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    Summary
    EudraCT Number:2008-006931-11
    Sponsor's Protocol Code Number:CPKC412A2114
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2009-07-08
    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 ConcernedSweden - MPA
    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.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/03/214
    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 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 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
    Relapsed or refractory leukemia in paediatric patients
    E.1.1.1Medical condition in easily understood language
    Relapsed or refractory leukemia in paediatric patients
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To estimate the maximum tolerated dose(s) (MTD (s)) and/or to identify the recommended dose for expansion (RDE) 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
    Secondary Objectives:
    • To characterize the safety and tolerability of midostaurin, including acute and chronic toxicities
    • To characterize the population PK and trough 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

    Exploratory Objectives:
    • To determine the presence of activating mutations or WToverexpression 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 pts.
    • To correlate baseline levels of FLT3 phosphorylation with activating FLT3 mutations and clinical outcome in AML pts.
    • 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 Information not present in EudraCT
    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.
    6. Parent or legal guardian and/or the patient must give written
    informed consent, according to local law and regulations.
    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, with a minimum wash-out time of previous chemotherapy of 72 hours. For intrathecal chemotherapy, the minimum wash-out time is 48 hours (other exceptions for intrathecal chemotherapy are noted in Section 6.6.5)
    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; except for sorafenib.
    7. Use of CYP3A4/5 enzyme inducing or inhibiting drugs or CYP3A4/5 enzyme inducing or inhibiting herbal supplements while on study treatment
    8. The use of corticosteroids while on study drug (exceptions are noted in Section 6.6.5)
    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 or prior to first dosing
    • 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. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 3 months after the last exposure to midostaurin.
    Highly effective contraception methods include:
    • Total abstinence (when this is in line with the preferred and usual
    lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
    • Male partner sterilization (at least 6 months prior to screening).
    During the study the vasectomized male partner should be the sole partner for that subject.
    OR:
    • Combination of any two of the following (a+b or a+c, or b+c):
    a) Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
    b) Placement of an intrauterine device (IUD) or intrauterine system
    (IUS)
    c) Barrier methods of contraception: Condom or Occlusive cap
    (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
    In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment
    17. Sexually active males unless they use a condom during intercourse while taking midostaurin and for at least 3 months after the last exposure to midostaurin. They should not father a child until three months after the end of the study. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.
    18. Patients/parents unwilling or unable to comply with the protocol
    E.5 End points
    E.5.1Primary end point(s)
    To estimate the maximum tolerated dose (MTD (s)) or to identify the recommended dose for expansion (RDE) for two age groups (≥ 3 months and ≤ 2 years and >2 years and < 18 years) of pediatric patients with AML or MLL based on the rate of dose-limiting toxicity (DLT) of midostaurin administered orally.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout study conduct
    E.5.2Secondary end point(s)
    • Safety: Adverse drug reactions and serious adverse drug reactions, changes in hematology and chemistry values, vital signs and electrocardiograms
    • Pharmacokinetics: Population PK and trough levels of midostaurin and metabolites.
    • Efficacy: Best clinical response; bone marrow and peripheral blood status; time to response; duration of response; overall survival
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout study conduct
    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 Information not present in EudraCT
    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
    Tolerability, MTD
    Identification of the recommended dose for expansion (RDE)
    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 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 Information not present in EudraCT
    E.8.1.7.1Other trial design description
    patients will be stratified into two age groups
    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 EEA8
    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
    LVLS
    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 months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months3
    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.1.1.4.1Number of subjects for this age range: 10
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 2
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 9
    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
    Paediatric pupulation >3 months of age
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 19
    F.4.2.2In the whole clinical trial 22
    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 Decision2009-08-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-07-16
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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