Phase II, Multicentric Randomized Trial, Evaluating the Efficacy of Fluoropyrimidine-based Standard Chemotherapy, Associated to Either Cetuximab or Bevacizumab, in KRAS Wild-type Metastatic Colorectal Cancer Patients With Progressive Disease After Receiving First-line Treatment With Bevacizumab
- Histologically or cytologically proven adenocarcinoma of the colon expressing
non-mutated (wild-type) KRAS.
- Progressive metastatic disease after first-line treatment with chemotherapy alone:
based on 5-FU (iv or per os) with irinotecan or oxaliplatin associated to
- Prior adjuvant chemotherapy (of the primary tumor) with fluoropyrimidine and
oxaliplatin is allowed if the time interval between the end of this chemotherapy and
the beginning of the first-line metastatic treatment is ≥ 6 months.
- Measurable disease (at least one measurable metastatic lesion) according to the
RECIST V1.1 criteria (the lesion should not be located in a previous field of
- Previous radiotherapy is authorized if discontinued ≥ 15 days prior to randomization
and if the measurable metastatic lesions are outside the radiation area.
- Sites of disease evaluated within 28 days prior to randomization with
thoracic-abdominal-pelvic CT scan (or abdominal-pelvic MRI plus Chest Xray)
- Age ≥18 years
- Patient with ECOG 0 or 1
- Life Expectancy ≥ 3 months
- Hematologic function (polynuclear neutrophiles ≥ 1.5.109/L ; platelets ≥ 100.109/L ;
hemoglobin ≥ 9 g/dL
- Hepatic transaminases ≤ 2.5 times upper limit of normal (ULN) (≤ 5 ULN in case of
hepatic metastases), alkaline phosphatases ≤ 2.5 ULN (≤ 5 ULN in case of hepatic
metastases), total bilirubinemia ≤ 1.5 ULN
- Renal function (creatinemia ≤1.5 ULN; creatine clearance ≥ 50 mL/mn (Cockcroft and
Gault) ; urine test strip < 2+. If proteinuria is ≥ +2 at inclusion, the serum urea
test must be redone and show proteinuria ≤ 1 g/L within 24 h)
- Completion of the EORTC QLQ-C30 quality of life form
- Negative pregnancy test for women of child-bearing age
- Information given to the patient and signed informed consent
- Public Health insurance coverage
- Known meningeal or brain metastases
- Pre-treatment with anti-EGFR
- Specific contraindication or known hypersensitivity to one treatment product
- Patient with known allergy or hypersensitivity to monoclonal antibodies (bevacizumab,
- Clinically significant affection of the coronaries or myocardial infarction within 6
months prior to inclusion.
- Peripheral neuropathy of grade > 1 (CTCAE scale version 4.0).
- Known depletion of the dihydropyrimidine dehydrogenase (DPD).
- Acute intestinal obstruction or sub-obstruction, history of inflammatory intestinal
disease or extended resection of the small intestine. Presence of a colic prosthesis.
- Uncontrolled Arterial hypertension (systolic pressure > 150 mmHg and/or diastolic
pressure > 100 mmHg with and without antihypertensive medication. Patients with high
hypertension are eligible if antihypertensive medication lowers their arterial
pressure to the level of acceptability specified by the inclusion criteria.
- History of hypertensive crisis or hypertensive encephalopathy
- Other concomitant malignancy or history cancer (except carcinoma in situ of the
cervix, or non melanoma skin cancer, with curative intent treatment, when considered
in complete remission for at least 5 years before randomization.
- Any treatment including an experimental drug, or participation in another clinical
trial within 28 days preceding inclusion.
- Persons deprived of liberty or under guardianship.
- Psychological, familial, sociological or geographical condition potentially hampering
compliance with the study protocol and follow-up schedule.