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    Summary
    EudraCT Number:2012-001499-12
    Sponsor's Protocol Code Number:BRF116013
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-11-23
    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 ConcernedGermany - BfArM
    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 Children and Adolescent Subjects with Advanced BRAF V600-Mutation Positive Solid Tumors.
    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.
    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/260/2017
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services 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 Services AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Pharma GmbH
    B.5.2Functional name of contact pointMedizinischer Infoservice (MCC)
    B.5.3 Address:
    B.5.3.1Street AddressRoonstrasse 25
    B.5.3.2Town/ cityNürnberg
    B.5.3.3Post code90429
    B.5.3.4CountryGermany
    B.5.4Telephone number +49 911 273-12100 
    B.5.5Fax number +49 911 27312160
    B.5.6E-mailinfoservice.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 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 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.3.9.2Current sponsor codeDRB436
    D.3.9.3Other descriptive nameDABRAFENIB MESYLATE
    D.3.9.4EV Substance CodeSUB128623
    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 DRB436
    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 codeDRB436
    D.3.9.3Other descriptive nameDABRAFENIB MESYLATE
    D.3.9.4EV Substance CodeSUB128623
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 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 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.3.9.2Current sponsor codeDRB436
    D.3.9.3Other descriptive nameDABRAFENIB MESYLATE
    D.3.9.4EV Substance CodeSUB128623
    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: 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 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.3.1Product nameDabrafenib
    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.3.9.2Current sponsor codeDRB436
    D.3.9.3Other descriptive nameDABRAFENIB MESYLATE
    D.3.9.4EV Substance CodeSUB128623
    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: 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 Yes
    D.2.1.1.1Trade name Tafinlar
    D.2.1.1.2Name of the Marketing Authorisation holderEU/1/13/865/003 and EU/1/13/865/004
    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 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.3.9.2Current sponsor codeDRB436
    D.3.9.3Other descriptive nameDABRAFENIB MESYLATE
    D.3.9.4EV Substance CodeSUB128623
    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: 6
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 DRB436
    D.3.4Pharmaceutical form Dispersible tablet
    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 codeDRB436
    D.3.9.3Other descriptive nameDABRAFENIB MESYLATE
    D.3.9.4EV Substance CodeSUB128623
    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.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
    E.1.1.1Medical condition in easily understood language
    Advanced solid tumors with BRAF V600 gene mutation
    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 LLT
    E.1.2Classification code 10049280
    E.1.2Term Solid tumour
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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
    E.2.2Secondary objectives 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 pharmacokinetics approach
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    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 disease, 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;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 aceptable methods of birth control (see Section 7.1). Additionally, females of childbearing potential must have a negative serum pregnancytest within 7 days prior to the first dose of study medication. Sexually active males, who do not agree to abstinence, must be willing to use a condom during intercourse while taking the study drug, and for 16 weeks after stopping treatment and should not father a child in this period.
    8. Must have adequate organ function as defined by the following values:
     Adequate bone marrow function defined as:
     Absolute neutrophil count (ANC) ≥1000 /μL;
     Hemoglobin ≥8.0 g/dL (may receive red blood cell transfusions)
     Platelets ≥ 5,000/μL (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment
    9. Adequate renal and metabolic function defined as:
     Calculated eGFR (Schwartz formula, http://www.medcalc.com/pedigfr.html), or radioisotope GFR ≥90 mL/min/1.73 m2; or
     A serum creatinine within the institutional reference range upper limitof normal (for age/gender, if available);
    10. 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 ifdisease under treatment involves the liver (requires radiographic confirmation of liver involvement)
    11. 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.
    E.4Principal exclusion criteria
    1. Part 2 ONLY: Previous treatment with dabrafenib, another RAF inhibitor, or a MEK inhibitor (exception: prior treatment with sorafenib ispermitted);
    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 theinvestigational 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, or (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, including major surgery, 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 graft 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 orlarge 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 Novartis Medical Lead;
    17. Hepatitis B Virus, or Hepatitis C Virus infection (subjects with laboratory evidence of Hepatitis B Virus clearance may be enrolled);
    18. Pregnant females as determined by positive human chorionic gonadotropin (hCG) test at screening or prior to dosing;
    19. Lactating females who are actively breast feeding.
    E.5 End points
    E.5.1Primary end point(s)
    1.Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by number of subjects with adverse events (AEs)
    Safety and tolerability parameters will include recording of AEs, in Part 1 and Part 2 of the study.
    2.Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in ECG readings Safety and tolerability parameters will include the electrocardiogram (ECG) readings at Baseline and at end of Part 1 and Part 2 of the study.
    3.Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in ECHO findings Safety and tolerability parameters will include recording of
    echocardiogram (ECHO) at Baseline and at end of Part 1 and Part 2 of the study.
    4.Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in laboratory values Safety and tolerability parameters will include laboratory values at Baseline and at end of Part 1 and Part 2 of the study.
    5.Safety and tolerability of dabrafenib dose that achieves similar exposures to the dabrafenib adult dose as assessed by change from Baseline in vital signs Safety and tolerability parameters will include vital signs at Baseline and at end of Part 1 and Part 2 of the study.
    6.Maximum concentration (Cmax) of dabrafenib dose(s) To calculate the dabrafenib dose(s) for chronic dosing in pediatric subjects (infants, children, and adolescents), the Cmax of dabrafenib that achieves similar exposure to the dabrafenib adult dose will be evaluated.
    7.Area under the concentration-time curve over the dosing interval (AUC(0-τ)) and AUC from zero to infinity (AUC(0-inf)) of dabrafenib dose(s)
    To calculate the dabrafenib dose(s) for chronic dosing in pediatric subjects (infants, children, and adolescents) the AUC(0-τ) and AUC(0- inf) of dabrafenib that achieves similar exposure to the dabrafenib adult dose will be evaluated.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1-5. : Up to 6 months
    6-7. Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0,
    0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
    E.5.2Secondary end point(s)
    1. Pre-dose (trough) concentration (Ctau)
    2. The AUC(0-t) and AUC(0-tau) of dabrafenib and its metabolites. Pharmacokinetic data will include area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC[0-t]), AUC(0-tau) of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
    3. Apparent clearance following oral dosing (CL/F) (dabrafenib only)
    4. Cmax of dabrafenib, and its metabolites Pharmacokinetic data will include Cmax of dabrafenib and its
    metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
    5.Time from administration to Cmax (tmax) of dabrafenib and its metabolites. Pharmacokinetic data will include tmax of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib
    [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
    6.Elimination half life (t½) of dabrafenib and its metabolites . Pharmacokinetic data will include t½ of dabrafenib and its metabolites (hydroxy-dabrafenib [GSK2285403], carboxy-dabrafenib [GSK2298683], and desmethyl-dabrafenib [GSK2167542]).
    7.Longer term safety and tolerability of dabrafenib as assessed by number of subjects with AEs. Safety and tolerability parameters will include recording of AEs, in Part 1 and Part 2 of the study.
    8.Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in ECG readings. Safety and tolerability parameters will include the electrocardiogram (ECG) readings at Baseline and at end
    of Part 1 and Part 2 of the study
    9.Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in laboratory values. Safety and tolerability parameters will include laboratory values at Baseline and at end of Part 1 and Part 2 of the study.
    10.Longer term safety and tolerability of dabrafenib as assessed by change from Baseline in vital signs. Safety and tolerability parameters will include vital signs at Baseline and at end of Part 1 and Part 2 of the study.
    11.Overall tumor response of dabrafenib . Anti-tumor activity will be assessed based on clinical evidence and the response evaluation criteria in solid tumors (RECIST) version 1.1 criteria for solid tumors, response assessment in neuro-oncology (RANO) criteria (glioma subjects) and langerhans cell histiocytosis (LCH) scoring system.
    12.Effect of age and weight on CL/F of dabrafenib. The CL/F data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
    13.Effect of age and weight on volume of distribution (V/F) of dabrafenib. The V/F data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
    14.Effect of age and weight on absorption rate (ka) of dabrafenib. The ka data with the effect of age and weight using a population pharmacokinetic approach will be evaluated.
    15.Effect of age and weight on coefficients for significant covariates of dabrafenib . The coefficients for significant covariates data with the effect of age and weight using a population pharmacokinetic approach
    will be evaluated.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Day 1-Predose, Day 15-Predose
    2-6. Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose.
    7-11. Up to 6 months
    12-15. Day 1-Predose, 0.5, 2 and 4 hours post dose; Day 15-Predose, 0, 0.5, 1, 2, 3, 4, 6 and 8 hours post dose
    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 Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) 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
    Study to Determine the Safety, Tolerability and Pharmacokinetics
    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 EEA14
    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
    Australia
    Canada
    Denmark
    France
    Germany
    Israel
    Italy
    Spain
    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
    The study will be considered completed when the last subject enrolled (without disease progression or withdraw from the study for another reason) has been in the study for a minimum of 6 months AND, for
    those subjects still benefiting from treatment, the rollover protocol is open to enroll pediatric subjects.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days6
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days6
    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: 85
    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: 6
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 35
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 44
    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
    This is a pediatric population less than 18 years of age at consent, Parent or LAR provides consent, and subjects (depending on local law) provide assent based on age and cognitive ability
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 38
    F.4.2.2In the whole clinical trial 83
    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 and for subjects still benefitting from treatment with dabrafenib, subjects will be given the option to transition to the rollover study, where subjects continue receiving dabrafenib alone as specified in rollover study, provided subjects are still benefiting from dabrafenib.

    Subjects who are no longer receiving dabrafenib will be offered Follow- Up from Novartis consisting of a visit every 3 months (±15 days) for a period of 2 years.
    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 Decision2015-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-09
    P. End of Trial
    P.End of Trial StatusOngoing
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