bevacizumab-based chemotherapy adapted to bevacizumab pharmacokinetics in 1st-line treatment

Conditions: Unresectable Metastatic Colorectal Cancer

Summary: bevacizumab is a standard drug for metastatic colorectal cancer (mcrc) in combination with cytotoxic chemotherapy. however, inter-individual pharmacokinetic variability was observed for bevacizumab and an exposure-response relationship for efficacy was described for bevacizumab in mcrc patients treated with 1st-line bevacizumab-based chemotherapy.

the primary objective is to evaluate the effect of doubling the dose of bevacizumab in mcrc patients whose initial serum bevacizumab concentration is ≤15.5 mg/l on progression-free survival (pfs). this project is a multicenter, double-blind, randomized trial in two parallel groups. the primary endpoint is progression-free survival (pfs)

Eligibility criteria:
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.