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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    2014-002172-92
    Trial protocol
    DE   DK   NL   FR  
    Global end of trial date
    08 Oct 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Apr 2020
    First version publication date
    17 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AZA-AML-004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02450877
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 908-673-9100, ClinicalTrialDisclosure@Celgene.com
    Scientific contact
    Bouchra Benettaib, Celgene Corporation, 01 908 673 9194, BBenettaib@Celgene.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    01 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Oct 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main 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 acute myeloid leukemia (AML) subjects at molecular relapse after complete response (CR1) when compared to no treatment with regard to the progression-free rate (PFR) at Day 84 (±4 days) post randomization.
    Protection of trial subjects
    Patient Confidentiality, Informed Consent, Archiving of Essential Documents,
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Aug 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Netherlands: 2
    Worldwide total number of subjects
    7
    EEA total number of subjects
    7
    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)
    0
    Children (2-11 years)
    6
    Adolescents (12-17 years)
    1
    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
    Seven children were enrolled from 3 centers located in Denmark, Germany and the Netherlands.

    Pre-assignment
    Screening details
    The Randomized Part of the study was not conducted. The study was transitioned to a single-arm study (N=20) Phase 2 non-Celgene sponsored study.

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

    Arms
    Arm title
    Azacitidine
    Arm description
    Participants received azacitidine 100 mg/m^2 by intravenous administration on days 1 to 7 of each 28-day treatment cycle for a maximum of 3 cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Vidaza
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Azacitidine 100 mg/m^2 by IV administration on days 1 to 7 of each 28 day treatment cycle.

    Number of subjects in period 1
    Azacitidine
    Started
    7
    Completed
    5
    Not completed
    2
         Death
    1
         Disease Relapse
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Azacitidine
    Reporting group description
    Participants received azacitidine 100 mg/m^2 by intravenous administration on days 1 to 7 of each 28-day treatment cycle for a maximum of 3 cycles.

    Reporting group values
    Azacitidine Total
    Number of subjects
    7 7
    Age Categorical
    Units: Subjects
        Children (2-11 years)
    6 6
        Adolescents (12-17 years)
    1 1
    Age Continuous
    Units: years
        median (full range (min-max))
    6.7 (2 to 12) -
    Gender Categorical
    Units: Subjects
        Female
    2 2
        Male
    5 5
    Race
    Units: Subjects
        White
    7 7
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    7 7
    World Health Organization Acute Myeloid Leukemia Classification
    Eligible subjects must have had a documented diagnosis of AML with at least one of the following molecular aberrations t(8;21), RUNX1-RUNX1T1, inv(16), CBFb/MYH11, t(9;11), MLL-AF9, NPM1 mutation, or FLT3-ITD mutation. A subject was counted more than once if there was several AML diagnoses. t(8;21), RUNX1-RUNX1T1 = 3 inv(16), CBFb/MYH11 = 4 FLT3-ITD mutation = 1
    Units: Subjects
        t(8;21), RUNX1-RUNX1T1
    3 3
        inv(16), CBFb/MYH11
    4 4
    Duration of the Disease
    Units: Months
        median (full range (min-max))
    10.320 (9.00 to 13.11) -

    End points

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    End points reporting groups
    Reporting group title
    Azacitidine
    Reporting group description
    Participants received azacitidine 100 mg/m^2 by intravenous administration on days 1 to 7 of each 28-day treatment cycle for a maximum of 3 cycles.

    Primary: Part 1 Safety Run In: Number of Participants with Dose Limiting Toxicities (DLT)

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    End point title
    Part 1 Safety Run In: Number of Participants with Dose Limiting Toxicities (DLT) [1]
    End point description
    Dose limiting toxicities were evaluated during the Part 1 Safety Run-in period in the first 6 subjects during Cycle 1. The severity grading was determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03. A DLT is defined as below: Hematologic DLT: • Grade 3 or 4 hematologic toxicity requiring treatment delay > 21 days (disease-related Grade 3 or 4 hematologic toxicity was not counted as a DLT) Non-Hematologic DLT: • Grade 4 nonhematologic toxicity (excluding transient transaminase elevation) • Grade 3 nonhematological toxicity lasting more than 7 days despite optimal treatment with standard supportive measures • Grade 5 Adverse Events (AEs) considered related to study treatment The safety population was defined as all subjects who received at least 1 dose of study therapy if assigned to receive azacitidine.
    End point type
    Primary
    End point timeframe
    Cycle 1 (28 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: No statistical analysis was performed.
    End point values
    Azacitidine
    Number of subjects analysed
    6
    Units: Participants
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Treatment Emergent Adverse Events (TEAE)

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    End point title
    Number of Participants with Treatment Emergent Adverse Events (TEAE) [2]
    End point description
    Treatment emergent adverse events were defined as any AEs occurring or worsening on or after the first treatment of the study medication and up to and including 28 days after the last dose. The intensity of AEs was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (version 4.0, May 2009). For all other AEs not described in the NCI-CTCAE criteria, the intensity was assessed by the investigator as mild (grade 1), moderate (grade 2), severe (grade 3), life-threatening (grade 4) or death (grade 5). The safety population was defined as all subjects who received at least 1 dose of study therapy if assigned to receive azacitidine.
    End point type
    Primary
    End point timeframe
    From the first dose of investigational product (IP) up to and including 28 day after the last dose of azacitidine; up to 01 November 2019; median treatment duration was 12.00 weeks, with minimum and maximum durations of 8.0 and 13.9 weeks, respectively.
    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: No statistical analysis was performed.
    End point values
    Azacitidine
    Number of subjects analysed
    7
    Units: Participants
        ≥1 TEAE
    7
        ≥1 Grade 3 or Higher TEAE
    7
        ≥1 Treatment-related TEAE
    7
        ≥1 Treatment-related Grade 3 or Higher TEAE
    5
        ≥1 Serious TEAE
    3
        ≥1 Treatment-related Serious TEAE
    1
        ≥1 TEAE Leading to Death
    0
        ≥1 TEAE Leading to IP Discontinuation
    0
        ≥1 TEAE Leading to IP Dose Reduction
    0
        ≥1 TEAE Leading to IP Dose Interruption
    2
    No statistical analyses for this end point

    Secondary: Number of Participants with a Molecular Response [by Minimal Residual Disease (MRD)] at Day 84

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    End point title
    Number of Participants with a Molecular Response [by Minimal Residual Disease (MRD)] at Day 84
    End point description
    The number of participants with a molecular response was defined as the number of subjects with molecular response [1 log or more decrease in defined MRD molecular markers from baseline for all subject-specific genes or aberrations in peripheral blood (PB) samples and bone marrow (BM) aspirates]. The ITT population included participants who were enrolled in the study regardless of whether or not they received any of the study treatment.
    End point type
    Secondary
    End point timeframe
    Date of Enrollment to Day 84
    End point values
    Azacitidine
    Number of subjects analysed
    7
    Units: Participants
    1
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of Azacitidine

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    End point title
    Maximum Plasma Concentration (Cmax) of Azacitidine
    End point description
    Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration versus time. The pharmacokinetic (PK) population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
    End point type
    Secondary
    End point timeframe
    Subjects ≤20 kg, pre-dosing at Cycle 1 Day 5 and 6 (C1 D5,D6) and post dose at Cycle 1 Day 7 (C1D7) at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5,D6 and D7, post dose on C1D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
    End point values
    Azacitidine
    Number of subjects analysed
    6
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    1556.633 ± 201.6
    No statistical analyses for this end point

    Secondary: Time to Maximum Plasma Concentration (Tmax) of Azacitidine

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    End point title
    Time to Maximum Plasma Concentration (Tmax) of Azacitidine
    End point description
    Tmax was defined as the observed time to maximum plasma concentration of azacitidine. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
    End point type
    Secondary
    End point timeframe
    Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
    End point values
    Azacitidine
    Number of subjects analysed
    6
    Units: Hours
        median (full range (min-max))
    0.090 (0.08 to 0.53)
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration Versus Time Curve from Time 0 to the Last Quantifiable Concentration (AUC0-t) of Azacitidine

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    End point title
    Area Under the Plasma Concentration Versus Time Curve from Time 0 to the Last Quantifiable Concentration (AUC0-t) of Azacitidine
    End point description
    AUC0-t was defined as the area under the plasma concentration-time curve from time zero to the last quantifiable time point, for azacitidine, calculated by the linear trapezoidal rule. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
    End point type
    Secondary
    End point timeframe
    Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
    End point values
    Azacitidine
    Number of subjects analysed
    6
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    885.652 ± 86.3
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Curve from Time 0 to 24 Hours Post-dose (AUC0-24) of Azacitidine

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    End point title
    Area Under the Plasma Concentration-time Curve from Time 0 to 24 Hours Post-dose (AUC0-24) of Azacitidine
    End point description
    Area under the plasma concentration-time curve from time 0 to 24 hours post- dose of azacitidine following multiple doses of azacitidine. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
    End point type
    Secondary
    End point timeframe
    Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
    End point values
    Azacitidine
    Number of subjects analysed
    6
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    899.647 ± 87.8
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Curve from Time Zero 0 Infinity (AUC∞) of Azacitidine

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    End point title
    Area Under the Plasma Concentration-time Curve from Time Zero 0 Infinity (AUC∞) of Azacitidine
    End point description
    Area under the plasma concentration-time curve from time zero to infinity, extrapolated to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity and was calculated according to the following equation: AUC∞ = AUCt + (Ct/λz), where Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz. If AUC% Ext was > 25%, AUC∞ was not be reported. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
    End point type
    Secondary
    End point timeframe
    Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hou
    End point values
    Azacitidine
    Number of subjects analysed
    5
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    787.616 ± 88.8
    No statistical analyses for this end point

    Secondary: Terminal Phase Rate Constant (λz) of Azacitdine

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    End point title
    Terminal Phase Rate Constant (λz) of Azacitdine
    End point description
    Terminal phase rate constant, determined by linear regression of the terminal points of the log-linear plasma concentration-time curve. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
    End point type
    Secondary
    End point timeframe
    Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
    End point values
    Azacitidine
    Number of subjects analysed
    6
    Units: L/hr
        geometric mean (geometric coefficient of variation)
    1.489 ± 59.5
    No statistical analyses for this end point

    Secondary: Terminal Phase Half-life (t½) of Azacitidine

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    End point title
    Terminal Phase Half-life (t½) of Azacitidine
    End point description
    Terminal phase half-life was calculated according to the following equation: t½ = 0.693/λz. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
    End point type
    Secondary
    End point timeframe
    Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
    End point values
    Azacitidine
    Number of subjects analysed
    5
    Units: Hours
        geometric mean (geometric coefficient of variation)
    0.380 ± 32.2
    No statistical analyses for this end point

    Secondary: Apparent Total Plasma Clearance (CL/) of Azacitidine

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    End point title
    Apparent Total Plasma Clearance (CL/) of Azacitidine
    End point description
    Apparent total clearance was calculated as Dose/AUC∞. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
    End point type
    Secondary
    End point timeframe
    Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
    End point values
    Azacitidine
    Number of subjects analysed
    5
    Units: mL/hr
        geometric mean (geometric coefficient of variation)
    127199.754 ± 73.3
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution (Vz/F) of Azacitidine

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    End point title
    Apparent Volume of Distribution (Vz/F) of Azacitidine
    End point description
    Apparent volume of distribution of azacitidine was calculated according to the equation Vz = (CL)/λz. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
    End point type
    Secondary
    End point timeframe
    Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
    End point values
    Azacitidine
    Number of subjects analysed
    5
    Units: Liters
        geometric mean (geometric coefficient of variation)
    70.24 ± 83.7
    No statistical analyses for this end point

    Secondary: Kaplan Meier Estimate of Leukemia-free Survival (LFS)

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    End point title
    Kaplan Meier Estimate of Leukemia-free Survival (LFS)
    End point description
    Leukemia-free survival was defined as the time from study enrollment until disease progression (identified as clinical progression/clinical relapse) or death. Subjects alive and disease progression free at the time of the statistical analysis were censored at the time they were last known to be alive. The Intent to Treat population included participants who were enrolled in the study regardless of whether or not they received any of the study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of study enrollment until the end of the safety run-in period; median follow-up time was 14.5 months (14.0 months to 36.0 months)
    End point values
    Azacitidine
    Number of subjects analysed
    7 [3]
    Units: months
        median (confidence interval 95%)
    99999 (2.3 to 99999)
    Notes
    [3] - 99999 = Median not calculable; more than 50% of subjects had not had a LFS event at time of analysis
    No statistical analyses for this end point

    Secondary: Minimal Residual Disease Level (MRD) at Day 84

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    End point title
    Minimal Residual Disease Level (MRD) at Day 84
    End point description
    Minimal residual disease was analyzed using real-time polymerase chain reaction (RQ-PCR) of a subject specific fusion gene or aberration. MRD level was used to evaluate response based on following guideline: - Molecular stabilization was defined as < 1 log decrease or increase of specific PCR marker from baseline. - Molecular progression was defined as ≥ 1 log increase of specific PCR marker from baseline to a level of 5 x 10^-4 or above in the absence of signs of clinical relapse, in MRD-negative subjects. The rise had to be at least 1 log (10-fold) greater than previous sensitivity to a level of 5 x 10^-4 or above. - Molecular improvement was defined as ≥ 1 log decrease of specific PCR marker from baseline. - Clinical relapse was defined as at least 5% blasts in peripheral blood (PB) and/or BM and/or proven histological extramedullary relapse. The population included are the subjects with Day 84 information and completed treatment period
    End point type
    Secondary
    End point timeframe
    Enrollment to Day 84
    End point values
    Azacitidine
    Number of subjects analysed
    7 [4]
    Units: MRD Level In Bone Marrow
        median (full range (min-max))
    0.0041 (0.001 to 0.083)
    Notes
    [4] - Levels in bone marrow are for 4 subjects at day 84
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate of Overall Survival

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    End point title
    Kaplan-Meier Estimate of Overall Survival
    End point description
    Overall survival was defined as the time from study enrollment (safety run-in part) until death from any cause. Subjects alive at the time of the statistical analysis were censored at the time they were last known to be alive. The ITT population included participants who were enrolled in the study regardless of whether or not they received any of the study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of study enrollment until the end of the safety run-in period; up to 09 October 2019; median follow-up time was 14.5 months (range: 14.0 months to 36.0 months)
    End point values
    Azacitidine
    Number of subjects analysed
    7 [5]
    Units: months
        median (confidence interval 95%)
    99999 (2.4 to 99999)
    Notes
    [5] - 99999 = median overall survival not reached due to low number of events.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of the first dose of study drug up to and including 28 days after the last dose of study drug. Median treatment duration was 12.00 weeks, with minimum and maximum duration of 8.0 and 13.9 weeks, respectively.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Azacitidine 100mg/m^2
    Reporting group description
    -

    Serious adverse events
    Azacitidine 100mg/m^2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 7 (42.86%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Azacitidine 100mg/m^2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    General disorders and administration site conditions
    Catheter site erythema
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Face oedema
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    3
    Influenza like illness
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Injection site reaction
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    3
    Irritability
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 7 (42.86%)
         occurrences all number
    10
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    3
    Blood creatinine increased
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Cardiac failure
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2
    Nasal congestion
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Leukopenia
         subjects affected / exposed
    3 / 7 (42.86%)
         occurrences all number
    5
    Neutropenia
         subjects affected / exposed
    7 / 7 (100.00%)
         occurrences all number
    20
    Thrombocytopenia
         subjects affected / exposed
    3 / 7 (42.86%)
         occurrences all number
    10
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    3
    Neuralgia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Aphthous ulcer
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    3 / 7 (42.86%)
         occurrences all number
    5
    Mucous stools
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    3
    Nausea
         subjects affected / exposed
    5 / 7 (71.43%)
         occurrences all number
    11
    Stomatitis
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Night sweats
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    3
    Pruritus
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Pruritus generalised
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Rash generalised
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    Flank pain
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    2
    Hyperkalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    3
    Hypermagnesaemia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Hyperphosphataemia
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Infections and infestations
    Device related infection
         subjects affected / exposed
    2 / 7 (28.57%)
         occurrences all number
    3
    Fungal skin infection
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    2
    Viral tonsillitis
         subjects affected / exposed
    1 / 7 (14.29%)
         occurrences all number
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jan 2015
    • To address Germany’s Federal Institute of Drugs and Medical Devices (BfArM) concerns regarding blood volumes, this amendment reduced the amount of blood being collected for PK. Each collection timepoint now required 1 mL of blood instead of 2 mL of blood. Also, for pediatric subjects weighing ≤ 20 kg, in order to minimize blood collection for these smaller children, only 5 timepoints were collected for PK assessments on Cycle 1 Day 7 (5 minutes postdose, 30 minutes postdose, 1 hour postdose, 4 hours postdose and 6 hours postdose), as opposed to the 7 collection timepoints required for subjects weighing > 20 kg (prior to dosing, 5 minutes postdose, 30 minutes postdose, 1 hour postdose, 2 hours postdose, 4 hours postdose and 6 hours postdose). • To address BfArM’s concerns regarding dose reductions due to renal impairment and to be consistent with the azacitidine investigator’s brochure, dose reduction guidelines based on fluctuations in serum creatinine were added to the protocol. The statement that dose adjustments were not allowed was removed. • In order to further minimize blood collection for this pediatric population, the blood volumes for hematology assessments were reduced from 2 mL to 1 mL at each timepoint. • The detailed guidance to destroy/return used or unused azacitidine vials was replaced with protocol template language that the clinical research associate was to review with the site the process for return/disposal/destruction of the IV vials.
    14 May 2015
    Clarification: the collection of the samples for confirmation of MR was to occur within 7 days of the detection of MR. Clarification: confirmation of MR required PB and BM MRD levels to be higher than the MRD level in the PB at the time of detection. Clarification: point of entry of subjects into the Long-term Follow-up Period (LTFUP) after 28 day safety follow-up was clarified for the Safety Run-in Part (SRI) and for the Randomized Part (RP).. Clarification: if HSCT was performed during the LTFU, a clinic visit had to occur pre-HSCT and at 3 and 6 months post-HSCT to have BM samples collected. Inclusion criteria regarding first CR1 for both SRI Part and RP were revised. For the RP, the collection of SAEs related to HSCT was added to the LTFU Period. Clarification: specific predrug eligibility criteria had to be verified prior to randomizing the subject into the RP. A 14-day visit window was added to Day 1 of Cycles 2 and 3 in the SRI Part and the EA of the RP. Clarification: the LTFU Period would last for 2 years from last subject enrolled/randomized. Guidances added for pregnancy testing for females ≥8 years or achieved menarche and for subjects <18 who reached the age of 18 while being treated that they had to agree to undergo physician approved reproductive education and discuss the side effects of study therapy with study doctor. Clarification: archived BM aspirate from initial diagnosis needed to be sent to the central laboratory in the RP only. Windows for PK blood sampling timepoints were added Clarification: in the Randomized Part, the central laboratory would use the BM aspirate sample from initial diagnosis to confirm the molecular aberrations Clarification: added about the IV solution preparation and administration time. Clarification: added about the treatment delay exception in start of 2nd and 3rd cycles due to renal toxicity
    26 Oct 2017
    • Molecular response (MR) at Day 84 (± 4 days) (or end of Cycle 3, if not the same date) was included as a secondary efficacy endpoint for the Safety Run-in Part. MR at end of Cycle 3 or Day 84 (± 4 days) (or end of Cycle 3, if not the same date) was added to evaluate the preliminary efficacy of the IP in the Safety Run-in Part prior to start of the Randomized Portion and to minimize subject exposure if the IP was not efficacious. • The secondary endpoints of changes in DNA methylation (assessments of BM samples using Nano-HELP assay) and MRD at 3 and 6 months post-HSCT were deleted in the Safety Run-in Part . A decision was made to evaluate these in the Randomized Phase only since sufficient patient information would be available for informative analysis. Deletion of these endpoints in a Safety Run-in would minimize unnecessary assessment and subject burden, especially in regard to frequent BM biopsies that are not standard of care. • Sample size of the Safety Run-in Part was increased from 12 to 18 to allow 6 additional subjects to enroll to assess preliminary efficacy prior to start of the Randomized Portion and to minimize subject exposure if the IP was not efficacious. 6 subjects had already been enrolled to the 100 mg/m2 dose of AZA. If this dose was deemed not safe or tolerable, 6 additional subjects were to be enrolled in a 75 mg/m2 cohort. Once the safe and tolerable dose level was determined, 6 further subjects were to be treated at the highest tolerated dose to gain preliminary efficacy, for a potential sample size of 18 patients (6 subjects in 100 mg/m2 cohort, 6 subjects in the 75 mg/m2 cohort, 6 subjects to assess preliminary efficacy). The Long-term Follow-up was reduced to 1 year from the last dose of IP instead of 2 years from last subject enrolled since there were no safety concerns and 1 year of information post last dose would provide enough safety information and should allow sufficient time to follow the subjects through HSCT.

    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 Randomized Part of the study was not conducted. The study was transitioned to a single-arm study (N=20) Phase 2 non-Celgene sponsored study.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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