Phase II Trial to Assess FOLFIRI+Aflibercept Efficacy in Patients With Oxaliplatin-pretreated Metastatic Colorectal Cancer With or Without ACE Polymorphisms

Inclusion criteria

• Signed and dated informed consent, and willing and able to comply with protocol requirements,
• Histologically proven adenocarcinoma of the colon and/or rectum,
• Metastatic disease confirmed.
• Existence of at least one measurable unidimensional lesion using CT or MRI based on the RECIST criteria, version 1.1
• Patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed after an oxaliplatin-containing regimen.
• Age ≥18 years
• World Health Organization (WHO) Performance status (PS) 0-2,
• Hematological status: neutrophils (ANC) ≥1.5x109 /L; platelets ≥100x109 /L; haemoglobin ≥9g/dL
• Adequate renal function: serum creatinine level < 1.5 x ULN
• Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alkaline phosphatase (ALP) <5xULN
• Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour.
• Regular follow-up feasible.
• For female patients of childbearing potential, negative serum pregnancy test
• 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

• Uncontrolled hypercalcemia,
• Pre-existing permanent neuropathy (NCI grade >2)
• Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive ncephalopathy,
• 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,
• History or evidence upon physical examination of CNS metastasis unless adequately treated (e.g. non irradiated CNS metastasis, seizure not controlled with standard medical therapy),
• Known Gilbert's syndrome
• Intolerance to atropine sulfate or loperamide
• Known dihydropyrimidine dehydrogenase deficiency
• Treatment with CYP3A4 inducers unless discontinued > 7 days prior to inclusion
• 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: i/ adequately treated insitu carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ 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 excipient to study drugs,
• History of myocardial infarction and/or stroke within 6 months prior to inclusion, NYHA class III and IV congestive heart failure
• Bowel obstruction.