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    Summary
    EudraCT Number:2019-001875-35
    Sponsor's Protocol Code Number:PRODIGE71-BEVAMAINT
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-07-25
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2019-001875-35
    A.3Full title of the trial
    BEVAMAINT - A randomized phase III study comparing maintenance treatment with fluoropyrimidine + bevacizumab versus fluoropyrimidine after induction chemotherapy for a metastatic colorectal cancer
    BEVAMAINT - Essai de phase III comparant le traitement d'entretien par fluoropyrimidine + bévacizumab versus fluoropyrimidine après chimiothérapie d'induction pour un cancer colorectal métastatique
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    BEVAMAINT - A clinical trial comparing 2 maintenance treatments for patient with a metastatic colorectal cancer
    BEVAMAINT - Essai clinique visant à comparer 2 traitements d'entretiens de chimiothérapie chez des patients atteints de cancer colorectal métastatique
    A.3.2Name or abbreviated title of the trial where available
    PRODIGE 71-BEVAMAINT
    PRODIGE 71-BEVAMAINT
    A.4.1Sponsor's protocol code numberPRODIGE71-BEVAMAINT
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCentre Hospitalier Universitaire (CHU) de Dijon
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportINCA-PHRC_K
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFédération Francophone de Cancérologie Digestive (FFCD)
    B.5.2Functional name of contact pointDaniel Gonzalez
    B.5.3 Address:
    B.5.3.1Street AddressFaculté de Médecine, 7 Boulevard Jeanne d'Arc, BP 87900
    B.5.3.2Town/ cityDijon cedex
    B.5.3.3Post code21079
    B.5.3.4CountryFrance
    B.5.4Telephone number+33380393404
    B.5.5Fax number+33380381841
    B.5.6E-maildaniel.gonzalez@u-bourgogne.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name AVASTIN
    D.2.1.1.2Name of the Marketing Authorisation holderROCHE
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameBEVACIZUMAB
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.4EV Substance CodeSUB16402MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number5 to 7.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Unresectable metastatic colorectal cancer with measurable hepatic lesions (according to RECIST V1.1)
    Cancer colorectal métastatique avec lésions hépatiques mesurables (selon critère RECIST V1.1)
    E.1.1.1Medical condition in easily understood language
    Colorectal cancer with metastasis in liver
    Cancer colorectal avec métastases au foie
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10052358
    E.1.2Term Colorectal cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare efficacy maintenance therapy (i.e. Time to Treatment Failure) with bevacizumab + fluoropyrimidine versus fluoropyrimidine alone after induction chemotherapy (with doublet (fluoropyrimidine or TAS102 + irinotecan or oxaliplatin) or triplet (fluoropyrimidine + irinotecan + oxaliplatin) +/- cetuximab, panitumumab, bevacizumab, aflibercept or others targeted therapy, or IAH chemotherapy.
    Comparer l’efficacité des traitements d'entretien (via la détermination du temps jusqu’à échec du traitement) avec le bévacizumab + fluoropyrimidine vs fluoropyrimidine seule après une bichimiothérapie d'induction (fluoropyrimidine ou trifluridine-tipiracil + irinotécan ou oxaliplatine) ou une trichimiothérapie d'induction (fluoropyrimidine + irinotécan + oxaliplatine) +/- cetuximab, panitumumab, bévacizumab, ou autre thérapie ciblée ou chimiothérapie IAH
    E.2.2Secondary objectives of the trial
    - Toxicity according NCI-CTC v4.0
    - Quality of life (according QLQ-C30)
    - Progression-free survival (PFS1) – according investigator and centralized review (RECIST V1.1)
    - Progression-free survival 2 (PFS2)
    - Overall survival (OS)
    - Toxicité selon NCI-CTC v4.0
    - Qualité de vie (selon QLQ-C30)
    - Survie sans progression 1 (SSP1) - selon l'investigateur et selon la relecture centralisée (RECIST V1.1)
    - Survie sans progression 2 (SSP2)
    - Survie globale (SG)
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Blood (plasma) will be collected in all patients in order to allow translational research projects (Centre de Ressource Biologique EPIGENETEC, UMR-S 1147, Paris, France, Headed by Prof. Pierre Laurent-Puig) in order to identify predictive biomarkers of treatment efficacy (for more details see “ancillary studies”) through circulating tumor DNA (baseline and kinetic) and tumor block collection.
    Le sang (plasma) sera prélevé chez tous les patients afin de réaliser des projets de recherche translationnelle (Centre de Ressource Biologique EPIGENETEC, UMR-S 1147, Paris, France, dirigé par le Professeur Pierre Laurent-Puig) sur l’identification de biomarqueurs prédictifs de l'efficacité du traitement (pour plus de détails voir "études ancillaires") incluant au moins la détection de ADNtc (de base et en cinétique), et la collecte de blocs tumoraux.
    E.3Principal inclusion criteria
    - Histologically confirmed metastatic colorectal adenocarcinoma
    - Measurable or non-measurable lesion before the induction treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
    - Metastatic, unresectable disease according local practice after induction treatment
    - ECOG performance status ≤ 2
    - Disease control (complete response, partial response or stable disease) after 4-6 months of frontline induction chemotherapy with doublet (fluoropyrimidine + irinotecan or oxaliplatin) or triplet (fluoropyrimidine + irinotecan + oxaliplatin) +/- (cetuximab, panitumumab, bevacizumab, aflibercept or others targeted therapy, or IAH chemotherapy
    - Life expectancy > 3 months
    - Age ≥ 18 years
    - Patient is at least 4 weeks from any major surgery
    - Neutrophils > 1500/mm3, platelets > 100 000/mm3, haemoglobin ≥ 9 g/dL
    - Creatinin clearance > 30 ml/min (MDRD) – if creatinin clearance comprised between 30 and 50 ml/min, see smPCs for dose adjustments
    - Proteinuria ≤ 2+ (dipstick urinalysis) (if more than 2+, so proteinuria at 24 hours must be ≤ 1g)
    - Patient is able to understand, sign, and date the written informed consent
    - Evidence of post-menopausal status or negative urinary or serum pregnancy test for pre-menopausal female patients
    - Male and female patients of childbearing potential agree to use a highly effective contraceptive measure
    - Patient affiliated to a social security system
    - Adénocarcinome colorectal métastatique histologiquement prouvé avant la chimiothérapie d’induction
    - Lésion mesurable ou non mesurable avant la chimiothérapie d'induction selon les critères RECIST 1.1
    - Maladie métastatique, non résécable selon la pratique du centre après chimiothérapie d’induction
    - Indice de performance ECOG ≤ 2
    - Contrôle de la maladie (réponse complète, réponse partielle ou maladie stable) après 4 à 6 mois d’une bichimiothérapie (fluoropyrimidine ou trifluridine-tipiracil + irinotécan ou oxaliplatine) ou d’une trichimiothérapie (fluoropyrimidine + irinotécan + oxaliplatine) d’induction en première ligne +/- (cétuximab, panitumumab, bévacizumab, ou autres traitements ciblés, ou chimiothérapie IAH.
    - Espérance de vie > 3 mois
    - Âge ≥ 18 ans
    - Pas d’intervention chirurgicale majeure dans les 4 semaines avant la randomisation.
    - Neutrophiles > 1500/mm3, plaquettes > 100 000/mm3, hémoglobine ≥ 9 g/dL
    - Clairance de la créatinine > 30 ml/min (MDRD) - si la clairance de la créatinine se situe entre 30 et 50 ml/min, voir les RCP pour les adaptations de doses
    - Protéinurie ≤ 2+ (bandelette urinaire) (si plus de 2+ alors la protéinurie des 24h doit ≤ 1g)
    - Patient est capable de comprendre, de signer et de dater le consentement éclairé
    - Preuve de la ménopause ou test de grossesse urinaire ou sérique négatif pour les femmes non ménopausées
    - Méthode de contraception médicalement efficace pour les patients en âge de procréer, hommes ou femmes
    - Patient affilié à un système de sécurité sociale
    E.4Principal exclusion criteria
    - Myocardial infarction less than 6 months, severe coronaropathy or severe cardiac dysfunction
    - Follow-up impossible
    - Patients with totally resected metastases (R0/R1) after induction chemotherapy
    - Patient with a hand-foot syndrome > 1 before maintenance treatment
    - Known brain or leptomeningeal metastases
    - Other concomitant or previous malignancy, except: adequately treated in situ carcinoma in complete remission for >5 years
    - Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy
    - Pregnancy or breast feeding
    - Treatment with sorivudine or analogs (brivudine)
    - Treatment with phenytoin or analogs
    - Partial or complete DPD deficiency (Uracilemia ≥ 16 ng/ml)
    - Peptic ulcer not healed after treatment
    - Any contraindication to bevacizumab or fluoropyrimidine treatments
    - Infarctus du myocarde, coronaropathie grave ou dysfonction cardiaque grave dans les 6 mois précédent l’inclusion
    - Suivi impossible
    - Patients réséqués de l’ensemble de leurs métastases (R0/R1) après une chimiothérapie d'induction
    - Syndrome Mains-Pieds > 1 avant la chimiothérapie d’entretien
    - Métastase cérébrale ou métastase leptoméningée connue
    - Autre tumeur maligne concomitante ou antérieure, excepté : carcinome in situ traité et en rémission complète pendant plus de 5 ans.
    - Hypertension non contrôlée (définie comme une tension artérielle systolique > 150 mmHg et/ou une tension artérielle diastolique > 100 mmHg), ou antécédents d’hypertension ou d'encéphalopathie hypertensive.
    - Patiente enceinte ou allaitante
    - Traitement par sorivudine ou analogues (brivudine)
    - Traitement par phénytoïne ou analogues
    - Déficit complet et partiel en DPD (Uracilémie ≥ 16 ng/ml)
    - Ulcère gastro-duodénal non guéri
    - Toute contre-indications au traitement par bévacizumab ou fluoropyrimidine
    E.5 End points
    E.5.1Primary end point(s)
    The Time-to-Treatment Failure (TTF) will be calculated from date of randomization (after the end of induction chemotherapy) to first radiological progression (according to RECIST 1.1) or death or start of a new chemotherapy (induction regimen or second line) or end of maintenance treatment without further chemotherapy, even if there is no radiological progression.
    Patients alive with no radiological progression and under maintenance treatment will be censored at the date of last news.
    Le temps jusqu’à échec de la stratégie thérapeutique (TTF) est défini comme le délai entre la date de randomisation (après la fin de la chimiothérapie d'induction) et la première progression radiologique (selon RECIST 1.1) ou jusqu’au décès ou jusqu’au début d'une nouvelle chimiothérapie (chimiothérapie d'induction ou 2ème ligne), ou jusqu’à la fin de la chimiothérapie d’entretien s’il n’y a pas de ligne de chimiothérapie ultérieure, même s'il n'y a aucune progression radiologique.
    Les patients vivants sans progression radiologique et sous traitement d'entretien seront censurés à la date de dernières nouvelles.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The Time-to-treatment failure (TTF) is estimated at 1 year after the last patient is randomized.
    Le temps jusqu'à échec du traitement est estimé à 1 an après la randomisation du dernier patient.
    E.5.2Secondary end point(s)
    Safety profile
    Toxicities will be graded according to the NCI-CTC v 4.0 criteria before each cycle.

    Quality of life (QoL)
    QoL will be assessed at each evaluation with QLQ-C30 questionnaire.

    Progression-free survival (PFS1):
    PFS1 is defined as the time between randomization and the first radiological progression (according to RECIST 1.1) or death (whatever occurs first). Patients alive and without progression will be censored at the date of last news.

    Progression-free survival 2 (PFS2):
    PFS2 is defined as the time between the end of maintenance treatment (whatever the reason is) and the radiological progression after this end of maintenance treatment or death whatever the cause. Patients alive and without progression will be censored at the date of last news.

    Overall Survival (OS):
    OS is defined as the time between randomization and death (any cause). Patients alive will be censored at the date of last news.
    Tolérance :
    Les toxicités seront évaluées selon le NCI-CTC v 4.0 avant chaque cycle.

    Qualité de vie (QoL) :
    La qualité de vie sera évaluée à chaque évaluation au moyen du questionnaire QLQ-C30.

    Survie sans progression (SSP1) :
    La SSP1 est définie comme le temps entre la randomisation et la première progression radiologique (selon le RECIST 1.1) ou le décès (quel que soit le premier événement). Les patients vivants et sans progression seront censurés à la date de dernières nouvelles.

    Survie sans progression 2 (SSP2) :
    La SSP2 est définie comme le temps entre la fin du traitement d'entretien (quel que soit la raison) et la progression radiologique après cette fin de traitement d'entretien ou du décès (quelle qu'en soit la cause). Les patients vivants et sans progression seront censurés à la date des dernières nouvelles.

    Survie globale (SG) :
    La SG est définie comme le temps entre la randomisation et le décès (quelle qu'en soit la cause). Les patients vivants seront censurés à la date des dernières nouvelles.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All these endoints will be evaluated at 2 years after the last patient is randomised. Overall survival can be re-evaluated later.
    Tout ces critères seront évalués 2 ans après que le dernier patient soit randomisé. La survie globale pourra être réévaluée plus tard.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned70
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last Visit last patient
    Dernière visite du dernier patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state400
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After the subject has ended the participation in the trial, following treatment and follow-up of patient will continue according the recomendations of the "Thésaurus National de Cancérologie Digestive" (TNCD)
    Après la fin de la participation à l'essai du sujet, le traitement ultérieur et lle suivi du patient seront réalisés conformément aux recommandations du "Thésaurus National de Cancérologie Digestive" (TNCD)
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-09-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-06
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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