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    Summary
    EudraCT Number:2014-002172-92
    Sponsor's Protocol Code Number:AZA-AML-004
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-12-17
    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 number2014-002172-92
    A.3Full title of the trial
    A randomized, multicenter, open-label, Phase 2 study with a safety run-in part to evaluate safety, pharmacodynamics and efficacy of azacitidine compared to no anticancer treatment in children and young adults with acute myeloid leukemia in molecular relapse after first complete remission.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Two parts study, the first part is to determine the dose of azacitidine and the second part is to evaluate the effect of azacitidine compared to no treatment, in children and young adults following a molecular relapse of acute myeloid leukemia after the first complete remission.
    A.4.1Sponsor's protocol code numberAZA-AML-004
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/031/2014
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCelgene Corporation
    B.1.3.4CountryUnited States
    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 supportCelgene Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelgene Corporation
    B.5.2Functional name of contact pointClinicalTrialDisclosure
    B.5.3 Address:
    B.5.3.1Street Address9225 Indian Creek Parkway, Suite 900
    B.5.3.2Town/ cityOverland Park, Kansas
    B.5.3.3Post code66210
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1-888-260-1599
    B.5.5Fax number+1 913-266-0394
    B.5.6E-mailClinicalTrialDisclosure@celgene.com
    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 Vidaza 25 mg/ml powder for suspension for injection
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe 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/3/07/509
    D.3 Description of the IMP
    D.3.1Product nameAzacitidine
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAZACITIDINE
    D.3.9.1CAS number 320-67-2
    D.3.9.4EV Substance CodeSUB05624MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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
    Treatment of children and young adults with molecular relapse of acute myeloid leukemia (AML) after first complete remission (CR1).
    E.1.1.1Medical condition in easily understood language
    Acute Myeloid Leukemia is a type of cancer that starts in cells that form new blood cells. AML starts in the bone marrow but in most cases it quickly moves into the blood.
    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 LLT
    E.1.2Classification code 10000886
    E.1.2Term Acute myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Safety Run-in Part
    -To establish a safe and tolerable dose of azacitidine to be used in the randomized part of the study.

    Randomized Part
    -To evaluate the effect of azacitidine treatment in AML subjects at molecular relapse after CR1 when compared to no treatment with regard to the progression-free rate (PFR) at Day 84 (±4 days) postrandomization.
    E.2.2Secondary objectives of the trial
    Safety Run-in Part
    -To establish azacitidine plasma pharmacokinetic (PK) parameters in subjects with molecular relapse AML after CR1 and to assess efficacy.

    Randomized Part
    -To evaluate the safety, pharmacodynamics (PD), and efficacy of azacitidine treatment in subjects with molecular relapse AML after CR1.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    •Patients≥ 3months and less than 21 years old, who (subject and when applicable parental/ legal representative(s)) must understand and voluntarily sign an Informed Consent or Informed Assent Form.
    Note: for the Safety Run-in, Patients≥ 3months and less than 18 years old at the time of informed consent/assent
    •At the time of signing the ICF/IAF, patients must have documented diagnosis of Acute Myeloid Leukemia and documentation of molecular remission confirmed at the start of last consolidation course or within 1 month after completion of consolidation treatment.
    •Safety Run-In (At the time of signing ICF/IAF): Detection of molecular relapse within the 7 days prior to signing consent/assent and confirmation of molecular relapse during the screening period.
    Randomized Part (At the time of pre-drug verification visit); Detection of molecular relapse within the 7 days prior to signing consent/assent and confirmation of relapse during the screening period.
    E.4Principal exclusion criteria
    •Concomitant treatment with any other anticancer therapy except those specific in protocol and no maintenance therapy after end of consolidation therapy and confirmed remission.
    •Hematopoietic Stem Cell Transplantation within previous 3 months
    •Pregnant or breastfeeding females
    •Patients with a current disease that can interfere with protocol procedures or study treatment
    •Hypersensitivity to azacitidine
    •Symptomatic CNS-involvement or isolated extramedullary disease at initial diagnosis.
    •FAB type M3 leukemia (acute promyelocytic leukemia)
    •Therapy-related AML
    • AML of Down syndrome or other congenital syndromes giving rise to leukemia or
    treatment complications.
    •Symptomatic cardiac disorders (CTCAE Grade 3 or 4).
    E.5 End points
    E.5.1Primary end point(s)
    Safety Run-in Part :

    -Identification of a safe and tolerable dose for the randomized part of the study
     -Assessment of treatment-related dose-limiting toxicities (DLTs)
     -Frequency and severity of treatment-related AEs

    Randomized Part :

    -Progression-free rate at Day 84 (±4 days) post randomization: Proportion of subjects free from clinical progression (clinical relapse and death from any cause) and from molecular progression (defined as lack of stabilization or lack of decrease in molecular aberrations concerning FLT3-ITD mutated, CBF leukemias (eg, t(8;21) and/or inv(16)), MLL-gene rearrangements or NPM1-mutations using central assessment of BM samples by the central laboratories identified for the study, obtained at time points identically prespecified in both randomization arms) at Day 84 (±4 days) post randomization.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety Run-in:
    The rate of the following treatment-related DLTs as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAEs) version 4.0, occurring during Cycle 1 only will be considered in determining the tolerability of the 100 mg/m2 dose of azacitidine.
    Once 6 subjects have completed their first cycle of treatment (if not having stopped earlier due to a DLT), safety will be evaluated by an external independent Safety Monitoring Committee (SMC) and investigators on the trial.

    Randomized part:
    PFR at Day 84 (±4 days) post randomization, will be assessed at Day 80 to 88 (approximately end of Cycle 3 of active treatment) post randomization for both the control and the experimental arm.
    E.5.2Secondary end point(s)
    Safety Run-Part :
    1. Molecular response at Day 84 (+/- 4 days) post Cycle 1 Day 1 (or end of Cycle 3, if not the same date)
    2.Azacitidine plasma PK parameters
    3.Leukemia-free survival (LFS)
    4.Minimal residual disease pre- HSCT
    5.Overall survival

    Randomized Part:
    1. Changes in DNA methylation (assessments of BM samples using Nano- HELP assay)
    2. Leukemia-free survival
    3. Proportion treated with HSCT
    4. MRD pre- HSCT, and 3 and 6 months post-HSCT
    5. Overall survival
    6. Molecular response
    7. Treatment-related mortality/morbidity
    8. Toxicity after HSCT
    9. Safety
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety run-in
    1.Cycle 1
    2.Screening, C1D15,C2D1,C3D1, D84 (±4 days) post randomization, and pre-, and 3 and 6 mths post-HSCT
    3.at F/U period for up to 2 yrs from enrollment of last subject
    4.Screening,C2D1 and C3D1,D84 (±4 days) post randomization, and pre-, and 3 and 6 months post-HSCT.If the treatment is discont prior 3 cycles, MRD analysis will continue every 28 days until relapse
    5.during the F/U period for up to 2 yrs from enrollment of the last subject
    Randomised part:
    Evaluation of each end point is done as for safety run in phase see (1-5) and incl:
    6.MRD analysis; screening period every 28 days from ICF/IAF, at the Predrug Verification Visit,C2D1 and C2D1,at D84 (±4 days) post randomization, and finally pre-, and 3 and 6 mths post-HSCT
    7/8/9.Monitored real time

    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 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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    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 Yes
    E.8.2.3.1Comparator description
    watch and wait for the randomised part
    E.8.2.4Number of treatment arms in the trial2
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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 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
    Is the date of the last visit of the last subject to complete the study, or the date of receipt of the last data point from the last subject that is required for primary, secondary, and/or exploratory analysis, as prespecified in the protocol and/or the Statistical Analysis Plan, whichever is the later date.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months0
    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.1.1Number of subjects for this age range: 80
    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: 48
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 22
    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
    children aged from 3 months will be involved.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state42
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 365
    F.4.2.2In the whole clinical trial 365
    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)
    It is specified in the protocol that patients should be treated as per standard of care after they discontinue from the study. Some patients who reach the required MRD levels will go on to transplant (which is also the standard of care). If they do not reach the required MRD levels, they will have another line of chemotherapy (as per the institution’s standard of care) and then transplant (also in line with standard of 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 Decision2014-12-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-06-22
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-10-08
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