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    Summary
    EudraCT Number:2008-006931-11
    Sponsor's Protocol Code Number:CPKC412A2114
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2009-07-16
    Trial results View 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 number2008-006931-11
    A.3Full title of the trial
    A phase I/II, open-label, dose-escalating study to evaluate the safety, tolerability and pharmacokinetics of twice daily oral midostaurin and to evaluate the preliminary clinical and pharmacodynamic response in pediatric patients with relapsed or refractory leukemia
    A.3.2Name or abbreviated title of the trial where available
    N/A
    A.4.1Sponsor's protocol code numberCPKC412A2114
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberN/A
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 namemidostaurin
    D.3.2Product code PKC412
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNmidostaurin
    D.3.9.2Current sponsor codePKC412
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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
    in pediatric patients with relapsed or refractory leukemia
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the maximum tolerated dose (MTD) for two age groups (≥3 months to ≤2 years: >2years to <18 years) of pediatric patients with AML or MLL based on the rate of dose-limiting toxicity (DLT) of midostaurin administered orally in dose ranges studied in adults.
    E.2.2Secondary objectives of the trial
    • To characterize the safety and tolerability of midostaurin, including acute
    and chronic toxicities
    • To characterize the peak and trough levels of single and repeated doses
    of midostaurin and its metabolite(s),
    • To determine the response rates, time to relapse and overall survival of
    patients treated with midostaurin.
    • To determine the presence of activating mutations or WT-overexpression
    of the FLT3 gene in MLL-rearranged ALL and AML samples
    • To correlate baseline levels of FLT3 phosphorylation with FLT3
    expression levels and clinical outcome in MLL patients
    • To correlate baseline levels of FLT3 phosphorylation with activating FLT3
    mutations and clinical outcome in AML patients
    • To evaluate changes in FLT3 phosphorylation following treatment with
    midostaurin, and correlate changes with clinical outcome
    • To evaluate changes in FLT3 phosphorylation following treatment with
    midostaurin, and correlate with pharmacokinetic data
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients must have a documented diagnosis of one of the following
    leukemias:
    • MLL-rearranged ALL, refractory to standard induction treatment or in
    first or subsequent relapse
    • FLT3-mutated AML refractory to standard induction (after failure of at
    least 2 different induction chemotherapy regimens) or refractory to reinduction
    at 1st relapse (after failure of the first re-induction course), or
    in second or greater relapse
    2. Patients must be less than 18 years of age and ≥3 months of age.
    3. Patients must have a Lansky/Karnofsky performance status ≥ 60.
    4. Patients must have the following laboratory values reflecting appropriate
    organ function:
    • AST and ALT ≤ 5x Upper Limit of Normal (ULN),
    • Serum Bilirubin ≤ 1.5 x ULN,
    • Serum Creatinine ≤ 2 x ULN.
    5. Patients must have an expected survival of greater than 8 weeks.
    E.4Principal exclusion criteria
    1. Patients with symptomatic leukemic CNS involvement.
    2. Patients with isolated extramedullary leukemia.
    3. Patients must have recovered from prior cytotoxic chemotherapy, and a
    minimum wash-out time of previous chemotherapy of 72 hours should be
    taken into account.
    4. Patients who had prior allogeneic, syngeneic or autologous bone marrow
    or stem cell transplant less than 2 months from Day 1
    5. Patients who have received any investigational agent within 30 days or 5
    half lives, whichever is greater, prior to Day 1. An investigational agent is
    an agent with no approved medical uses in adults or pediatrics.
    6. Patients who have had prior treatment with a FLT3 inhibiting drug or
    investigational agent.
    7. Use of CYP3A4/5 enzyme inducing or inhibiting drugs or herbal
    supplements while on study treatment
    8. The use of corticosteroids while on study drug
    9. Patients who have had any surgical procedure, excluding central venous
    catheter placement or other minor procedures (e.g. skin or bone marrow
    biopsy), within 14 days of Day 1.
    10. Patients with any other known disease concurrent severe and/or
    uncontrolled medical condition (e.g. cardiovascular disease including
    congestive heart failure or active uncontrolled infection) which could
    compromise participation in the study.
    11. Patients with an abnormal chest X-ray and/or any pulmonary infiltrate
    including those suspected to be of infectious origin. In particular, patients
    with resolution of clinical symptoms of pulmonary infection but with
    residual pulmonary infiltrates on chest x-ray are not eligible until
    pulmonary infiltrates have completely resolved.
    12. Patients with known impairment of gastrointestinal (GI) function or GI
    disease that may significantly alter the absorption of midostaurin,
    including active graft-versus-host disease of the liver or the gut.
    13. Patients with a known confirmed diagnosis of HIV infection or active viral
    hepatitis.
    14. Patients with a left ventricular shortening fraction < 27% as determined by
    MUGA scan or echocardiogram
    15. Patients with abnormal ECG including:
    • QTcF ≥ 450 ms, PR ≥200 msec, QRS complex ≥110 msec, at
    screening
    • Any cardiac conduction abnormality
    • Any morphologic abnormality
    • Any ST/T wave abnormality
    • Any atrial or ventricular arrhythmia
    16. Female patients who are pregnant or breast feeding or patients of
    reproductive potential not employing an effective method of birth control.
    Barrier contraceptives must be used throughout the trial by both sexes, if
    applicable.
    17. Males of reproductive potential unwilling to comply with contraceptive
    requirements
    18. Patients/parents unwilling or unable to comply with the protocol
    E.5 End points
    E.5.1Primary end point(s)
    • Safety: Occurrence of dose-limiting toxicities (DLTs)
    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 Yes
    E.6.13.1Other scope of the trial description
    MTD, tolerability
    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
    first study in pediatric
    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 No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    After discontinuation of study treatment, patients will be follewed up for survival untille death.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    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.1.1.1In 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.1.1.5Children (2-11years) Yes
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 22
    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)
    not different from normal treatment
    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 Decision2009-08-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-10-30
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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