Bevacizumab-based Chemotherapy Adapted to Bevacizumab Pharmacokinetics in 1st-line Treatment

Inclusion Criteria:

* Patients aged ≥18 years.
* Histologically proven metastatic colorectal adenocarcinoma (on primary tumor and/or metastases) inoperable, well documented, i.e. not compatible with complete oncological resection at inclusion.
* For whom treatment with bevacizumab is indicated.
* For women of childbearing age: effective contraception.
* ECOG Performance status (PS) 0-2.
* No prior treatment of metastatic disease (in the case of adjuvant treatment, interval between the end of chemotherapy and relapse \> 6 months if fluoropyrimidine alone or \> 12 months if FOLFOX).
* At least one evaluable or measurable lesion assessed by computed tomography (CT) according to RECIST v1.1 criteria.
* Life expectancy greater than 3 months.
* Adequate hematological, renal and hepatic biological parameters: neutrophils ≥ 1.5x109/L; platelets ≥ 100x109/L; hemoglobin ≥ 9 g/dL; serum creatinine \<150 μmol/L; bilirubinemia ≤ 1.5 x upper limit of normal (ULN), alkaline phosphatase \< 5xULN; proteinuria \< 2+ (urine dipstick) or ≤ 1 g/24h.
* Written informed consent signed by the patient.
* Patient affiliated to a French social security system.

Randomization criteria in the experimental phase:

\- Serum concentration of bevacizumab on D14 ≤ 15.5 mg/L (measured just before the 2nd infusion of bevacizumab).

Exclusion Criteria:

Less than 6 months from the end of any prior chemotherapy, radiotherapy or adjuvant surgery.

* Patient with a known non-indication or contraindication to first-line chemotherapy based on bevacizumab.
* Cardiovascular contraindication to the prescription of bevacizumab: heart failure, cardiovascular event within 6 months, NYHA ≥ 2 (New York Heart Association), poorly controlled arterial hypertension, history of hypertensive crisis or hypertensive encephalopathy; Grade 3/4 anterior venous thromboembolism (NCI-CTCAE)
* Inadequate hematological, hepatic and renal function
* Urine test strip for proteinuria ≥ 2+ unless proteinuria \< 1 g / 24 hours is demonstrated.
* Current or recent (within 10 days of study enrollment) use of aspirin (\>325 mg/day) or clopidogrel (\>75 mg/day).
* Current or recent use (within 10 days before the first dose of bevacizumab) of oral or parenteral therapeutic anticoagulants or thrombolytic agents for therapeutic purposes.
* Untreated CNS metastases or treatment of brain metastases, either by surgical or radiological techniques, must have been completed more than 4 weeks before the first study treatment.
* Surgical procedure (including open biopsy, surgical resection, wound revision, or other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to study enrollment or anticipation of study need for major surgery during the study.
* Serious non-healing wound, active ulcer or untreated bone fracture.
* Other neoplasias (previous or current), except:

  * i/ carcinoma in situ of the cervix adequately treated,
  * ii/ basal cell or squamous cell carcinoma of the skin,
  * iii/ cancer in complete remission for more than 5 years.
* Other illnesses, which, according to the doctor, are life-threatening to the patient and/or which are uncontrolled.
* Primary tumor in place and symptomatic (occlusion, hemorrhage).
* Pregnant or breastfeeding women.
* Patients unable to give consent.
* Patients under guardianship, curatorship or legal protection.