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    Summary
    EudraCT Number:2015-004015-20
    Sponsor's Protocol Code Number:CDRB436G2201
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2017-11-15
    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 number2015-004015-20
    A.3Full title of the trial
    Phase II open-label global study to evaluate the effect of dabrafenib in combination with trametinib in children and
    adolescent patients with BRAF V600 mutation positive relapsed or refractory High Grade Glioma (HGG) P/260/2017
    Studio internazionale, di fase II, in aperto, per valutare l’effetto di dabrafenib in combinazione con trametinib in bambini e adolescenti con glioma ad alto grado recidivante o refrattario positivo per mutazione di BRAF V600
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of efficacy and safety of dabrafenib in combination with trametinib in pediatric patients with BRAF V600 mutation positive relapsed or refractory HGG tumors
    Studio sull’efficacia e sulla sicurezza di dabrafenib in combinazione con trametinib in pazienti pediatrici con glioma ad alto grado recidivante o refrattario positivo per mutazione di BRAF V600
    A.4.1Sponsor's protocol code numberCDRB436G2201
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/259/2017
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma AG
    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 supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNOVARTIS FARMA S.p.A
    B.5.2Functional name of contact pointDrug Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressLargo Umberto Boccioni, 1
    B.5.3.2Town/ cityORIGGIO
    B.5.3.3Post code21040
    B.5.3.4CountryItaly
    B.5.4Telephone number+390296541
    B.5.5Fax number+39029659066
    B.5.6E-mailinfo.studiclinici@novartis.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 Tafinlar
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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.3.2Product code DRB436
    D.3.4Pharmaceutical form Capsule, hard
    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 INNdabrafenib
    D.3.9.1CAS number 1195765-45-7
    D.3.9.2Current sponsor codeDRB436
    D.3.9.3Other descriptive nameDABRAFENIB
    D.3.9.4EV Substance CodeSUB45696
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 Tafinlar
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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.3.2Product code DRB436
    D.3.4Pharmaceutical form Capsule, hard
    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 INNdabrafenib
    D.3.9.1CAS number 1195768-06-9
    D.3.9.2Current sponsor codeDRB436
    D.3.9.3Other descriptive nameDABRAFENIB
    D.3.9.4EV Substance CodeSUB45696
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number75
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Mekinist
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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.3.2Product code TMT212
    D.3.4Pharmaceutical form 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 INNtrametinib
    D.3.9.1CAS number 1187431-43-1
    D.3.9.2Current sponsor codeTMT212
    D.3.9.3Other descriptive nameTRAMETINIB DIMETHYL SULFOXIDE
    D.3.9.4EV Substance CodeSUB45696
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    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: 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 Mekinist
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm 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.3.2Product code TMT212
    D.3.4Pharmaceutical form 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 INNtrametinib
    D.3.9.1CAS number 1187431-43-1
    D.3.9.2Current sponsor codeTMT212
    D.3.9.3Other descriptive nameTRAMETINIB DIMETHYL SULFOXIDE
    D.3.9.4EV Substance CodeSUB45696
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 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.3.2Product code TMT212
    D.3.4Pharmaceutical form Powder for oral solution
    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 INNtrametinib
    D.3.9.1CAS number 1187431-43-1
    D.3.9.2Current sponsor codeTMT212
    D.3.9.3Other descriptive nameTRAMETINIB DIMETHYL SULFOXIDE
    D.3.9.4EV Substance CodeSUB45696
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.41
    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
    Paediatric patients with BRAF V600 mutation positive relapsed or refractory High Grade Glioma (HGG)
    Pazienti pediatrici con glioma ad alto grado recidivante o refrattario positivo per mutazione di BRAF V600
    E.1.1.1Medical condition in easily understood language
    Children and adolescents with a form of brain tumor called high-grade glioma, which is characterised by a mutation in the BRAF V600 gene
    Bambini e adolescenti con glioma ad alto grado recidivante o refrattario positivo per mutazione di BRAF V600
    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 10065443
    E.1.2Term Malignant glioma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the anti-tumor activity of dabrafenib in combination with trametinib, as measured by overall response rate (ORR) to the combination therapy by investigator assessment using the RANO criteria.
    Valutare l’attività antitumorale di dabrafenib in combinazione con trametinib misurata tramite il tasso di risposta generale (Overall Response Rate – ORR) alla terapia in combinazione definita dallo sperimentatore utilizzando i criteri RANO.
    E.2.2Secondary objectives of the trial
    1. Evaluate ORR by central independent review
    2. Evaluate duration of response (DOR) by investigator and central independent review
    3. Evaluate time to response (TTR) by investigator and central independent review
    4. Evaluate progression free survival (PFS) by investigator and central independent review
    5. Evaluate overall survival (OS)
    6. Evaluate the safety profile of dabrafenib in combination with trametinib in children and adolescents
    7. Characterize the pharmacokinetics of dabrafenib, its metabolites and trametinib in the study population
    1. Valutare la ORR tramite revisione indipendente centralizzata
    2. Valutare la durata della risposta (Duration Of Response - DOR) tramite revisione da parte dello sperimentatore e revisione
    indipendente centralizzata
    3. Valutare il tempo alla risposta (Time To Response – TTR) tramite revisione da parte dello sperimentatore e revisione indipendente centralizzata
    4. Valutare la sopravvivenza libera da progressione (Progression Free Survival – PFS) tramite revisione da parte dello sperimentatore e revisione indipendente centralizzata
    5. Valutare la sopravvivenza globale (Overall Survival – OS)
    6. Valutare il profilo di sicurezza di dabrafenib in combinazione con trametinib nella popolazione in studio
    7. Caratterizzare la farmacocinetica di dabrafenib, i suoi metaboliti e di trametinib nella popolazione in studio
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Key Inclusion criteria:
    - Male or female between ≥ 6 and <18 years of age at the time of signing the informed
    consent form
    - Relapsed, progressed, or failed to respond to frontline therapy. Frontline therapy is
    presumed to be optimal surgical approach (biopsy or resection) with radiation and/or
    chemotherapy.
    - Histologically confirmed diagnosis of High Grade Glioma (Grade III or IV glioma as
    defined by WHO histological classification system, revised 2016, see Appendix 4),
    including anaplastic pleomorphic xanthoastrocytoma (aPXA) and anaplastic
    gangliogliomas.
    - Locally determined and centrally confirmed measurable disease with minimal biperpendicular diameter that must be at least twice the imaging slice thickness to be used for efficacy assessments. (Both local and centrally confirmed results must show
    measurable disease to meet eligibility)
    - BRAF V600 mutation-positive tumor as locally determined using molecular methods in a
    CLIA-approved laboratory or equivalent, or at a Novartis designated central reference
    laboratory upon request
    - Tumor tissue (newly obtained or archival paraffin blocks/slides) must be available and
    subsequently provided to Novartis for central confirmatory testing of HGG histopathology
    and BRAF mutational status.
    - Performance score of ≥50% according to the Karnofsky/Lansky performance status scale
    - Females of child-bearing potential must be willing to practice acceptable methods of birth control. Additionally, females of childbearing potential must have a negative serum
    pregnancy test within 7 days prior to day 1
    - Must have adequate bone marrow function in the absence of growth factor support and is defined as:
     -Absolute neutrophil count (ANC) ≥1000/μL;
     -Platelets ≥75,000/μL and transfusion independent, defined as not receiving platelet
    transfusions within a 7 day period prior to meeting this enrollment criteria
     -Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)
    - Adequate renal function defined as:
     -Calculated eGFR (Schwartz formula, http://www.medcalc /pedigfr.html), or
    radioisotope GFR ≥90 mL/min/1.73 m2; or
     -A serum creatinine within the testing lab reference range (for age/gender, if available)
    - Adequate liver function defined as:
     -Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN)
    for age
     -AST and ALT ≤2.5 x ULN
    - Adequate cardiac function defined as:
     -LVEF greater than or equal to institutional LLN by ECHO (while not receiving
    medications for cardiac function)
     -Corrected QT (QTcF) interval ≤480 msecs.
    - Able to swallow capsules:
     -If less than 12 years old, must be ≥ 16kg body weight
     -If ≥ 12 years old, must be ≥ 19kg body weight
    - If receiving glucocorticoids, patient must be on a stable or weaning dose for at least 7 days prior to the first dose of study treatment.
    - Written informed consent/assent must be obtained prior to any protocol specific screening procedures being performed.
    - Pazienti di sesso maschile o femminile di età compresa tra ≥ 6 e <18 anni.
    - Diagnosi confermata istologicamente di glioma ad alto grado (HGG) (glioma di Grado III o IV in base al sistema di classificazione istologica WHO, revisione 2016), compreso xantoastrocitoma pleomorfo anaplastico (anaplastic Pleomorphic Xanthoastrocytoma -
    aPXA) e ganglioglioma anaplastico.
    - Malattia recidivante, in progressione o che non ha risposto alla terapia di prima linea.
    - Tumore positivo per mutazione di BRAF V600 come determinato a livello locale utilizzando metodi molecolari in un laboratorio approvato CLIA o equivalente, o presso un laboratorio centralizzato di riferimento designato da Novartis su richiesta.
    - Malattia misurabile determinata a livello locale e confermata a livello centralizzato.
    - Disponibilità di tessuto tumorale (di archivio o fresco) da fornire per il test confermatorio centralizzato dell’istopatologia dell’HGG e dello stato mutazionale BRAF.
    - Punteggio Karnofsky/Lansky di performance ≥50%.
    - Adeguata funzionalità del midollo osseo in assenza di supporto del fattore di crescita.
    - Adeguata funzionalità renale, funzionalità epatica e funzionalità cardiaca.
    - Pazienti in grado di deglutire le capsule; i pazienti devono avere un peso corporeo ≥16 kg se di età inferiore ai 12 anni, oppure ≥19 kg se di età ≥12 anni.
    - Se in trattamento con glucocorticoidi, i pazienti devono essere in trattamento a dose stabile o nella fase di riduzione del dosaggio da almeno 7 giorni prima della prima somministrazione del trattamento in studio.
    E.4Principal exclusion criteria
    - Malignancy OTHER than BRAF V600 mutant HGG.
    - Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK
    inhibitor, or ERK inhibitor.
    - Cancer therapy (chemotherapy with delayed toxicity, immunotherapy, biologic therapy,
    vaccine therapy) or investigational drugs within 3 weeks preceding the first dose of study
    treatment.
    - Radiotherapy to CNS glioma lesions within 3 months prior to first dose of study treatment, unless there is clear evidence of radiologic progression outside of the field of radiation.
    - History of malignancy with confirmed activating RAS mutation or with BRAF fusion
    such as BRF-KIAA1549. Note: Prospective RAS testing is not required. However, if the
    results of previous RAS testing are known, they must be used in assessing eligibility.
    - Current use of a prohibited medication or herbal preparation or requires any of these
    medications during the study. See Section 6.4 for details.
    - Unresolved toxicity greater than NCI CTCAE v 4.03 grade 2 from previous anti-cancer
    therapy, including major surgery, except those that in the opinion of the investigator are
    not clinically relevant given the known safety/toxicity profile of the study treatment (e.g.,
    alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid based
    chemotherapy).
    - History of allergic reactions attributed to compounds of similar chemical or biologic
    composition to dabrafenib, trametinib and their excipients.
    - Autologous or allogeneic stem cell transplant within 3 months prior to the first dose of
    study treatment
    - History or current diagnosis of cardiac disease indicating significant risk of safety for
    patients participating in the study such as uncontrolled or significant cardiac disease,
    including any of the following:
     recent myocardial infarction (within last 6 months),
     uncontrolled congestive heart failure,
     unstable angina (within last 6 months),
     clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias (e.g.,
    sustained ventricular tachycardia, and clinically significant second or third degree AV
    block without a pacemaker) except sinus arrhythmia within the past 24 weeks prior to
    the first dose of study treatment
     coronary angioplasty or stenting (within last 6 months)
     intra-cardiac defibrillators
     abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram
    (patients with grade 1 abnormalities can be enrolled on study. Patients with moderate valvular thickening should NOT be enrolled)
    - Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease or
    uncontrolled infection), psychological, familial, sociological, or geographical conditions
    that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol
    - Presence of active GI disease or other condition (e.g., small bowel or large bowel
    resection) that will interfere significantly with the absorption of drugs.
    - A history of Hepatitis B Virus, or Hepatitis C Virus infection (patients with laboratory
    evidence of cleared Hepatitis B Virus and/or Hepatitis C Virus may be enrolled).
    - Women of child-bearing potential, defined as all women physiologically capable of
    becoming pregnant (e.g. are menstruating), unless they are using highly effective methods of contraception during dosing of study treatment and for 4 months after stopping study medication. Effective contraception methods include:
     Total abstinence (when this is in line with the preferred and usual lifestyle of the
    patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
    methods) and withdrawal are not acceptable methods of contraception
     Female sterilization (have had surgical bilateral oophorectomy with or without
    hysterectomy), total hysterectomy, or bilateral tubal ligation or tubal occlusion at least
    six weeks before taking study treatment. In case of oophorectomy alone, only when
    the reproductive status of the woman has been confirmed by follow up hormone level
    assessment is she considered not of child bearing potential.
     Male sterilization (at least 6 months prior to screening). For female patients on the
    study, the vasectomized male partner should be the sole partner for that patient.
     Placement of a non-hormonal intrauterine device (IUD) or intrauterine system (IUS)
    with a documented failure rate of less than 1% per year. Double-barrier contraception:
    condom and occlusive cap (diaphragm or cervical/vault caps) with a vaginal
    spermicidal agent (foam/gel/cream/suppository).
    - Patologia maligna DIVERSA da HGG con mutazione BRAF V600.
    - Pregresso trattamento con dabrafenib o altro inibitore RAF, trametinib o altro inibitore MEK o un inibitore ERK.
    - Terapia antitumorale (chemioterapia con tossicità ritardata, immunoterapia, terapia biologica, terapia vaccinale) o farmaci
    sperimentali nelle 3 settimane precedenti la prima somministrazione di trattamento in studio.
    - Radioterapia alle lesioni SNC del glioma nei 3 mesi precedenti la prima somministrazione del trattamento in studio, a meno che non vi sia chiara evidenza di progressione radiologica al di fuori del campo di radiazione.
    - Anamnesi di patologia maligna con mutazione attivante RAS confermata o con fusione di BRAF quale BRF-KIAA1549.
    - Attuale uso di un farmaco o di una preparazione erboristica proibiti oppure necessità di assumere tali trattamenti durante lo studio. Fare riferimento alla Sezione 6.4 del protocollo per i dettagli.
    - Tossicità non risolta superiore a grado 2 in base alla classificazione NCI CTCAE v 4.03 da pregressa terapia antitumorale, compreso intervento chirurgico maggiore, ad eccezione di quelli che a giudizio dello sperimentatore non sono clinicamente rilevanti dati il profilo di sicurezza/tossicità noto del trattamento in studio (ad es. alopecia e/o neuropatia periferica correlata a chemioterapia a base di platino o alcaloidi della Vinca).
    - Anamnesi di reazioni allergiche attribuite a composti di composizione chimica o biologica simile a dabrafenib, trametinib e loro eccipienti.
    - Trapianto autologo o allogenico di cellule staminali nei 3 mesi precedenti la prima somministrazione di trattamento in studio
    [NOTA: i pazienti con evidenza di malattia attiva da trapianto contro l’ospite sono esclusi indipendentemente dal tempo trascorso].
    - Anamnesi o attuale diagnosi di patologia cardiaca che indica un rischio significativo di sicurezza per i pazienti partecipanti allo
    studio, come patologia cardiaca non controllata o significativa.
    - Condizioni mediche non controllate (ad es. diabete mellito, ipertensione, patologia epatica o infezione non controllata),
    condizioni psicologiche, familiari, sociologiche o geografiche che non consentono l’aderenza al protocollo; oppure indisponibilità o
    incapacità di seguire le procedure richieste nel protocollo.
    - Presenza di patologia gastrointestinale attiva o altra condizione (ad es. resezione dell’intestino tenue o dell’intestino crasso) che
    interferiscono in modo significativo con l’assorbimento dei farmaci.
    - Anamnesi di infezione da virus dell’epatite B o virus dell’epatite C (i pazienti con evidenza di laboratorio dell’eliminazione del virus dell’epatite B/virus dell’epatite C possono essere arruolati nello studio).
    - Donne potenzialmente fertili, definite come tutte le donne fisiologicamente in grado di iniziare una gravidanza (ad es. che hanno
    il ciclo mestruale), a meno che non utilizzino metodi contraccettivi di efficacia elevata durante la somministrazione del trattamento
    in studio e per 4 mesi dopo l’interruzione del farmaco in studio. Nota: i metodi contraccettivi ormonali non sono consentiti a causa
    delle potenziali interazioni farmaco-farmaco con dabrafenib.
    - Donne in gravidanza o allattamento.
    - Uomini sessualmente attivi a meno che non utilizzino il preservativo durante lo studio e per 12 settimane dopo l’interruzione del trattamento in studio e che acconsentano a non concepire un figlio durante questo periodo.
    E.5 End points
    E.5.1Primary end point(s)
    ORR, proportion of patients with a best overall confirmed Complete Response (CR) or Partial Response (PR) by investigator assessment per Response Assessment in Neuro-Oncology (RANO) criteria.
    ORR, proporzione di pazienti con la best overall confirmed Complete Response (CR) o la Partial Response (PR) sulla base del parere dello sperimentatore mediante criteri valutati con Response Assessment in Neuro-Oncology (RANO)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Patients will be assessed at screening (before initiation of study treatment) and every 8 weeks for the first year on treatment, and every 16 weeks thereafter for efficacy using RANO criteria.
    I pazienti verranno esaminati allo screening (prima dell’inizio del trattamento in studio) ed ogni 8 settimane per il primo anno di trattamento, ed ogni 16 settimane successivamente per valutare
    l’efficacia di trattamento mediante i criteri RANO.
    E.5.2Secondary end point(s)
    1. ORR by central independent review assessment per RANO criteria
    2. DOR, calculated as the time from the date of the first documented confirmed response (CR or PR) to the first documented progression or death due to any cause, as assessed separately by investigator and central independent reviewer per RANO criteria.
    3. TTR, calculated as the time from the start date of study treatment to first documented confirmed response CR or PR (which must be confirmed subsequently) as assessed separately by investigator and independent central reviewer per RANO criteria
    4. PFS, defined as time from first dose of study treatment to progression or death due to any cause, as assessed separately by central independent reviewer and investigator per RANO criteria
    5. OS, defined as the time from first dose of study treatment to death due to any cause
    6. Incidence of adverse events and serious adverse events, changes in laboratory results, vital signs, ECG and ECHO
    7. Plasma concentration-time profiles of dabrafenib, its metabolites and trametinib and PK parameters
    1. ORR mediante valutazione indipendente centralizzata secondo i criteri RANO
    2.DOR, calcolato come il tempo dalla data del primo confirmed Complete Response (CR) o Partial Response (PR) o dalla morte dovuta a qualunque causa, valutata separatamente dagli sperimentatori e dal revisore indipendente centrale secondo i criteri RANO.
    3. TTR, calcolato come il tempo dalla data di inizio del trattamento di studio al primo CR o PR (che deve essere confermato successivamente) come valutato separatamente dallo sperimentatore e dal revisore indipendente centrale secondo i criteri RANO.
    4. PFS, definito come il tempo dalla prima dose di trattamento allo studio fino alla progressione o la morte per qualsiasi causa, valutata separatamente dallo sperimentatore e dal revisore indipendente centrale secondo i criteri RANO.
    5. OS, definito come il tempo dalla prima dose di trattamento di studio a morte per qualsiasi causa
    6. Incidenza di AE e SAE, variazioni in risultati del laboratorio, segni vitali, ECG e ECHO
    7. Profili di concentrazione nel tempo di dabrafenib nel plasma, dei suoi metaboliti e di trametinib e PK
    E.5.2.1Timepoint(s) of evaluation of this end point
    Patients will be assessed at screening (before initiation of study treatment) and every 8 weeks for the first year on treatment, and every 16 weeks thereafter for efficacy using RANO criteria.
    I pazienti verranno esaminati allo screening (prima dell’inizio del
    trattamento in studio) ed ogni 8 settimane per il primo anno di trattamento, ed ogni 16 settimane successivamente per valutare
    l’efficacia di trattamento mediante i criteri RANO.
    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 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 No
    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 trial1
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    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
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Italy
    Japan
    Netherlands
    Spain
    Sweden
    Switzerland
    United Kingdom
    United States
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months7
    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 Yes
    F.1.1Number of subjects for this age range: 40
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 25
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Minors
    Minori
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Majority of patients with pediatric high-grade glioma are incurable
    La maggior parte dei pazienti con glioma ad alto grado è incurabile
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 40
    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 discontinuation of study treatment, patients will be followed for safety for at least 30 days after the last dose of study treatment except in the case of death, loss to follow-up or withdrawal of consent.Tumor evaluations during this period will continue until documented disease progression by RANO criteria, withdrawal of consent by subject to tumor status follow-up.All patients will be followed for survival once they discontinue study treatment and tumor evaluations for at least 2 years.
    Dopo la sospensione del trattamento , i pazienti saranno seguiti per la sicurezza per almeno 30 giorni dopo l'ultima dose di trattamento eccetto in caso di morte, perdita al follow-up o di revoca del consenso. Le valutazioni tumorali durante questo periodo continueranno fino a documentata progressione di malattia secondoRANO, ritiro del consenso al follow-up dello stato tumorale. Tutti i pazienti saranno seguiti una volta per la sopravvivenza e per le valutazionitumorali per almeno 2 anni.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-04-09
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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