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    Summary
    EudraCT Number:2019-001317-16
    Sponsor's Protocol Code Number:TRAIN_2019
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-10-16
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2019-001317-16
    A.3Full title of the trial
    The TRAIN study: TRAmetinib In Neurofibromatosis type 1 related symptomatic plexiform neurofibromas
    De TRAIN studie: TRAmetinib voor Neurofibromatose type 1 gerelateerde pleximorme neurofibromen
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The TRAIN study: TRAmetinib In Neurofibromatosis type 1 related symptomatic plexiform neurofibromas
    De TRAIN studie: TRAmetinib voor Neurofibromatose type 1 gerelateerde pleximorme neurofibromen
    A.3.2Name or abbreviated title of the trial where available
    TRAIN study: Trametinib in NF1-PNF
    TRAIN studie: Trametinib bij NF1-PNF
    A.4.1Sponsor's protocol code numberTRAIN_2019
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorErasmusMC
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportStichting NF
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportNovartis
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus MC
    B.5.2Functional name of contact pointClinical trial information
    B.5.3 Address:
    B.5.3.1Street AddressDr. Molewaterplein 40
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015GD
    B.5.3.4CountryNetherlands
    B.5.6E-mailw.taal@erasmusmc.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Mekinist
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    Adult patients (age >17 years) with (mosaic) NF1 with inoperable symptomatic plexiform neurofibromas
    E.1.1.1Medical condition in easily understood language
    Adult patients (age >17 years) with (mosaic) NF1 with inoperable symptomatic plexiform neurofibromas
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10029267
    E.1.2Term Neurofibroma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10029270
    E.1.2Term Neurofibromatosis, type 1 (von Recklinghausen's disease)
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Response to trametinib treatment defined as a tumor volume decreases from baseline of ≥20%, monitored by using volumetric MRI analysis
    E.2.2Secondary objectives of the trial
    Patient reported outcomes of pain and disability and quality of life
    The effect of trametinib on disfigurement
    Safety and tolerability of trametinib
    The duration of response
    The incidence of surgical interventions
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patient with (mosaic) NF1
    2. Patients with a clinically significant symptomatic plexiform neurofibroma (PNF), such as (but not limited to) head and neck lesions that could compromise the airway or great vessels, brachial or lumbar plexus lesions that could cause nerve compression and loss of function, lesions that could result in major deformity (e.g., orbital lesions) or are significantly disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and painful lesions. This will be determined by the treating physician.
    3. Signed, written informed consent
    4. Age: 18 or higher
    5. Karnofsky performance level of ≥70%
    6. No standard treatment options = inoperable PNF
    PNF that cannot be surgically completely removed without risk for substantial morbidity due to invasiveness, high vascularity or encasement of, or close proximity to, vital structures of the PNF.
    7. At least one measurable PNF, defined as a well-demarcated lesion of at least 3 cm measured in one dimension.
    8. Able to swallow and retain orally administered medication.
    9. Female Subjects of Childbearing Potential must have negative pregnancy test within 7 days prior study treatment and agrees to use highly effective contraception
    10. Normal hematological function: Hemoglobin (Hb)≥6 mmol/l, absolute neutrophil count (ANC)≥1.5x109/l, and platelets≥100x109/l
    11. Normal hepatic function: bilirubin <1.5x the upper limit of normal (UNL), unless gilbert then: bilirubin <3xUNL and AST/ALT <5xUNL
    12. Normal renal function: creatinine <1.5xUNL
    E.4Principal exclusion criteria
    1. Prior treatment with MEK inhibitor(s)
    2. Inability to undergo MRI and/or contraindication for MRI examinations
    3. History of a malignancy within 5 years of inclusion, except squamous cell carcinoma of the skin, cervical premalignant lesions and other curatively treated malignancy
    4. Prior radiotherapy less than 6 weeks prior to enrollment
    5. Prior major surgery less than 4 weeks prior to enrollment
    6. An investigational agent within the past 30 days.
    7. Enzyme-inducing anticonvulsants, anti-coagulants (including platelet aggregation inhibitors) or other prohibited medication(s) or requirement for prohibited medications
    8. Left ventricular dysfunction, New York Heart Association Class II, III, or IV heart failure, acute coronary syndrome within the past 6 months, clinically significant uncontrolled arrhythmias, and uncontrolled hypertension.
    9. A history of retinal vein occlusion (RVO) or predisposing factors for RVO, including uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes
    10. Risk factors for gastrointestinal perforation, including history of diverticulitis, metastases to the gastrointestinal tract and concomitant use of medications with a recognized risk of gastrointestinal perforation
    11. Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses, or renal transplant, including any patient known to have hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) will be excluded.
    12. Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
    13. Any serious and/or unstable pre-existing medical disorder, psychiatric disorder, or other conditions that could interfere with subject’s safety
    14. Known severe hypersensitivity to trametinib or any excipient of trametinib or history of allergic reactions attributed to compounds of similar chemical or biologic composition to trametinib
    15. Pregnant, lactating or actively breastfeeding female subjects
    E.5 End points
    E.5.1Primary end point(s)
    Response evaluation will be based on up to three selected most clinically relevant PN which will be followed by volumetric MRI analysis. Response is assessed at the time of follow-up MRI scans which are performed every 24 weeks. For the purpose of determining the level of response, measurements from the follow-up scans are compared to the tumor size in the pretreatment MRI scan using volumetric data analysis.
    • Objective Response (OR): A ≥20% reduction in the sum of the volume of all index lesions
    • Stable Disease (SD): A <20% increase and <20% reduction in the sum of the volume of all index lesions.
    • Progressive Disease (PD): A ≥20% increase in the volume of at least one of the index PN compared to the pretreatment volume measured prior to the start of the current treatment phase. The appearance of new discrete subcutaneous neurofibromas does not qualify for disease progression. Worsening of existing symptoms or the appearance of new symptoms that persist for more than 7 days and that are felt to be definitely related to the PN should be evaluated by repeating the MRI.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Response is assessed at the time of follow-up MRI scans which are performed every 24 weeks.
    E.5.2Secondary end point(s)
    NF1 patients with PNF derive clinical benefit from trametinib treatment:
    • Patient reported outcomes of pain and disability and quality of life:
    o Numeric (pain) rating scale (NRS)
    o Pain Interference (PROMIS)
    o QLQ – SF36
    • Regular photos will be taken every 24 weeks to judge the effect of trametinib on disfigurement.
    • Adverse events reporting according to CTCAEv5.0
    • Time to first significant progression defined as >20% volumetric growth of the index lesion(s)
    • Incidence of surgical interventions
    E.5.2.1Timepoint(s) of evaluation of this end point
    Every 24 weeks.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state30
    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)
    None
    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 Decision2019-10-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-30
    P. End of Trial
    P.End of Trial StatusOngoing
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