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    Summary
    EudraCT Number:2013-000390-70
    Sponsor's Protocol Code Number:DACOGENAML2004
    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:2014-02-12
    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 number2013-000390-70
    A.3Full title of the trial
    Phase 1-2 Safety and Efficacy Study of DACOGEN in Sequential Administration With Cytarabine in Children With Relapsed or Refractory Acute Myeloid Leukemia.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Safety and Efficacy Study of DACOGEN in Sequential Administration With Cytarabine in Children With Relapsed or Refractory Acute Myeloid Leukemia.
    A.4.1Sponsor's protocol code numberDACOGENAML2004
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/225/2013
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorJanssen-Cilag International NV
    B.1.3.4CountryBelgium
    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 supportJanssen Research & Development, LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJanssen-Cilag International NV
    B.5.2Functional name of contact pointClinical Registry Group
    B.5.3 Address:
    B.5.3.1Street AddressArchimedesweg 29-2333CM
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333CM
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31(0)715242166
    B.5.5Fax number+31(0)715242110
    B.5.6E-mailClinicalTrialsEU@its.jnj.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 DACOGEN
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag International NV
    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/3/06/370
    D.3 Description of the IMP
    D.3.1Product nameDacogen
    D.3.4Pharmaceutical form Powder for concentrate 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 INNDECITABINE
    D.3.9.1CAS number 2353-33-5
    D.3.9.4EV Substance CodeSUB06932MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    Relapsed or Refractory Acute Myeloid Leukemia
    E.1.1.1Medical condition in easily understood language
    Cancer of White Blood Cells
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objectives of the Phase 1 portion of Study DACOGENAML2004 are:
    •to determine the maximum tolerable dose (MTD) of cytarabine (up to 2 g/m2 per day x 5) that can be administered on Days 8-12 following treatment with DACOGEN 20 mg/m2 per day on Days 1-5 of a 28-day cycle.
    •to determine PK parameters including maximum plasma concentration (Cmax), Area under the concentration x time curve (AUC), time to maximum plasma concentration (tmax), and clearance (Cl) of decitabine on Day 5 of Cycle 1.
    The primary objective of the Phase 2 portion of Study DACOGENAML2004 is to determine the response rate (CR + CRi) in children with relapsed or refractory AML when treated with DACOGEN 20 mg/m2 per day on Days 1-5 followed by cytarabine at the determined MTD on Days 8-12 for up to 4 cycles of treatment.
    E.2.2Secondary objectives of the trial
    The secondary objectives are to evaluate the safety profile of DACOGEN 20 mg/m2 per day administered on Days 1 to 5 allowed by cytarabine on Days 8 to 12 for up to 4 cycles of therapy and to describe the duration of CR + CRi and evaluate the overall response (CR + CRi + PR) to treatment.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Histological diagnosis of acute myeloid leukemia (AML) according to the World Health Organization (WHO) classification
    - Diagnosis of AML which has relapsed or is refractory to standard of care and no curative therapy exists
    - Karnofsky or Lansky score of at least 50
    - Must be recovered from acute toxicity of any prior treatment
    - Must have adequate organ function according to protocol-defined
    criteria
    - Agrees to protocol-defined use of effective contraception
    - Female participants of childbearing potential must have a negative serum or urine pregnancy test at Day 1 of Cycle 1
    - Female participants must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction
    - Male participants must not donate sperm during the study and for 3 months after receiving the last dose of study drug.
    E.4Principal exclusion criteria
    - Prior treatment with decitabine or azacitidine
    - Acute promyelocytic leukemia (M3 subtype in the French-American-British [FAB] classification system)
    - Symptomatic central nervous system involvement of acute myeloid leukemia (AML)
    - AML associated with congenital syndromes such as Down syndrome, Fanconi anemia, Bloom syndrome, Kostmann syndrome or Diamond-Blackfan anemia, or bone marrow failure associated with inherited syndromes
    - White blood cell count greater than 40,000 cells/mL
    - Known allergies, hypersensitivity, or intolerance to decitabine or cytarabine or their excipients
    - Contraindications to the use of cytarabine per local prescribing information or prior adverse reactions to cytarabine which would prevent further use
    - Currently enrolled in an interventional investigational study
    - Female who is pregnant, or breast-feeding, or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug (however, the period after which it becomes safe to become pregnant after the last dose of treatment is not known)
    - Male who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug
    - Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient or that could prevent, limit, or confound the protocol-specified assessments
    - Any social or medical condition that in the investigator’s opinion renders the participant unfit for study participation
    - History of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically active liver disease
    -History of human immunodeficiency virus (HIV) antibody positive
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1:
    For the Phase 1 portion of the study the primary endpoint will be DLT in the determination of the MTD (up to 2 g/m2 per day) of cytarabine given on Days 8 to 12 following the administration of DACOGEN at 20 mg/m2 on Days 1 to 5. DLTs are defined as the following
    • Hematological DLT will be defined as failure to recover to an absolute neutrophil count (ANC) of 0.5 x 109/L (common terminology criteria for adverse events [CTCAE] Grade
    3) and non-transfusion dependent platelet count of 25 x 109/L (CTCAE Grade 3) due to documented bone marrow aplasia/hypoplasia (malignant infiltration or other cause excluded), by Day 42. Bone marrow aplasia/hypoplasia is defined as overall marrow cellularity less than 25%.
    •Non-hematological DLT is defined as: any Grade ≥3 toxicity possibly, probably or definitely related to study drug that persists for >5 days; any Grade 2 toxicity that persists for >7 days and that is intolerable to the patient.

    Phase 2:
    In the Phase 2 portion of this study the primary end point will be the CR +CRi rate as determined using IWG criteria. The response status of each patient will be determined prior to each cycle of DACOGEN + cytarabine after the first cycle. The best response up to 4 cycles of DACOGEN + cytarabine for each subject will be used to determine the rate of CR + CRi.

    Please refer to Page 40 & 41 of Protocol.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 4 cycles of treatment.
    E.5.2Secondary end point(s)
    • Safety profile of DACOGEN 20 mg/m2 per day on Days 1-5 followed by cytarabine Days 8-12 for up to 4 cycles of therapy.
    • Duration of CR + CRi
    • Overall response (CR + CRi + PR)
    • Event-free survival (EFS), defined as the time from first dose of study drug to relapse from CR, death, or second malignancy for subjects who achieve CR; subjects who do not achieve CR will be considered to have an event on the day of the first dose of study drug. Other alternative EFS definitions may be considered.
    •Overall survival
    •To determine the PK profile of DACOGEN in children with AML

    Other Secondary Endpoints:
    •To explore pharmacodynamic effects of DACOGEN with respect to DNA
    hypomethylation status and gene expression
    •To explore predictive markers for response to DACOGEN.
    • Levels of DACOGEN in the CSF if samples are collected as part of other required medical care.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Time of progression/relapse, withdrawal, or death, for up to 3 years after last participant enrolment.
    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 Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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 1-2 Safety and Efficacy Study
    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 Information not present in EudraCT
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Information not present in EudraCT
    E.8.1.5Parallel group Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    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.8.2.4Number of treatment arms in the trial1
    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 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 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 months6
    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 months6
    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: 33
    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: 4
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 17
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 12
    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.4.2.1In the EEA 33
    F.4.2.2In the whole clinical trial 33
    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)
    The End of Treatment Visit should occur 30 days after the last dose of single agent DACOGEN after which the subjects will enter the Follow-up Phase of the study. In the event subjects continue to derive benefit at study end, DACOGEN will continue to be supplied by the Company.
    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 Decision2014-02-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-07-01
    P. End of Trial
    P.End of Trial StatusCompleted
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