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    Summary
    EudraCT Number:2018-002222-23
    Sponsor's Protocol Code Number:P170932J
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-12-14
    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 number2018-002222-23
    A.3Full title of the trial
    Cobimetinib for BRAF-wild-type histiocytoses : a randomized, placebo-controlled, double blind study
    Cobimetinib pour le traitement des histiocytoses sans mutation BRAFV600E : Une étude randomisée, contrôlée en double aveugle versus placebo
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    NA
    NA
    A.3.2Name or abbreviated title of the trial where available
    COBRAH
    COBRAH
    A.4.1Sponsor's protocol code numberP170932J
    A.5.4Other Identifiers
    Name:NANumber:NA
    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 SponsorAPHP
    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 supportAPHP
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAPHP
    B.5.2Functional name of contact pointchef de projets
    B.5.3 Address:
    B.5.3.1Street Address1 avenue Claude Vellefaux
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number33140 27 52 66
    B.5.5Fax number33144 84 17 01
    B.5.6E-mailcoralie.villeret@aphp.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 No
    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 nameCobimetinib (GDC-0973)
    D.3.2Product code RO5514041/F04
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Histiocytoses are rare multisystemic disorders characterized by accumulation of histiocytes in various organs. patients with BRAF-wild type.
    NA
    E.1.1.1Medical condition in easily understood language
    histologically confirmed L or R group histiocytoses without BRAFV600E mutation detected with the use of a real-time polymerase chain reaction
    Have a measurable disease according to the PERCIST
    na
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate that the rate of objective metabolic response (complete or partial) according to PERCIST criteria is higher under cobimetinib versus placebo
    Démontrer que le taux de réponse métabolique objective (complète ou partielle) selon les critères PERCIST est plus élevé sous cobimétinib par rapport au placebo
    E.2.2Secondary objectives of the trial
    To compare the progression-free survival as assessed by the investigator and duration of response at W12
    To compare the tumor assessments and CRP levels at W12
    To assess the adverse event and serious adverse events
    To assess the overall survival
    To determine the overall metabolic response to cobimetinib with PERCIST criteria after 36 weeks of treatment by cobimetinib.
    Comparer la survie sans progression évaluée par l'investigateur et la durée de la réponse à W12
    Comparer les réponses tumorales et les dosages sanguins de CRP à W12
    Évaluer les effets indésirables et les effets indésirables graves
    Evaluer la survie globale
    Déterminer la réponse métabolique globale au cobimétinib avec les critères PERCIST après 36 semaines de traitement par le cobimétinib.

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Eligible patients should be at least 18 years of age,
    Have a histologically confirmed L or R group histiocytoses without BRAFV600E mutation detected with the use of a real-time polymerase chain reaction
    Have a measurable disease according to the PERCIST criteria with :
    - presence of at least one severe organ involvement (heart, vascular, central nervous system) OR
    - a multisystemic disease with ≥ 3 organs involvement AND failure of a first-line treatment or contra-indication to these treatments
    Accepting effective contraception (2 forms) during treatment duration (men and women childbearing potential)
    Signed informed consent
    Les patients éligibles doivent être âgés d'au moins 18 ans.
    Avoir une histiocytose confirmée histologiquement du groupe L ou R sans mutation BRAFV600E en biologie moléculaire sur le tissu
    Avoir une maladie mesurable selon les critères PERCIST avec:
    - présence d'au moins une atteinte grave d'un organe (cœur, vasculaire, système nerveux central) OU
    - une maladie multisystémique avec une atteinte de ≥ 3 organes ET l'échec d'un traitement de première ligne ou une contre-indication à ces traitements
    Accepter une contraception efficace (2 méthodes) pendant la durée du traitement
    Consentement éclairé signé
    E.4Principal exclusion criteria
    Hypersensibility to cobimetinib
    Patients with severe hepatic, renal and cardiac functions
    Patients with myopathies at baseline
    Patients with retinal detachment at baseline
    Patients with inherited disorders of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
    patients with high bleeding risk.
    Allergies to iodized contrast media
    Simultaneous participation in another medical research
    Pregnancy or breast-feeding.
    No affiliation to the French Health Care System “sécurité sociale”
    Hypersensibilité au cobimétinib
    Patients ayant des atteintes des fonctions hépatiques, rénales et cardiaques sévères
    Patients atteints de myopathies
    Patients avec décollement de la rétine
    Patients présentant des troubles héréditaires d'intolérance au galactose, de déficit en Lapp lactase ou de malabsorption du glucose-galactose
    Patients à haut risque de saignement.
    Allergies aux produits de contraste iodés
    Participation simultanée à une autre recherche médicale
    Grossesse ou allaitement.
    Absence d’ affiliation au système de santé français «sécurité sociale»
    E.5 End points
    E.5.1Primary end point(s)
    The objective metabolic response according to PERCIST criteria (Haroche, et al. 2015) is defined by the PET response and will be used to evaluate the overall therapeutic response at month 3 (W12).
    La réponse métabolique objective selon les critères PERCIST (Haroche, et al. 2015) est définie sur la TEP et sera utilisée pour évaluer la réponse thérapeutique globale au troisième mois (W12).
    E.5.1.1Timepoint(s) of evaluation of this end point
    For PERCIST criteria, a quantitative analysis of uptake will be performed using the standard uptake value (SUV). Fitting regions of interest covering pathologic uptake will be used to define target lesions. PERCIST will be used to classify the patients as complete metabolic response, partial metabolic response (reduction of a minimum of 30% in target lesions), stable metabolic disease or progressive metabolic disease.
    Pour les critères PERCIST, une analyse quantitative de l'absorption sera réalisée à l'aide des SUV (standard uptake value ). Les régions d’intérêt seront utilisées pour définir les lésions cibles. PERCIST sera utilisé pour classer les patients en réponse métabolique complète, en réponse métabolique partielle (réduction d'au moins 30% des lésions cibles), en maladie métabolique stable ou en maladie métabolique progressive.
    E.5.2Secondary end point(s)
    The secondary endpoints include overall survival, progression-free survival as assessed with PERCIST criteria (defined as the time between the date of randomization and the first documented event of disease progression or death), duration of response and safety. Tumor assessments will be carried out at baseline and every 12 weeks.
    Les critères secondaires incluent la survie globale, la survie sans progression évaluée par les critères PERCIST (définis comme le temps écoulé entre la date de randomisation et le premier événement documenté de progression ou de décès de la maladie), la durée de la réponse et la sécurité. Des évaluations de tumeurs seront effectuées au départ et toutes les 12 semaines.
    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 No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) No
    E.8.2.2Placebo Yes
    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 concerned5
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    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) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients No
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state
    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 Decision2019-01-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-05
    P. End of Trial
    P.End of Trial StatusOngoing
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