Efficacy of FOLFOX Versus FOLFOX Plus Aflibercept in K-ras Mutant Patients With Resectable Liver Metastases

• Histologically proven CRC with 1 to 8 metachronous or synchronous liver metastases considered to be completely resectable
• Primary tumor (or liver metastasis) of CRC must be KRAS status "mutant"
• Patients must have undergone complete resection (R0) of the primary tumor at least 4 weeks before randomization. Or for patients with synchronous metastases the primary tumor can be resected (R0) at the same time as the liver metastases if: the patient has a non-obstructive primary tumor and is able to receive preoperative chemotherapy (3-4 months) before surgery1.
• Measurable hepatic disease by RECIST version 1.1
• Patients must be 18 years old or older
• A World Health Organization (WHO) performance status of 0 or 1
• Previous adjuvant chemotherapy for primary CRC is allowed if completed at least 12 months before inclusion in this study
• All the following tests should be done within 4 weeks prior to randomization:
• Hematological status: neutrophils (ANC) = 1.5x10 9/L; platelets = 100x10 9/L; haemoglobin = 9g/dL
• Serum creatinine = 1.5 times the upper limit of normal (ULN)
• Proteinuria \< 2+ (dipstick urinalysis) or =1g/24hour.
• Liver function: serum bilirubin = 1.5 x upper normal limit (ULN), alkaline phosphatase \< 5xULN
• Magnesium ≥ lower limit of normal (LLN)
• Patients with a buffer range from the normal values of +/- 5% for hematology and +/- 10% for biochemistry are acceptable. This will not apply for Renal Function, including Creatinine.
• Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 14 days prior to the first dose of study treatment.
• Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
• Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment.
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Patient should be willing and able to comply with protocol requirements
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

• Evidence of extra-hepatic metastasis (of CRC)
• Previous chemotherapy for metastatic disease or surgical treatment (e.g. surgical resection or radiofrequency ablation) for liver metastasis. Radiotherapy alone is allowed if given pre or post protocol treatment
• Previous exposure to VEGF/VEGFR targeting therapy within the last 12 months
• Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to randomization
• Gilbert's syndrome
• History of myocardial infarction and/or stroke within 6 months prior to randomization
• Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure > 100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy
• History or evidence upon physical examination of CNS metastasis
• Bowel obstruction
• Uncontrolled hypercalcemia
• Pre-existing permanent neuropathy (NCI grade = 2)
• Known allergy to any excipient to study drugs