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    Summary
    EudraCT Number:2012-001499-12
    Sponsor's Protocol Code Number:BRF116013
    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:2014-08-14
    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 number2012-001499-12
    A.3Full title of the trial
    Phase I/IIa, 2-Part, Multi-Center, Single-Arm, Open-Label Study to Determine the Safety, Tolerability and Pharmacokinetics of
    Oral Dabrafenib in Pediatric Subjects Aged 1 Month to <18 Years with Advanced BRAF V600-Mutation Positive Solid
    Tumors
    Estudio Fase I/IIa de dos partes, multicéntrico, abierto, con un solo grupo para determinar la seguridad, tolerabilidad y farmacocinética de dabrafenib oral en sujetos pediátricos de 12 meses a <18 años de edad con tumores sólidos avanzados con mutación BRAF V600 positiva.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to determine the safety and dose of oral dabrafenib in children with tumors that have the BRAF V600 gene mutation.
    Estudio para determinar la seguridad y dosis de dabrafenib oral en niños con tumores que tienen mutación del gen BRAF V600.
    A.3.2Name or abbreviated title of the trial where available
    Phase I/II GSK2118436 peds study
    A.4.1Sponsor's protocol code numberBRF116013
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/024/2012
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGlaxoSmithKline, 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 supportGlaxoSmithKline
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline
    B.5.2Functional name of contact pointCentro de Información
    B.5.3 Address:
    B.5.3.1Street AddressC/Severo Ochoa, 2 (P.T.M.)
    B.5.3.2Town/ cityTres Cantos (Madrid)
    B.5.3.3Post code28760
    B.5.3.4CountrySpain
    B.5.4Telephone number34902202700
    B.5.5Fax number34918070479
    B.5.6E-mailes-ci@gsk.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDabrafenib
    D.3.2Product code GSK2118436
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Yes
    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.3.9.2Current sponsor codeGSK2118436
    D.3.9.3Other descriptive nameN-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDabrafenib
    D.3.2Product code GSK2118436
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Yes
    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.3.9.2Current sponsor codeGSK2118436
    D.3.9.3Other descriptive nameN-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 Tafinlar
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline Trading Services Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDabrafenib
    D.3.2Product code GSK2118436
    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.3.9.2Current sponsor codeGSK2118436
    D.3.9.3Other descriptive nameN-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt
    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: 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 Tafinlar
    D.2.1.1.2Name of the Marketing Authorisation holderGlaxoSmithKline Trading Services Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDabrafenib
    D.3.2Product code GSK2118436
    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.3.9.2Current sponsor codeGSK2118436
    D.3.9.3Other descriptive nameN-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt
    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: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDabrafenib
    D.3.2Product code GSK2118436
    D.3.4Pharmaceutical form Powder for oral suspension
    D.3.4.1Specific paediatric formulation Yes
    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.3.9.2Current sponsor codeGSK2118436
    D.3.9.3Other descriptive nameN-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Advanced solid tumors with BRAF V600 gene mutation
    Tumores sólidos avanzados con mutación BRAF V600.
    E.1.1.1Medical condition in easily understood language
    Advanced solid tumors with BRAF V600 gene mutation
    Tumores sólidos avanzados con mutación 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 17.0
    E.1.2Level PT
    E.1.2Classification code 10028980
    E.1.2Term Neoplasm
    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
    The Primary objective of the trial:

    To determine the safe and tolerable dabrafenib dose(s) for chronic dosing in pediatric subjects (infants, children, and adolescents) that achieves similar exposures to the dabrafenib adult dose,
    in subjects with BRAF V600 mutation positive tumors
    Determinar la seguridad y dosis tolerable de dabrafenib para la administración crónica en sujetos pediátricos (niños y adolescentes), que alcance exposiciones a dabrafenib similares a la dosis en adultos, en sujetos con tumores con mutación BRAF V600 positiva.
    E.2.2Secondary objectives of the trial
    The Secondary objective of the trial:

    ? To characterize the pharmacokinetics of dabrafenib, and its metabolites
    ? To characterize the longer term safety and tolerability of dabrafenib
    ? To assess any preliminary anti-tumor activity of dabrafenib
    ? To determine the effect of age and weight on the pharmacokinetics of
    dabrafenib using a population
    - Caracterizar la farmacocinética de dabrafenib y sus metabolitos
    - Caracterizar la seguridad a largo plazo y la tolerabilidad de dabrafenib
    - Evaluar cualquier actividad antitumoral preliminar de dabrafenib
    - Determinar el efecto de la edad y el peso sobre la farmacocinética de dabrafenib utilizando metodología de farmacocinética de población
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A subject will be eligible for inclusion in this study only if all of the following criteria apply:
    1. Written informed consent ? a signed informed consent and/or assent (as age appropriate) will be obtained according to institutional guidelines;
    2. Male or female >=12 months and <18 years of age at the time of signing the informed consent form:
    3. Recurrent, refractory disease or progressive disease after having received at least one standard therapy for their disease;
    NOTE: Subjects with metastatic (and surgically unresectable) melanoma can be enrolled for first-line treatment; Melanoma subjects with CNS involvement may be enrolled.
    4. At least one evaluable lesion;
    5. BRAF V600 mutation-positive tumor as confirmed in a CLIA-approved laboratory or equivalent (the local BRAF testing may be subject to subsequent verification by centralized testing; centralized testing can confirm V600E and V600K mutations only);
    6. Performance score of >=50% according to the Karnofsky/Lansky performance status scale [Yates, 1908] (Appendix 3);
    NOTE: Subjects with a performance status of <=50% can be enrolled if the subject's confinement to bed and inability to carry out activities is due solely to cancer-related pain, as assessed by the investigator.
    7. Females of child-bearing potential must be willing to practice acceptable methods of birth control (see Section 7.1). Additionally, females of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study medication;
    8. Must have adequate organ function as defined by the following values:
    Adequate bone marrow function defined as:
    - Absolute neutrophil count (ANC) ?1000/?L;
    - Hemoglobin >=8.0 g/dL (may receive red blood cell transfusions)
    - Platelets >=75,000/?L (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment
    Adequate renal and metabolic function defined as:
    - Calculated eGFR (Schwartz formula, http://www.medcalc.com/pedigfr.html), or radioisotope GFR ?90 mL/min/1.73m2; or
    - A serum creatinine within the institutional reference range upper limit of normal (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; AST/ALT may be <5 x ULN at baseline if liver metastases are present (requires radiographic confirmation of liver metastases)
    Adequate cardiac function defined as:
    - LVEF of either >=50% by ECHO or greater than institutional LLN by ECHO (while not receiving medications for cardiac function)
    - Corrected QT (QTcB) interval <450 msecs.
    1. Consentimiento informado por escrito - se debe obtener un consentimiento informado por escrito y/o asentimiento (según proceda para la edad) de acuerdo con la Legislación Local.
    2. Hombres o mujeres de edad >=12 meses y <18 años en el momento de la firma del consentimiento.
    3. Enfermedad recurrente, enfermedad refractaria o enfermedad progresiva después de haber recibido al menos un tratamiento estándar para su enfermedad.
    NOTA: Los sujetos con melanoma metastásico (y no resecable) pueden ser reclutados para tratamiento de primera línea; los sujetos con melanoma y afectación del SNC pueden ser reclutados.
    4. Al menos una lesión evaluable.
    5. Tumor con mutación BRAF V600 positiva confirmada en el laboratorio aprobado por CLIA o equivalente (el análisis BRAF local puede ser sometido a verificación posterior en un laboratorio centralizado; el análisis centralizado sólo puede confirmar mutaciones V600E y V600K).
    6. Puntuación del estado funcional >=50% en la escala de Karnofsky-Lansky [Yates, 1908] (Apéndice 3).
    NOTA: Los sujetos con un estado funcional <=50% pueden ser reclutados si el sujeto está encamado e incapacitado para realizar actividades sólo a causa del dolor relacionado con el cáncer, evaluado por el investigador.
    7. Las mujeres potencialmente fértiles deben ser capaces de utilizar métodos anticonceptivos aceptables (ver la Sección 7.1). Además, deben tener una prueba de embarazo en suero negativa en los 7 días anteriores a la primera dosis de medicación del estudio.
    8. Deben tener una función orgánica adecuada, definida por los siguientes valores:
    - Adecuada función de la médula ósea definida como:
    - Recuento absoluto de neutrófilos (RAN) >=1000 µL
    - Hemoglobina >=8 g/dL (pueden recibir transfusiones de hematíes)
    - Plaquetas >=75.000/µL (independiente de la transfusión, definido como no haber recibido transfusiones de plaquetas en un periodo de 7 días anterior al reclutamiento)
    9. Adecuada función renal y metabólica, definida como:
    - FG calculada (fórmula de Schwartz, http://www.medcalc.com/pedigfr.html) o FG por radioisótopos >=90 mL/min/1,73 m2; o
    - Creatinina sérica dentro del límite superior normal del rango de referencia del centro (para la edad/sexo, si está disponible).
    10. Adecuada función hepática, definida como:
    - Bilirrubina (conjugada + no conjugada) <=1,5 x límite superior normal (LSN) para la edad
    - AST y ALT <=2,5 x LSN; AST/ALT puede ser <5 x LSN en la evaluación basal si hay metástasis hepáticas (requiere confirmación radiográfica de las metástasis hepáticas).
    11. Adecuada función cardiaca, definida como:
    - FEVI >=50% mediante ECO o por encima del LIN del centro mediante ECO (sin estar recibiendo medicación para la función cardiaca)
    - Intervalo QT corregido (QTcB) <450 mseg.
    E.4Principal exclusion criteria
    A subject will not be eligible for inclusion in this study if any of the following criteria apply:
    1. Part 2 ONLY: Previous treatment with dabrafenib, another RAF inhibitor, or a MEK inhibitor (exception: prior treatment with sorafenib is permitted);
    2. Malignancy OTHER than the BRAF mutant malignancy under study
    3. Had chemotherapy or radiotherapy within 3 weeks (or 6 weeks for nitrosoureas or mitomycin C) prior to administration of the first dose of study treatment;
    4. The subject has received an investigational product within the following time period prior to the first dosing day in the current study: 28 days or 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is warranted by the data);
    5. History of another malignancy;
    Exception: (a) Subjects who have been successfully treated and are disease-free for 3 years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission, are eligible
    6. Current use of a prohibited medication (Section 8.2) or herbal preparation or requires any of these medications during the study;
    7. Unresolved toxicity greater than NCI CTCAE v4.0 [NCI, 2009] Grade 2 or higher from previous anti-cancer therapy except those that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profile of dabrafenib (e.g., alopecia and/or peripheral neuropathy related to platinum or vinca alkaloid based chemotherapy);
    8. Has leukaemia;
    9. History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib and its excipients;
    10. Autologous or allogeneic stem cell transplant within 3 months prior to enrolment
    [NOTE: subjects with evidence of active graph versus host disease are excluded];
    11. History of myocardial infarction, severe or unstable angina, peripheral vascular disease or familial QTc prolongation;
    12. Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram
    (NOTE: subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study);
    13. Moderate valvular thickening;
    14. Known, uncontrolled cardiac arrhythmias (except sinus arrhythmia) within the past 24 weeks;
    15. 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;
    16. 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. If clarification is needed as to whether a condition will significantly affect absorption of drugs, contact the GSK medical monitor;
    17. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus, or Hepatitis C Virus infection (subjects with laboratory evidence of Hepatitis B Virus clearance may be enrolled);
    18. Subjects with known G6PD deficiency;
    19. Pregnant females as determined by positive human chorionic gonadotropin (hCG) test at screening or prior to dosing;
    20. Lactating females who are actively breast feeding.
    1. SÓLO para la Parte 2: Tratamiento previo con dabrafenib, otro inhibidor RAF o un inhibidor MEK (excepción: el tratamiento previo con sorafenib está permitido).
    2. OTRO tumor maligno distinto del tumor con mutación BRAF en estudio.
    3. Haber recibido quimioterapia o radioterapia en las 3 semanas (o 6 semanas para las nitrosoureas o la mitomicina C) anteriores a la administración de la primera dosis del tratamiento del estudio.
    4. El sujeto ha recibido un producto en investigación en el siguiente periodo de tiempo anterior al primer día de tratamiento del estudio actual: 28 días o 5 semividas o el doble de la duración del efecto biológico del producto en investigación (lo que esté justificado por los datos).
    5. Historia de otro cáncer.
    Excepción: (a) Sujetos que hayan sido tratados con éxito y estén libres de enfermedad durante 3 años, (b) historia de carcinoma cutáneo distinto del melanoma completamente resecado, (c) carcinoma in situ tratado con éxito, o (d) LLC en remisión estable.
    6. Uso actual de medicación prohibida (Sección 8.2) o de productos herbales o que necesite cualquiera de estas medicaciones durante el estudio.
    7. Toxicidad no resuelta de Grado 2 o superior según los NCI CTCAE v4.0 [NCI, 2009] de una terapia antineoplásica previa excepto la que a juicio del investigador no sea clínicamente relevante dado el perfil de seguridad/toxicidad conocido de dabrafenib (ej., alopecia y/o neuropatía periférica relacionados con quimioterapia a base de platino o vinca alcaloides).
    8. Sujetos con leucemia.
    9. Historia de reacciones alérgicas atribuidas a compuestos de composición química o biológica similar a dabrafenib y sus excipientes.
    10. Trasplante de células madre autólogo o alogénico en los 3 meses anteriores al reclutamiento [NOTA: los sujetos con evidencia de injerto activo frente a la enfermedad del huésped están excluidos].
    11. Historia de infarto de miocardio, angina grave o inestable, enfermedad vascular periférica o prolongación de QTc familiar.
    12. Morfología valvular cardiaca anormal (>= grado 2) documentada mediante ecocardiograma (NOTA: los sujetos con anomalías de grado 1 [es decir, regurgitación/estenosis leve] pueden entrar en el estudio).
    13. Engrosamiento valvular moderado.
    14. Arritmias cardiacas no controladas conocidas (excepto la arritmia sinusal) en las últimas 24 semanas.
    15. Enfermedades no controladas (ej., diabetes mellitus, hipertensión, hepatopatía o infección no controlada), trastornos psicológicos, problemas familiares, sociológicos o geográficos que impiden el cumplimiento del protocolo; o sujetos que no están dispuestos o son incapaces de seguir los procedimientos del protocolo.
    16. Presencia de enfermedad GI activa u otras condiciones (ej., resección de intestino delgado o grueso) que interferirán significativamente con la absorción de los fármacos. Si se necesita aclaración de si una condición afectará significativamente a la absorción de los fármacos, contactar con el Monitor Médico de GSK.
    17. Historia conocida de infección por el virus de la inmunodeficiencia humana (VIH), virus de la hepatitis B o el virus de la hepatitis C (los sujetos con evidencia de laboratorio de eliminación del virus de la hepatitis B pueden ser reclutados).
    18. Sujetos con deficiencia conocida de G6PD.
    19. Mujeres embarazadas, determinado por una prueba de embarazo [gonadotropina corionica humana (hCG)] positiva en la selección o antes de la administración de la dosis.
    20. Mujeres en periodo de lactancia que estén amamantando a sus hijos.
    E.5 End points
    E.5.1Primary end point(s)
    Safety, including adverse events (AEs), serious adverse events (SAEs), electrocardiogram (ECG), echocardiograms (ECHO), changes in laboratory values and vital signs Pharmacokinetics, including Cmax, AUC(0-t) and AUC(0-?) of dabrafenib
    Seguridad: Acontecimientos adversos (AA); ECG, ECO, cambios en los valores de laboratorio y constantes vitales. Farmacocinética: Cmax, [AUC (0-t) y AUC (0-?) de dabrafenib.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety endpoints will be evaluated throughout a subject's participation in the study. Pharmacokinetic endpoints will be evaluated primarily over the first 15 days of treatment.
    Las variables de seguridad se evaluarán a lo largo de la participación del sujeto en el estudio. Las variables farmacocinéticas se evaluarán principalmente durante los primeros 15 días del tratamiento.
    E.5.2Secondary end point(s)
    Pharmacokinetics, including Ct (trough), Cmax, tmax and t½ of dabrafenib and its metabolites (GSK2285403, GSK2167542 and GSK2298683)

    Safety, including AEs; ECG; changes in laboratory values and vital signs

    Efficacy, including tumor response
    Farmacocinética: Ct (valle), AUC(0-t), AUC(0-tau), aclaramiento aparente tras la administración oral (CL/F) (sólo de dabrafenib), Cmax, tmax y t½ de dabrafenib y sus metabolitos (GSK2285403, GSK2167542 and GSK2298683), si procede.
    Seguridad: AA, ECG, cambios en los valores de laboratorio y constantes vitales.
    Eficacia: Respuesta tumoral.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety endpoints will be evaluated throughout a subject?s participation in the study. Pharmacokinetic endpoints will be evaluated primarily over the first 15 days of treatment.
    Las variables de seguridad y eficacia se evaluarán a lo largo de la participación del sujeto en el estudio. Las variables farmacocinéticas se evaluarán principalmente durante los primeros 15 días del tratamiento.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase I/IIa Study to Determine the Safety, Tolerability and Pharmacokinetics in Pediatric subjects
    E.7.2Therapeutic exploratory (Phase II) No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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
    Canada
    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
    Última visita del último paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months24
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months24
    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: 58
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 3
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 25
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 30
    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 No
    F.3.3.7Others No
    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 20
    F.4.2.2In the whole clinical trial 58
    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 study participation in the current study and for subjects still benefitting from treatment with dabrafenib, subjects will be given the option to transition to the rollover study (BRF114144), where subjects continue receiving GSK2118436 alone as specified in rollover study BRF114144, provided subjects are still benefiting from GSK2118436.
    Tras la participación en este estudio los sujetos que todavía se sigan beneficiando del tratamiento con dabrafenib tendrán la opción de pasar a un estudio de continuación (BRF114144) en el que recibirán GSK2118436 solo como se especifica en el estudio de continuación BRF114144, siempre que los sujetos se sigan beneficiando de GSK2118436.
    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 Decision2014-10-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-14
    P. End of Trial
    P.End of Trial StatusOngoing
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