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    Summary
    EudraCT Number:2011-004011-24
    Sponsor's Protocol Code Number:GO27826
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-09-21
    Trial results View 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 number2011-004011-24
    A.3Full title of the trial
    A PHASE III, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF VEMURAFENIB (RO5185426) ADJUVANT THERAPY IN PATIENTS WITH SURGICALLY RESECTED, CUTANEOUS BRAF-MUTANT MELANOMA AT HIGH RISK FOR RECURRENCE
    STUDIO DI FASE III, RANDOMIZZATO, IN DOPPIO CIECO, CONTROLLATO CON PLACEBO DELLA TERAPIA ADIUVANTE CON VEMURAFENIB (RO5185426) IN PAZIENTI CON MELANOMA CUTANEO BRAF-MUTANTE, RESECATO CHIRURGHICAMENTE, AD ALTO RISCHIO DI RECIDIVA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Vemurafenib (RO5185426) in Comparison With Placebo as Adjuvant Therapy in Previously Untreated Patients With Adequately Resected Melanoma (BRIM 8)
    Studio con Vemurafenib (RO5185426) confrontato con placebo come terapia adiuvante in pazienti non trattati con melanoma cutaneo resecato chirurgicamente (BRIM8)
    A.3.2Name or abbreviated title of the trial where available
    BRIM8
    BRIM8
    A.4.1Sponsor's protocol code numberGO27826
    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 organisationROCHE SPA
    B.5.2Functional name of contact pointCountry head Clin Ops Italy
    B.5.3 Address:
    B.5.3.1Street AddressViale G.B. Stucchi 110
    B.5.3.2Town/ cityMonza
    B.5.3.3Post code20900
    B.5.3.4CountryItaly
    B.5.4Telephone number039 2475070
    B.5.5Fax number039 2475085
    B.5.6E-mailsergio.scaccabarozzi@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 Yes
    D.2.1.1.1Trade name Zelboraf 240 mg Film-coated Tablets
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Products Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.9.2Current sponsor codeRO5185426-006
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Melanoma (patients with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma or patients with Stage IIIC cutaneous melanoma)
    Melanoma (pazienti con melanoma cutaneo resecato di stadio IIC, IIIA o IIIB o pazienti con melanoma cutaneo di stadio IIIC)
    E.1.1.1Medical condition in easily understood language
    skin cancer
    tumore della cute
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.0
    E.1.2Level PT
    E.1.2Classification code 10025670
    E.1.2Term Malignant melanoma stage III
    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 15.0
    E.1.2Level SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 15.0
    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.1.3Condition 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 vemurafenib adjuvant treatment administered over a 52-week period in patients with completely resected BRAFV600 mutation–positive, cutaneous melanoma, as measured by DFS
    L’obiettivo primario di questo studio è valutare l’efficacia del trattamento adiuvante con vemurafenib somministrato in un periodo di 52 settimane in pazienti con melanoma cutaneo positivo alla mutazione BRAFV600, completamente resecato, misurata attraverso la sopravvivenza libera da malattia (Disease-Free Survival, DFS)
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of vemurafenib adjuvant treatment administered over a 52-week period, as measured by OS • To evaluate the efficacy of vemurafenib adjuvant treatment administered over a 52-week period, as measured by DMFS • To evaluate the safety and tolerability of vemurafenib in the adjuvant setting • To assess quality of life as measured by EORTC QLQ-C30 • To describe the pharmacokinetics of vemurafenib in the adjuvant setting, assess between-patient variability of PK parameters, and explore and quantify potential covariates that may contribute to between-patient differences in PK parameters, using a population PK approach
    -Valutare l’efficacia del trattamento adiuvante con vemurafenib somministrato in un periodo di 52 settimane, misurata attraverso la sopravvivenza globale (OS) e attraverso la sopravvivenza libera da metastasi a distanza (DMFS);-Valutare la sicurezza e la tollerabilità di vemurafenib in contesto adiuvante; -Valutare la qualità della vita misurata attraverso il QLQ-C30 dell’Organizzazione Europea per la Ricerca e il Trattamento del Cancro (European Organisation for Research and Treatment of Cancer, EORTC) -Descrivere la farmacocinetica di vemurafenib in contesto adiuvante, valutare la variabilità dei parametri farmacocinetici (PK) tra pazienti, ed esplorare e quantificare le potenziali covariate che potrebbero contribuire alle differenze tra pazienti nei parametri PK, usando un approccio di popolazione PK
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Male or female patients age ≥ 18 years •Patients with completely resected, histologically confirmed, Stage IIC or Stage III, cutaneous melanoma where the BRAFV600 mutation status of the current primary tumor or involved lymph node is determined to be positive using the cobas BRAF V600 Mutation Test. Patients with Stage IIIA disease must have at least one lymph node metastasis measuring > 1 mm in diameter •ECOG performance status of 0 or 1 •Life expectancy of at least 5 years •Adequate hematologic, liver, and renal function
    -Pazienti maschi o femmine di età  18 anni -Pazienti con melanoma cutaneo positivo alla mutazione BRAFV600 (di Stadio patologico IIC o Stadio III che sia stato completamente resecato. Nota: i pazienti con malattia in Stadio IIIA devono avere almeno una metastasi linfonodale della misura di &gt;1 mm di diametro -ECOG performance status di 0 o 1 -Aspettativa di vita di almeno 5 anni -Adeguata funzionalità ematologica, epatica e renale
    E.4Principal exclusion criteria
    •History of any systemic therapy (i.e., chemotherapy, biologic or targeted therapy, or hormonal therapy) or limb perfusion therapy for the treatment or prevention of melanoma, including interferon-alpha-2b and pegylated interferon-alpha-2b •History of radiotherapy for the treatment of melanoma •Invasive malignancy other than melanoma at the time of enrollment or within 3 years prior to first study drug administration except for adequately treated (with curative intent) basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, in situ ductal adenocarcinoma of the breast, in situ prostate cancer, limited stage bladder cancer, or other cancers from which the patient has been disease-free for at least 3 years •History of or current clinical, radiographic, or pathologic evidence of intransit metastases, satellite lesions or recurrent lymph node involvement after resection of a primary melanoma with previous lymph node involvement •History or current radiographic or pathologic evidence of distant metastases •History of clinically significant cardiac dysfunction including serious arrhythmias requiring treatment (except for atrial fibrillation and paroxysmal supraventricular tachycardia), history of myocardial infarction within 6 months prior to randomization, and history of congenital long QT syndrome or QTc interval > 450 ms at baseline •Current, recent (within 28 days prior to randomization) or planned use of any investigational product outside of this study
    -Anamnesi di qualsiasi terapia sistemica (ovvero, chemioterapia, terapia biologica o mirata, oppure terapia ormonale) per il trattamento o la prevenzione del melanoma, inclusi interferone-alfa-2b e interferone-alfa-2b pegilato -Anamnesi di radioterapia per il trattamento del melanoma -Neoplasia invasiva diversa dal melanoma al momento dell’arruolamento o nei 3 anni precedenti la prima somministrazione del farmaco dello studio, eccetto per il carcinoma a cellule squamose o basocellulare della pelle adeguatamente trattato (con intento curativo), carcinoma della cervice in situ, adenocarcinoma duttale della mammella in situ, carcinoma della prostata in situ, cancro della vescica in stadio limitato, o altri carcinomi da cui il paziente è libero dalla malattia da almeno 3 anni precedenti al Ciclo 1, Giorno 1 -Anamnesi di attuale evidenza clinica, radiografica o patologica di metastasi in transito o lesioni satellite -Anamnesi di disfunzione cardiaca o polmonare clinicamente significativa -Attuale, recente (nei 28 giorni precedenti alla randomizzazione) utilizzo, o utilizzo pianificato, di qualsiasi prodotto sperimentale al di fuori di questo studio
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint, Disease Free Survival (DFS), is defined as the time from randomization until the date of the first local, regional, or distant melanoma recurrence; occurrence of new primary melanoma; or death from any cause. DFS will be assessed by the investigator.
    La sopravvivenza libera da malattia (Disease-free survival, DFS) sarà definita come il tempo trascorso dalla randomizzazione alla data della prima recidiva di melanoma locale, regionale o distante, all’insorgenza di nuovo melanoma primario, oppure al decesso per qualsiasi causa. La DFS sarà valutata dallo sperimentatore.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The final analysis of the primary endpoint of DFS for Cohort 1 will take place when approximately 190 DFS events have occurred and for Cohort 2 when approximately 146 DFS events have occurred.
    L'analissi finale di endpoint primario di DFS verrà effettuata quando si saranno verificati circa 190 eventi di DFS per la coorte 1 e 146 eventi per la coorte 2
    E.5.2Secondary end point(s)
    - Overall Survival: Overall Survival (OS) is defined as the time from randomization until the date of death from any cause. - DMFS: Distant metastasis-free survival (DMFS) is defined as the time from randomization until the date of diagnosis of distant (i.e., nonlocoregional) metastasis or death from any cause.
    -OS:tempo trascorso dalla randomizzazione alla data del decesso per qualsiasi causa. -DMFS: tempo trascorso dalla randomizzazione fino alla data di diagnosi delle metastasi distanti (ovvero, non locoregionali) o decesso per qualsiasi causa.
    E.5.2.1Timepoint(s) of evaluation of this end point
    - The first OS interim analysis in each cohort will be performed at the time of the final DFS analysis for the cohort (projected to occur for each cohort approximately 37 months after the first patient is randomized). The second OS interim analysis will be performed for Cohorts 1 and 2 after the occurrence of 178 and 136 deaths, respectively (projected to occur at approximately Month 59). The final OS analysis for Cohorts 1 and 2 will be performed after the occurrence of approximately 251 and 177 deaths, respectively (projected to occur at approximately Month 88 in each cohort). - DMFS will be analyzed at the time of the final DFS analysis in each cohort – viz., when approximately 190 DFS events have occurred for Cohort 1 and 146 for cohort 2
    -la prima interim analisi di OS sarà eseguita al tempo dell'analissi di DFS (circa 37 mesi dopo la randomizzazione del primo paziente); la seconda interim analissi di OS verrà effettuata per le coorti 1 e 2 quando si saranno verificate rispettivamente 178 e 136 morti (circa dopo 59 mesi) . l'ultima interim analisi di OS sarà effettuata quando si saranno verificate circa 251 e 177 morti (circa dopo 88 mesi); DMFS sarà analizzata al tempo dell'analisi di DFS per ciascuna delle due coorti
    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 Yes
    E.6.13.1Other scope of the trial description
    tolerability, quality of life
    Tollerabilità, qualità della vita
    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 EEA76
    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
    Argentina
    Australia
    Brazil
    Canada
    Israel
    New Zealand
    Switzerland
    Turkey
    Ukraine
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    All patients will be followed for melanoma recurrence for up to 5 years and OS for up to 7 years after Cycle 1, Day 1 of study treatment. Patients who exhibit recurrence of melanoma prior to completion of Year 5 of the study will be followed for OS. No study-related observations (including survival status) are planned after the completion of Year 7 of follow-up.
    tutti i pazienti saranno seguiti per le ricorrenze di melanoma fino a 5 anni e per sopravvivenza globale (OS) fino a 7 anni dopo il primo ciclo di trattamento.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months93
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months93
    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.1.1Number of subjects for this age range: 0
    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: 400
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 325
    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 state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 320
    F.4.2.2In the whole clinical trial 725
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After the study treatment period, patients will enter a follow-up period
    where they will not be treated unless they withdraw from the study or
    the study is terminated/closed. Given that the patient is not on study
    drug at the end of the study, it is not deemed necessary for vemurafenib to be supplied to patients post study. Decisions concerning the care of the patient after completion of participation in this study, will be left with the patients' treating physician
    Al termine del periodo di trattamento i pazienti entreranno in un periodo di follow-up senza trattamento, a meno che non escano dallo studio o lo studio sia concluso. poichè i pazienti non sono più in trattamento con vemurafenib, non è necessario fornire il farmaco. Decisioni riguardanti alle cure da prestare ai pazienti al termine del trattamento vengono lasciate al medico curante.
    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 Decision2012-09-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-09-17
    P. End of Trial
    P.End of Trial StatusCompleted
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