Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   36401   clinical trials with a EudraCT protocol, of which   5997   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2013-003596-35
    Sponsor's Protocol Code Number:MEK116540
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-07-08
    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 ConcernedUK - MHRA
    A.2EudraCT number2013-003596-35
    A.3Full title of the trial
    An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the MEK Inhibitor Trametinib in Children and Adolescents Subjects with Cancer or Plexiform Neurofibromas and Trametinib in Combination with Dabrafenib in Children and Adolescents with Cancers Harboring V600 mutation.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Test Trametinib and dabrafenib in Children and Adolescents Subjects with Cancer
    A.4.1Sponsor's protocol code numberMEK116540
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/259/2017
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma 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 Pharmaceuticals UK Limited
    B.5.2Functional name of contact pointMedica Information Services
    B.5.3 Address:
    B.5.3.1Street Address200 Frimley Business Park
    B.5.3.2Town/ cityFrimley, Camberley
    B.5.3.3Post codeGU16 7SR
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 1276 698370
    B.5.6E-mailmedinfo.uk@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 nameTrametinib
    D.3.2Product code TMT212
    D.3.4Pharmaceutical form Film-coated 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 INNtrametinib
    D.3.9.2Current sponsor codeTMT212
    D.3.9.3Other descriptive nameTRAMETINIB DIMETHYL SULFOXIDE
    D.3.9.4EV Substance CodeSUB167251
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.125
    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 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.3.1Product nameTrametinib
    D.3.2Product code TMT212
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtrametinib
    D.3.9.2Current sponsor codeTMT212
    D.3.9.3Other descriptive nameTRAMETINIB DIMETHYL SULFOXIDE
    D.3.9.4EV Substance CodeSUB167251
    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: 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.3.1Product nameTrametinib
    D.3.2Product code TMT212
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNtrametinib
    D.3.9.2Current sponsor codeTMT212
    D.3.9.3Other descriptive nameTRAMETINIB DIMETHYL SULFOXIDE
    D.3.9.4EV Substance CodeSUB167251
    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: 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 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 nameTrametinib
    D.3.2Product code TMT212
    D.3.4Pharmaceutical form Powder for oral solution
    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 INNtrametinib
    D.3.9.2Current sponsor codeTMT212
    D.3.9.3Other descriptive nameTRAMETINIB DIMETHYL SULFOXIDE
    D.3.9.4EV Substance CodeSUB167251
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.05
    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 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: 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 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 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: 7
    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: 8
    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
    Children and Adolescents with Cancers Harboring V600 mutations
    E.1.1.1Medical condition in easily understood language
    Children and Adolescents with Cancers Harboring V600 mutations
    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 10029260
    E.1.2Term Neuroblastoma
    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
    To determine the safe and tolerable trametinib dose(s) for chronic continuous daily dosing in pediatric subjects (infants, children, and adolescents) that achieves similar exposures (trough concentration [Ct]) to the recommended adult dose.
    E.2.2Secondary objectives of the trial
    - To characterize the pharmacokinetics of trametinib
    - To characterize the safety and tolerability of trametinib
    - To assess any preliminary anti-tumor activity of trametinib
    - To determine the effect of covariates such as age and weight on the pharmacokinetics of trametinib using a population pharmacokinetics approach
    -To characterize the pharmacokinetics of trametinib and dabrafenib when administered in combination
    -To characterize the safety and tolerability of trametinib and dabrafenib when administered in combination
    - To determine the safe and tolerable dabrafenib dose(s) when administered in combination with the recommended trametinib dose for chronic continuous daily dosing in pediatric subjects (infants, children, and adolescents) that achieves similar exposures (trough concentration) to the recommended adult dose
    - To assess any preliminary anti-tumor activity of trametinib in combination with dabrafenib
    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) for study participation including pharmacokinetics sampling will be obtained according to institutional guidelines;

    2. Male or female between one month and < 18 years of age (inclusive) at the time of signing the informed consent form

    3. Part C and Part D subjects between 12 months and < 18 years of age, inclusive

    4. Part A subjects < 2 years of age will not be included in the initial dose escalation

    5. Must have a disease that is relapsed/refractory to all potentially curative standard treatment regimens or must have a current disease for which there is no known curative therapy, or therapy proven to prolong survival with an acceptable quality of life.

    6. Prior therapy: The subject’s disease (i.e. cancer, NF-1 with PN, or LCH) must have relapsed after or failed to respond to frontline curative therapy or there must not be other potentially curative treatment options available. Curative therapy may include surgery, radiation therapy, chemotherapy, or any combination of these modalities. Subjects must have recovered to grade ≤1 from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment.

    7. Performance score of ≥50% according to the Karnofsky / Lansky performance status scale.

    8. 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 start of study drugs;
    9. In France, subjects will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
    10.10. Must have adequate multi organ function as defined by the following
    values: renal function - 24 hr creatinine clearance (revised Schwartz
    formula), or radioisotope glomerular filtration rate (GFR) >=60 milliliter
    (mL) per minute per 1.73 meter square (mL/min/1.73m^2); or a serum
    creatinine <=upper limit of normal (ULN) for age and gender; liver
    functions as bilirubin (sum of conjugated + unconjugated) <=1.5 x ULN
    for age, alanine aminotransferase (ALT) <=2.5 x ULN; for the purposes
    of enrollment and toxicity monitoring the ULN for ALT will be 45 unit per
    liter (U/L); cardiac function - corrected QT (QTcB) interval <480
    milliseconds (msec), left ventricular ejection fraction (LVEF) >=lower
    limit of normal (LLN) by ECHO.
    •Able to swallow and retain enterally (per oral [PO] or nasogastric or
    gastric tube) administered medication and does not have any clinically
    significant gastrointestinal abnormalities that may alter absorption such
    as malabsorption syndrome or major resection of the stomach or bowels.
    •Adequate Blood Pressure Control defined as: Blood pressure <= the
    95th percentile for age, height, and gender.
    Other protocol-defined inclusion criteria, including some for each part,
    may apply
    E.4Principal exclusion criteria
    1. Lactating or pregnant female.

    2. History of another malignancy including resected non-melanomatous skin cancer

    3. Subjects with Neurofibromatosis Type-1 (NF-1) associated optic pathway tumors are excluded if they are actively receiving therapy for the optic pathway tumor or do not meet criteria for Plexiform Neurofibroma or malignant solid tumor

    4. Subjects with a history of NF-1 related cerebral vascular anomaly (such as Moyamoya)

    5. Subjects with NF-1 actively receiving therapy for the optic pathway tumour

    6. Subjects with NF-1 and only Plexiform Neurofibroma (PN) lesions that cannot be evaluated by volumetric analysis

    7. Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject’s safety, obtaining informed consent or compliance to the study procedures

    8. Any prohibited medication(s) as described in Section 9.2.

    9. Any medications for treatment of left ventricular systolic dysfunction

    10. Part B cohorts 1, 2 and 3: Previous treatment with dabrafenib, trametinib or another MEK inhibitor (exception: prior treatment with sorafenib is permitted).
    Patients who have had prior dabrafenib therapy may enroll into cohort B4.
    Patients who have had prior dabrafenib therapy and had benefit from that therapy as determined by the investigator, are allowed in Part C or Part D

    11. Administration of an investigational study treatment within 30 days preceding the first dose of study treatment(s) in this study

    12. Have a known hypersensitivity reaction or idiosyncrasy to drugs chemically related to study treatment or excipients that contraindicate their participation

    13. Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, or liver metastases)

    14. History of hepatic sinusoid obstructive syndrome (Venoocculsive disease) within the prior 3 months

    15. History of heparin-induced thrombocytopenia

    16. History of interstitial lung disease or pneumonitis

    17. History or current evidence of retinal vein occlusion (RVO)

    18. For subjects with solid tumors that are not primary central nervous system (CNS) tumors or NF-1 associated plexiform neurofibromas, subjects with symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression are excluded

    19. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection

    20. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events Grade 2 or higher from previous anti-cancer therapy, except alopecia

    21. Presence of active gastrointestinal disease or other condition 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 Medical Lead for guidance to enrol the subject

    22. A history or evidence of cardiovascular risk including: a QT interval
    corrected for heart rate using the Bazett's formula (QTcB) >=480 msec;
    a history or evidence of current clinically significant uncontrolled
    arrhythmias (clarification: Subjects with atrial fibrillation controlled for
    >30 days prior to dosing are eligible); a history of acute coronary
    syndromes (including myocardial infarction or unstable angina),
    coronary angioplasty, or stenting within 6 months prior to
    randomization; a history or evidence of current >=Class II congestive
    heart failure as defined by the New York Heart Association (NYHA)
    guidelines; subjects with intra-cardiac defibrillators; abnormal cardiac
    valve morphology (>=grade 2) documented by echocardiogram
    (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]
    can be entered on study). Subjects with moderate valvular thickening
    should not be entered on study. Subjects with prosthetic valves can be
    considered eligible provided they meet the criteria as stated above;
    Treatment refractory hypertension defined as a blood pressure of
    systolic >140 millimeter of mercury (mmHg) and/or diastolic >90 mmHg
    (or above 95th age-specific percentile listed in protocol), which cannot
    be controlled by anti-hypertensive therapy.
    E.5 End points
    E.5.1Primary end point(s)
    1.Safety Assessment of trametinib as assessed by Adverse Events (AEs)
    2.Safety Assessment of trametinib as assessed by electrocardiogram
    (ECG). Single 12-lead ECGs will be obtained to assess safety
    3.Safety Assessment of trametinib as assessed by echocardiogram
    (ECHO) ECHOs will be performed to assess cardiac ejection fraction and
    cardiac valve morphology
    4.Safety Assessment of trametinib as assessed by changes in laboratory
    values. Laboratory assessments will include Hematology, Clinical
    Chemistry, Routine Urinalysis and Other screening tests
    5.Safety Assessment of trametinib assessed by changes in vital signs
    Vital sign measurements will include systolic and diastolic blood
    pressure, temperature, respiration rate and pulse rate
    6.To determine the dose of trametinib that achieves similar exposures
    (Ctau) to the recommended adult dose
    E.5.1.1Timepoint(s) of evaluation of this end point
    1-5. From screening up to 63 months .
    6. Days 15 and 22
    E.5.2Secondary end point(s)
    1.PK Assessment of trametinib parameters including Ctau (trough
    concentration), area under the concentration-time curve over a period of
    time (AUC [0-t]), area under the concentration-time curve over the
    dosing interval (AUC [0-tau]), apparent clearance following oral dosing
    (CL/F), maximum observed concentration (Cmax), Time of occurrence of
    Cmax (tmax) and half-life (t1/2) of trametinib.
    2.Safety and tolerability assessments for trametinib for AEs
    3.Safety and tolerability assessments for trametinib for ECG.
    12-lead ECGs will be performed to assess safety and tolerability
    4.Safety and tolerability assessments for trametinib for changes in
    laboratory values. Laboratory parameter including chemistry and
    hematology
    5.Safety and tolerability assessments for trametinib for vital signs.
    Vital sign measurements will include systolic and diastolic blood
    pressure, temperature, respiration rate and pulse rate
    6.Tumor response for trametinib. Disease assessments will be conducted
    and utilize disease specific response criteria (e.g. RECIST, RANO)
    7.Effect of age and weight on the PK of trametinib. PK parameter will
    include CL/F, volume of distribution (V/F), absorption rate (ka), and
    coefficients for significant covariates
    8.PK assessment of trametinib and dabrafenib when administered in
    combination. PK parameters include Ctau, AUC (0-t), AUC (0-tau), CL/F,
    Cmax, tmax, and Cavg
    9.Palatability of trametinib and/or dabrafenib in pediatric subjects
    assessed by palatability questionnaire.
    To be completed after the first dose of study drug and no later than Day
    8 (+/-3 days). Subjects will complete a form to evaluate the various
    properties of the suspension (e.g., bitterness, sweetness, appearance,
    texture and overall taste).
    10.Safety Assessment of trametinib and dabrafenib when administered
    in combination as assessed by Adverse Events (AEs)
    11.Safety Assessment of trametinib and dabrafenib when administered
    in combination as assessed by ECGs. 12-lead ECGs will be performed to
    assess safety and tolerability
    12.Safety Assessment of trametinib and dabrafenib when administered
    in combination as assessed by Echo.
    13.Safety Assessment of trametinib and dabrafenib when administered
    in combination as assessed by changes in laboratory values. Laboratory
    parameter including chemistry, hematology and urinalysis.
    14.Safety Assessment of trametinib and dabrafenib when administered
    in combination as assessed by changes in vital sign values. Vital sign
    measurements will include systolic and diastolic blood pressure,
    temperature, respiration rate and pulse rate
    15.Safe and tolerable doses of dabrafenib when administered with
    trametinib for chronic continuous daily dosing in pediatric subjects as
    assessed by AEs.
    16.Safe and tolerable doses of dabrafenib when administered with
    trametinib for chronic continuous daily dosing in pediatric subjects as
    assessed by ECGs. 12-lead ECGs will be performed to assess safety and
    tolerability
    17.Safe and tolerable doses of dabrafenib when administered with
    trametinib for chronic continuous daily dosing in pediatric subjects as
    assessed by Echo.
    18.Safe and tolerable doses of dabrafenib when administered with
    trametinib for chronic continuous daily dosing in pediatric subjects as
    assessed by changes in lab values. Laboratory parameter including
    chemistry, hematology and urinalysis.
    19.Safe and tolerable doses of dabrafenib when administered with
    trametinib for chronic continuous daily dosing in pediatric subjects as
    assessed by changes in vital sings.
    Vital sign measurements will include systolic and diastolic blood
    pressure, temperature, respiration rate and pulse rate.
    20.Safe and tolerable doses of dabrafenib when administered with
    trametinib for chronic continuous daily dosing in pediatric subjects as
    assessed by steady state Ctau of trametinib and by steady state AUC (0-
    12) of dabrafenib
    21.Tumor response for trametinib in combination with dabrafenib.
    Disease assessments will be conducted and utilize disease specific
    response criteria (e.g. RECIST, RANO)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Day 15 and Day 22
    2-6. From screening up to 63 months
    7. Day 15 and Day 22
    8. Day 1, Day 15 and Day 22 of Part C and Part D
    9. Day 8
    10-19. From screening up to 63 months
    20. Day 15 and Day 22 of Part C and Part D
    21. From screening up to 63 months
    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 Yes
    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
    Paediatric
    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 Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Trametinib in Combination with Dabrafenib
    E.8.2.4Number of treatment arms in the trial4
    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
    Australia
    Canada
    France
    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 years5
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months8
    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: 145
    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: 15
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 39
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 91
    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
    Male or female between one month and < 18 years of age (inclusive) at the time of signing the informed consent form for study participation including pharmacokinetics sampling will be obtained according to institutional guidelines.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 145
    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)
    The investigator is responsible for ensuring that consideration has been given for the post-study care of the subject’s medical condition whether or not GSK is providing specific post-study treatment.

    For full details of post trial treatment, please refer to Section 6.6 Treatment after the End of the Study in the protocol (pages 80-81).
    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 Decision2014-08-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-15
    P. End of Trial
    P.End of Trial StatusOngoing
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA