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    Clinical Trial Results:
    A Phase 2, Randomized, Controlled, Open-Label, Clinical Study of the Efficacy and Safety of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute Myelogenous Leukemia

    Summary
    EudraCT number
    		 2015-000221-37
    Trial protocol
    		 CZ   NL   ES   BE   DE   IE   BG   FR   IT  
    Global end of trial date
    23 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2022
    First version publication date
    28 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Pevonedistat-2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02610777
    WHO universal trial number (UTN)
    		 U1111-1169-6540
    Other trial identifiers
    		 REec: REec-2016-2145, Israel: Pevonedistat-2001CTID
    Sponsors
    Sponsor organisation name
    Millennium Pharmaceuticals, Inc.
    Sponsor organisation address
    40 Landsdowne Street, Cambridge, MA, United States, 02139
    Public contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, TrialDisclosures@takeda.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study is to evaluate the efficacy and safety of pevonedistat plus azacitidine versus single-agent azacitidine in participants with HR-MDS or CMML, or low-blast AML.
    Protection of trial subjects
    All the participants were required to read and sign the Informed Consent Form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Apr 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    United States: 45
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Czechia: 4
    Worldwide total number of subjects
    120
    EEA total number of subjects
    66
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    27
    From 65 to 84 years
    92
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 45 investigative sites in the United States [US], Canada, Belgium, Bulgaria, Czech Republic, Germany, France, Israel, Italy, Spain, and Ireland from 14 April 2016 to 23 July 2021.

    Pre-assignment
    Screening details
    		 Participants diagnosed with myelomonocytic, and myelogenous leukemia were randomized into two groups in 1:1 ratio to receive single-agent azacitidine or azacitidine + pevonedistat.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Azacitidine 75 mg/m^2
    Arm description
    		 Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Azacitidine intravenous or subcutaneous formulation.

    Arm title
    		 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Arm description
    		 Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 and pevonedistat 20 mg/m^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pevonedistat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Pevonedistat intravenous or subcutaneous formulation.

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Azacitidine intravenous or subcutaneous formulation.

    Number of subjects in period 1
    		Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Started
    62
    58
    Response Evaluable Population (REP)
    53
    55
    Completed
    0
    0
    Not completed
    62
    58
         Adverse event, serious fatal
    50
    47
         Consent withdrawn by subject
    2
    2
         Site Terminated by Sponsor
    9
    8
         Lost to follow-up
    1
    -
         Reason not Specified
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Azacitidine 75 mg/m^2
    Reporting group description
    		 Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).

    Reporting group title
    Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Reporting group description
    		 Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 and pevonedistat 20 mg/m^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).

    Reporting group values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2 Total
    Number of subjects
    		 62 58
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.5 ± 8.87 71.7 ± 9.63 -
    Gender categorical
    Units: Subjects
        Male
    		 21 16 37
        Female
    		 41 42 83
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 4 7
        Not Hispanic or Latino
    		 55 52 107
        Unknown or Not Reported
    		 4 2 6
    Race (NIH/OMB)
    Units: Subjects
        Asian
    		 3 1 4
        Black or African American
    		 3 2 5
        White
    		 54 52 106
        Unknown or Not Reported
    		 2 3 5
    Height
    Units: centimeter (cm)
        arithmetic mean (standard deviation)
    		 169.12 ± 10.857 168.87 ± 7.510 -
    Body Surface Area
    Units: square meter (m^2)
        arithmetic mean (standard deviation)
    		 1.92 ± 0.265 1.88 ± 0.201 -
    Weight
    Units: kilogram (kg)
        arithmetic mean (standard deviation)
    		 79.19 ± 18.471 75.95 ± 13.716 -

    End points

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    End points reporting groups
    Reporting group title
    Azacitidine 75 mg/m^2
    Reporting group description
    		 Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).

    Reporting group title
    Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Reporting group description
    		 Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 and pevonedistat 20 mg/m^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).

    Primary: Overall Survival (OS) 

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    End point title
    		 Overall Survival (OS) 
    End point description
    OS was defined as the time from the date of randomization to the date of death due to any cause. Participants without documented death at the time of the analysis were censored at the date the participant was last known to be alive. The Kaplan Meier estimates was used for the analysis. ITT Population was defined as all participants who were randomized.
    End point type
    Primary
    End point timeframe
    From date of randomization until death (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    62
    58
    Units: months
        median (confidence interval 95%)
    19.0 (13.57 to 27.73)
    21.8 (18.53 to 30.88)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.464 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.861
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.577
         upper limit
    		 1.286
    Notes
    [1] - Hazard Ratio (HR) was based on an unstratified Cox proportional hazard regression model with treatment as a factor. P-value is from an unstratified log-rank test.

    Secondary: Event-Free Survival (EFS)

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    End point title
    		 Event-Free Survival (EFS)
    End point description
    EFS is defined as the time from the date of randomization to the date of the occurrence of an event. An event is defined as death or transformation to AML for HR MDS/CMML participants, whichever occurs first, or defined as death for low-blast AML participants. HR MDS/CMML participants without documented EFS event will be censored at the date of the last response assessment. HR MDS/CMML participants with no response assessment and no death will be censored at the date of randomization. Low-blast AML participants without documentation of death will be censored at the date the participant was last known to be alive. HR MDS/CMML participants who received alternative antineoplastic therapy before death or transformation to AML will be censored at the date of last adequate assessment prior to starting alternate antineoplastic therapy. The Kaplan-Meier estimate was used for the analysis. ITT Population was defined as all participants who were randomized.
    End point type
    Secondary
    End point timeframe
    From date of randomization until transformation to AML, or death due to any cause (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    62
    58
    Units: months
        median (confidence interval 95%)
    17.6 (11.96 to 20.50)
    21.0 (17.41 to 28.02)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.092 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.706
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.469
         upper limit
    		 1.061
    Notes
    [2] - P-value is based on the unstratified log-rank test. HR:unadjusted stratified Cox proportional hazard regression with treatment as factor.HR<1:better prevention of EFS in combination arm than azacitidine arm.

    Secondary: Six-month Survival Rate

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    End point title
    		 Six-month Survival Rate
    End point description
    Six-month survival rate was defined as the percentage of participants that survived at the end of the Month 6 from randomization. Percentage of participants was based on Kaplan-Meier estimate of probability. ITT Population was defined as all participants who were randomized. Overall number analyzed are the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    50
    53
    Units: percentage of participants
        number (confidence interval 95%)
    0.806 (0.684 to 0.885)
    0.914 (0.805 to 0.963)
    No statistical analyses for this end point

    Secondary: One-year Survival Rate

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    End point title
    		 One-year Survival Rate
    End point description
    One-year survival rate was defined as the percentage of participants that survived at the end of the first year from randomization. Percentage of participants was based on Kaplan-Meier estimate of probability. ITT Population was defined as all participants who were randomized. Overall number analyzed are the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    42
    49
    Units: percentage of participants
        number (confidence interval 95%)
    0.677 (0.546 to 0.778)
    0.845 (0.723 to 0.916)
    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
    Disease responses for HR MDS or CMML=based on the modified International Working Group (IWG) response criteria for MDS and for low-blast AML on the revised IWG response criteria for AML.CR for HR MDS or CMML:≤5% myeloblasts with normal maturation of all cell lines in the bone marrow ≥11 gram/deciliter (g/dL) hemoglobin (Hb), ≥100*10^9/liter (/L) platelets (plt), ≥1.0*10^9/L absolute neutrophil count (ANC) and 0% blasts in peripheral blood.CR for low-blast AML: morphologic leukemia-free state,ANC of more than 1.0*10^9/L and plt of ≥1.0*10^9/L,transfusion independence,and no residual evidence of extramedullary leukemia.CR with incomplete blood count recovery for low-blast AML:some participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (TTP)(<100*10^9/L).Response-Evaluable Population (REP) included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment.
    End point type
    Secondary
    End point timeframe
    From date of randomization until CR (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    53
    55
    Units: percentage of participants
        number (not applicable)
    36
    45
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.312 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Absolute Rate Difference
    Point estimate
    9.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.83
         upper limit
    		 28.04
    Notes
    [3] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone.

    Secondary: Time to AML Transformation in HR MDS or CMML Participants

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    End point title
    		 Time to AML Transformation in HR MDS or CMML Participants
    End point description
    Time to AML transformation in HR MDS and CMML participants is defined as time from randomization to documented AML transformation. Participants without documented AML transformation at the time of the analysis are censored at the date of the last assessment. Participants who died before progression to AML are censored at the date of death. Transformation to AML is defined, according to World Health Organization (WHO) classification, as a participant having >20% blasts in the blood or marrow and increase of blast count by 50%. ITT Population was defined as all participants who were randomized. Overall number of participants analyzed is the number of participants with data available for analyses. 999= The median, lower limit and upper limit of 95% confidence interval (CI) was not estimable due to lower number of participants with the event.
    End point type
    Secondary
    End point timeframe
    From date of randomization until transformation to AML (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    43
    41
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.267 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.562
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 1.579
    Notes
    [4] - P-value is from an unstratified log-rank test. Hazard ratio (HR) is based on an unstratified Cox proportional hazard regression model with treatment as a factor.

    Secondary: Percentage of Participants With CR and Partial Remission (PR)

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    End point title
    		 Percentage of Participants With CR and Partial Remission (PR)
    End point description
    Disease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML:≤5% myeloblasts with normal maturation of all cell lines in bone marrow, ≥11 g/dL Hb; ≥100*10^9/L plt; ≥1.0*10^9/L ANC and 0% blasts in peripheral blood. PR for HR MDS/CMML:considered achieved if all CR criteria is met except for bone marrow blasts decreased by ≥50%over pretreatment but still >5%. CR for low-blast AML:morphologic leukemia-free state, ANC of >1.0*10^9/L and plt of≥100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CRi for low-blast AML:fulfill criteria for CR except for residual neutropenia (<100*10^9/L)/TTP(<100*10^9/L). PR for low-blast AML:all hematological values for CR but with decrease of ≥50% in percentage of blasts to 5%-25% in bone marrow aspirate. REP: all participants who received ≥1 dose of study drug, had Baseline and ≥1 postbaseline disease assessment.
    End point type
    Secondary
    End point timeframe
    From date of randomization until CR and PR (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    53
    55
    Units: percentage of participants
        number (not applicable)
    45
    51
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56 [5]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Absolute Rate Difference
    Point estimate
    5.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.19
         upper limit
    		 24.44
    Notes
    [5] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone.

    Secondary: Percentage of Participants With Overall Response

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    End point title
    		 Percentage of Participants With Overall Response
    End point description
    Disease responses (HR MDS/CMML): modified IWG criteria for MDS; low-blast (LB) AML: revised IWG criteria for AML. Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ CR with Cri+PR.HR MDS/CMML-CR:≤5%myeloblasts with normal maturation of bone marrow (BM) cell lines,≥11g/dL Hb,≥100*10^9/L plt,≥1.0*10^9/L ANC,0% blasts in peripheral blood; PR:CR criteria met except BM blasts≥50%less over pretreatment but still>5%; HI:hb increase (inc)≥1.5g/dL if baseline<11g/dL;plt inc≥30*10^9/L if baseline>20*10^9/L/Inc. from <20*10^9/L->20*10^9/L, ANC inc. by 100%;absolute inc. of>0.5*10^9/L if baseline<100*10^9/L. LB AML-CR:morphologic leukemia-freestate>1.0*10^9ANC, ≥100*10^9/L plt, transfusion independence, no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L;PR:all CR hematological values but≥50%less in BM aspirate. REP: all participants who received ≥1 dose of study drug, had Baseline and ≥1 postbaseline disease assessment.
    End point type
    Secondary
    End point timeframe
    From date of randomization until CR, PR, or hematologic improvement (HI) (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    53
    55
    Units: percentage of participants
        number (not applicable)
    62
    71
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.343 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Absolute Rate Difference
    Point estimate
    8.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.09
         upper limit
    		 26.38
    Notes
    [6] - P-value was obtained from a stratified Cochran-Mantel-Haenszel chi-square test stratified by low-blast AML. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone.

    Secondary: Percentage of Participants With CR in low-blast AML

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    End point title
    		 Percentage of Participants With CR in low-blast AML
    End point description
    Disease response for low-blast AML is based on the revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=1.0*10^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (TTP) (<100*10^9/L). REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Overall number analyzed are the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    From date of randomization until CR (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    15
    17
    Units: percentage of participants
        number (not applicable)
    60.0
    41.2
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.296 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Absolute Rate Difference
    Point estimate
    -18.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -52.91
         upper limit
    		 15.26
    Notes
    [7] - P-value is from an unstratified Cochran-Mantel-Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone.

    Secondary: Percentage of Participants With CR and PR by Cycle 4

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    End point title
    		 Percentage of Participants With CR and PR by Cycle 4
    End point description
    Disease responses for HR MDS/CMML per modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.CR for HR MDS/CMML:≤5% myeloblasts with normal maturation of all cell lines in BM,≥11 g/dL Hb;≥100*10^9/L plt;≥1.0*10^9/L ANC and 0% blasts in peripheral blood.PR for HR MDS/CMML:achieved if all CR criteria is met except for BM blasts decreased by≥50% over pretreatment but still>5%.CR for low-blast AML:morphologic leukemia-free state,ANC of>1.0*10^9/L and plt of≥100*10^9/L,transfusion independence,no residual evidence of extramedullary leukemia.CRi for low-blast AML:fulfill all criteria for CR except for residual neutropenia (<100*10^9/L)/TTP (<100*10^9/L).PR for low-blast AML:all hematological values for CR but with decrease of ≥50% in percentage of blasts to 5%-25% in BM aspirate.REP:all participants who received ≥1 dose of study drug,had Baseline and ≥1 postbaseline disease assessment.N=number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    From date of randomization until CR and PR, by Cycle 4 (cycle length=28 days)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    38
    38
    Units: percentage of participants
        number (not applicable)
    21.1
    31.6
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.301 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Absolute Rate Difference
    Point estimate
    10.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.13
         upper limit
    		 30.18
    Notes
    [8] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone.

    Secondary: Percentage of Participants With CR by Cycle 4 

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    End point title
    		 Percentage of Participants With CR by Cycle 4 
    End point description
    Disease responses for HR MDS or CMML were based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML. CR for HR MDS or CMML: <=5% myeloblasts with normal maturation of all cell lines in bone marrow, and >=11 g/dL Hb, >=100*10^9/L plt, ANC >=1.0*10^9/L and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Overall number (N) analyzed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    From date of randomization until CR by Cycle 4 (cycle length is equal to [=] 28 days)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    38
    38
    Units: percentage of participants
        number (not applicable)
    13.2
    26.3
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.152 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Absolute Rate Difference
    Point estimate
    13.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.49
         upper limit
    		 30.81
    Notes
    [9] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone.

    Secondary: Percentage of Participants With Overall Response by Cycle 4 

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    End point title
    		 Percentage of Participants With Overall Response by Cycle 4 
    End point description
    Disease responses (HR MDS/CMML): modified IWG criteria for MDS;LB AML:revised IWG criteria for AML.Overall response(HR MDS/CMML)=CR,PR/HI,LB AML=CR+ CR with Cri+PR.HR MDS/CMML-CR:≤5%myeloblasts with normal maturation of BM cell lines,≥11g/dL Hb,≥100*10^9/L plt,≥1.0*10^9/L ANC,0% blasts in peripheral blood;PR:CR criteria met except BM blasts≥50%less over pretreatment but still>5%; HI:hb inc≥1.5g/dL if baseline<11g/dL;plt inc≥30*10^9/L if baseline>20*10^9/L/Inc. from <20*10^9/L->20*10^9/L,ANC inc. by 100%;absolute inc. of>0.5*10^9/L if baseline<100*10^9/L.LB AML-CR:morphologic leukemia-freestate>1.0*10^9ANC,≥100*10^9/L plt,transfusion independence,no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia<1.0*10^9/L/TTP<100*10^9/L;PR:all CR hematological values but≥50%less in BM aspirate.REP was analysed.N=number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    From date of randomization until CR, PR or HI, by Cycle 4 (cycle length=28 days)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    38
    38
    Units: percentage of participants
        number (not applicable)
    44.7
    57.9
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.254 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Absolute Rate Difference
    Point estimate
    13.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.12
         upper limit
    		 35.44
    Notes
    [10] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone.

    Secondary: Percentage of Participants With CR in low-blast AML by Cycle 4 

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    End point title
    		 Percentage of Participants With CR in low-blast AML by Cycle 4 
    End point description
    Disease response for low-blast AML is based on revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and ptl of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for low blast AML participants which is included as the overall number of participants analyzed.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until CR by Cycle 4 (cycle length=28 days)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    15
    17
    Units: percentage of participants
        number (not applicable)
    40.0
    35.3
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.787 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Absolute Rate Difference
    Point estimate
    -4.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.33
         upper limit
    		 28.92
    Notes
    [11] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test. Absolute difference >0 represent better response achieved on pevonedistat combination compared to azacitidine treatment alone.

    Secondary: Duration of Complete Remission (CR) and Partial Remission (PR)

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    End point title
    		 Duration of Complete Remission (CR) and Partial Remission (PR)
    End point description
    Duration of CR=first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML).Disease responses (HR MDS/CMML) are based on modified IWG response criteria for MDS and for low-blast AML on revised IWG response criteria for AML.For HR MDS/CMML-CR:≤5%myeloblasts with normal maturation of all BM cell lines,≥11 g/dL Hb,≥100*10^9/L plt,≥1.0*10^9/L neutrophils,0% blasts in peripheral blood;PR:all CR criteria met except BM blasts ≥50% decrease over pretreatment but still >5%;low-blast AML-CR:morphologic leukemia-free state,>1.0*10^9/L ANC,plt ≥100*10^9/L,transfusion independence,no residual evidence of extramedullary leukemia;CRi:fulfill CR criteria except residual neutropenia <1.0*10^9/L/TTP <100*10^9/L;PR:all CR hematological values but with a decrease of ≥50% in blasts percentage to 5%-25% in bone marrow aspirate. REP was analysed.N=CR and PR responders. 999=Upper limit of full range was not estimable due to lower number of participants with event.
    End point type
    Secondary
    End point timeframe
    From date of randomization until CR or PR (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    24
    28
    Units: months
        median (confidence interval 95%)
    12.9 (8.31 to 999)
    18.6 (10.15 to 999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.436 [12]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.719
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.313
         upper limit
    		 1.653
    Notes
    [12] - P-value is from an unstratified log-rank test. Hazard ratio was based on an unstratified Cox proportional hazard regression model and treatment as a factor in the model.

    Secondary: Duration of Complete Remission (CR)

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    End point title
    		 Duration of Complete Remission (CR)
    End point description
    Duration of CR is first documented CR to the first documentation of PD or relapse from CR (participants with low-blast AML) or relapse after CR or PR (participants with HR MDS/CMML). Disease responses for HR MDS or CMML are based on the Modified IWG Response Criteria for MDS and for low-blast AML on the Revised IWG Response Criteria for AML.CR for HR MDS or CMML≤5% myeloblasts with normal maturation of all cell lines in the bone marrow,≥11 g/dL Hgb,≥100*10^9/L pl,≥1.0*10^9/L neutrophils;0% blasts in peripheral blood.CR for low-blast AML:morphologic leukemia-free state,neutrophils of<1.0*10^9/L;pl of≥100*10^9/L,transfusion independence,no residual evidence of extramedullary leukemia.CRi for low-blast AML: participants fulfill all of the criteria for CR except for residual neutropenia (<1.0*10^9/L) or thrombocytopenia (pl<100*10^9/L). REP was analysed.N=complete responders.999=upper limit of full range was not estimable due to lower number of participants with event.
    End point type
    Secondary
    End point timeframe
    From date of randomization until CR (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    19
    25
    Units: months
        median (full range (min-max))
    12.9 (8.31 to 999)
    18.6 (9.00 to 999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.62 [13]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.789
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.308
         upper limit
    		 2.02
    Notes
    [13] - P-value is from an unstratified log-rank test. Hazard ratio was based on an unstratified Cox proportional hazard regression model and treatment as a factor in the model.

    Secondary: Duration of Overall Response

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    End point title
    		 Duration of Overall Response
    End point description
    OR Duration:Response(RE)to first documentation of PD/relapse(RS)fromCR for low-blast(LB)AML/RS afterCR/PR forHRMDS/CMML.Disease REs(HRMDS/CMML):modifiedIWG criteria(CA) forMDS;LBAML:revisedIWG CA forAML.Overall RE(HRMDS/CMML)=CR,PR/HI,LB AML=CR+CR Cri+PR.HRMDS/CMML-CR:≤5%myeloblasts withBMcell lines’ normal maturation,≥11g/dL Hb,≥100*10^9/L plt,≥1.0*10^9/L ANC,0%blasts(bs) in peripheral blood;PR:CR CA met except BM bs≥50%less over pretreatment,still>5%; HI:hb increase(IE)≥1.5g/dL if baseline(BL)<11g/dL;plt IE≥30*10^9/L if BL>20*10^9/L IEfrom<20*10^9/L->20*10^9/L,ANC IEby100%;absoluteIE>0.5*10^9/L ifBL<100*10^9/L.LBAML-CR:MorphologicLeukemia(LA)-freestate>1.0*10^9 ANC,≥100*1^9/Lplt,transfusion independence,no extramedullaryLA residual(RL)evidence;CRi:fulfil CR CAexcept RLneutropenia<1.0*10^9/L/TTP<100*10^9/L;PR:all CR HematologicValues,≥50%less in BM aspirate.SubjectsAnalyzed=REP responders.999=full range UpperLimit inestimable,less subjects with event.
    End point type
    Secondary
    End point timeframe
    From date of randomization until CR, PR or HI (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    33
    39
    Units: months
        median (full range (min-max))
    14.0 (12.62 to 999)
    20.6 (10.71 to 999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.565 [14]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.395
         upper limit
    		 1.662
    Notes
    [14] - P-value is from an unstratified log-rank test. Hazard ratio was based on an unstratified Cox proportional hazard regression model and treatment as a factor in the model.

    Secondary: Duration of Complete Remission (CR) in Low-blast AML

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    End point title
    		 Duration of Complete Remission (CR) in Low-blast AML
    End point description
    Disease responses for low-blast AML is based on revised IWG response criteria for AML. CR for low-blast AML: morphologic leukemia-free state, ANC of more than 1.0*10^9/L and plt of >=100*10^9/L, transfusion independence, no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery for low-blast AML: some participants fulfill all criteria for CR except for residual neutropenia (<1.0*10^9/L)/TTP (<100*10^9/L). REP included all participants who received at least 1 dose of study drug and had a Baseline and at least 1 postbaseline disease assessment. Data is reported for AML participants which is included as the overall number of participants analyzed.
    End point type
    Secondary
    End point timeframe
    From date of randomization until CR (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    4
    4
    Units: months
        median (full range (min-max))
    10.2 (0.2 to 10.2)
    12.6 (5.6 to 44.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.383 [15]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.057
         upper limit
    		 3.109
    Notes
    [15] - P-value is from an unstratified log-rank test. Hazard ratio was based on an unstratified Cox proportional hazard regression model and treatment as a factor in the model.

    Secondary: Time to First CR or PR

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    End point title
    		 Time to First CR or PR
    End point description
    Time to first CR or PR: time from randomization to first documented CR or PR, whichever occurs first. Disease responses (HR MDS/CMML) based on modified IWG response criteria for MDS; low-blast AML on revised IWG response criteria for AML. HR MDS/CMML-CR:≤5% myeloblasts with normal maturation of all BM cell lines,≥11 g/dL Hb,≥100*10^9/L plt,≥1.0*10^9/L ANC,0% blasts in peripheral blood;PR: all CR criteria met except BM blasts ≥50% decrease over pretreatment but still >5%;For low-blast AML-CR:morphologic leukemia-free state,>1.0*10^9/L ANC, plt ≥100*10^9/L, transfusion independence,no residual evidence of extramedullary leukemia;CR with incomplete blood count recovery:fulfill CR criteria except residual neutropenia <1.0*10^9/L/TTP <100*10^9/L; PR:all CR hematological values but with a decrease of ≥50% in the percentage of blasts to 5% to 25% in the BM aspirate.REP was analysed.999=Upper limit of 95% CI was not estimable due to lower number of participants with event.
    End point type
    Secondary
    End point timeframe
    From date of randomization until CR or PR (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    53
    55
    Units: months
        median (confidence interval 95%)
    13.2 (6.4 to 999)
    8.3 (4.5 to 999)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.498 [17]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.206
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.699
         upper limit
    		 2.081
    Notes
    [16] - HR is based on an unstratified Cox proportional hazard regression model with treatment as a factor. HR>1 for the treatment indicates a shorter time to first CR, CRi or PR in the Pevonedistat Combination arm compared to the Azacitidine only arm.
    [17] - P-value is from an unstratified log-rank test.

    Secondary: Time to Subsequent Therapy

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    End point title
    		 Time to Subsequent Therapy
    End point description
    Time to subsequent therapy is defined as time from randomization to the date of the first subsequent therapy. Subsequent therapy is defined as agent(s) with antileukemic/anti-MDS activity. Participants who discontinue study treatment to receive single-agent azacitidine off study did not be counted as receiving subsequent therapy. ITT Population was defined as all participants who were randomized. 999=The median, lower limit and upper limit of 95% CI was not estimable due to lower number of participants with the event.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to approximately 5 years
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    62
    58
    Units: months
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    HR is based on an unstratified Cox proportional hazard regression model with treatment as a factor. HR>1 for the treatment indicates a shorter time to first CR, CRi or PR in the Pevonedistat Combination arm compared to the Azacitidine only arm.
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.888 [18]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.905
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.226
         upper limit
    		 3.62
    Notes
    [18] - P-value is from an unstratified log-rank test.

    Secondary: Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence 

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    End point title
    		 Percentage of Participants With Red Blood Cells (RBCs) and Platelet-transfusion Independence 
    End point description
    A participant was defined as RBC or platelet-transfusion independent if he/she received no RBC or platelet transfusions for a period of at least 8 weeks before the first dose of study drug through 30 days after the last dose of any study drug. Rate of transfusion independence was defined as number of participants who became transfusion independent divided by the number of participants who were transfusion dependent at Baseline. ITT Population included all participants who were randomized. Overall number analyzed are the number of participants from a subset of the ITT Population who were transfusion dependent at Baseline. Number analyzed is the number of participants who were transfusion dependent at Baseline for the specified category.
    End point type
    Secondary
    End point timeframe
    8 weeks before randomization through 30 days after last dose of any study drug (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    26
    26
    Units: percentage of participants
    number (not applicable)
        RBCs-transfusion Independence(n=26,26)
    50.0
    69.2
        Platelet-transfusion Independence(n=10,5)
    60.0
    80.0
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Percentage of Participants With Platelet-transfusion Independence
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.454 [19]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Absolute Rate Difference
    Point estimate
    20
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.381
         upper limit
    		 66.381
    Notes
    [19] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Percentage of Participants With RBCs-transfusion Independence
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.162 [20]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Absolute Rate Difference
    Point estimate
    19.231
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.925
         upper limit
    		 45.386
    Notes
    [20] - P-value is from an unstratified Cochran-Mantel Haenszel chi-square test.

    Secondary: Percentage of Participants With at least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML

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    End point title
    		 Percentage of Participants With at least 1 Inpatient Hospital Admissions Related to HR MDS, CMML or Low-blast AML
    End point description
    Inpatient hospital admission data was collected through transformation to AML (HR MDS/CMML participants) or disease progression (low-blast AML participants) or until initiation of subsequent therapy (all participants), whichever occurred first. Transformation to AML is defined, according to WHO Classification, as a participant having 20% blasts in the blood or marrow and increase of blast count by 50%. Percentage of participants was calculated as the total number of events divided by the total number of subject-years in each group. ITT Population included all participants who were randomized.
    End point type
    Secondary
    End point timeframe
    From date of randomization until transformation to AML or until initiation of subsequent therapy (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    62
    58
    Units: percentage of participants
        number (confidence interval 95%)
    0.4811 (0.37956 to 0.58265)
    0.5878 (0.42606 to 0.74953)
    No statistical analyses for this end point

    Secondary: Time to Progressive Disease (PD), Relapse, or Death

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    End point title
    		 Time to Progressive Disease (PD), Relapse, or Death
    End point description
    Time from randomization until PD/transformation to AML/relapse/death due to any cause, whichever occurs first. Relapse after CR or PR in MDS/CMML: return to pretreatment bone marrow blast % or decrement of >=50% from maximum remission levels in ANC or plt, reduction in Hb concentration by >=1.5 g/dL or transfusion dependence. PD: at least 50% decrement from maximum remission in ANC or plt, or reduction in Hb by>=2g/dL or transfusion dependence;participants with <5% blasts: >=50% increase (inc) in blasts to >5%; 5%-10%: >=50% inc to >10%; 10%-20%: >=50% inc to>20%;20%-30%:>=50% inc to >30%. Relapse after CR in Low blast AML: reappearance of leukemic blasts in peripheral blood or >=5% blasts in bone marrow not attributable to any cause (example, bone marrow regeneration after consolidation therapy). If there are no circulating blasts, bone marrow contains 5%-20% blasts, a repeat analysis is performed a week later. ITT Population was defined as all participants who were randomized.
    End point type
    Secondary
    End point timeframe
    From date of randomization until PD, relapse or death (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    62
    58
    Units: months
        median (full range (min-max))
    13.6 (9.40 to 16.53)
    15.2 (12.39 to 20.83)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Azacitidine 75 mg/m^2 v Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.266 [22]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.521
         upper limit
    		 1.198
    Notes
    [21] - HR is based on an unstratified Cox proportional hazard regression model with treatment as a factor. A HR<1for the treatment indicates a better prevention of PD, relapse after CR or PR, or death in the Pevonedistat Combination arm compared to the Azacitidine only arm.
    [22] - P-value is from an unstratified log-rank test.

    Secondary: Number of Participants Reporting one or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants Reporting one or More Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    Adverse event=any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.SAE=any untoward medical occurrence that:results in death;is life-threatening;requires inpatient hospitalization or prolongation of existing hospitalization;results in persistent or significant disability/incapacity;leads to a congenital anomaly/birth defect in the offspring of the participant or is a 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.TEAE=any adverse event occurring after the start of pevonedistat administration of the treatment period.Safety Population=all enrolled participants who receive at least 1 dose of any study drug azacitidine alone or pevonedistat + azacitidine.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    62
    58
    Units: participants
        TEAEs
    62
    57
        SAEs
    40
    40
    No statistical analyses for this end point

    Secondary: Number of Participants in the Safety Analysis Population With Clinically Significant Laboratory Abnormalities Reported as TEAEs

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    End point title
    		 Number of Participants in the Safety Analysis Population With Clinically Significant Laboratory Abnormalities Reported as TEAEs
    End point description
    Laboratory assessments included clinical chemistry, hematology, and urinalysis. Safety Population included all enrolled participants who receive at least 1 dose of any study drug azacitidine alone or pevonedistat + azacitidine.
    End point type
    Secondary
    End point timeframe
    From first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    62
    58
    Units: participants
        Neutropenia
    21
    21
        Anaemia
    29
    19
        Neutrophil count decreased
    6
    12
        Thrombocytopenia
    15
    16
    No statistical analyses for this end point

    Secondary: Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status

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    End point title
    		 Number of Participants With Change From Baseline Values in Eastern Cooperative Oncology Group (ECOG) Performance Status
    End point description
    Number of participants with change from Baseline in ECOG performance status was measured on 6 point scale to assess participant’s performance status, where: Grade 0(Normal activity. Fully active, able to carry on all pre-disease activities without restriction); Grade 1(Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work); Grade 2(In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours); Grade 3(In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours); Grade 4(100% bedridden. Completely disabled, cannot carry on any self-care, totally confined to bed or chair); Grade 5(Dead). ITT population=all participants who were randomized in the Safety Population. Only categories for which there was at least 1 participant are reported.
    End point type
    Secondary
    End point timeframe
    From first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    62
    58
    Units: participants
        Baseline: 0; Overall: 0
    13
    9
        Baseline: 0; Overall: 1
    15
    13
        Baseline: 0; Overall: 2
    3
    3
        Baseline: 0; Overall: 3
    0
    2
        Baseline: 0; Overall: 4
    2
    0
        Baseline: 1; Overall: 1
    17
    18
        Baseline: 1; Overall: 2
    5
    8
        Baseline: 1; Overall: 3
    5
    2
        Baseline: 2; Overall: 2
    2
    3
    No statistical analyses for this end point

    Secondary: Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Values Reported as TEAEs

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    End point title
    		 Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Values Reported as TEAEs
    End point description
    ECG assessments included QT, QRS duration, PR interval, ventricular rate, QTcB, QTcF. Safety Population included all enrolled participants who receive at least 1 dose of any study drug azacitidine alone or pevonedistat + azacitidine.
    End point type
    Secondary
    End point timeframe
    From first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    62
    58
    Units: participants
        Atrial fibrillation
    4
    4
        Tachycardia
    1
    4
    No statistical analyses for this end point

    Secondary: Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline Values in Vital Signs Reported as TEAEs

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    End point title
    		 Number of Participants in the Safety Analysis Population With Clinically Significant Change From Baseline Values in Vital Signs Reported as TEAEs
    End point description
    Vital signs assessments included diastolic and systolic blood pressure, heart rate, and body temperature. Safety Population included all enrolled participants who receive at least 1 dose of any study drug azacitidine alone or pevonedistat + azacitidine.
    End point type
    Secondary
    End point timeframe
    From first dose up to 30 days after administration of the last dose of any study drug (up to approximately 5 years)
    End point values
    		 Azacitidine 75 mg/m^2 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Number of subjects analysed
    62
    58
    Units: participants
        Pyrexia
    25
    22
        Hypotension
    3
    6
    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 after administration of the last dose of any study drug (up to approximately 5 years)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events, abnormal laboratory findings, and vital signs. 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
    Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2
    Reporting group description
    		 Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 and pevonedistat 20 mg/m^2, infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).

    Reporting group title
    Azacitidine 75 mg/m^2
    Reporting group description
    		 Azacitidine 75 mg/m^2, infusion, intravenously or subcutaneously, on Day 1 through Day 5, Days 8 and 9 in 28-day treatment cycles until unacceptable toxicity, relapse, transformation to AML (for participants with HR MDS or CMML), or progressive disease (for participants with low-blast AML).

    Serious adverse events
    		 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2 Azacitidine 75 mg/m^2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 58 (68.97%)
    40 / 62 (64.52%)
         number of deaths (all causes)
    47
    50
         number of deaths resulting from adverse events
    8
    11
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung carcinoma cell type unspecified recurrent
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myelodysplastic syndrome transformation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Prostate cancer
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthenia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 58 (5.17%)
    6 / 62 (9.68%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung infiltration
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural hypotension
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Embolic stroke
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cauda equina syndrome
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    13 / 58 (22.41%)
    15 / 62 (24.19%)
         occurrences causally related to treatment / all
    6 / 20
    8 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Parophthalmia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal ulcer perforation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastritis erosive
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic gastritis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic lesion
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anuria
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis reactive
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in jaw
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral viral infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 58 (13.79%)
    7 / 62 (11.29%)
         occurrences causally related to treatment / all
    2 / 12
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pseudomonas infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 58 (6.90%)
    4 / 62 (6.45%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Sinusitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Azacitidine 75 mg/m^2 + Pevonedistat 20 mg/m^2 Azacitidine 75 mg/m^2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 58 (87.93%)
    58 / 62 (93.55%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    7 / 58 (12.07%)
    0 / 62 (0.00%)
         occurrences all number
    11
    0
    Hypotension
         subjects affected / exposed
    6 / 58 (10.34%)
    0 / 62 (0.00%)
         occurrences all number
    7
    0
    Hypertension
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Pallor
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    4 / 58 (6.90%)
    7 / 62 (11.29%)
         occurrences all number
    5
    7
    Fatigue
         subjects affected / exposed
    12 / 58 (20.69%)
    25 / 62 (40.32%)
         occurrences all number
    20
    33
    Chills
         subjects affected / exposed
    4 / 58 (6.90%)
    7 / 62 (11.29%)
         occurrences all number
    4
    7
    Asthenia
         subjects affected / exposed
    18 / 58 (31.03%)
    13 / 62 (20.97%)
         occurrences all number
    28
    20
    Injection site reaction
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Malaise
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    4
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    6
    Oedema peripheral
         subjects affected / exposed
    12 / 58 (20.69%)
    9 / 62 (14.52%)
         occurrences all number
    17
    12
    Pyrexia
         subjects affected / exposed
    21 / 58 (36.21%)
    22 / 62 (35.48%)
         occurrences all number
    36
    34
    Peripheral swelling
         subjects affected / exposed
    5 / 58 (8.62%)
    0 / 62 (0.00%)
         occurrences all number
    6
    0
    Pain
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    22 / 58 (37.93%)
    21 / 62 (33.87%)
         occurrences all number
    31
    25
    Productive cough
         subjects affected / exposed
    6 / 58 (10.34%)
    4 / 62 (6.45%)
         occurrences all number
    7
    5
    Pleural effusion
         subjects affected / exposed
    0 / 58 (0.00%)
    5 / 62 (8.06%)
         occurrences all number
    0
    5
    Oropharyngeal pain
         subjects affected / exposed
    4 / 58 (6.90%)
    6 / 62 (9.68%)
         occurrences all number
    4
    6
    Nasal congestion
         subjects affected / exposed
    5 / 58 (8.62%)
    4 / 62 (6.45%)
         occurrences all number
    5
    5
    Epistaxis
         subjects affected / exposed
    13 / 58 (22.41%)
    6 / 62 (9.68%)
         occurrences all number
    27
    7
    Dyspnoea
         subjects affected / exposed
    13 / 58 (22.41%)
    16 / 62 (25.81%)
         occurrences all number
    15
    21
    Dyspnoea exertional
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 58 (10.34%)
    7 / 62 (11.29%)
         occurrences all number
    6
    8
    Depression
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 62 (0.00%)
         occurrences all number
    5
    0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 58 (6.90%)
    5 / 62 (8.06%)
         occurrences all number
    6
    8
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 58 (6.90%)
    4 / 62 (6.45%)
         occurrences all number
    7
    8
    Blood bilirubin increased
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    8
    0
    Blood creatinine increased
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Neutrophil count decreased
         subjects affected / exposed
    12 / 58 (20.69%)
    6 / 62 (9.68%)
         occurrences all number
    22
    18
    Platelet count decreased
         subjects affected / exposed
    7 / 58 (12.07%)
    7 / 62 (11.29%)
         occurrences all number
    10
    19
    Weight decreased
         subjects affected / exposed
    5 / 58 (8.62%)
    5 / 62 (8.06%)
         occurrences all number
    7
    5
    White blood cell count decreased
         subjects affected / exposed
    4 / 58 (6.90%)
    6 / 62 (9.68%)
         occurrences all number
    12
    11
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    5 / 58 (8.62%)
    4 / 62 (6.45%)
         occurrences all number
    5
    4
    Fall
         subjects affected / exposed
    8 / 58 (13.79%)
    6 / 62 (9.68%)
         occurrences all number
    11
    6
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Tachycardia
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Headache
         subjects affected / exposed
    3 / 58 (5.17%)
    8 / 62 (12.90%)
         occurrences all number
    4
    10
    Dizziness
         subjects affected / exposed
    8 / 58 (13.79%)
    9 / 62 (14.52%)
         occurrences all number
    11
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    19 / 58 (32.76%)
    27 / 62 (43.55%)
         occurrences all number
    38
    51
    Thrombocytopenia
         subjects affected / exposed
    15 / 58 (25.86%)
    15 / 62 (24.19%)
         occurrences all number
    38
    36
    Neutropenia
         subjects affected / exposed
    21 / 58 (36.21%)
    21 / 62 (33.87%)
         occurrences all number
    70
    52
    Febrile neutropenia
         subjects affected / exposed
    0 / 58 (0.00%)
    5 / 62 (8.06%)
         occurrences all number
    0
    7
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    19 / 58 (32.76%)
    17 / 62 (27.42%)
         occurrences all number
    27
    28
    Constipation
         subjects affected / exposed
    21 / 58 (36.21%)
    29 / 62 (46.77%)
         occurrences all number
    39
    38
    Abdominal pain
         subjects affected / exposed
    3 / 58 (5.17%)
    10 / 62 (16.13%)
         occurrences all number
    5
    12
    Stomatitis
         subjects affected / exposed
    0 / 58 (0.00%)
    5 / 62 (8.06%)
         occurrences all number
    0
    5
    Nausea
         subjects affected / exposed
    21 / 58 (36.21%)
    28 / 62 (45.16%)
         occurrences all number
    35
    39
    Haemorrhoids
         subjects affected / exposed
    5 / 58 (8.62%)
    0 / 62 (0.00%)
         occurrences all number
    6
    0
    Vomiting
         subjects affected / exposed
    14 / 58 (24.14%)
    13 / 62 (20.97%)
         occurrences all number
    22
    17
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    4 / 58 (6.90%)
    5 / 62 (8.06%)
         occurrences all number
    5
    6
    Rash maculo-papular
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Pruritus
         subjects affected / exposed
    3 / 58 (5.17%)
    8 / 62 (12.90%)
         occurrences all number
    3
    8
    Petechiae
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    4
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Dysuria
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Haematuria
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 58 (0.00%)
    5 / 62 (8.06%)
         occurrences all number
    0
    6
    Muscle spasms
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Back pain
         subjects affected / exposed
    9 / 58 (15.52%)
    8 / 62 (12.90%)
         occurrences all number
    11
    9
    Arthralgia
         subjects affected / exposed
    6 / 58 (10.34%)
    12 / 62 (19.35%)
         occurrences all number
    7
    15
    Musculoskeletal pain
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    4
    Pain in extremity
         subjects affected / exposed
    10 / 58 (17.24%)
    4 / 62 (6.45%)
         occurrences all number
    12
    5
    Myalgia
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Oral herpes
         subjects affected / exposed
    0 / 58 (0.00%)
    6 / 62 (9.68%)
         occurrences all number
    0
    7
    Oral candidiasis
         subjects affected / exposed
    3 / 58 (5.17%)
    4 / 62 (6.45%)
         occurrences all number
    3
    4
    Nasopharyngitis
         subjects affected / exposed
    7 / 58 (12.07%)
    4 / 62 (6.45%)
         occurrences all number
    10
    4
    Bronchitis
         subjects affected / exposed
    0 / 58 (0.00%)
    7 / 62 (11.29%)
         occurrences all number
    0
    7
    Pneumonia
         subjects affected / exposed
    3 / 58 (5.17%)
    8 / 62 (12.90%)
         occurrences all number
    3
    8
    Urinary tract infection
         subjects affected / exposed
    5 / 58 (8.62%)
    5 / 62 (8.06%)
         occurrences all number
    10
    17
    Respiratory tract infection
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 58 (18.97%)
    13 / 62 (20.97%)
         occurrences all number
    12
    17
    Dehydration
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    5
    Hyperkalaemia
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    10
    Hypocalcaemia
         subjects affected / exposed
    4 / 58 (6.90%)
    4 / 62 (6.45%)
         occurrences all number
    6
    5
    Hyponatraemia
         subjects affected / exposed
    4 / 58 (6.90%)
    4 / 62 (6.45%)
         occurrences all number
    16
    8
    Hypomagnesaemia
         subjects affected / exposed
    3 / 58 (5.17%)
    5 / 62 (8.06%)
         occurrences all number
    3
    7
    Hypokalaemia
         subjects affected / exposed
    4 / 58 (6.90%)
    11 / 62 (17.74%)
         occurrences all number
    5
    18
    Hypophosphataemia
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2015
    The following changes were made in amendment 1: Revise study population to include participants with low-blast acute myelogenous leukemia (AML). Revise the number of participants expected to be enrolled in the study. Clarify definition of progressive disease for participants with low-blast AML. Clarify timing of event-free survival (EFS) visit for participants with higher-risk MDS (HR MDS), chronic myelomonocytic leukemia (CMML), or AML. Revise primary endpoint to reflect the addition of participants with low-blast AML. Revise secondary endpoints to reflect the addition of participants with low-blast AML. Delete secondary endpoint regarding collection of pevonedistat plasma concentrations since this information is captured in a secondary objective. Update statistical methods section to revise hazard ratio calculations and confidence intervals along with the estimated number of EFS events required. Add description of analyses for secondary efficacy endpoints. Revise section on timing of interim analyses (IA).
    13 Sep 2016
    Clarify that relapse includes relapse from complete remission (CR) and partial remission (PR) for participants with MDS/CMML, and relapse from CR for participants with AML. Add cytogenetic CR as an exploratory objective and endpoint. Add evaluation of minimal residual disease in participants who achieve CR in Cycle 4 or Cycle 7 as an exploratory objective and endpoint. Add relapse after CR as a response criterion for AML. Add cytogenetic CR as a response criterion for AML.
    16 Nov 2017
    Realign the analysis of the primary objective and endpoint as related to the change in the definition of an event for participants with low-blast AML. Specify the change in the follow-up process for participants with low-blast AML. Specify the trigger initiating the timing of the overall survival final analysis and other factor(s) that might affect the duration of the study. Clarify that Kaplan-Meier estimates and CIs of 6-month and 1-year survival rates will be provided based on the intent-to-treat population.
    27 Jul 2018
    The following changes were made in amendment 4: Clarify definition of safety population for purposes of analysis. Specify changes in general methodology for analysis of efficacy. Specify analyses of primary efficacy endpoint OS. Clarify methodology for analysis of secondary efficacy endpoints, including those that are response-related. Clarify populations for analyses of health-related quality of life.

    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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