Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   42517   clinical trials with a EudraCT protocol, of which   7000   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .

    Clinical Trials marked as "Trial now transitioned" were transitioned to the Clinical Trial Regulation 536/2014 and can be further followed in the Clinical Trial Information System  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2015-005097-37
    Sponsor's Protocol Code Number:ImmunoCobiVem_2015
    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:2018-01-26
    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 number2015-005097-37
    A.3Full title of the trial
    A phase II, multicenter, open-label, randomized-controlled trial evaluating the efficacy and safety of a sequencing schedule of cobimetinib plus vemurafenib followed by immunotherapy with an anti- PD-L1 antibody atezolizumab for the treatment in patients with unresectable or metastatic BRAF V600 mutant melanoma.
    Essai clinique multicentrique, ouvert et randomisé de phase II visant à déterminer l’efficacité et la sécurité d'une thérapie séquentielle à base de cobimétinib et de vémurafénib, suivie d’une immunothérapie par anticorps anti-PD-L1 atézolizumab pour traiter des patients présentant un mélanome inopérable ou métastatique avec mutation BRAFV600.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A phase II, multicenter, open-label, randomized-controlled trial evaluating the efficacy and safety of a sequencing schedule of cobimetinib plus vemurafenib followed by immunotherapy with an anti- PD-L1 antibody atezolizumab for the treatment in patients with unresectable or metastatic BRAF V600 mutant melanoma
    Essai clinique multicentrique, ouvert et randomisé de phase II visant à déterminer l’efficacité et la sécurité d'une thérapie séquentielle à base de cobimétinib et de vémurafénib, suivie d’une immunothérapie par anticorps anti-PD-L1 atézolizumab pour traiter des patients présentant un mélanome inopérable ou métastatique avec mutation BRAFV600.
    A.3.2Name or abbreviated title of the trial where available
    ImmunoCobiVem
    ImmunoCobiVem
    A.4.1Sponsor's protocol code numberImmunoCobiVem_2015
    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 SponsorUniversity Hospital Essen
    B.1.3.4CountryGermany
    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 supportHoffmann-La Roche
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital Essen
    B.5.2Functional name of contact pointDepartment of Dermatology
    B.5.3 Address:
    B.5.3.1Street AddressHufelandstraße 55
    B.5.3.2Town/ cityEssen
    B.5.3.3Post code45122
    B.5.3.4CountryGermany
    B.5.4Telephone number492017234342
    B.5.5Fax number492017235935
    B.5.6E-maildirk.schadendorf@uk-essen.de
    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 Zelboraf
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNvemurafenib
    D.3.9.1CAS number 918504-65-1
    D.3.9.3Other descriptive nameVEMURAFENIB
    D.3.9.4EV Substance CodeSUB32161
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number240
    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.IMP: 2
    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 Cotellic
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCOBIMETINIB
    D.3.9.3Other descriptive nameCOBIMETINIB
    D.3.9.4EV Substance CodeSUB122319
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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.IMP: 3
    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 Tecentriq
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical form Concentrate and solvent for concentrate for 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 INNATEZOLIZUMAB
    D.3.9.3Other descriptive nameATEZOLIZUMAB
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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) Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with unresectable or metastatic BRAF V600 mutant melanoma.
    Patients présentant un mélanome inopérable ou métastatique avec mutation BRAFV600.
    E.1.1.1Medical condition in easily understood language
    Patients with unresectable or metastatic BRAF V600 mutant melanoma.
    Patients présentant un mélanome inopérable ou métastatique avec mutation BRAFV600.
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    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
    The objectives of the study are to assess the best timing of treatment approaches targeting the Ras/Raf signalling pathway by BRAF and MEK inhibition and targeting immunologic checkpoint control with an antiPD-L1 antibody in patients with unresectable or metastatic BRAFV600 mutant melanoma. Furthermore the safety of the study treatment will be assessed. The following endpoints will help to address the study objectives:
    Primary endpoint:
    Time to Second Objective Disease Progression (PFS2) defined as time from start of run-in phase (date of first intake of study drug) to second objective disease progression according to RECIST v. 1.1. (PD2) following randomization or death from any cause.
    L'objectif de l'étude est de déterminer la séquence optimale d’un traitement ciblé de la voie de signalisation Ras/Raf par inhibiteurs de BRAF et MEK ainsi que par le blocage du point de contrôle immunitaire avec un anticorps anti-PD-L1 chez des patients présentant un mélanome inopérable ou métastatique avec mutation BRAFV600.
    La sécurité du traitement de l’étude sera également analysée.
    Les paramètres d’évaluation suivants aideront à répondre aux objectifs de l’étude :
    Objectif primaire :
    Durée jusqu'à la deuxième progression objective de la maladie (PFS2), définie comme la durée écoulée depuis le début de la phase de pré-inclusion (date de la première prise des médicaments de l’étude) jusqu'à la date de la deuxième progression objective de la maladie (PD2) selon RECIST v. 1.1.
    E.2.2Secondary objectives of the trial
    Among others:
    -Safety
    -Overall Survival (OS) of a patient defined as the time from start of run-in phase (date of first intake of study drug) until documented date of death
    -Overall survival rate at 12 months and 24 months defined as the rate of patients alive 12 months and 24 months, respectively after start of run-in phase (date of first intake of study drug)
    -12-months and 24-months disease control rate (DCR). DCR is defined as the rate of patients showing complete response (CR) or partial response (PR) or stable disease (SD) at 12 months and at 24 months after start of run-in phase (date of first intake of study drug). CR, PR, and SD are defined according to RECIST v1.1 Criteria
    -Rate of patients with progressive disease who could not cross-over to subsequent line of therapy due to deterioration of ECOG status and/or brain metastases
    (...)
    -Sécurité
    -Survie globale (OS) du patient définie comme la drée écoulée depuis le début de la phase de pré-inclusion (date de la première prise des médicaments de l’étude) jusqu’à la date du décès documentée.
    -Taux de survie globale à 12 mois et 24 mois, défini comme la proportion de patients vivants à 12 ou 24 mois, en partant du début de la phase de pré-inclusion (date de la première prise du médicament à l’étude)
    -Taux de contrôle de la maladie (DCR) à 12 et 24 mois. La DCR est définie comme la proportion de patients présentant une rémission complète (CR) ou partielle (PR) ou une maladie stable (SD) à 12 et à 24 mois en partant du début de la phase de pré-inclusion (date de la première prise des médicaments à l’étude). La CR, la PR et la SD sont définies selon les critères RECIST v1.1.
    -Proportion des patients présentant une maladie progressive, qui ne peuvent passer au traitement stipulé ci-après en raison d’une détérioration du statut ECOG et/ou de métastases cérébrales
    (...)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Be willing and able to provide written informed consent for the trial.
    2. Male or female patient being  18 years of age on day of signing informed consent.
    3. Histologically confirmed diagnosis of locally advanced, unresectable or metastatic melanoma AJCC (unresectable stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c) without active or untreated brain metastases; all known CNS lesions must have been treated with stereotactic therapy or surgery at least 4 weeks prior to the first dose of trial treatment AND the patient must be without evidence of clinical or radiographic disease progression in the CNS for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms must have returned to baseline, the patient must have no evidence of new or enlarging brain metastases, and the patient must not have used steroids in dosing exceeding 10 mg daily of prednisone equivalent for at least 3 weeks prior to trial treatment.
    4. No previous therapy for the advanced or metastatic stage. Prior adjuvant therapy is permitted (e.g. IFN, IL-2-therapy, chemo- or radiotherapy). Prior adjuvant therapy has to be terminated (last dose) at least 28 days before enrolment. Patients who are in follow-up period of a clinical trial in adjuvant setting and progressing may be enrolled / randomized.
    5. Measurable disease, i.e., present with at least one measurable lesion per RECIST, version 1.1, for the definition of a measureable lesion.
    6. Presence of BRAF mutation (V600) in tumor tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion prior to enrolment.
    7. Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion.
    8. Have a performance status of 0 or 1 on the ECOG Performance Scale.
    9. Demonstrate adequate organ function as defined in the study protocol. All screening labs should be performed within 28 days of treatment initiation.
    10. Adequate cardiac function:
     Left ventricular ejection fraction (LVEF) ≥ 50% as determined by multigated acquisition (MUGA) scan or echocardiogram
     QTc interval ≤ 450 ms
    11. All prior treatment-related toxicities (except alopecia) following adjuvant therapy must be ≤ Grade 1 according to the CTCAE (version 4.03) at the time of randomization.
    Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
    12. Able to take oral medications.
    13. Patient is deemed by the investigator to have the initiative and means to be compliant with the protocol.
    14. Female subject of childbearing potential should have a negative urine pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
    15. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use a highly effective form of contraception according to CTFG during the course of this study and for at least 6 months after completion of study therapy. Birth control methods which may be considered as highly effective can achieve a failure rate of less than 1% per year when used consistently and correctly.
    - Females of childbearing potential are defined as sexually mature women without prior oophorectomy or hysterectomy who have had menses within the last 12 months. - Females are not considered to be of childbearing potential if amenorrheic for > 12 months and follicle-stimulating hormone (FSH) levels ≥ 40 IU/L.
    - For females who have been amenorrheic for ≥ 2 years, the requirement for FSH measurement at screening will be waived.
    - Highly effective forms of contraception include hormonal contraception (combined or progesterone-only) associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomy (must have received medical assessment of the surgical process) and sexual abstinence (complete avoidance of heterosexual intercourse), according to the CTFGs “Recommendations related to contraception and pregnancy testing in clinical trials”. Please note that potential interactions between vemurafenib and hormonal contraceptives may decrease the effectiveness of hormonal contraceptives.
    1. Le patient a la volonté et la capacité de signer le formulaire de consentement éclairé.
    2. Patient de sexe masculin ou féminin âgé de 18 ans ou plus à la date de signature du consentement éclairé.
    3. Mélanome AJCC inopérable ou métastatique localement avancé (stade inopérable IIIB, IIC, IVM1a, IVM1b, IVM1c) histologiquement démontré sans métastases cérébrales actives ou non traitées ; toutes les lésions du SNC connues doivent avoir été traitées par traitement stéréotaxique au moins 4 semaines avant la première dose du médicament à l’étude ET les patients ne doivent présenter aucun signe clinique ou radiographique de progression dans le SNC au moins 4 semaines avant la première dose du médicament de l’étude ; de même, tous les symptômes neurologiques doivent être revenus aux valeurs de départ, le patient ne doit présenter aucun signe de nouvelles métastases cérébrales ou de croissance des métastases cérébrales existantes et le patient ne doit avoir pris aucun stéroïde à une dose équivalent à plus de 10 mg de prednisone par jour au moins 3 semaines avant le début du traitement.
    4. Pas de traitement antérieur au stade avancé ou métastatique.
    Un traitement adjuvant antérieur est autorisé (p. ex. IFN, thérapie IL-2, chimiothérapie ou radiothérapie). La dernière dose dans le cadre du traitement adjuvant antérieur doit avoir été administré au moins 28 jours avant l’inclusion. Les patients présentant une progression au cours de la période de suivi d'une étude clinique dans le cadre d'un traitement adjuvant peuvent être inclus dans l’étude.
    5. Maladie mesurable ; cela signifie que le patient doit présenter au moins une lésion mesurable selon RECIST (définition d'une lésion mesurable selon les critères RECIST Version 1.1
    6. Présence d’une mutation BRAF (V600) dans le tissu tumoral d'un échantillon tumoral archivé ou d’une nouvelle biopsie par forage ou excisionnelle d’une lésion tumorale avant l’inclusion
    7. Un tissu d’échantillons tumoraux archivés ou d’une nouvelle biopsie par forage ou excisionnelle d’une lésion tumorale est mis à disposition.
    8. Statut de performance ECOG de 0 ou 1.
    9. Fonction organique adéquate comme défini dans le protocole. Tous les tests de laboratoire de sélection doivent avoir été effectués dans les 28 jours qui précèdent le traitement à l’étude.
    10. Fonction cardiaque adéquate :
     Fraction d’éjection ventriculaire gauche (LVEF) ≥ 50 %, mesurée par ventriculographie isotopique MUGA ou échocardiogramme
     Intervalle QTc ≤ 450 ms
    11. Tous les effets secondaires du traitement adjuvant antérieur (à l’exception de l’alopécie) doivent être ≤ grade 1 selon CTCAE (version 4.03) à la date de la randomisation.
    Remarque : Les patients présentant une neuropathie ≤ grade 2 constituent une exception à ce critère et peuvent être inclus dans l’étude.
    12. Patients aptes à prendre le médicament par voie orale.
    13. Patients aptes à respecter les exigences du protocole selon l'appréciation du médecin investigateur.
    14. Les femmes en âge de procréer doivent présenter un test urinaire de grossesse négatif dans les 72 heures qui précèdent la première administration du médicament à l’étude. Si le test urinaire s'avère positif ou ne peut être confirmé comme négatif, il est nécessaire d’effectuer un test sérique de grossesse.
    15. Les femmes en âge de procréer et les hommes dont la partenaire féminine est en âge de procréer doivent utiliser une méthode contraceptive hautement efficace (selon le CTFG) pendant la durée de l’étude et au moins 6 mois après la fin du traitement de l’étude. Les méthodes contraceptives hautement efficaces atteignent un indice de Pearl inférieur à 1 lorsqu'elles sont correctement utilisées. - Sont considérées comme aptes à procréer les femmes ayant atteint la maturité sexuelle sans ovariectomie ou hystérectomie antérieures qui ont eu leurs menstruations au cours des 12 derniers mois.
    - Les femmes présentant une aménorrhée > 12 mois et des valeurs ≥ 40 IU/L pour l’hormone folliculo-stimulante (FSH) ne sont pas considérées comme aptes à procréer. - Chez les femmes présentant une aménorrhée ≥ 2 ans, la détermination de la FSH n’est pas nécessaire. - Sont considérées comme méthodes contraceptives hautement efficaces les contraceptifs hormonaux (préparations combinées ou préparations simples à base de progestérone), qui préviennent l'ovulation, les pessaires intra-utérins (stérilets), les systèmes intra-utérins (stérilets hormonaux), la ligature bilatérale des trompes, la vasectomie (l’intervention chirurgicale doit être vérifiée par un médecin) et l’abstinence sexuelle (absence totale de relations sexuelles hétérosexuelles), selon les « Recommendations related to contraception and pregnancy testing in clinical trials » de la CTFG. Veuillez noter que les interactions possibles entre vémurafénib et un contraceptif hormonal peut réduire l’efficacité de la contraception hormonale.
    E.4Principal exclusion criteria
    1. Use of any investigational or non-registered product within the 30 days before registration.
    2. Diagnosis of immunodeficiency or receiving systemic steroid therapy in dosing exceeding 10 mg daily of prednisone equivalent or any other form of immunosuppressive therapy within 7 days prior to study Day 1.
    3. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
    4. Prior therapy with a BRAF inhibitor (including but not limited to vemurafenib, dabrafenib, encorafenib and / or MEK inhibitor (including but not limited to trametinib, AZD6244, Binimetinib, Cobimetinib) also in an adjuvant setting.
    5. Prior major surgery. Note: Subjectsmay be enrolled if they have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
    6. Known additional malignancy that is progressing or requires active treatment within 3 years prior to the study. Exceptions include adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy without evidence or recurrence.
    7. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
    8. History of leptomeningeal metastases
    9. History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO) or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, history of hyperviscosity or hypercoagulability syndromes).
    10. History of retinal degenerative disease.
    11. History of allogenic bone marrow transplantation or organ transplantation.
    12. History of Gilbert’s syndrome
    13. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
     History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6 months prior to screening.
     Symptomatic chronic heart failure, history or current evidence of clinically significant cardiac arrhythmia and / or conduction abnormality < 6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia.
     History of congenital long QT syndrome or mean (average of triplicate measurements) QTc measured using Fridericia’s method > 450 ms at baseline or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus).
    14. Uncontrolled arterial hypertension despite medical treatment.
    15. Patients who have neuromuscular disorders which are associated with elevated CK (e. g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
    16. Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, small bowel resection).
    17. Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids in dosing exceeding 10 mg daily of prednisone equivalent or immunosuppressive agents.
    18. Evidence of interstitial lung disease or active, non-infectious pneumonitis.
    19. Active infection requiring systemic therapy.
    20. Pregnancy or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
    21. Positive test for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
    22. Positive test for Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
    23. Known hypersensitivity reaction to any of the components of study treatment.
    24. Medical, psychiatric, cognitive or other conditions, including known alcohol or drug abuse that would not permit the subject to complete the study or sign informed consent.
    25. Patients taking non-topical medication known to be a strong inhibitor of CYP3A4. However, patients who either discontinue their treatment or switch to another medication at least three days prior to registration / randomization are eligible.
    26. Patients having received a live, attenuated vaccine within 4 weeks prior to the first dose of trial treatment.
    27. Legal incapacity or limited legal capacity.
    28. Presence of uveal melanoma
    1. Prise d'un médicament expérimental ou d'un médicament non autorisé dans les 30 jours précédant l’inclusion.
    2. Diagnostic d'une immunodéficience ou patients traités par stéroïdes systémiques à une dose équivalente à plus de 10 mg de prednisone par jour ou toute forme de traitement immunosuppresseur dans les 7 jours précédant le jour 1 de l'étude.
    3. Traitement antérieur par anticorps anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 ou antigène-4 associé au lymphocyte T cytotoxique (CTLA-4) (dont ipilimumab ou autres anticorps ou médicament visant spécifiquement la co-stimulation des lymphocytes T).
    4. Traitement antérieur - y compris dans le cadre d'un traitement adjuvant - par inhibiteur de BRAF (incluant, sans s'y limiter, vémurafénib, dabrafénib, encorafénib et / ou inhibiteur de MEK (incluant, sans s'y limiter, tramétinib, AZD6244, binimétinib, cobimétinib).
    5. Intervention chirurgicale majeure préalable. Remarque : Les patients peuvent inclus dans l’étude s'ils sont suffisamment remis des effets secondaires et / ou complications de l'intervention avant le début du traitement à l'étude.
    6. Autre tumeur maligne connue, évolutive ou nécessitant un traitement actif dans les 5 ans précédant le début de l’étude.
    Les exceptions incluent les carcinomes basocellulaires de la peau traités de manière adéquate, les carcinomes épidermoïdes de la peau ou les cancers du col de l’utérus in situ non détectables ou non récidivants après un traitement potentiellement curatif.
    7. Métastases actives connues du système nerveux central (CNS) et/ou carcinomatose méningée.
    8. Antécédents de métastases leptoméningées
    9. Présence ou antécédents de choriorétinopathie séreuse centrale (CRSC) ou d’occlusion veineuse rétinienne (OVR) ou facteurs prédisposant à une OVR ou une CRSC (par exemple : glaucome incontrôlé ou hypertension oculaire, diabète sucré incontrôlé, antécédents de syndrome d'hyperviscosité ou d'hypercoagulabilité).
    10. Antécédents de maladie dégénérative de la rétine.
    11. Antécédents de greffe de moelle osseuse allogène ou greffe d’organe.
    12. Présence d'un syndrome de Gilbert
    13. Fonction cardiovasculaire altérée ou maladies cardiovasculaires cliniquement significatives, dont :
     Antécédents de syndromes coronaires aigus (dont infarctus du myocarde, angor instable, pontage coronarien, angioplastie coronarienne ou stenting) dans les 6 mois précédant la sélection.
     Insuffisance cardiaque chronique symptomatique, antécédents ou signes d’une arythmie cardiaque cliniquement significative et / ou troubles de la conduction < 6 mois avant la sélection, à l’exception d’une fibrillation auriculaire et d’une tachycardie supraventriculaire paroxystique.
     Antécédents de syndrome du QT long congénital ou intervalle QTc moyen (moyenne de trois mesures) selon la méthode Fridericia > 450 ms au début de l’essai ou écarts non corrigibles d’électrolytes sériques (sodium, calcium, magnésium, phosphore).
    14. Hypertension artérielle incontrôlée malgré un traitement médicamenteux.
    15. Patients présentant des troubles neuromusculaires associés à des valeurs CK élevées.
    16. Altération des fonctions gastro-intestinales ou maladie gastro-intestinale .
    17. Maladie auto-immune active, ayant dû être traitée de façon systémique au cours des 3 derniers mois ou antécédents connus de maladie auto-immune jugée cliniquement sévère, ou de syndrome nécessitant un traitement systémique par stéroïdes à une dose équivalente à plus de 10 mg de prednisone par jour ou médicaments immunosuppresseurs.
    18. Signe de maladie interstitielle pulmonaire ou pneumonie non infectieuse active.
    19. Infection active nécessitant un traitement systémique.
    20. Femmes enceintes ou allaitantes ou femmes et hommes qui souhaitent concevoir des enfants pendant la durée prévue de l'étude,en partant de la phase de sélection ou de la visite de sélection jusqu'à 120 jours après administration du dernier médicament de l'étude.
    21. Test positif à une infection au VIH.
    22. Test positif à une infection au virus de l'hépatite B ou de l’hépatite C.
    23. Hypersensibilité connue aux substances ou excipients des traitements de l’étude.
    24. Condition médicale, psychiatrique, cognitive ou autre état de santé, y compris abus d’alcool ou de drogues connus interférant avec l’obtention du consentement éclairé ou la capacité à poursuivre l’étude jusqu'à son terme.
    25. Patients prenant un médicament systémique constituant un puissant inhibiteur du CYP3A4. Toutefois, les patients qui arrêtent ce médicament au moins 3 jours avant l’inscription / la randomisation ou qui passent à un autre médicament, peuvent également être inclus dans l’étude.
    26. Patients ayant reçu un vaccin vivant atténué dans les 4 semaines avant la première administration du médicament à l’étude.
    27. Incapacité ou capacité limitée du patient.
    28. Présence d'un mélanome de la choroïde
    E.5 End points
    E.5.1Primary end point(s)
    Time to Second Objective Disease Progression (PFS2) defined as time from start of run-in phase (date of first intake of study drug) to second objective disease progression according to RECIST v. 1.1. (PD2) following randomization or death from any cause.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time to Second Objective Disease Progression (PFS2) defined as time from start of run-in phase (date of first intake of study drug) to second objective disease progression according to RECIST v. 1.1. (PD2) following randomization or death from any cause.
    E.5.2Secondary end point(s)
    -Safety
    Safety as a secondary endpoint is defined as all adverse events ≥ Grade 3 according to CTCAE, Version 4.03 criteria and all SAEs, regardless of causal relationship to the administration of the investigational agents will be assessed.
    Overall Survival (OS) of a patient defined as the time from start of run-in phase (date of first intake of study drug) until documented date of death
    -Overall survival rate at 12 months and 24 months defined as the rate of patients alive 12 months and 24 months, respectively after the start of run-in phase (date of first intake of study drug)
    -12-months and 24-months disease control rate (DCR). DCR is defined as the rate of patients showing complete response (CR) or partial response (PR) of stable disease (SD) at 12 months and at 24 months after the start of run-in phase (date of first intake of study drug)). CR, PR, and SD are defined according to RECIST v1.1 Criteria
    -Rate of patients with progressive disease who could not cross-over to subsequent line of therapy due to deterioration of ECOG status and/or symptomatic brain metastases
    -From vemurafenib + cobimetinib to atezolizumab (Arm A)
    -From atezolizumab to vemurafenib + cobimetinib (Arm B)
    -PFS1 defined as time from start of run-in phase (date of first intake of study drug) until the first documented tumor progression date (PD1) or death by any cause
    -PFS3 defined as time from the first documented tumor progression date (PD1) until the second documented tumor progression date (PD2) after randomization or death by any cause.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Patients will be treated up to second disease progression after randomization, death or unacceptable toxicity.
    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 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Order of treatment
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA27
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Germany
    Greece
    Russian Federation
    Serbia
    E.8.7Trial has a data monitoring committee No
    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
    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
    E.8.9.2In all countries concerned by the trial years3
    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: 106
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 158
    F.4.2.2In the whole clinical trial 176
    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)
    Following the end of treatment evaluation or the end of treatment for any other cause, patients will be treated and followed according to the local guidelines.
    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 Decision2018-03-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-04-10
    P. End of Trial
    P.End of Trial StatusOngoing
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2022 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA