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    Summary
    EudraCT Number:2016-000847-16
    Sponsor's Protocol Code Number:D1532C00057
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-01-29
    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
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2016-000847-16
    A.3Full title of the trial
    A Phase 1/2 Study of the Mitogen Activated Protein Kinase Kinase(MEK) 1 Inhibitor Selumetinib (AZD6244, ARRY-142886, Hydrogen Sulfate) in Children With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas (PN)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase I/II trial of selumetinib with neurofibromatosis 1
    A.3.2Name or abbreviated title of the trial where available
    Selumetinib for children with Nervous System Tumors
    A.4.1Sponsor's protocol code numberD1532C00057
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01362803
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/137/2016
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNational Cancer Institute, Cancer Therapy Evaluation Program
    B.1.3.4CountryUnited States
    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 supportNIH
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportAstraZeneca
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNational Cancer Institute
    B.5.2Functional name of contact pointBrigitte Widemann
    B.5.3 Address:
    B.5.3.1Street Address9000 Rockville Pike
    B.5.3.2Town/ cityRockville
    B.5.3.3Post code20892
    B.5.3.4CountryUnited States
    B.5.4Telephone number001301 496-7387
    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 nameselumetinib
    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 INNselumetinib Hydrogen sulfate
    D.3.9.1CAS number 943332-08-9
    D.3.9.2Current sponsor codeAZD6244 Hydrogen Sulfate
    D.3.9.3Other descriptive nameAZD6244 Hyd-Sulfate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 25
    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 nameAZD6244 white 10 mg capsule
    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 INNselumetinib Hydrogen Sulfate
    D.3.9.1CAS number 943332-08-9
    D.3.9.2Current sponsor codeAZD6244 Hydrogren Sulfate
    D.3.9.3Other descriptive nameSELUMETINIB SULFATE
    D.3.9.4EV Substance CodeSUB36237
    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
    Neurofibromatosis type 1 (NF1)
    E.1.1.1Medical condition in easily understood language
    NF1
    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 10029267
    E.1.2Term Neurofibroma
    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
    Determine the maximum tolerated dose and extended tolerability. (Phase I)

    Evaluate the confirmed partial and complete response rate using volumetric MRI analysis in children and young adults with NF1 and inoperable PN with PN related morbidity at the time of enrollment (Phase II)
    E.2.2Secondary objectives of the trial
    Phase I
    •Determine effect of growth rate on PN
    •Study PK
    •Measure adherence of chronic dosing
    •Define toxicities
    Phase II
    •Evaluate response rate of all patients, and those with “typical PN” versus “nodular PN” versus “solitary nodular PN”
    •Determine long-term tolerability and safety
    •Determine duration of response
    •Evaluate effect on bone mineral density
    •Characterize effect on pain, quality of life, and physical functioning.
    •Determine baseline functional impairments secondary to PN, and effect on function
    •Determine effect on PN growth rate based on volumetric analysis of MRI studies
    •Determine TPP free survival in progressive PN, and compare PFS to placebo arm of the R115777 randomized trial
    •Determine day1 and steady state PK
    •Evaluate bone marrow derived precursor cells and cytokines pre- and post- treatment
    •Evaluate effect on changes in the size of optic pathway tumors or other gliomas
    •Evaluate effect on ERK phosphorylation in PBMC
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age Phase I: greater than 3 years and less than or equal to 18 years at the time of study enrollment.
    Age Phase II: greater than 2 years of age and less than or equal to 18 years of age. BSA greater than or equal to 0.55 m2.
    2.Diagnosis: Patients with NF1 and inoperable PN, defined as PN that cannot be surgically completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. In addition to PN, all study subjects must have either positive genetic testing for NF1 or have at least one other diagnostic criterion for NF1 listed below:
    - Six or more cafe-au-lait macules (greater than or equal to 0.5cm in prepubertal subjects or greater than or equal to 1.5 cm in post pubertal subjects)
    - Freckling in axilla or groin
    - Optic glioma
    - Two or more Lisch nodules
    - A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)
    - A first-degree relative with NF1
    3.Measurable disease: Patients must have at least one measurable PN, defined as a lesion of at least 3 cm measured in one dimension. Patients who underwent surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable as per criteria above.
    4.Prior Therapy: Patients with NF1 will only be eligible if complete tumor resection is not considered to be feasible without substantial risk or morbidity, or if a patient with a surgical option refuses surgery.
    5.Performance status: Patients greater than or equal to 16 years of age must have a Karnofsky performance level of greater than or equal to70%, and children < 16 years old must have a Lansky performance of greater than or equal to 70%.
    6.Normal Hematologic, Hepatic, Renal and Cardiac Function
    7.Informed Consent: written informed consent from all patients or their legal guardians (if the patient is < 18 years old).
    8. Durable Power of Attorney (DPA): All patients greater than or equal to 18 years of age will be offered the opportunity to assign DPA so that another person can make decisions about their medical care if they become incapacitated or cognitively impaired.

    E.4Principal exclusion criteria
    1. Pregnant or breast-feeding females are excluded due to potential risks of fetal and teratogenic adverse events of an investigational agent. Pregnancy tests must be obtained prior to enrollment on this study in girls, age 9 or older. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Abstinence is an acceptable method of birth control.
    2.Phase I: Patients who anticipate the need for surgical intervention within the first three cycles (3 months), as surgical intervention during the period of DLT evaluation may affect analysis of adherence and/or make the subject inevaluable.
    3.An investigational agent within the past 30 days.
    4.Ongoing radiation therapy, chemotherapy, hormonal therapy directed at the tumor, immunotherapy, or biologic therapy.
    5.Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses, or renal transplant, including any patient known to have hepatitis C, or human immunodeficiency virus (HIV) will be excluded. Patients with HIV who have adequate CD4 count, not requiring antiretroviral medication, may be enrolled.
    6.Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
    7.Inability to swallow capsules, since capsules cannot be crushed or broken.
    8.Inability to undergo MRI and/or contraindication for MRI examinations following the MRI protocol. Prosthesis or orthopedic or dental braces that would interfere with volumetric analysis of target PN on MRI.
    9.Refractory nausea and vomiting, chronic grastointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
    10.Prior treatment with selumetinib or another specific MEK1/2 inhibitor (unless the subject meets criteria for re-treatment.
    11. Evidence of an optic glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancer requiring treatment with chemotherapy or radiation therapy.
    12. Supplementation with vitamin E greater than 100% of the daily recommended dose.
    13. Patients not acheiveing adequate blood pressure in spite of antihypertensive therapy for control of blood pressure.
    14. Cardiac Function: a) known inherited coronary disease, b) Symptomatic heart failure (NYHA Class II-IV prior or current cardiomyopathy, or severe valvular heart disease), c) Prior or current cardiomyopathy, d) Sever valvular heart disease, 3) History of atrial fibrillation
    15. Ophthalmologic conditions: 1.Current or past history of central serous retinopathy; 2.Current or past history of retinal vein occlusion; 3.Known intraocular pression (IOP) greater than 21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of IOP); patients with controlled glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) may be eligible after discussion with the study chair. 4.Subjects with any other significant abnormality on ophthalmic examination (performed by an ophthalmologist) should be discussed with the Study Chair for potential eligibility. 5.Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study

    E.5 End points
    E.5.1Primary end point(s)
    Phase I: Maximum tolerated dose and extended tolerability assessed from adverse event reports
    Phase I: Plasma pharmacokinetic parameters
    Phase II: Confirmed response rate using volumetric analysis
    E.5.1.1Timepoint(s) of evaluation of this end point
    Maximum tolerated dose and extended tolerability evaluated over 3 cycles (1 cycle = 28 days)
    Pharmacokinetics in cycles 1-3
    Volumetric analysis conducted at regular intervals
    E.5.2Secondary end point(s)
    Phase I: Growth rate of PN using volumetric analysis
    Phase I and II: Long-term tolerability and safety
    Phase II: Duration of response
    Phase II: Effects on pain, quality of life and physical functioning
    Phase II: Pharmacodynamic effects
    E.5.2.1Timepoint(s) of evaluation of this end point
    Volumetric analysis conducted at regular intervals
    Long-term tolerability and safety for up to 7 years
    Functional and quality of life assessments conducted at regular intervals
    Blood samples for pharmacodynamic biomarkers in cycles 1-3
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic 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 Yes
    E.6.13.1Other scope of the trial description
    Phase I/II
    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/II
    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.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    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
    Last Subject Last Visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years12
    E.8.9.2In all countries concerned by the trial months7
    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: 104
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 50
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 54
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 Information not present in EudraCT
    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 Information not present in EudraCT
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Paediatric
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 104
    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
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
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