Unresectable Metastatic Colorectal Cancer
Conditions
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)
Interventions
DRUGAvastin, 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.
Sponsors
University Hospital, Tours
CHU DE BESANCON
Gustave Roussy, Cancer Campus, Grand Paris
University Hospital, Clermont-Ferrand
CHU de Reims
CHU de Brest
Pitié-Salpêtrière Hospital
University Hospital, Rouen
Poitiers University Hospital
Institut Paoli-Calmettes
Rennes University Hospital
University Hospital, Toulouse
AP-HP, Hôpital Saint-Louis
HCL Hôpital Edouard Hériot
Centre Hospitalier Universitaire Dijon
Nantes University Hospital
Centre Hospitalier Universitaire, Amiens
Hôpital Privé Jean Mermoz
AP-HP, Hôpital Henri Mondor
Hopital Paul Brousse
CHG de St-Malo
Polyclinique de Blois
University Hospital, Caen
Central Hospital, Nancy, France
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
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.
Intervention model description
This project is a multicenter, double-blind, randomized trial in two parallel groups.
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The primary endpoint is progression-free survival (PFS) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety profile | Up to approximately 10 months | Number of Participants Who Experienced an Adverse Event (AE) per NCI-CATCAE5.0 classification |
| Overall Survival (OS) | Up to approximately 25 months | 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. |
| Best Overall Response Rate (BORR) Per RECIST1.1 | Up to approximately 10 months | 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. |
| Depth of response (DpR) | Up to approximately 10 months | 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. |
| rate of secondary resection of metastases | Up to approximately 10 months | secondary resection of initially unresectable metastases of colorectal cancer |
| Patient quality of life | Up to approximately 10 months | 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) |
| Serum concentrations of bevacizumab | on day 14 of the first administration, and at 2 months from randomization (= 3 months from the first course) | Serum concentrations of bevacizumab in order to evaluate the effect of doubling the administered dose of bevacizumab. |
| Medical-economic analysis | up to death | 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. |
Countries
France
Contacts
CONTACTThierry Lecomte
CONTACTAdeline MOUSSET
PRINCIPAL_INVESTIGATORChristophe Borg
Besançon, FRANCE
PRINCIPAL_INVESTIGATORMichel Ducreux
Gustave Roussy, FRANCE
PRINCIPAL_INVESTIGATORCaroline Petorin
Clermont-Ferrand, FRANCE
PRINCIPAL_INVESTIGATOROlivier Bouché
Reims, FRANCE
PRINCIPAL_INVESTIGATORJean-Philippe Metges
Brest, FRANCE
PRINCIPAL_INVESTIGATORJean-Baptiste Bachet
Pitié- Salpétrière, FRANCE
PRINCIPAL_INVESTIGATORFrédéric Di Fiore
Rouen, FRANCE
PRINCIPAL_INVESTIGATORDavid Tougeron
Poitiers, FRANCE
PRINCIPAL_INVESTIGATORAstrid Lièvre
Rennes, FRANCE
PRINCIPAL_INVESTIGATORRosine Guimbaud
Toulouse , FRANCE
PRINCIPAL_INVESTIGATORThomas Aparicio
St Louis , FRANCE
PRINCIPAL_INVESTIGATORThomas Walter
Edouard Hériot, FRANCE
PRINCIPAL_INVESTIGATORCôme Lepage
Dijon, FRANCE
PRINCIPAL_INVESTIGATORYann Touchefeu
Nantes, FRANCE
PRINCIPAL_INVESTIGATORVincent Hautefeuille
Amiens, FRANCE
PRINCIPAL_INVESTIGATORPascal Artru
Jean Mermoz, FRANCE
PRINCIPAL_INVESTIGATORChristophe Tournigand
Henri Mondor, France
PRINCIPAL_INVESTIGATORPascal Hammel
Paul Brousse, FRANCE
PRINCIPAL_INVESTIGATORRomain Desgrippes
St-Malo, FRANCE
PRINCIPAL_INVESTIGATORPhilippe Laplaige
Blois, FRANCE
PRINCIPAL_INVESTIGATORKarine Bouhier-Leporrier
Caen, FRANCE
PRINCIPAL_INVESTIGATORMarie Muller
Nancy, france
Outcome results
None listed