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

Официальное название

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

Обзор

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.

Подробное описание

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)

Вмешательства

• Препарат Avastin, 25 Mg/mL Intravenous Solution
  Experimental group/ 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. Control group: 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,

Первичные конечные точки

• The primary endpoint is progression-free survival (PFS) [Срок оценки: up to death]

Вторичные конечные точки (8)

• Safety profile [Срок оценки: Up to approximately 10 months]
• Overall Survival (OS) [Срок оценки: Up to approximately 25 months]
• Best Overall Response Rate (BORR) Per RECIST1.1 [Срок оценки: Up to approximately 10 months]
• Depth of response (DpR) [Срок оценки: Up to approximately 10 months]
• rate of secondary resection of metastases [Срок оценки: Up to approximately 10 months]
• Patient quality of life [Срок оценки: Up to approximately 10 months]
• Serum concentrations of bevacizumab [Срок оценки: on day 14 of the first administration, and at 2 months from randomization (= 3 months from the first course)]
• Medical-economic analysis [Срок оценки: up to death]

Критерии участия

Критерии включения

• 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).

Критерии исключения

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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

Франция · 4 центра

• BORG — Besançon
• Caroline Petorin — Clermont-Ferrand
• Ducreux — Gustave Roussy
• David Tougeron — Poitiers

Идентификаторы

NCT: NCT06642844 · DR230009

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗