This study consist of 4-months induction first-line chemotherapy with the G.O.N.O. FOLFOXIRI regimen plus bevacizumab followed by maintenance with bevacizumab or bevacizumab plus metronomic chemotherapy (with capecitabine and cyclophosphamide) in mCRC patients.

The main objective of this study is to preliminarily evaluate the potential effects of the combination of a metronomic chemotherapy with capecitabine and cyclophosphamide to maintenance bevacizumab on pharmacodynamic and clinical parameters among mCRC patients.

Inclusion Criteria:

• Histologically proven diagnosis of colorectal cancer.
• Not resectable metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease.
• At least one measurable lesion according to RECIST criteria.
• Male or female of 18-75 years of age.
• ECOG PS < 2 if aged < 71 years, ECOG PS = 0 if aged 71-75 years;
• Life expectancy of at least 12 weeks.
• 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;
• Neutrophils 1.5 x 109/L, Platelets 100 x 109/L, Hgb >9 g/dl.
• Total bilirubin 1.5 time the upper-normal limits (UNL) of the institutional normal values and ASAT (SGOT) and/or ALAT (SGPT) 2.5 x UNL, or 5 x UNL in case of liver metastases, alkaline phosphatase 2.5 x UNL, 5 x UNL in case of liver metastases.
• Creatinine clearance >50 mL/min or serum creatinine 1.5 x UNL.
• Urine dipstick of proteinuria <2+. Patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate <1 g of protein/24 hr.
• Written informed consent to treatment and translational analyses.

Exclusion Criteria:

• Radiotherapy to any site within 4 weeks before the study.
• Previous treatment with bevacizumab
• Untreated brain metastases or spinal cord compression or primary brain tumours.
• History or evidence upon physical examination of CNS disease unless adequately treated.
• Symptomatic peripheral neuropathy > 2 grade NCIC-CTG criteria;
• Serious, non-healing wound, ulcer, or bone fracture.
• Evidence of bleeding diathesis or coagulopathy.
• Uncontrolled hypertension.
• Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication.
• Current or recent (within 10 days prior to study treatment start) ongoing treatment with anticoagulants for therapeutic purposes.
• Chronic, daily treatment with high-dose aspirin (>325 mg/day).
• Treatment with any investigational drug within 30 days prior to enrollment.
• Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of basal and squamous cell carcinoma or cervical cancer in situ.
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study.
• Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
• Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study (barrier contraceptive measure or oral contraception).