FOLFOXIRI) In Combination With Bevacizumab In Patients With Metastatic Colorectal Cancer

This is a single-arm, open-label, multicentre phase II study evaluating the safety and efficacy of the combination of the G.O.N.O. FOLFOXIRI regimen with bevacizumab as first-line treatment of 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