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    Summary
    EudraCT Number:2018-002988-25
    Sponsor's Protocol Code Number:ML-DS2018
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2020-03-17
    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 ConcernedGermany - BfArM
    A.2EudraCT number2018-002988-25
    A.3Full title of the trial
    Phase III Clinical Trial for CPX-351 in Myeloid Leukemia in Children with Down Syndrome 2018
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical Trial for the Treatment of Myeloid Leukemia in Children with Down Syndrome
    A.4.1Sponsor's protocol code numberML-DS2018
    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 SponsorGesellschaft für Pädiatrische Onkologie & Hämatologie (GPOH gGmbH)
    B.1.3.4CountryGermany
    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 supportJazz Pharmaceuticals Germany
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Clinic Frankfurt
    B.5.2Functional name of contact pointProf. Jan-Henning Klusmann (LKP)
    B.5.3 Address:
    B.5.3.1Street AddressTheodor-Stern-Kai 7
    B.5.3.2Town/ cityFrankfurt
    B.5.3.3Post code60590
    B.5.3.4CountryGermany
    B.5.4Telephone number00496963015094
    B.5.6E-mailKKJM-Direktor@kgu.de
    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 Vyxeos liposomal 44mg/100mg Pulver für ein Konzentrat zur Herstellung einer infusionslösung
    D.2.1.1.2Name of the Marketing Authorisation holderJazz Pharmaceuticals Ireland Ltd.
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/11/942
    D.3 Description of the IMP
    D.3.1Product nameVyxeos
    D.3.2Product code CPX-351
    D.3.4Pharmaceutical form Powder for concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Intravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCytarabine
    D.3.9.1CAS number 147-94-4
    D.3.9.3Other descriptive nameCYTARABINE
    D.3.9.4EV Substance CodeSUB06880MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDAUNORUBICIN
    D.3.9.1CAS number 20830-81-3
    D.3.9.4EV Substance CodeSUB06917MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number44
    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
    Myeloid Leukemia in Children with Down Syndrome
    E.1.1.1Medical condition in easily understood language
    Myeloid Leukemia in Children with Down Syndrome
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    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
    • Achieving an EFS, which is not inferior to the ML-DS 2006 trial: 5yr-EFS; 87±3%
    E.2.2Secondary objectives of the trial
    • Reduction of toxicity: severe adverse events (CTCAE v4.0 grade III or higher)
    • Identification of prognostic factors concerning the risk of relapse, toxicity and poor outcome
    • Evaluate the role of different methods in the determination of minimal residual disease measurement
    • Evaluation of somatic SNVs as a predictive biomarker: relation of patients’ outcome to the specific somatic SNVs
    • Exploration of the role of trisomy 8 as a predictive biomarker
    • Exploration of molecular resistance/relapse mechanisms
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    An extensive research program will be performed, comprising molecular analyses (whole genome and transcriptome sequencing), xenograft mouse modeling and drug screening using left over material from bone marrow aspirations at diagnosis and during treatment. The role of coding and non-coding RNAs in the pathogenesis of ML-DS will be explored.
    E.3Principal inclusion criteria
    • Myeloid Leukemia (ML) or Myelodysplastic Syndrome (MDS), according to WHO
    • Trisomy 21: Down syndrome or mosaic
    • Age: > 6 months and ≤ 4 years of age with/without GATA1 mutation OR > 4 years of age < 6 years of age with GATA1 mutation
    • Morphology/Immunophenotyping: FAB M0, M6 or M7
    • Lansky performance score at least equal to 50; or Karnofsky performance status at least equal to 50, whichever is applicable
    • Understand and voluntarily provide written permission of parental/legal representative(s) to the ICF prior to conducting any study related assessments/procedures, also concerning data and tumor material transfer according to ICH/GCP and national/local regulations
    • Able to adhere to the study visit schedule and other protocol requirements
    • Acceptance that vaccination with live vaccines is not possible while participating in the trial
    E.4Principal exclusion criteria
    • Children with Transient Abnormal Myelopoiesis (TAM), according to WHO

    • Cytogenetics: AML with recurrent genetic abnormalities (WHO 2016)

    • Previous allogeneic bone marrow, stem cell or organ transplantation

    • Evidence of invasive fungal infection or other severe systemic infection requiring treatment doses of systemic/parenteral therapy including known active viral infection with human immunodeficiency virus (HIV) or Hepatitis Type B and C

    • Symptomatic cardiac disorders (CTCAE 4.0 Grade 3 or 4)

    • Diagnosed Wilson’s Disease

    • Major surgery within 21 days of the first dose.

    • Any anti-cancer therapy (e.g., intensive chemotherapy, biologics or radiotherapy) for more than 14 days or within 4 weeks before start of therapy, except low-dose cytarabine for the treatment of TAM.

    • Concomitant treatment with any other anticancer therapy except those specified in protocol during the study therapy

    • Treated by any investigational agent in a clinical study within previous 4 weeks

    • History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product

    • Former Enrolment to this study

    • The patient concerned has been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
    E.5 End points
    E.5.1Primary end point(s)
    Event-free survival (EFS), defined as time from diagnosis to the first event or last follow-up. Events are death from any cause, failure to achieve remission, relapse, and secondary malignancy. Failure to achieve remission is considered as an event on day 0.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 150 are included and the 5-yrs-follow up is over.
    E.5.2Secondary end point(s)
    • Overall survival (OS), as defined as the time of diagnosis to death from any cause or last follow-up.
    • Disease-free survival (DFS)
    • Early Response Rate (CR, CRp, CRi)) after induction
    • Treatment-related mortality (TRM)
    • Minimal residual disease (FACS and NGS)
    • Adverse events (according to NCI CTCAE v4.0)
    • Duration of myelosuppression
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 150 are included and the 5-yrs-follow up is over.
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 Yes
    E.8.1.7.1Other trial design description
    Prospective, open-label, non-randomized, historically-controlled phase II/III trial
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Historic Controll
    E.8.2.4Number of treatment arms in the trial1
    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 concerned30
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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
    Austria
    Denmark
    France
    Germany
    Hungary
    Italy
    Netherlands
    Norway
    Poland
    Portugal
    Slovakia
    Slovenia
    Spain
    Sweden
    Switzerland
    European Union
    Czechia
    Greece
    E.8.7Trial has a data monitoring committee Yes
    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 patient first visit (LPFV):
    Q1 2028
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    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: 150
    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: 30
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 120
    F.1.1.6Adolescents (12-17 years) No
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Little Children, aged <6 yrs with Down-Syndrome
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 150
    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, but the protocol gives a Follow up recommendation in regular patient care
    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 Decision2020-08-10
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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