Bevacizumab-based Chemotherapy Tailored to the Pharmacokinetics of Bevacizumab in First-line Treatment of Unresectable Metastatic Colorectal Cancer: a Randomized, Multicenter, Double-blind Phase 3 Study
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 244
- 试验地点
- 4
- 主要终点
- The primary endpoint is progression-free survival (PFS)
研究概览
简要总结
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.
详细描述
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)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
Double blinding (patients and investigators) will be applied to this trial with respect to the dose of bevacizumab administered throughout the study, except in specific circumstances such as in emergency cases, and only if knowledge of the dose is likely to influence management.
The dose of bevacizumab will be administered in 2 preparations and in the following order:
- 1. Preparation at 5 mg/kg, open label;
- 2. Preparation at 5 mg/kg or placebo, blinded.
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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-
- •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).
排除标准
- •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.
研究组 & 干预措施
Experimental: Group A
Patients randomized to the experimental group of the trial will receive bevacizumab as an IV infusion at a dose of 10 mg/kg, administered in 2 preparations of 5 mg/kg, every 2 weeks. Patients will receive treatment until progression, patient refusal, or unacceptable toxicity.
干预措施: Avastin, 25 Mg/mL Intravenous Solution (Drug)
Active comparator: Group B
Patients randomized to the control group of the trial will receive bevacizumab at a dose of 5 mg/kg and placebo (NaCl) every two weeks. Patients will receive treatment until progression, patient refusal, or unacceptable toxicity.
干预措施: Avastin, 25 Mg/mL Intravenous Solution (Drug)
结局指标
主要结局
The primary endpoint is progression-free survival (PFS)
时间窗: up to death
The SS was defined as the time interval for randomized patients between the date of start of treatment and date of first clinical and/or radiological progression or death whatever the cause, in depending on what survives first.of first clinical and/or radiological progression or death whatever the cause, in depending on what survives first.progression (PD) per RECIST 1.1 or death due to any cause, whichever occurs first. A patient alive without progression will be censored on the date from the last follow-up visit.
次要结局
- Safety profile(Up to approximately 10 months)
- Overall Survival (OS)(Up to approximately 25 months)
- Best Overall Response Rate (BORR) Per RECIST1.1(Up to approximately 10 months)
- Depth of response (DpR)(Up to approximately 10 months)
- rate of secondary resection of metastases(Up to approximately 10 months)
- Patient quality of life(Up to approximately 10 months)
- Serum concentrations of bevacizumab(on day 14 of the first administration, and at 2 months from randomization (= 3 months from the first course))
- Medical-economic analysis(up to death)