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    Clinical Trial Results:
    A Feasibility Trial of MLN4924 (Pevonedistat, TAK 924, IND#142772) Given in Combination With Azacitidine, Fludarabine, and Cytarabine, in Children, Adolescents, and Young Adults With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

    Summary
    EudraCT number
    		 2019-002935-27
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    22 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Apr 2022
    First version publication date
    02 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ADVL1712
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03813147
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Children's Oncology Group
    Sponsor organisation address
    800 Royal Oaks Dr Suite 210, Monrovia, United States, 91016
    Public contact
    Children’s Oncology Group, Thaila Beeles, tbeeles@childrensoncologygroup.org
    Scientific contact
    Children’s Oncology Group, Thalia Beeles, tbeeles@childrensoncologygroup.org
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002117-PIP01-17
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Sep 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to evaluate tolerability, feasibility of pevonedistat, to define and describe toxicities, and to characterize the pharmacokinetics (PK) of pevonedistat.
    Protection of trial subjects
    All the participants or parents or patient’s guardian were required to read and sign the inform consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 May 2019
    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
    United States: 12
    Worldwide total number of subjects
    12
    EEA total number of subjects
    0
    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)
    5
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at approximately 19 investigative sites in the United States of America from 16 May 2019 up to 22 September 2020.

    Pre-assignment
    Screening details
    		 Pediatric participants diagnosed with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome were enrolled in the single group to receive pevonedisat 20 mg/m^2 in combination with other chemotherapeutic agents.

    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
    		 Pevonedistat 20 mg/m^2
    Arm description
    		 Pevonedistat (20 mg/m^2 for participants ≥1 year of age; 15 mg/m^2 for participants less than 1 year of age), intravenous (IV) over 60 minutes on Days 1, 3, and 5. Azacitidine 75 mg/m^2 IV over 15 minutes once daily (QD) on Days 1-5. Fludarabine phosphate 30 mg/m^2 IV over 30 minutes QD and cytarabine 2000 mg/m^2 IV over 1-3 hours QD on Days 6-10 in 35 day cycle for 1 Cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pevonedistat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pevonedistat IV injection.

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cytarabine IV injection.

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Azacitidine IV injection.

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fludarabine IV injection.

    Number of subjects in period 1
    		Pevonedistat 20 mg/m^2
    Started
    12
    Completed
    0
    Not completed
    12
         Withdrawal of Consent
    1
         Lost to follow-up
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pevonedistat 20 mg/m^2
    Reporting group description
    		 Pevonedistat (20 mg/m^2 for participants ≥1 year of age; 15 mg/m^2 for participants less than 1 year of age), intravenous (IV) over 60 minutes on Days 1, 3, and 5. Azacitidine 75 mg/m^2 IV over 15 minutes once daily (QD) on Days 1-5. Fludarabine phosphate 30 mg/m^2 IV over 30 minutes QD and cytarabine 2000 mg/m^2 IV over 1-3 hours QD on Days 6-10 in 35 day cycle for 1 Cycle.

    Reporting group values
    		 Pevonedistat 20 mg/m^2 Total
    Number of subjects
    		 12
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.8 ( 6.54 ) -
    Gender categorical
    Units: Subjects
        Male
    		 5 5
        Female
    		 7 7
    Race
    Units: Subjects
        White
    		 9 9
        Unknown
    		 3 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 4
        Non-Hispanic and Latino
    		 8 8

    End points

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    End points reporting groups
    Reporting group title
    Pevonedistat 20 mg/m^2
    Reporting group description
    		 Pevonedistat (20 mg/m^2 for participants ≥1 year of age; 15 mg/m^2 for participants less than 1 year of age), intravenous (IV) over 60 minutes on Days 1, 3, and 5. Azacitidine 75 mg/m^2 IV over 15 minutes once daily (QD) on Days 1-5. Fludarabine phosphate 30 mg/m^2 IV over 30 minutes QD and cytarabine 2000 mg/m^2 IV over 1-3 hours QD on Days 6-10 in 35 day cycle for 1 Cycle.

    Primary: Maximum Tolerated Dose (MTD) of Pevonedistat in Combination With with Azacitidine, Fludarabine, and Cytarabine

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    End point title
    		 Maximum Tolerated Dose (MTD) of Pevonedistat in Combination With with Azacitidine, Fludarabine, and Cytarabine [1]
    End point description
    The MTD is the maximum dose at which fewer than one-third of participants experience dose limiting toxicities (DLTs). DLT Analysis Set included all participants who must receive at least 85% of the prescribed dose per protocol guidelines and must have the appropriate toxicity monitoring studies performed to be considered evaluable for dose limiting toxicity. 9999 = MTD could not be established.
    End point type
    Primary
    End point timeframe
    Cycle 1 (Cycle length = 35 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: mg/m^2
        number (not applicable)
    9999
    No statistical analyses for this end point

    Primary: Recommended Phase 2 Dose (RP2D) of Pevonedistat in Combination With with Azacitidine, Fludarabine, and Cytarabine

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    End point title
    		 Recommended Phase 2 Dose (RP2D) of Pevonedistat in Combination With with Azacitidine, Fludarabine, and Cytarabine [2]
    End point description
    The RP2D is the maximum dose at which fewer than one-third of participants experience DLTs. DLT Analysis Set included all participants who must receive at least 85% of the prescribed dose per protocol guidelines and must have the appropriate toxicity monitoring studies performed to be considered evaluable for dose limiting toxicity. 9999 = RP2D could not be established.
    End point type
    Primary
    End point timeframe
    Cycle 1 (Cycle length = 35 days)
    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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: mg/m^2
        number (not applicable)
    9999
    No statistical analyses for this end point

    Primary: Percentage of Participants with Dose Limiting Toxicities (DLTs) of Pevonedistat

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    End point title
    		 Percentage of Participants with Dose Limiting Toxicities (DLTs) of Pevonedistat [3]
    End point description
    Dose-limiting hematological and non-hematological toxicities were defined differently. All Grade 3 or greater non-hematological toxicity not clearly related to the underlying disease and attributable to protocol therapy will be considered a DLT. Hematological DLT attributable to protocol therapy was defined as failure to recover to a peripheral absolute neutrophil count (ANC) > 500 per meter cube (/m^3) and platelets > 20,000 per millimeter square (/mm^2) by 50 days from the start of fludarabine and cytarabine administration, not due to presence of leukemia or severe infection. DLT Analysis Set included all participants who must receive at least 85% of the prescribed dose per protocol guidelines and must have the appropriate toxicity monitoring studies performed to be considered evaluable for dose limiting toxicity.
    End point type
    Primary
    End point timeframe
    Cycle 1 (Cycle length = 35 days)
    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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: percentage of participants
        number (not applicable)
    25.0
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Experienced At Least one Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of Participants Who Experienced At Least one Treatment Emergent Adverse Events (TEAEs) [4]
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered drug; it does not necessarily have to have a causal relationship with the treatment. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and within 30 days of the last administration of study drug. Safety Analysis Set included all participants who received at least one dose of the study drug.
    End point type
    Primary
    End point timeframe
    Up to 30 days post last dose (Up to 2.5 months)
    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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: percentage of participants
        number (not applicable)
    100.00
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Experienced At Least one Serious Adverse Events (SAE)

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    End point title
    		 Percentage of Participants Who Experienced At Least one Serious Adverse Events (SAE) [5]
    End point description
    An SAE was defined as any untoward medical occurrence that: 1) results in death, 2) is life-threatening, 3) requires inpatient hospitalization or prolongation of existing hospitalization, 4) results in persistent or significant disability/incapacity, 5) leads to a congenital anomaly/birth defect in the offspring of the participant or 6) is an medically important event that satisfies any of the following: a) May require intervention to prevent items 1 through 5 above. b) May expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization. Safety Analysis Set included all participants who received at least one dose of the study drug.
    End point type
    Primary
    End point timeframe
    Up to 30 days post last dose (Up to 2.5 months)
    Notes
    [5] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: percentage of participants
        number (not applicable)
    50.0
    No statistical analyses for this end point

    Primary: Percentage of Participants with Clinically Significant Abnormal Laboratory Values

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    End point title
    		 Percentage of Participants with Clinically Significant Abnormal Laboratory Values [6]
    End point description
    The laboratory assessments included hematology, serum chemistry and urinalysis. Any laboratory value outside of reference range and deemed abnormal as assessed by the investigator are reported. Safety Analysis Set included all participants who received at least one dose of the study drug.
    End point type
    Primary
    End point timeframe
    Up to 30 days post last dose (Up to 2.5 months)
    Notes
    [6] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: percentage of participants
        number (not applicable)
    0.0
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Experienced At Least one Treatment Emergent Adverse Events in Relationship to Study Drug

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    End point title
    		 Percentage of Participants Who Experienced At Least one Treatment Emergent Adverse Events in Relationship to Study Drug [7]
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered drug; it does not necessarily have to have a causal relationship with the treatment. A TEAE is any AE either reported for the first time or worsening of a pre-existing event after first dose of study drug and within 30 days of the last administration of study drug. Safety Analysis Set included all participants who received at least one dose of the study drug.
    End point type
    Primary
    End point timeframe
    Up to 30 days post last dose (Up to 2.5 months)
    Notes
    [7] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: percentage of participants
        number (not applicable)
    100.0
    No statistical analyses for this end point

    Primary: Cmax: Maximum Observed Plasma Concentration of Pevonedistat Cycle 1 Day 1

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    End point title
    		 Cmax: Maximum Observed Plasma Concentration of Pevonedistat Cycle 1 Day 1 [8]
    End point description
    Pharmacokinetic (PK) Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [8] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    206.6 ( 42.16 )
    No statistical analyses for this end point

    Primary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Pevonedistat Cycle 1 Day 1

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    End point title
    		 Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Pevonedistat Cycle 1 Day 1 [9]
    End point description
    PK Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [9] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: hours
        median (full range (min-max))
    1.1 (1 to 3)
    No statistical analyses for this end point

    Primary: Cmax: Maximum Observed Plasma Concentration of Pevonedistat Cycle 1 Day 5

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    End point title
    		 Cmax: Maximum Observed Plasma Concentration of Pevonedistat Cycle 1 Day 5 [10]
    End point description
    PK Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [10] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: ng/mL
        geometric mean (standard deviation)
    229.8 ( 35.29 )
    No statistical analyses for this end point

    Primary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Pevonedistat Cycle 1 Day 5

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    End point title
    		 Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Pevonedistat Cycle 1 Day 5 [11]
    End point description
    Pharmacokinetic (PK) Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [11] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: hours
        median (full range (min-max))
    1.1 (1 to 3)
    No statistical analyses for this end point

    Primary: AUC (0-24 h): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of Pevonedistat Cycle 1 Day 1

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    End point title
    		 AUC (0-24 h): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of Pevonedistat Cycle 1 Day 1 [12]
    End point description
    PK Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [12] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: h*ng/mL
        geometric mean (standard deviation)
    783.3 ( 26.43 )
    No statistical analyses for this end point

    Primary: AUC (0-infinity): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Pevonedistat Cycle 1 Day 1

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    End point title
    		 AUC (0-infinity): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Pevonedistat Cycle 1 Day 1 [13]
    End point description
    PK Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable. Number analysed are the number of participants with data available for analysis at the given timepoint.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [13] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    11
    Units: h*ng/ml
        geometric mean (standard deviation)
    790.4 ( 26.98 )
    No statistical analyses for this end point

    Primary: AUC (0-24 h): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of Pevonedistat Cycle 1 Day 5

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    End point title
    		 AUC (0-24 h): Area Under the Plasma Concentration-Time Curve From Time 0 to Time 24 Hours of Pevonedistat Cycle 1 Day 5 [14]
    End point description
    PK Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [14] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: h*ng/ml
        geometric mean (standard deviation)
    869.8 ( 23.68 )
    No statistical analyses for this end point

    Primary: AUC (0-infinity): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Pevonedistat Cycle 1 Day 5

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    End point title
    		 AUC (0-infinity): Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity of Pevonedistat Cycle 1 Day 5 [15]
    End point description
    PK Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [15] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: h*ng/mL
        geometric mean (standard deviation)
    899.3 ( 23.64 )
    No statistical analyses for this end point

    Primary: CL: Clearance of Pevonedistat Cycle 1 Day 1

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    End point title
    		 CL: Clearance of Pevonedistat Cycle 1 Day 1 [16]
    End point description
    PK Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable. Number analysed are the number of participants with data available for analysis at the given timepoint.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [16] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    11
    Units: Liter per hour
        geometric mean (standard deviation)
    30.1 ( 71.23 )
    No statistical analyses for this end point

    Primary: CL: Clearance of Pevonedistat Cycle 1 Day 5

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    End point title
    		 CL: Clearance of Pevonedistat Cycle 1 Day 5 [17]
    End point description
    PK Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [17] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: Liter per hour
        geometric mean (standard deviation)
    26.9 ( 63.73 )
    No statistical analyses for this end point

    Primary: T1/2: Elimination Half-Life of Pevonedistat Cycle 1 Day 1

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    End point title
    		 T1/2: Elimination Half-Life of Pevonedistat Cycle 1 Day 1 [18]
    End point description
    PK Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable. Number analysed are the number of participants with data available for analysis at the given timepoint.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [18] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    11
    Units: hours
        arithmetic mean (standard deviation)
    4.5 ( 1.33 )
    No statistical analyses for this end point

    Primary: T1/2: Elimination Half-Life of Pevonedistat Cycle 1 Day 5

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    End point title
    		 T1/2: Elimination Half-Life of Pevonedistat Cycle 1 Day 5 [19]
    End point description
    PK Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [19] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: hours
        arithmetic mean (standard deviation)
    4.9 ( 1.20 )
    No statistical analyses for this end point

    Primary: Vz: Volume of Distribution in Plasma of Pevonedistat Cycle 1 Day 1

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    End point title
    		 Vz: Volume of Distribution in Plasma of Pevonedistat Cycle 1 Day 1 [20]
    End point description
    PK Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable. Number analysed are the number of participants with data available for analysis at the given timepoint.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [20] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    11
    Units: Litre
        geometric mean (standard deviation)
    184.1 ( 105.54 )
    No statistical analyses for this end point

    Primary: Vz: Volume of Distribution in Plasma of Pevonedistat Cycle 1 Day 5

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    End point title
    		 Vz: Volume of Distribution in Plasma of Pevonedistat Cycle 1 Day 5 [21]
    End point description
    PK Analysis Set included all participants in the Safety Analysis Set and for whom at least 1 PK parameter is evaluable.
    End point type
    Primary
    End point timeframe
    Pre-dose (before start of pevonedistat infusion) and at multiple timepoints (Up to 2 hours) post end of infusion on Days 1 and 5 Cycle 1 Day 5 (Cycle length = 35 days)
    Notes
    [21] - 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: The statistical analysis was not planned to be reported for this endpoint.
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: Litre
        geometric mean (standard deviation)
    183.8 ( 78.51 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Complete Remission with Partial Recovery of Platelet Count (CRp)

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    End point title
    		 Percentage of Participants With Complete Remission with Partial Recovery of Platelet Count (CRp)
    End point description
    CRp was defined by NCI CTCAE Version 5.0 as attainment of an M1 bone marrow (< 5% blasts) and no evidence of circulating blasts or extramedullary disease and with recovery of ANC > 1000/uL and platelet transfusion independence (defined as no platelet transfusions x 1 week). Response-Evaluable Analysis Set included all participants who receive at least one dose of Pevonedistat, have a baseline disease assessment, and have at least one post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to Cycle 1 (Cycle length= 35 days)
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: percentage of participants
        number (not applicable)
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Complete Remission (CR)

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    End point title
    		 Percentage of Participants With Complete Remission (CR)
    End point description
    CR was defined by National Cancer Institue (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 as attainment of an M1 bone marrow (< 5% blasts and adequate marrow cellularity) with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral blood counts (ANC >= 1000 per microliter [/uL] and platelet count > 100,000/uL). Response-Evaluable Analysis Set included all participants who receive at least one dose of Pevonedistat, have a baseline disease assessment, and have at least one post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to Cycle 1 (Cycle length= 35 days)
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: percentage of participants
        number (not applicable)
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Complete Remission with Incomplete Blood Count Recovery (CRi)

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    End point title
    		 Percentage of Participants With Complete Remission with Incomplete Blood Count Recovery (CRi)
    End point description
    CRi was defined by NCI CTCAE Version 5.0 as attainment of an M1 bone marrow (<5% blasts) and no evidence of circulating blasts or extramedullary disease and with ANC < 1000/uL or platelet count < 100,000/uL without platelet transfusion independence (defined as no platelet transfusions x 1 week). Response-Evaluable Analysis Set included all participants who receive at least one dose of Pevonedistat, have a baseline disease assessment, and have at least one post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to Cycle 1 (Cycle length = 35 days)
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: percentage of participants
        number (not applicable)
    25.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Partial Response (PR)

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    End point title
    		 Percentage of Participants With Partial Response (PR)
    End point description
    PR was defined by NCI CTCAE Version 5.0 as attainment of M2 marrow status (> 5% or < 25% blasts cells and adequate cellularity) and at least 50% decrease in bone marrow blast percent from baseline. Bone marrow must have adequate cellularity (e.g. > 10% if a biopsy is performed) to determine response. A repeat bone marrow aspiration within 14 days may be required to distinguish between a PR and increased blasts caused by bone marrow regeneration, and is left to the discretion of the investigator. Response-Evaluable Analysis Set included all participants who receive at least one dose of Pevonedistat, have a baseline disease assessment, and have at least one post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to Cycle 1 (Cycle length= 35 days)
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: percentage of participants
        number (not applicable)
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Overall Complete Remission Rate

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    End point title
    		 Percentage of Participants With Overall Complete Remission Rate
    End point description
    Overall complete remission rate was defined as percentage of participants with CR, CRp and CRi.CR was defined as attainment of an M1 bone marrow (<5% blasts and adequate marrow cellularity) with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral blood counts (ANC>=1000/uL and platelet count >100,000/uL).CRp was defined as attainment of an M1 bone marrow (<5% blasts) and no evidence of circulating blasts or extramedullary disease and with recovery of ANC >1000/uL and platelet transfusion independence.CRi was defined as attainment of an M1 bone marrow (<5% blasts) and no evidence of circulating blasts or extramedullary disease and with ANC < 1000/uL or platelet count < 100,000/uL without platelet transfusion independence.Response-Evaluable Analysis Set included all participants who receive at least one dose of Pevonedistat, have a baseline disease assessment, and have at least one post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to Cycle 1 (Cycle length = 35 days)
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: percentage of participants
        number (not applicable)
    25.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Treatment Failure (TF)

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    End point title
    		 Percentage of Participants With Treatment Failure (TF)
    End point description
    TF was defined by NCI CTCAE Version 5.0 as 1. An increase in the extent of bone marrow infiltration by leukemic cells (absolute increase of >= 20% blasts). 2. Development of extramedullary disease (EMD). 3. M2 marrow that does not qualify for PR status. 4. An M1 marrow with circulating blasts. 5. > 25% blasts in the bone marrow after Cycle 1 of therapy. 6. Participants who have persistent central nervous system (CNS) disease despite 6 doses of intrathecal (IT) cytarabine or IT triples. Response-Evaluable Analysis Set included all participants who receive at least one dose of Pevonedistat, have a baseline disease assessment, and have at least one post-baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    Up to Cycle 1 (Cycle length = 35 days)
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: percentage of participants
        number (not applicable)
    75.0
    No statistical analyses for this end point

    Secondary: Duration of Complete Response

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    End point title
    		 Duration of Complete Response
    End point description
    Duration of disease response in months is defined as the time measured in months, from the date of first documented disease response to the date of first documentation of relapse or progression. For participant without relapse or disease progression, duration of disease was censored at the last disease assessment date. Response-Evaluable Analysis Set included all participants who receive at least one dose of Pevonedistat, have a baseline disease assessment, and have at least one post-baseline disease assessment. 9999 = Median and full range of duration of complete response was not estimable due to fewer number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to Cycle 1 (Cycle length = 35 days)
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    12
    Units: months
        median (full range (min-max))
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Pharmacodynamic Parameter mRNA Transcript Levels of Pevonedistat

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    End point title
    		 Pharmacodynamic Parameter mRNA Transcript Levels of Pevonedistat
    End point description
    Not Applicable
    End point type
    Secondary
    End point timeframe
    Not Applicable
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    0 [22]
    Units: Not Applicable
        number (not applicable)
    Notes
    [22] - The data is not available because the panned analysis was not conducted for this endpoint.
    No statistical analyses for this end point

    Secondary: Pharmacodynamic Parameter NEDDylated Protein Analysis

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    End point title
    		 Pharmacodynamic Parameter NEDDylated Protein Analysis
    End point description
    End point type
    Secondary
    End point timeframe
    Not Applicable
    End point values
    		 Pevonedistat 20 mg/m^2
    Number of subjects analysed
    0 [23]
    Units: Not Applicable
        number (not applicable)
    Notes
    [23] - The data is not available because the panned analysis was not conducted for this endpoint.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose up to 30 days post last dose (Up to 2.5 months)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Pevonedistat 20 mg/m^2
    Reporting group description
    		 Pevonedistat (20 mg/m^2 for participants ≥1 year of age; 15 mg/m^2 for participants less than 1 year of age), intravenous (IV) over 60 minutes on Days 1, 3, and 5. Azacitidine 75 mg/m^2 IV over 15 minutes once daily (QD) on Days 1-5. Fludarabine phosphate 30 mg/m^2 IV over 30 minutes QD and cytarabine 2000 mg/m^2 IV over 1-3 hours QD on Days 6-10 in 35 day cycle for 1 Cycle.

    Serious adverse events
    		 Pevonedistat 20 mg/m^2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 12 (50.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pevonedistat 20 mg/m^2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Hypertension
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Fatigue
         subjects affected / exposed
    8 / 12 (66.67%)
         occurrences all number
    8
    Oedema peripheral
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    4
    Face oedema
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Localised oedema
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Pain
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    4
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Chills
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Pelvic pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Tachypnoea
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    4
    Hypoxia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Atelectasis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Productive cough
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nasal congestion
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Irritability
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    10 / 12 (83.33%)
         occurrences all number
    11
    Lymphocyte count decreased
         subjects affected / exposed
    10 / 12 (83.33%)
         occurrences all number
    10
    Neutrophil count decreased
         subjects affected / exposed
    8 / 12 (66.67%)
         occurrences all number
    8
    Blood bicarbonate decreased
         subjects affected / exposed
    8 / 12 (66.67%)
         occurrences all number
    8
    Platelet count decreased
         subjects affected / exposed
    7 / 12 (58.33%)
         occurrences all number
    7
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 12 (50.00%)
         occurrences all number
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 12 (50.00%)
         occurrences all number
    6
    Blood bilirubin increased
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Blood creatinine increased
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Weight decreased
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Blood calcium decreased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Ejection fraction decreased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Cardiac murmur
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Lipase increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    International normalised ratio increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Haemoglobin increased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Infusion related reaction
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Fall
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Vascular access complication
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    6 / 12 (50.00%)
         occurrences all number
    6
    Sinus bradycardia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Angina pectoris
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Palpitations
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Dizziness
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Paraesthesia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Dyskinesia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Somnolence
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Tremor
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 12 (83.33%)
         occurrences all number
    10
    Febrile neutropenia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Haemolysis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Lymph node pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Eye disorders
    Eye disorder
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Vision blurred
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Vitreous floaters
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 12 (50.00%)
         occurrences all number
    6
    Vomiting
         subjects affected / exposed
    6 / 12 (50.00%)
         occurrences all number
    6
    Nausea
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Stomatitis
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    4
    Diarrhoea
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Mouth haemorrhage
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Abdominal distension
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Anal incontinence
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Ascites
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Dental caries
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Gingival pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Lip pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Oral pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Tooth discolouration
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    5
    Pruritus
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Alopecia
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Dry skin
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Hyperhidrosis
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Pain of skin
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Petechiae
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Purpura
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Skin ulcer
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Glycosuria
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Micturition urgency
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Pollakiuria
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    3
    Bone pain
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Arthralgia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Joint range of motion decreased
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Limb mass
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Sepsis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Phlebitis infective
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Skin infection
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    9 / 12 (75.00%)
         occurrences all number
    9
    Hyponatraemia
         subjects affected / exposed
    8 / 12 (66.67%)
         occurrences all number
    9
    Hyperphosphataemia
         subjects affected / exposed
    7 / 12 (58.33%)
         occurrences all number
    7
    Hypoalbuminaemia
         subjects affected / exposed
    7 / 12 (58.33%)
         occurrences all number
    7
    Hypokalaemia
         subjects affected / exposed
    7 / 12 (58.33%)
         occurrences all number
    7
    Hypophosphataemia
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Decreased appetite
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Hypocalcaemia
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Hypermagnesaemia
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    4
    Hypercalcaemia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Hypomagnesaemia
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Hyperkalaemia
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Hyperuricaemia
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Acidosis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Hypernatraemia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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