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    Summary
    EudraCT Number:2015-004015-20
    Sponsor's Protocol Code Number:CDRB436G2201
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-10-10
    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 ConcernedSpain - AEMPS
    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
    Estudio de fase II abierto global para evaluar el efecto de dabrafenib en combinación con trametinib en pacientes niños y adolescentes con Glioma de Alto Grado (HGG) recidivante o refractario con mutación BRAF V600 positiva
    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
    Estudio de eficacia y seguridad de dabrafenib en combinación con trametinib en pacientes pediatricos con Glioma de Alto Grado (HGG) recidivante o refractario con mutación BRAF V600 positive.
    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 Farmacéutica S.A.
    B.1.3.4CountrySpain
    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 Farmacéutica S.A.
    B.5.2Functional name of contact pointDepartamento Médico Oncología (GMO)
    B.5.3 Address:
    B.5.3.1Street AddressGran Vía de les Corts Catalanes, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number34 900353036
    B.5.5Fax number34 93 2479903
    B.5.6E-maileecc.novartis@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)
    Pacientes pediatricos con Glioma de Alto Grado (HGG) recidivante o refractario con mutación BRAF V600 positiva
    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
    Niños o adolescentes con un tipo de tumor cerebral llamado Glioma de Alto Grado, que se caracteriza por una mutación en gen 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.
    El objetivo principal es evaluar la actividad antitumoral de dabrafenib en combinación con trametinib determinado mediante la tasa de respuesta global (ORR) de la terapia combinada mediante evaluación por el investigador utilizando los criterios 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. Evaluar ORR mediante revisión independiente central
    2. Evaluar la duración de la respuesta (DOR) por el investigador y mediante revisión independiente central
    3. Evaluar el tiempo hasta la respuesta (TTR) por el investigador y mediante revisión independiente centra
    4. Evaluar la supervivencia libre de progresión (PFS) por el investigador y mediante revisión independiente central
    5. Evaluar la supervivencia global (OS)
    6. Evaluar el perfil de seguridad de dabrafenib en combinación con trametinib en la población del estudio
    7. Caracterizar la farmacocinética de dabrafenib, sus metabolitos y trametinib en la población del estudio
    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/microL;
     -Platelets >/=75,000/mmL 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.
    Criterios de inclusión clave:
    - Ambos sexos >/=6 y < 18 años de edad.
    - Diagnóstico histológicamente confirmado de Glioma de Alto Grado (glioma de Grado III o IV según la definición del sistema de clasificación histológica de la OMS, revisado 2016), incluyendo xantoastrocitoma pleomórfico anaplásico (aPXA) y ganglioglioma anaplásico.
    - Enfermedad recidivante, que haya progresado, o sin respuesta a la terapia de primera línea.
    - Tumor positivo a mutación BRAF V600, determinado localmente utilizando métodos moleculares en un laboratorio aprobado CLIA o equivalente, o en un laboratorio de referencia central designado por Novartis bajo solicitud.
    - Enfermedad medible determinada localmente y confirmada centralmente.
    - Debe proporcionarse tejido tumoral (de archivo o de nueva obtención) para análisis confirmatorio central de histopatología HGG y estadio de la mutación BRAF.
    - Puntuación de estado funcional de Karnofsky/Lansky >/=50%.
    - Función de la médula ósea adecuada en ausencia de soporte con factor de crecimiento.
    - Función renal, función hepática, y función cardiaca adecuadas.
    - Debe ser capaz de tragar cápsulas; debe tener un peso >/= 16 kg si tiene menos de 12 años, o >/=19 kg si tiene >/= 12 años.
    - Si está recibiendo glucocorticosteroides, el paciente debe estar con una dosis estable o en proceso de disminución de dosis durante al menos 7 días antes de la primera dosis del tratamiento del 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).
    Criterios de exclusión clave:
    - Neoplasia DISTINTA de HGG BRAF V600 mutado.
    - Tratamiento previo con dabrafenib u otro inhibidor RAF, trametinib u otro inhibidor MEK, o un inhibidor ERK.
    - Terapia para el cáncer (quimioterapia con toxicidad retardada, inmunoterapia, terapia biológica, terapia con vacuna) o fármacos en investigación en las 3 semanas anteriores a la primera dosis del tratamiento del estudio.
    - Radioterapia para lesiones de glioma del SNC en los 3 meses previos a la primera dosis del tratamiento del estudio, a menos que exista evidencia clara de progresión radiológica fuera del campo de radiación.
    - Historia de neoplasia con mutación RAS activadora confirmada o con fusión BRAF como BRF-KIAA1549.
    - Uso actual de una medicación prohibida o preparación a base de hierbas o precisa alguna de estas medicaciones durante el estudio. Ver el Apartado 6.4 para detalles.
    - Toxicidad no resuelta superior al grado 2 del NCI CTCAE v 4.03 de una terapia anti-cáncer previa, incluyendo cirugía mayor, excepto los que en opinión del investigador no sean clínicamente relevantes dado el perfil conocido de seguridad/toxicidad del tratamiento del estudio (p.ej., alopecia y/o neuropatía periférica relacionada con quimioterapia basada en platino o alcaloides de la vinca).
    - Antecedentes de reacciones alérgicas atribuidas a compuestos de composición química o biológica similar a dabrafenib, trametinib y sus excipientes.
    - Trasplante autólogo o alogénico de células hematopoyéticas en los 3 meses previos a la primera dosis del tratamiento del estudio [NOTA: se excluyen los pacientes con evidencia de enfermedad de injerto contra huésped activa independientemente del tiempo transcurrido]
    - Antecedentes o diagnóstico actual de enfermedad cardiaca que indique un riesgo significativo de seguridad para los pacientes que participan en el estudio como enfermedad cardiaca no controlada o significativa.
    - Condiciones médicas no controladas (p.ej., diabetes mellitus, hipertensión, enfermedad hepática o infección no controlada), condiciones psicológicas, familiares, sociológicas, o geográficas que no permitan el cumplimiento con el protocolo; o que no quieran o sean incapaces de seguir los procedimientos exigidos en el protocolo.
    - Presencia de enfermedad GI activa y otra condición (p.ej., resección del intestino delgado o intestino grueso) que interferirá significativamente con la absorción de los fármacos.
    - Antecedentes de infección por Virus de la Hepatitis B o Virus de la Hepatitis C (los pacientes con evidencia analítica de Virus de la Hepatitis B y/o Virus de la Hepatitis C eliminado, pueden ser reclutados).
    - Mujeres en edad fértil, definidas como toda mujer psicológicamente capaz de quedar embarazada (p.ej., que estén con la menstruación), a menos que estén utilizando métodos anticonceptivos de elevada eficacia durante la administración de la dosis del tratamiento del estudio y durante 4 meses después de suspender la medicación del estudio. Nota: métodos anticonceptivos hormonales no están permitidos debido a las posibles interacciones farmacológicas con dabrafenib.
    - Mujeres que estén embarazadas o en periodo de lactancia activa.
    - Hombres sexualmente activos a menos que utilicen un preservativo durante el coito mientras estén en el estudio y durante 12 semanas después de suspender el tratamiento del estudio, y acepten no engendrar un hijo durante este 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, Respuesta Completa (CR) o Respuesta Parcial (PR) mediante evaluación por el investigador utilizando los criterios 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.
    Los pacientes sera evaluados en la visita de preselección (antes del inicio del tratamiento del studio) y cada 8 semanas durante el primer año de tratamiento y cada 16 semanas posteriormente para la eficacia usando los criterios de 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. Evaluar ORR mediante revisión independiente central
    2. Evaluar la duración de la respuesta (DOR) por el investigador y mediante revisión independiente central
    3. Evaluar el tiempo hasta la respuesta (TTR) por el investigador y mediante revisión independiente centra
    4. Evaluar la supervivencia libre de progresión (PFS) por el investigador y mediante revisión independiente central
    5. Evaluar la supervivencia global (OS)
    6. Evaluar el perfil de seguridad de dabrafenib en combinación con trametinib en la población del estudio
    7. Caracterizar la farmacocinética de dabrafenib, sus metabolitos y trametinib en la población del estudio
    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.
    Los pacientes serán evaluados en la visita de preselección (antes del inicio del tratamiento del studio) y cada 8 semanas durante el primer año de tratamiento y cada 16 semanas después para la eficacia ultilizando los criterios 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    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 months7
    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
    Menores
    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 mayoría de los pacientes pediátricos con glioma de alto grado son incurables.
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 25
    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.
    Después de la interrupción del tto. del estudio, los pacientes tendrán un seguimiento por seguridad durante al menos 30 días, tras la última dosis de tto,a excepción de muerte, pérdida de seguimiento o retirada del consentimiento (ICF) .Las evaluaciones de tumor durante este período continuarán hasta progresión de la enfermedad por los criterios RANO, o por retirada del ICF. Todos tendrán seguimiento para evaluar la supervivencia ,tras suspender el tto. y se evaluarán los tumores por 2 años mín.
    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 Decision2017-12-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-08
    P. End of Trial
    P.End of Trial StatusOngoing
    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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