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    Summary
    EudraCT Number:2016-002482-54
    Sponsor's Protocol Code Number:CO39262
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-15
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2016-002482-54
    A.3Full title of the trial
    A PHASE III, DOUBLE-BLINDED, RANDOMIZED, PLACEBO-CONTROLLED STUDY OF ATEZOLIZUMAB PLUS COBIMETINIB AND VEMURAFENIB VERSUS PLACEBO PLUS COBIMETINIB AND VEMURAFENIB IN PREVIOUSLY UNTREATED BRAFV600 MUTATION-POSITIVE PATIENTS WITH METASTATIC OR UNRESECTABLE LOCALLY ADVANCED MELANOMA
    STUDIO DI FASE III, IN DOPPIO CIECO, RANDOMIZZATO, CONTROLLATO CON PLACEBO PER LA VALUTAZIONE DI ATEZOLIZUMAB PI¿ COBIMETINIB E VEMURAFENIB RISPETTO A PLACEBO PI¿ COBIMETINIB E VEMURAFENIB IN PAZIENTI NON TRATTATI IN PRECEDENZA, AFFETTI DA MELANOMA METASTATICO O LOCALMENTE AVANZATO NON RESECABILE, POSITIVO ALLA MUTAZIONE BRAFV600
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Vemurafenib (vem), cobimetinib (cobi) & atezolizumab (atezo) triplet combination in advanced melanoma
    Tripla combinazione di vemurafenib, cobimetinib e atezolizumab in pazienti con melanoma avanzato
    A.3.2Name or abbreviated title of the trial where available
    na
    na
    A.4.1Sponsor's protocol code numberCO39262
    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 SponsorF. HOFFMANN - LA ROCHE LTD.
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportF. Hoffmann-La Roche Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd.
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number0041616881111
    B.5.5Fax number0041616919319
    B.5.6E-mailglobal.rochegenentechtrials@roche.com
    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 nameAtezolizumab
    D.3.2Product code RO5541267/F03
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNATEZOLIZUMAB
    D.3.9.1CAS number 1380723-44-3
    D.3.9.2Current sponsor codeRO5541267
    D.3.9.3Other descriptive nameMPDL3280A, Tecentriq
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.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 240 mg Film-coated Tablets
    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.3.1Product 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
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Zelboraf 240 mg Film-coated Tablets
    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.3.1Product 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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 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 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.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCobimetinib (GDC-0973)
    D.3.9.1CAS number 934660-93-2
    D.3.9.2Current sponsor codeRO5514041/F04
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 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/F09
    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 (GDC-0973)
    D.3.9.1CAS number 934660-93-2
    D.3.9.2Current sponsor codeRO5514041/F04
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 6
    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 GmbH AIC:EU/1/17/1220/001
    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 nameAtezolizumab
    D.3.2Product code [RO5541267]
    D.3.4Pharmaceutical form 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.3.9.2Current sponsor codeRO5541267
    D.3.9.3Other descriptive nameMPDL3280A, Tecentriq
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    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
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Unresectable locally advanced or metastatic melanoma
    MELANOMA METASTATICO O LOCALMENTE AVANZATO NON RESECABILE,
    E.1.1.1Medical condition in easily understood language
    Advanced melanoma
    melanoma avanzato
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10025669
    E.1.2Term Malignant melanoma stage II
    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 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    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 evaluate the efficacy of atezo + cob+ vem compared with placebo +cobi +vem
    valutare l'efficacia di atezo + cob+ vem rispetto a placebo +cobi +vem
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of atezo+ cobi +vem compared with placebo+ cobi +vem using objective response rate, duration of response, overall survival, change in quality of life, health reported outcomes and global health status.
    To evaluate the safety of atezolizumab + cobimetinib + vemurafenib compared to placebo + cobimetinib + vemurafenib.
    To evaluate the pharmacokinetics of atezolizumab, cobimetinib and vemurafenib and cobimetinib and vemurafenib when administered together.
    valutare l'efficacia di atezo + cob+ vem rispetto a placebo +cobi +vem usando il tasso di risposta obiettiva, durata della risposta, sopravvivenza globale, cambiamento di qualità di vita, risultati riferiti sulla salute e stato di salute globale.
    Per valutare la sicurezza di atezolizumab + cobimetinib + vemurafenib rispetto al placebo + cobimetinib + vemurafenib.
    Per valutare la farmacocinetica di atezolizumab, cobimetinib e vemurafenib e cobimetinib e vemurafenib quando somministrati insieme.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Signed informed consent form
    - Women and men, age >= 18 years
    - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
    - Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc (locally advanced) melanoma, as defined by the American Joint
    Committee on Cancer, 7th revised edition
    - Measurable disease, according to response evaluation criteria in solid tumours (RECIST), v1.1
    - Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to first dose of study drug treatment, with the exception of amylase, lipase, and LDH where
    up to 28 days is acceptable (using central laboratory result)
    – Amylase and lipase <= 1.5 x ULN
    –Absolute neutrophil count (ANC) >= 1.5 × 10 exp9/L
    –Platelet count >= 100 × 10 exp9/L
    –Hemoglobin >= 9 gram (g)/decilitre (dL)
    –Albumin >= 2.5 g/dL
    –Bilirubin <= 1.5 × the upper limit of normal (ULN)
    - AST and ALT = 2.0×ULN
    - ALP = 2.5×ULN or, for patients with documented liver or bone metastases, ALP = 5×ULN
    -Patients with documented liver or bone metastases: alkaline phosphatase <= 5 × ULN
    –Serum creatinine <= 1.5 × ULN or creatinine clearance (CrCl) >= 40 mL/min on the basis of measured CrCl from a 24-hour urine collection or
    Cockroft-Gault glomerular filtration rate estimation: (140-age) x (weight in kg) x (0.85 if female) 72 x (serum creatinine in milligram/dL)
    - Ability and capacity to comply with the study and follow-up procedure
    - For patients not receiving therapeutic anticoagulation: INR or aPTT =
    1.5×ULN within 28 days prior to initiation of study treatment
    - For patients receiving therapeutic anticoagulation: stable anticoagulant
    regimen and stable INR during the 28 days immediately preceding initiation of study treatment
    - For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method
    with a failure rate of <1% per year during the treatment period and for 6 months after the last dose of study treatment. Women must refrain from
    donating eggs during this same period.
    - For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
    • Firma del modulo di consenso informato
    • Uomini e donne di età >= 18 anni
    • Performance status sulla scala ECOG (Eastern Cooperative Oncology Group) 0 o 1
    • Melanoma di stadio IV (metastatico) o stadio IIIc non resecabile (localmente avanzato) confermato istologicamente, secondo la definizione dell’American Joint Committee on Cancer, 7a edizione
    • Malattia misurabile in base ai criteri RECIST v1.1
    • Adeguata funzione ematologica, epatica e renale, definita in base ai valori degli esami di laboratorio riportati di seguito ottenuti nei 14 giorni precedenti l’inizio del trattamento in studio, con l’eccezione di amilasi, lipasi e LDH dove è accettabile un risultato fino a 28 giorni prima ( utilizzando gli esiti del laboratorio centralizzato )
    – Amilasi e lipasi <= 1,5 x ULN
    – ANC >= 1.5 × 10 exp9/L
    – Conta piastrinica >= 100 × 10 exp9/L
    – Emoglobina >= 9 gram (g)/decilitre (dL)
    – Albumina sierica >= 2.5 g/dL
    – Bilirubina totale <= 1.5 × ULN
    – AST e ALT <= 2.0 x ULN
    - ALP <= 2,5 ¿ ULN o, per i pazienti con metastasi epatiche o ossee documentate, ALP ¿ 5 ¿ ULN
    - pazienti con metastasi epatiche o ossee documentate, ALP ¿ 5 ¿ ULN
    – Creatinina sierica <= 1.5 × ULN o clearance della creatinina (CrCl) >= 40 ml/min sulla base della CrCl misurata con la raccolta delle urine nelle 24 ore o con la stima della velocità di filtrazione glomerulare determinata con la formula di Cockcroft-Gault: CrCl= (140 - età) x (peso in kg) x (0.85 per le donne) /72 x (creatinina sierica in mg/dl)
    • Capacità di seguire il protocollo dello studio secondo il giudizio dello sperimentatore
    • Per i pazienti non sottoposti a terapia anticoagulante: INR o aPTT <= 1,5 x ULN nei 28 giorni precedenti l’inizio del trattamento in studio
    • Per i pazienti sottoposti a terapia anticoagulante: regime anticoagulante stabile e INR stabile nei 28 giorni immediatamente precedenti l’inizio del trattamento in studio
    • Per donne in età fertile: accettazione a praticare l’astinenza (astenersi dai rapporti eterosessuali) o a utilizzare metodi contraccettivi con un tasso di insuccesso < 1% per anno, durante il periodo di trattamento e per 6 mesi dopo l’ultima dose del trattamento in studio. Le donne devono astenersi dal donare le uova durante lo stesso periodo.
    • Per gli uomini: accettazione a praticare l’astinenza (astenersi dai rapporti eterosessuali) o a utilizzare metodi contraccettivi e accettazione ad astenersi dalla donazione di sperma
    E.4Principal exclusion criteria
    • Major surgical procedure other than for diagnosis within 4 weeks prior
    to initiation of study treatment, or anticipation of need for a major
    surgical procedure during the course of the study
    • Traumatic injury within 2 weeks prior to initiation of study treatment
    • Palliative radiotherapy within 14 days prior to initiation of study
    treatment
    • Active malignancy (other than BRAFV600 mutation-positive
    melanoma) or malignancy within 3 years prior to screening are
    excluded, with the exception of resected melanoma, resected basal cell
    carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC),
    resected carcinoma in situ of the cervix, resected carcinoma in situ of
    the breast, in situ prostate cancer, limited-stage bladder cancer, or any
    other curatively treated malignancies from which the patient has been
    disease-free for at least 3 years
    • History of or evidence of retinal pathology on ophthalmologic
    examination that is considered a risk factor for neurosensory retinal
    detachment, central serous chorioretinopathy, retinal vein occlusion
    (RVO), or neovascular macular degeneration
    • History of clinically significant cardiac dysfunction, including the
    following:
    -Poorly controlled hypertension, defined as sustained, uncontrolled,
    nonepisodic baseline hypertension consistently above 159/99 mmHg
    despite
    •Intervento di chirurgia maggiore per scopi diversi da quelli diagnostici nelle 4 sett precedenti la randomizzazione o previsione della necessità di una procedura chirurgica maggiore durante lo studio
    •Lesione traumatica nelle 2 sett precedenti l’inizio del trattamento in studio•Radioterapia palliativa nei 14 gg precedenti l’inizio del trattamento in studio •Neoplasia maligna attiva (diversa dal melanoma positivo alla mutazione BRAFV600) o neoplasia maligna nei 3 anni precedenti lo screening sono esclusi, ad eccezione del melanoma resecato, del basalioma resecato, del carcinoma squamoso della pelle resecato, del carcinoma in situ della cervice uterina resecato, del carcinoma in situ della mammella resecato, del carcinoma prostatico in situ, del carcinoma della vescica in stadio limitato o ogni altra neoplasie maligne trattate in modo curativo per la quale il paziente è libero dalla malattia per almeno 3 anni •Positività anamnestica per patologia retinica o sua evidenza all’esame oculistico, che sia considerata un fattore di rischio per il distacco della retina neurosensoriale, per la corioretinopatia sierosa centrale, per l’occlusione della vena retinica (RVO) o per la degenerazione maculare neovascolare
    •Positività anamnestica per disfunzione cardiaca clinicamente significativa, compresi:
    - Ipertensione controllata male, definita come sostenuta, incontrollata, l'ipertensione non basale della linea basale a livelli superiori a 159/99 mmHg
    nonostante la gestione medica ottimale
    •Lesioni a carico del SNC (meningite carcinomatosa) non trattate o in progressione attiva
    •Positività anamnestica per metastasi al tronco encefalico, al mesencefalo, al ponte o al midollo oppure nel raggio di 10 mm dall’apparato visivo (nervi ottici e chiasma)
    •Positività anamnestica per metastasi leptomeningea
    E.5 End points
    E.5.1Primary end point(s)
    PFS, defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator according to
    RECIST v1.1, or death from any cause, whichever occurs first
    •PFS, definita come tempo trascorso dalla randomizzazione alla prima progressione della malattia, determinata dallo sperimentatore con i criteri RECIST v1.1 o al decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo
    E.5.1.1Timepoint(s) of evaluation of this end point
    When 300 PFS events have occurred
    Quando 300 eventi PFS si sono verificati
    E.5.2Secondary end point(s)
    ¿PFS, defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first ¿Objective response, defined as a CR or PR on two consecutive occasions = 4 weeks apart, as determined by the investigator according to RECIST v1.1 ¿DOR, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first ¿OS, defined as the time from randomization to death from any cause ¿2-year landmark survival, defined as survival at 2 years ¿Time to deterioration in global health status, defined as the time from randomization to first observed = 10 point decrease in EORTC QLQ-C30 linearly transformed global health status scale score that is sustained for two consecutive assessments or followed by death while the patient is on treatment Time to deterioration in physical functioning, defined as the time from randomization to first observed =10 point decrease in EORTC QLQ-C30 linearly transformed physical functioning scale score that is sustained for two consecutive assessments or followed by death while the patient is on treatment
    ¿ PFS, definita come tempo trascorso dalla randomizzazione alla prima progressione della malattia, determinata dall¿IRC secondo i criteri RECIST v1.1 o al decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo ¿ Risposta obiettiva, definita come CR o PR in due occasioni consecutive ¿ a 4 settimane di distanza, determinata dallo sperimentatore con i criteri RECIST v1.1 ¿ DOR, definita come tempo trascorso dalla prima evidenza di risposta obiettiva documentata alla progressione della malattia (determinata dallo sperimentatore secondo i criteri RECIST v1.1) o al decesso per qualsiasi causa, a seconda di quale evento si verifichi per primo ¿ OS, definita come tempo trascorso dalla randomizzazione al decesso per qualsiasi causa ¿ Sopravvivenza a 2 anni, definita come sopravvivenza a 2 anni ¿ Tempo al peggioramento dello stato di salute generale, definito come tempo trascorso dalla randomizzazione alla prima riduzione osservata di >= 10 punti sulla scala EORTC QLQ-C30 mantenuta per due valutazioni consecutive o seguita da decesso mentre il paziente ¿ in trattamento ¿ Tempo al peggioramento delle funzionalit¿ fisiche, definito come tempo trascorso dalla randomizzazione alla prima riduzione osservata >= 10 punti sulla scala EORTC QLQ-C30 funzionalit¿ fisiche trasformata in modo lineare, mantenuta per due valutazioni consecutive o seguita da decesso mentre il paziente ¿ in trattamento
    E.5.2.1Timepoint(s) of evaluation of this end point
    OS ¿ analysis will be performed when approximately 385 deaths have occurred
    OS - l'analisi verr¿ effettuata quando si saranno verificati circa 385 decessi
    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 Yes
    E.6.7Pharmacodynamic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open 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 concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA90
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Austria
    Belgium
    Canada
    France
    Germany
    Greece
    Hungary
    Israel
    Italy
    Korea, Republic of
    Netherlands
    New Zealand
    Poland
    Portugal
    Russian Federation
    Spain
    Switzerland
    United Kingdom
    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
    The study will end when all patients enrolled have been followed until death, withdrawal of consent, lost to follow-up, or the Sponsor decides to end the trial, whichever occurs first. see protocol section 3.2
    Lo studio terminer¿ quando tutti i pazienti arruolati saranno stati sottoposti a follow-up fino a decesso, ritiro del consenso, perdita al follow-up oppure fino a quando lo sponsor non decida di terminare la sperimentazione, a seconda di quale evento si verifichi per primo, come indicato nella sezione 3.2 del protocollo.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    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 years7
    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: 250
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 250
    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 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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 334
    F.4.2.2In the whole clinical trial 500
    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)
    Currently, the Sponsor does not have any plans to provide cobimetinib,vemurafenib, and atezolizumab or any other study treatments or interventions to patients who have completed the study. The Sponsor may evaluate whether to continue providing cobimetinib, vemurafenib,
    and atezolizumab in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product.
    Attualmente, lo Sponsor non ha piani per fornire cobimetinib, vemurafenib e atezolizumab o qualsiasi altro trattamento o intervento di studio per i pazienti che hanno completato lo studio. Lo Sponsor pu¿ valutare se continuare a fornire cobimetinib, vemurafenib,
    e atezolizumab in conformit¿ con la policy globale Roche sull'Accesso continuato ai prodotti medicinali sperimentali.
    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 Decision2016-11-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-10-12
    P. End of Trial
    P.End of Trial StatusOngoing
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