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    Summary
    EudraCT Number:2015-005097-37
    Sponsor's Protocol Code Number:ImmunoCobiVem_2015
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-03-21
    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 ConcernedGermany - PEI
    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
    Multizentrische, offene, randomisierte, klinische Prüfung der Phase II zur Bestimmung der Wirksamkeit und Sicherheit einer sequentiellen Therapie mit Cobimetinib plus Vemurafenib gefolgt von einer Immuntherapie mit dem PD-L1-Antikörper Atezolizumab zur Behandlung von Patienten mit inoperablem oder metastasiertem Melanom mit BRAFV600 Mutation
    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
    A.3.2Name or abbreviated title of the trial where available
    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 LTD
    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 pointDepartement of Dermatology
    B.5.3 Address:
    B.5.3.1Street AddressHufelandstr. 55
    B.5.3.2Town/ cityEssen
    B.5.3.3Post code45147
    B.5.3.4CountryGermany
    B.5.4Telephone number00492017234342
    B.5.5Fax number00492017235935
    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 Cotellic
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH (RRG)
    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.3.1Product nameCobimetinib
    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.3.9.1CAS number 1369665-02-0
    D.3.9.3Other descriptive nameCOBIMETINIB HEMIFUMARATE
    D.3.9.4EV Substance CodeSUB168371
    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: 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 Zelboraf
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH (RRG)
    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.3.1Product nameVemurafenib
    D.3.2Product code RO5185426/F20
    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.3.9.2Current sponsor codeRO5185426/F20
    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: 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 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 nameAtezolizumab
    D.3.2Product code Atezolizumab
    D.3.4Pharmaceutical form Concentrate and solvent 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.3.9.2Current sponsor codeMPDL3280A, Tecentriq
    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) 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.IMP: 4
    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 GmbH (RRG)
    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.3.1Product nameVemurafenib
    D.3.2Product code RO5185426/F17
    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.3.9.2Current sponsor codeRO5185426/F17
    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: 5
    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 GmbH (RRG)
    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.3.1Product nameCobimetinib
    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.3.9.1CAS number 1369665-02-0
    D.3.9.3Other descriptive nameCOBIMETINIB HEMIFUMARATE
    D.3.9.4EV Substance CodeSUB168371
    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.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 locally advanced, unresectable or metastatic BRAFV600 mutant melanoma.
    E.1.1.1Medical condition in easily understood language
    Patients with locally advanced, unresectable or metastatic melanoma with a BRAFV600 mutation
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10025650
    E.1.2Term Malignant melanoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10025667
    E.1.2Term Malignant melanoma site/stage unspecified
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10027480
    E.1.2Term Metastatic malignant melanoma
    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 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 by time to second objective disease progression (PFS2).
    E.2.2Secondary objectives of the trial
    Safety and overall survival (OS) of a patient defined as the time from start of run-in phase until documented date of death. Overall survival rate at 12 months and 24 months after start of run-in phase. 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. 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.
    PFS1 defined as time from start of run-in phase 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.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The translational research program will focus on the discovery of biomarkers for improvement of melanoma therapy, and to evaluate the biologic effects of treatment sequence on the molecular profile and biomarker expression in tissue and plasma. Therefore tumor tissue and blood samples, respectively will be analyzed to assess the relationship of the tumor immune and signaling biomarker landscape and efficacy, to evaluate non-inherited genetic alterations of circulating free tumor-specific DNA in plasma and to assess and monitor the immunophenotype in peripheral blood mononuclear cells.

    The patient questionnaires will focus on the medication adherence of the patients. Paper-based as well as electronic documentation will be available. The patients can choose between both. Since the use of electronic systems for self-reported medication adherence is a new approach in melanoma research, the aim of this approach is to analyze both the patient group that opts for Alcedis eMARS as well as the patient group that opts for the paper-based documentation. Reasons for not participating in the Alcedis eMARS program will be documented. Furthermore the user-friendliness, practicality, and user satisfaction of Alcedis eMARS will be assessed by patient and investigator questionnaires. In addition the quality of life of the patients will be assessed. To address these objectives, standardized and study-specific patient questionnaires will be used. To analyze the investigator´s satisfaction with Alcedis eMARS, the investigator has to fill in specific questionnaires on different timepoints. Additionally, the self-reported medication adherence will be analyzed in both patient groups (patients using Alcedis eMARS or using the paper-based documentation) also taking the results of the pill-count done by the study centers into account.
    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 as following. All screening labs should be performed within 28 days of treatment initiation.
    9.1 Hematological:
    • Absolute neutrophil count ≥1,500 /mcL
    • Platelets ≥100,000 / mcL
    • Hemoglobin ≥9 g/dL OR ≥5.6 mmol/L
    • INR and aPTT < 1.5 x ULN
    9.2 Renal:
    • Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥50 mL/min for subject with creatinine levels > 1.5 X institutional ULN
    9.3 Hepatic:
    • Serum total bilirubin ≤ 1.5 X ULN
    • AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

    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 tothe 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 serum 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 forms 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.
    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.
    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.
    Note: Subjects with previously treated brain metastases may participate provided they are stable, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 3 weeks prior to trial treatment.
    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.
    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. Note: Subjects with vitiligo or controlled asthma/atopy would be an exception to this rule.
    Note: Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. /Note: Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not be excluded from the study.
    18.Evidence of interstitial lung disease or active, non-infectious pneumonitis.
    19.Active infection requiring systemic therapy.
    20.Pregnancy/breastfeeding/expecting to conceive or father children within the duration of the trial, starting with pre-screening or screening visit through at least 6 month after the last dose of trial treatment.
    21.Positive test for 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
    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
    Second Objective Disease Progression (PFS2)
    E.5.2Secondary end point(s)
    • 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 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
    • 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
    - Safety: during the whole study
    - Overall survival: study enrolement until the day of progression/death
    - Disease control rate and overall survival rate: at 12 months and 24 months.
    - 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: over the whole study
    -PFS1 and PFS3: measured by progressive disease 1 and 2
    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 No
    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 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 concerned20
    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
    Poland
    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 years5
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    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 state117
    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)
    No further treatment will be applied within the scope of the protocol as soon as it was decided to permanently discontinue study treatment. Further patient treatment will be performed according to updated national and international guidelines at the discretion of the investigator.
    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 Decision2016-06-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-05
    P. End of Trial
    P.End of Trial StatusOngoing
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