Trial in Metastatic Colorectal Cancer With FOLFIRI Plus Aflibercept as First Line Treatment (MINOAS)

Inclusion Criteria:

• Patients with histologically documented adenocarcinomas of colon or rectum with unresectable metastatic disease.
• No prior treatment for metastatic disease
• Metastatic liver disease assessable with diffusion-weighted Magnetic Resonance Imaging (MRI)
• No previous treatment with bevacizumab or Cetuximab or Panitumumab.
• Patients may have receive fluoropyrimidines with or without oxaliplatin as adjuvant treatment, if they have progressed > 12 months after the end of the last cycle of the adjuvant treatment
• Performance Status (ECOG) 0-2
• Life expectancy ≥ 3 months.
• Effective contraception for both male and female subjects if the risk of conception exists.
• Adequate laboratory parameters: Absolute neutrophils count ≥ 1.5 x 109 /L, Platelets ≥ 100 x 109 /L, Leucocytes > 3,000/mm; Hemoglobin> 10.5g/dl, creatinine clearance ≥ 60 ml/min, Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour, Magnesium ≥ lower limit of normal, Calcium ≥ lower limit of normal, total Bilirubin ≤ 1.5 times the upper limit of normal; aspartate and alanine aminotransferase ≤ 3 times of the upper normal limit in absence of liver metastases, or ≤5x Upper Normal Limits (UNL) in presence of liver metastases, alkaline phosphatases < 5x UNL
• All patients will have to sign written informed consent in order to participate in the study.
• 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:

• Known hypersensitivity reaction to the component of the treatment.
• Inability to underwent a diffusion-weighted MR Imaging at baseline and in predefined time points
• Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
• History or evidence upon physical examination of Central Nervous System (CNS) metastasis unless adequately treated (e.g. non irradiated CNS metastasis, seizure not controlled with standard medical therapy),
• Concomitant protocol 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 disease
• Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy.
• Gilbert's syndrome
• Intolerance to atropine sulfate or loperamide
• Known dihydropyrimidine dehydrogenase deficiency
• Treatment with 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
• Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days
• INR in absence of anticoagulation therapy > 1.25 or poorly controlled anti-coagulation therapy on coumadin or heparin compounds (INR >3.0)
• History of myocardial infarction and/or stroke within 6 months prior to randomization, New York Heart Association (NYHA) class III and IV congestive heart failure
• History of life threatening (grade 4) venous thromboembolic events (including pulmonary embolism) within 6 months prior to registration,
• Bowel obstruction
• Legal incapacity or limited legal capacity.
• Medical or psychological condition which in the opinion of the investigator would not permit the subject to complete the study or sign meaningful informed consent.
• A second primary tumour other than non-melanoma skin cancer or in situ cervical cancer.
• History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on chest CT scan.