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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Unresectable Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Avastin, 25 Mg/mL Intravenous Solution

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)

• Study Type: Interventional
• Enrollment (Estimated): 244
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Adeline MOUSSET; Phone Number: 0218370645; Email: a.fourmy@chu-tours.fr
• Study Contact Backup: Name: Thierry Lecomte; Phone Number: 0247475900; Email: thierry.lecomte@med.univ-tours.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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, patient refusal, or unacceptable toxicity.; Other Names: Control group; Experimental group
Active Comparator: 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.	Drug: 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, patient refusal, or unacceptable toxicity.; Other Names: Control group; Experimental group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary endpoint is progression-free survival (PFS)	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.	up to death

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety profile	Number of Participants Who Experienced an Adverse Event (AE) per NCI-CATCAE5.0 classification	Up to approximately 10 months
Overall Survival (OS)	OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of analysis were censored at the date of last known contact.	Up to approximately 25 months
Best Overall Response Rate (BORR) Per RECIST1.1	BORR is defined as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST)v1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions). Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.	Up to approximately 10 months
Depth of response (DpR)	DpR was defined as the relative change in the sum of the target lesions' longest diameters at their smallest attained sizes compared to baseline time.	Up to approximately 10 months
rate of secondary resection of metastases	secondary resection of initially unresectable metastases of colorectal cancer	Up to approximately 10 months
Patient quality of life	Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 and European Quality of Life 5 Dimensions 5 Level Version questionnaires Measure Description: The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. Participant responses to 30 questions are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. Higher scores meant a better level of function. The EQ-5D-5L is a generic tool for Patient-Reported Outcomes (PRO) measurement using 6 5 questions that can assess patients' quality of life, irrespective of the disease. . It includes a vertical EQ visual analog scale (EQ VAS, 0-100 points)	Up to approximately 10 months
Serum concentrations of bevacizumab	Serum concentrations of bevacizumab in order to evaluate the effect of doubling the administered dose of bevacizumab.	on day 14 of the first administration, and at 2 months from randomization (= 3 months from the first course)
Medical-economic analysis	A model-based cost-effectiveness analysis will be performed for estimating the Incremental Cost-Utility Ratio (cost per QALY gained) et the Incremental Cost-Effectiveness Ratio (cost per life-year gained) from the Healthcare system perspective.	up to death

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Collaborators: Centre Hospitalier Universitaire Dijon; CHU de Reims; Centre Hospitalier Universitaire, Amiens; Poitiers University Hospital; University Hospital, Caen; Rennes University Hospital; University Hospital, Toulouse; Nantes University Hospital; Institut Paoli-Calmettes; Gustave Roussy, Cancer Campus, Grand Paris; CHU de Nancy; CHU de Brest; CHU DE BESANCON; CHU de Clermont-Ferrand; AP-HP, Hôpital Pitié- Salpétrière; CHU de Rouen; AP-HP, Hôpital Saint-Louis; HCL Hôpital Edouard Hériot; Hôpital Privé Jean Mermoz; AP-HP, Hôpital Henri Mondor; AP-HP, Hôpital Paul Brousse; CHG de St-Malo; Polyclinique de Blois
• Investigators: Principal Investigator: Christophe Borg, Besançon, FRANCE; Principal Investigator: Michel Ducreux, Gustave Roussy, France; Principal Investigator: Caroline Petorin, Clermont-Ferrand, FRANCE; Principal Investigator: Olivier Bouché, Reims, FRANCE; Principal Investigator: Jean-Philippe Metges, Brest, FRANCE; Principal Investigator: Jean-Baptiste Bachet, Pitié- Salpétrière, FRANCE; Principal Investigator: Frédéric Di Fiore, Rouen, FRANCE; Principal Investigator: David Tougeron, Poitiers, FRANCE; Principal Investigator: Astrid Lièvre, Rennes, FRANCE; Principal Investigator: Rosine Guimbaud, Toulouse , FRANCE; Principal Investigator: Thomas Aparicio, St Louis , FRANCE; Principal Investigator: Thomas Walter, Edouard Hériot, FRANCE; Principal Investigator: Côme Lepage, Dijon, FRANCE; Principal Investigator: Yann Touchefeu, Nantes, FRANCE; Principal Investigator: Vincent Hautefeuille, Amiens, FRANCE; Principal Investigator: Pascal Artru, Jean Mermoz, FRANCE; Principal Investigator: Christophe Tournigand, Henri Mondor, France; Principal Investigator: Pascal Hammel, Paul Brousse, FRANCE; Principal Investigator: Romain Desgrippes, St-Malo, FRANCE; Principal Investigator: Philippe Laplaige, Blois, FRANCE; Principal Investigator: Karine Bouhier-Leporrier, Caen, FRANCE; Principal Investigator: Marie Muller, Nancy, France

Study record dates

Study Major Dates

• Study Start (Estimated): October 30, 2024
• Primary Completion (Estimated): October 30, 2028
• Study Completion (Estimated): October 30, 2029

Study Registration Dates

• First Submitted: March 8, 2024
• First Submitted That Met QC Criteria: October 14, 2024
• First Posted (Actual): October 15, 2024

Study Record Updates

• Last Update Posted (Actual): October 15, 2024
• Last Update Submitted That Met QC Criteria: October 14, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: DR230009

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No