BOS3: Randomized Phase II/III Trial Evaluating the Efficacy of FOLFOX Alone Versus FOLFOX Plus Aflibercept in K-ras Mutant as Perioperative Treatment in Patients With Resectable Liver Metastases From Colorectal Cancer.
- 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,
- 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
- 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.
- 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
- 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