Clinical trial NCT06642844: Bevacizumab-based Chemotherapy Adapted to Bevacizumab Pharmacokinetics in 1st-line Treatment
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Unresectable Metastatic Colorectal Cancer
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
Collaborators: name: CHU DE BESANCON
name: Gustave Roussy, Cancer Campus, Grand Paris
name: CHU de Clermont-Ferrand
name: CHU de Reims
name: CHU de Brest
name: AP-HP, Hôpital Pitié- Salpétrière
name: University Hospital, Rouen
name: Poitiers University Hospital
name: Institut Paoli-Calmettes
name: Rennes University Hospital
name: University Hospital, Toulouse
name: AP-HP, Hôpital Saint-Louis
name: HCL Hôpital Edouard Hériot
name: Centre Hospitalier Universitaire Dijon
name: Nantes University Hospital
name: Centre Hospitalier Universitaire, Amiens
name: Hôpital Privé Jean Mermoz
name: AP-HP, Hôpital Henri Mondor
name: AP-HP, Hôpital Paul Brousse
name: CHG de St-Malo
name: Polyclinique de Blois
name: University Hospital, Caen
name: Central Hospital, Nancy, France
First posted: 2024-10-15
Enrollment: 244
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This project is a multicenter, double-blind, randomized trial in two parallel groups.
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

Primary outcomes:
measure: The primary endpoint is progression-free survival (PFS)
timeFrame: up to death
Secondary outcomes:
measure: Safety profile
timeFrame: Up to approximately 10 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 25 months
measure: Best Overall Response Rate (BORR) Per RECIST1.1
timeFrame: Up to approximately 10 months
measure: Depth of response (DpR)
timeFrame: Up to approximately 10 months
measure: rate of secondary resection of metastases
timeFrame: Up to approximately 10 months
measure: Patient quality of life
timeFrame: Up to approximately 10 months
measure: Serum concentrations of bevacizumab
timeFrame: on day 14 of the first administration, and at 2 months from randomization (= 3 months from the first course)
measure: Medical-economic analysis
timeFrame: up to death
Other outcomes:
Locations:
Study officials:
affiliation: Besançon, FRANCE
name: Christophe Borg
role: PRINCIPAL_INVESTIGATOR
affiliation: Gustave Roussy, FRANCE
name: Michel Ducreux
role: PRINCIPAL_INVESTIGATOR
affiliation: Clermont-Ferrand, FRANCE
name: Caroline Petorin
role: PRINCIPAL_INVESTIGATOR
affiliation: Reims, FRANCE
name: Olivier Bouché
role: PRINCIPAL_INVESTIGATOR
affiliation: Brest, FRANCE
name: Jean-Philippe Metges
role: PRINCIPAL_INVESTIGATOR
affiliation: Pitié- Salpétrière, FRANCE
name: Jean-Baptiste Bachet
role: PRINCIPAL_INVESTIGATOR
affiliation: Rouen, FRANCE
name: Frédéric Di Fiore
role: PRINCIPAL_INVESTIGATOR
affiliation: Poitiers, FRANCE
name: David Tougeron
role: PRINCIPAL_INVESTIGATOR
affiliation: Rennes, FRANCE
name: Astrid Lièvre
role: PRINCIPAL_INVESTIGATOR
affiliation: Toulouse , FRANCE
name: Rosine Guimbaud
role: PRINCIPAL_INVESTIGATOR
affiliation: St Louis , FRANCE
name: Thomas Aparicio
role: PRINCIPAL_INVESTIGATOR
affiliation: Edouard Hériot, FRANCE
name: Thomas Walter
role: PRINCIPAL_INVESTIGATOR
affiliation: Dijon, FRANCE
name: Côme Lepage
role: PRINCIPAL_INVESTIGATOR
affiliation: Nantes, FRANCE
name: Yann Touchefeu
role: PRINCIPAL_INVESTIGATOR
affiliation: Amiens, FRANCE
name: Vincent Hautefeuille
role: PRINCIPAL_INVESTIGATOR
affiliation: Jean Mermoz, FRANCE
name: Pascal Artru
role: PRINCIPAL_INVESTIGATOR
affiliation: Henri Mondor, France
name: Christophe Tournigand
role: PRINCIPAL_INVESTIGATOR
affiliation: Paul Brousse, FRANCE
name: Pascal Hammel
role: PRINCIPAL_INVESTIGATOR
affiliation: St-Malo, FRANCE
name: Romain Desgrippes
role: PRINCIPAL_INVESTIGATOR
affiliation: Blois, FRANCE
name: Philippe Laplaige
role: PRINCIPAL_INVESTIGATOR
affiliation: Caen, FRANCE
name: Karine Bouhier-Leporrier
role: PRINCIPAL_INVESTIGATOR
affiliation: Nancy, france
name: Marie Muller
role: PRINCIPAL_INVESTIGATOR
References: