['metastatic colorectal cancer']
['aflibercept', 'irinotecan', '5-fluorouracil', 'folinic acid']

        Inclusion Criteria

          -  Histologically proven adenocarcinoma of the colon and/or rectum

          -  Metastatic disease confirmed clinically/radiologically

          -  Signed written informed consent

          -  No prior therapy for metastatic disease

          -  Duly documented inoperable metastatic disease, ie not suitable for complete curative
             surgical resection

          -  At least one measurable or evaluable lesion as assessed by Computed Tomography (CT)
             scan or MRI (Magnetic Resonance Imaging) according to Response Evaluation Criteria In
             Solid Tumors (RECIST) v1.1

          -  Age ≥18 years

          -  Eastern Cooperative Oncology Group (ECOG) Performance status (PS) 0-2

          -  Adequate hematological status:

               -  neutrophils (ANC) ≥1.5x109/L

               -  platelets ≥100x109/L

               -  haemoglobin ≥9g/dL

          -  Adequate renal function: serum creatinine level <1.5 mg/dl and Glomerular Filtration
             Rate>50 ml/min by Cockroft/Gault formula

          -  Adequate liver function:

               -  serum bilirubin ≤1.5 x upper normal limit (ULN)

               -  alkaline phosphatase

               -  aspartate aminotransferase (AST)

               -  alanine aminotransferase (ALT) < 5 x ULN

          -  Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour

          -  Regular follow-up feasible

          -  Baseline evaluations performed before registration: clinical and blood evaluations no
             more than 2 weeks (14 days) prior to registration, tumor assessment (chest X-ray,
             CT-scan or MRI, evaluation of non-measurable lesions) no more than 3 weeks (21 days)
             prior to registration

          -  First course of treatment planned less than 1 week (7 days) after registration

          -  For female patients of childbearing potential, negative serum pregnancy test within 1
             week (7 days) prior of starting study treatment

          -  Female patients must commit to using reliable and appropriate methods of contraception
             until at least three months after the end of study treatment (when applicable). Male
             patients with a partner of childbearing potential must agree to use contraception in
             addition to having their partner use another contraceptive method during the trial.

        Exclusion Criteria

          -  Exclusive presence of bone metastasis only

          -  Uncontrolled hypercalcemia

          -  Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or
             diastolic blood pressure >100 mmHg despite medical therapy), or history of
             hypertensive crisis, or hypertensive encephalopathy

          -  Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted
             therapy, immunotherapy)

          -  Treatment with any other investigational medicinal product within 28 days prior to
             study entry

          -  Other serious and uncontrolled non-malignant chronic disease

          -  History or presence of Central Nervous System (CNS) metastasis unless adequately
             treated (e.g. non irradiated CNS metastasis, seizures not controlled with standard
             medical therapy)

          -  Gilbert's syndrome

          -  Intolerance to atropine sulfate or loperamide

          -  Known dihydropyrimidine dehydrogenase deficiency

          -  Treatment with Cytochrome P450 3A4 (CYP3A4) inducers unless discontinued > 7 days
             prior to randomization

          -  Any of the following in 3 months prior to inclusion: grade 3-4 gastrointestinal
             bleeding (unless due to resected tumor), treatment resistant peptic ulcer disease,
             erosive esophagitis or gastritis, infectious or inflammatory bowel disease, or
             diverticulitis

          -  Other concomitant or previous malignancy, except:

               -  adequately treated in-situ carcinoma of the uterine cervix

               -  basal or squamous cell carcinoma of the skin

               -  cancer in complete remission for >5 years

          -  Any other serious and uncontrolled non-malignant disease, major surgery or traumatic
             injury within the last 28 days

          -  Pregnant or breastfeeding women

          -  Patients with known allergy to any excipients to study drugs

          -  History of myocardial infarction and/or stroke or other arterial thrombotic events or
             pulmonary embolism or unstable angina pectoris within 6 months prior to registration

          -  Poorly controlled cardiac arrhythmias

          -  Bowel obstruction

          -  History of severe tumour bleeding or bleeding disorders

          -  Poorly controlled anti-coagulation therapy (INR>3.0 on coumadin or heparin compounds)

          -  Palliative radiation therapy within 4 weeks prior to registration
      