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    Clinical Trial Results:
    Phase 1-2 Safety and Efficacy Study of DACOGEN in Sequential Administration With Cytarabine in Children With Relapsed or Refractory Acute Myeloid Leukemia

    Summary
    EudraCT number
    2013-000390-70
    Trial protocol
    GB   BE   DE   FR   NL   DK   ES  
    Global end of trial date
    28 Aug 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Mar 2018
    First version publication date
    16 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DACOGENAML2004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01853228
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    Archimedesweg 29, Leiden, Netherlands, 2333CM
    Public contact
    Clinical Registry group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000555-PIP01-09
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Aug 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the maximum tolerable dose (MTD) of cytarabine (up to 2 gram per square meter (g/m^2) per day*5 that can be administered on Days 8 to 12 following treatment with Dacogen 20 milligram per square meter (mg/m^2) per day on Days 1 to 5 of a 28 day cycle and decitabine pharmacokinetics (PK) parameters from blood sampling on Day 5 of Cycle 1 (Phase 1 portion); to determine the response rate using international working group (IWG) criteria (complete response [CR] + complete response with incomplete blood count recovery [CRi]) in children with relapsed or refractory acute myeloid leukemia (AML) when treated with Dacogen 20 mg/m^2 per day on Days 1 to 5 followed by cytarabine at the determined MTD on Days 8 to 12 for up to 4 cycles of treatment (Phase 2 portion).
    Protection of trial subjects
    Safety evaluations included monitoring of adverse events (AEs), clinical laboratory parameters (hematology, biochemistry and urinalysis) vital sign measurements, physical examination findings, and assessment of performance status.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Netherlands: 1
    Worldwide total number of subjects
    17
    EEA total number of subjects
    17
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    1
    Children (2-11 years)
    14
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Sixteen subjects were enrolled in Phase 1 (9 subjects in Cohort 1 [cytarabine 1 {grams per square meter} g/m^2] and 7 subjects in Cohort 2 [cytarabine 2 g/m^2]) and of these, 7 in Cohort 2 continued on to Phase 2. One additional patient was newly enrolled in Phase 2 of the study, making a total of 8 subjects evaluable in Phase 2.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Decitabine (Dacogen) + Cytarabine
    Arm description
    Subjects received 1 gram per square meter (g/m^2), 2 g/m^2, and 1.5 g/m^2 dose levels administered by intravenous infusion over 4 hours daily for 5 consecutive days (Day 8 to Day 12 of 28-day cycle) for the determination of the maximum tolerated dose in Phase 1 and maximum tolerated dose identified in Phase 1 was administered by intravenous infusion over 4 hours daily for 5 consecutive days (Day 8 to Day 12 of 28-day cycle) in Phase 2. Followed by this subjects received 20 milligram square per gram (mg/m^2) by intravenous infusion over 1 hour once daily for 5 consecutive days (Day 1 to Day 5 of 28-day cycle) in Phase 1 and Phase 2.
    Arm type
    Experimental

    Investigational medicinal product name
    Decitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Dacogen 20 mg/m^2/day on Days 1 to 5 intravenously.

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received no more than 2 g/m^2 per day*5 days cytarabine on Days 8 to 12 intravenously.

    Number of subjects in period 1
    Decitabine (Dacogen) + Cytarabine
    Started
    17
    Completed
    0
    Not completed
    17
         Progressive disease
    12
         Other
    1
         Physician decision
    1
         Proceed to transplant
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Decitabine (Dacogen) + Cytarabine
    Reporting group description
    Subjects received 1 gram per square meter (g/m^2), 2 g/m^2, and 1.5 g/m^2 dose levels administered by intravenous infusion over 4 hours daily for 5 consecutive days (Day 8 to Day 12 of 28-day cycle) for the determination of the maximum tolerated dose in Phase 1 and maximum tolerated dose identified in Phase 1 was administered by intravenous infusion over 4 hours daily for 5 consecutive days (Day 8 to Day 12 of 28-day cycle) in Phase 2. Followed by this subjects received 20 milligram square per gram (mg/m^2) by intravenous infusion over 1 hour once daily for 5 consecutive days (Day 1 to Day 5 of 28-day cycle) in Phase 1 and Phase 2.

    Reporting group values
    Decitabine (Dacogen) + Cytarabine Total
    Number of subjects
    17 17
    Title for AgeCategorical
    Units: subjects
        inUtero
    0 0
        pretermNewbornInfants (gestational age <37 wks)
    0 0
        newborns (0-27 days)
    0 0
        infants and toddlers(28 days-23 months)
    1 1
        Children (2-11 years)
    14 14
        Adolescents (12-17 years)
    2 2
        Adults (18-64 years)
    0 0
        From 65 to 84 years
    0 0
        85 years and over
    0 0
    Title for AgeContinuous
    Units: months
        arithmetic mean (standard deviation)
    73.3 ± 46.26 -
    Title for Gender
    Units: subjects
        Female
    4 4
        Male
    13 13

    End points

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    End points reporting groups
    Reporting group title
    Decitabine (Dacogen) + Cytarabine
    Reporting group description
    Subjects received 1 gram per square meter (g/m^2), 2 g/m^2, and 1.5 g/m^2 dose levels administered by intravenous infusion over 4 hours daily for 5 consecutive days (Day 8 to Day 12 of 28-day cycle) for the determination of the maximum tolerated dose in Phase 1 and maximum tolerated dose identified in Phase 1 was administered by intravenous infusion over 4 hours daily for 5 consecutive days (Day 8 to Day 12 of 28-day cycle) in Phase 2. Followed by this subjects received 20 milligram square per gram (mg/m^2) by intravenous infusion over 1 hour once daily for 5 consecutive days (Day 1 to Day 5 of 28-day cycle) in Phase 1 and Phase 2.

    Primary: Maximum Tolerated Dose (MTD) of Cytarabine

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    End point title
    Maximum Tolerated Dose (MTD) of Cytarabine [1]
    End point description
    The maximum tolerated dose (MTD) for cytarabine was based on the number of subjects experiencing a dose-limiting toxicity (DLT) by the end of Cycle 1. A non-hematological DLT is defined as: any Grade 3 toxicity that persists for greater than (>) 5 days or any Grade 2 toxicity that persists for >7 days and that is intolerable to the subject. A hematological DLT is defined as Grade 4 neutropenia or thrombocytopenia due to a hypoplastic bone marrow at Day 42, in the absence of malignant infiltration. The nominal duration of each cycle was 28 days. However, patients who have not experienced bone marrow recovery at Day 28 were followed up to Day 42. Failure of marrow recovery (improvement to Grade 3) by Day 42 was considered a DLT. The maximum duration of Cycle 1 was therefore be 42 days.
    End point type
    Primary
    End point timeframe
    Cycle 1 (42 days)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Decitabine (Dacogen) + Cytarabine
    Number of subjects analysed
    17
    Units: gram per square meter
        number (not applicable)
    2
    No statistical analyses for this end point

    Primary: Clearance of Decitabine

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    End point title
    Clearance of Decitabine [2]
    End point description
    Total clearance of drug after intravenously administration, calculated as: dose/area under the plasma concentration-time curve. Population included all enrolled subjects in this study assessed for pharmacokinetics (PK).
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 5: pre-infusion, 0.5 h during infusion, end of infusion, +5 min, +0.5h, +1h, and +2h after end infusion
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Decitabine (Dacogen) + Cytarabine
    Number of subjects analysed
    17
    Units: liter per hour square per meter
    median (full range (min-max))
        Less than (<) 1 month to <= 2
    160.6 (11.7 to 942.3)
        > 2 to <= 6 years
    152.1 (19.5 to 1061)
        > 6 to <= 12 years
    125.9 (13.3 to 951.3)
        > 12 to <= 16 years
    123.2 (11.4 to 832.6)
    No statistical analyses for this end point

    Primary: Volume of Distribution at Steady-State (Vss) of Decitabine

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    End point title
    Volume of Distribution at Steady-State (Vss) of Decitabine [3]
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Population included all enrolled subjects in this study assessed for PK.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 5: pre-infusion, 0.5 h during infusion, end of infusion, +5 min, +0.5h, +1h, and +2h after end infusion
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Decitabine (Dacogen) + Cytarabine
    Number of subjects analysed
    17
    Units: liter per square meter
    median (full range (min-max))
        < 1 month to <= 2 years
    35.9 (2.7 to 558.4)
        > 2 to <= 6 years
    36.5 (1.4 to 535.0)
        > 6 to <= 12 years
    31.8 (2.0 to 645.8)
        > 12 to <= 16 years
    35.9 (2.8 to 578.9)
    No statistical analyses for this end point

    Primary: Phase 2: Percentage of Subjects who Achieved CR or CRi

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    End point title
    Phase 2: Percentage of Subjects who Achieved CR or CRi [4]
    End point description
    Response rate was measured using international working group (IWG) criteria. Response rate is defined as complete remission (CR) and complete remission with incomplete blood count recovery (CRi) in children with relapsed or refractory acute myeloid leukemia. CRi is defined as morphologic CR with residual neutropenia (less than [<] 1,000/microliter) or thrombocytopenia <100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (>) 1,000/ microliter platelet count of >100,000/microliter and subject must be independent of transfusions for a minimum of 1 week before each marrow assessment. Here 'N' signifies number of subjects who were evaluable for this endpoint. Here 'n' signifies number of subjects analyzed for specific arm.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 28, Cycle 2 Day 28 and end of study treatment (approximately 3 years)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Decitabine (Dacogen) + Cytarabine
    Number of subjects analysed
    8
    Units: percentage of subjects
    number (not applicable)
        CRi (Cycle 1 Day 28) n=5
    20.0
        CRi (Cycle 2 Day 28) n=3
    66.7
        CRi End of Study Treatment (EOST) n=8
    12.5
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of Decitabine

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    End point title
    Maximum Plasma Concentration (Cmax) of Decitabine
    End point description
    The Cmax is the maximum observed plasma concentration of Decitabine. Population included all enrolled subjects in this study assessed for PK.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 5: pre-infusion, 0.5 h during infusion, end of infusion, +5 min, +0.5h, +1h, and +2h after end infusion
    End point values
    Decitabine (Dacogen) + Cytarabine
    Number of subjects analysed
    17
    Units: nanogram per milliliter (ng/mL)
    median (full range (min-max))
        Less than (<) 1 month to <= 2 years
    118.4 (17.6 to 1621)
        Greater than (>) 2 to <= 6 years
    123.1 (15.6 to 1012)
        > 6 to <= 12 years
    148.7 (16.5 to 1415)
        > 12 to <= 16 years
    151.4 (19.1 to 1303)
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve of Decitabine

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    End point title
    Area Under the Plasma Concentration-Time Curve of Decitabine
    End point description
    The AUC is the area under the plasma concentration-time curve of decitabine. Population included all enrolled subjects in this study assessed for PK.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 5: pre-infusion, 0.5 h during infusion, end of infusion, +5 min, +0.5h, +1h, and +2h after end infusion
    End point values
    Decitabine (Dacogen) + Cytarabine
    Number of subjects analysed
    17
    Units: nanogram*hour per milliliter (ng*h/mL)
    median (full range (min-max))
        < 1 month to <= 2 years
    124.8 (21.3 to 1708)
        > 2 to <= 6 years
    131.5 (19.3 to 1028)
        > 6 to <= 12 years
    158.9 (21.0 to 1508)
        > 12 to <= 16 years
    162.4 (24.2 to 1747)
    No statistical analyses for this end point

    Secondary: Phase 2: Duration of Response

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    End point title
    Phase 2: Duration of Response
    End point description
    Duration of response is defined as weeks from date of first response to earlier of date of first relapse or date of death. Population included all enrolled subjects. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From time of response to relapse, study completion/withdrawal, or death, whichever comes first, for up to 3 years after last participant enrollment
    End point values
    Decitabine (Dacogen) + Cytarabine
    Number of subjects analysed
    2
    Units: weeks
    number (not applicable)
        Subject 11
    44.6
        Subject 15
    6.3
    No statistical analyses for this end point

    Secondary: Phase 1 and Phase 2: Overall Response Rate

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    End point title
    Phase 1 and Phase 2: Overall Response Rate
    End point description
    Overall response rate is defined as complete remission (CR) +complete remission with incomplete blood count recovery (CRi)+partial remission (PR). CRi: morphologic CR with residual neutropenia (less than [<] 1,000/microliter) or thrombocytopenia <100,000/ microliter). CR is defined as morphologic leukemia-free state, with less than 5 percentage (%) blasts in aspirate sample with marrow spicules and with a count of greater than or equal to (>=) 200 nucleated cells, plus absolute neutrophil count (ANC) greater than (>) 1,000/ microliter platelet count of >100,000/microliter and subject must be independent of transfusions for a minimum of 1 week before each marrow assessment. PR: all the same hematologic values of a CR, but with a decrease of >=50% of the percentage of blasts to 5% to 25% in the bone marrow aspirate. Here 'N' signifies number of subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Up to approximately 4 years
    End point values
    Decitabine (Dacogen) + Cytarabine
    Number of subjects analysed
    8 [5]
    Units: Percentage of subjects
        number (not applicable)
    37.5
    Notes
    [5] - Population included who achieved the MTD of cytarabine for up to 4 cycles in the Phase 1 portion.
    No statistical analyses for this end point

    Secondary: Phase 1 and Phase 2: Overall Survival (OS)

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    End point title
    Phase 1 and Phase 2: Overall Survival (OS)
    End point description
    The OS is defined as the time from the date of first dose of study drug to date of death from any cause. If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant will be last known to be alive. Population included all enrolled subjects.
    End point type
    Secondary
    End point timeframe
    From enrollment to death or withdrawal, whichever comes first, for up to 3 years after last participant enrollment
    End point values
    Decitabine (Dacogen) + Cytarabine
    Number of subjects analysed
    17
    Units: months
        median (confidence interval 95%)
    5.1 (3.1 to 11.4)
    No statistical analyses for this end point

    Secondary: Phase 1 and Phase 2: Event-Free Survival

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    End point title
    Phase 1 and Phase 2: Event-Free Survival
    End point description
    Event free survival is defined as the time from first dose of study drug to relapse from CR, death, or second malignancy for subjects who achieve CR. Population included all enrolled subjects. -99999 indicates that the data for lower limit of CI was not estimable due to less number of participants with events. 99999 indicates that the data for lower limit of CI was not estimable due to less number of events.
    End point type
    Secondary
    End point timeframe
    From enrollment to progression/relapse, death, or withdrawal, whichever comes first, for up to 3 years after last subject enrollment
    End point values
    Decitabine (Dacogen) + Cytarabine
    Number of subjects analysed
    17
    Units: Days
        median (confidence interval 95%)
    1 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 1 and Phase 2: Number of Subjects Reporting Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Phase 1 and Phase 2: Number of Subjects Reporting Treatment-Emergent Adverse Events (TEAEs)
    End point description
    TEAEs are defined as adverse events with onset or worsening on or after date of first dose of study treatment. An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. The Safety Analysis Set included all enrolled subjects who received at least 1 dose of study drug (DACOGEN).
    End point type
    Secondary
    End point timeframe
    Approximately 4 years
    End point values
    Decitabine (Dacogen) + Cytarabine
    Number of subjects analysed
    17
    Units: subjects
    17
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening up to end of treatment (approximately 4 years)
    Adverse event reporting additional description
    An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. The Safety Analysis Set included all enrolled subjects who received at least 1 dose of study drug (DACOGEN).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Dacogen + Cytarabine
    Reporting group description
    Subjects received cytarabine on Days 8 to 12 intravenously following Dacogen 20 milligrams per square meter (mg/m*2/day) on Days 1 to 5 intravenously.

    Serious adverse events
    Dacogen + Cytarabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 17 (47.06%)
         number of deaths (all causes)
    14
         number of deaths resulting from adverse events
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences causally related to treatment / all
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Keratitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Complication Associated with Device
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin Exfoliation
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin Hyperpigmentation
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lung Infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Dacogen + Cytarabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 17 (100.00%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    General disorders and administration site conditions
    Catheter Site Haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Asthenia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Face Oedema
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Oedema Peripheral
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    8 / 17 (47.06%)
         occurrences all number
    30
    Psychiatric disorders
    Depressed Mood
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Irritability
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Vulvovaginal Inflammation
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Post Procedural Complication
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Fall
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Allergic Transfusion Reaction
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Procedural Pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Investigations
    Adenovirus Test Positive
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Alanine Aminotransferase Increased
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    12
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood Albumin Decreased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Weight Decreased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hypoxia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Tachypnoea
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Rhinitis Atrophic
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 17 (82.35%)
         occurrences all number
    64
    Febrile Neutropenia
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    9
    Leukopenia
         subjects affected / exposed
    6 / 17 (35.29%)
         occurrences all number
    14
    Lymphopenia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    4
    Thrombocytopenia
         subjects affected / exposed
    10 / 17 (58.82%)
         occurrences all number
    62
    Neutropenia
         subjects affected / exposed
    6 / 17 (35.29%)
         occurrences all number
    11
    Nervous system disorders
    Dizziness Postural
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    5
    Eye disorders
    Conjunctivitis Allergic
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Dry Eye
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Keratitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    3
    Anal Inflammation
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    5 / 17 (29.41%)
         occurrences all number
    5
    Ascites
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Haematemesis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Lip Haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    4 / 17 (23.53%)
         occurrences all number
    5
    Mouth Haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    9 / 17 (52.94%)
         occurrences all number
    13
    Tongue Haemorrhage
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    3
    Hepatocellular Injury
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    4
    Hepatomegaly
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Jaundice
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    8
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Decubitus Ulcer
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Butterfly Rash
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Erythema Multiforme
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Petechiae
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Lividity
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Pruritus Generalised
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    3
    Rash Maculo-Papular
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Skin Hyperpigmentation
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Product issues
    Device Occlusion
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 17 (17.65%)
         occurrences all number
    3
    Bone Pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Back Pain
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hypermagnesaemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Hyperferritinaemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Hyperphosphataemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hypernatraemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    6 / 17 (35.29%)
         occurrences all number
    9
    Hypomagnesaemia
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Hyponatraemia
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    9
    Hypophosphataemia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    2
    Infections and infestations
    Enterobacter Infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Lung Infection
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences all number
    2
    Hepatic Infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Fungal Infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pseudomonas Infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Pneumonia Klebsiella
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Paronychia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Staphylococcal Infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jun 2014
    The overall reason for the amendment INT-1 was to facilitate enrollment into the study and provide clarity on some aspects of the protocol.
    06 Oct 2015
    The overall reason for the amendment INT-2 was to correct errors noted in the selection criteria and typographical errors.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The Sponsor terminated the study earlier than planned due to lack of efficacy with 8 evaluable subjects in Phase 2 with no clinically meaningful anti-leukemic activity.
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    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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