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    Clinical Trial Results:
    A Phase Ib/II open label dose confirmation, proof of concept study of siremadlin in combination with venetoclax plus azacitidine in unfit adult AML participants who responded sub-optimally to first-line venetoclax plus azacitidine treatment and in participants with newly diagnosed unfit AML presenting with high-risk clinical features. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points and zeros where there is no data to report in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete rial results.

    Summary
    EudraCT number
    		 2021-001165-21
    Trial protocol
    		 HU   IT   ES   DE  
    Global end of trial date
    17 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 May 2025
    First version publication date
    01 May 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CHDM201I12201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05155709
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novatis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novatis.email@novartis.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
    17 Apr 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Apr 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the recommended dose of siremadlin in combination with venetoclax plus azacitidine to be explored further in the expansion phase (RDE), separately in Arm 1 and Arm 2.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaraion of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 May 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Türkiye: 1
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    14
    EEA total number of subjects
    3
    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)
    1
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 10 sites in 7 countries. The study aimed to evaluate two sub-populations of adult participants with unfit AML in two separate arms: participants who responded sub-optimally to first-line venetoclax plus azacitidine treatment & participants with newly diagnosed untreated AML presenting with high-risk clinical features.

    Pre-assignment
    Screening details
    		 28 participants were screened in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1: Adult participants with unfit AML
    Arm description
    		 Adult participants with unfit AML who responded sub-optimally to at least 2 and not more than 4 cycles of first-line venetoclax plus azacitidine therapy. Siremadlin was administered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m^2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Siremadlin
    Investigational medicinal product code
    HDM201
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Siremadlin (HDM201) was provided orally in the form of 10 mg, 20 mg and 30 mg (might have been included as an additional strength) capsules. Subjects were dosed at 20 mg.

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection, Powder for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Azacitidine was provided in 100 mg (formulation provided as approved by regulations) was provided as powder for suspension for injection, or powder for solution for subcutaneous injection or intravenous infusion.

    Investigational medicinal product name
    Venetoclax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Venetoclax was provided in the form of 10 mg, 50 mg and 100 mg tablets. Subjects were dosed at 400 mg dose per day.

    Arm title
    		 Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Arm description
    		 Adult participants with unfit AML who were newly diagnosed and presenting with high-risk clinical features (which related to factors conferring to a low likelihood of response to venetoclax plus azacitidine) and with adverse genetic risk stratification (according to ELN 2022) (Except TP53 mutation positive participants). Siremadlin was administered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m^2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Siremadlin
    Investigational medicinal product code
    HDM201
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Siremadlin (HDM201) was provided orally in the form of 10 mg, 20 mg and 30 mg (might have been included as an additional strength) capsules. Subjects were dosed at 20 mg.

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for suspension for injection, Powder for solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Azacitidine was provided in 100 mg (formulation provided as approved by regulations) was provided as powder for suspension for injection, or powder for solution for subcutaneous injection or intravenous infusion.

    Investigational medicinal product name
    Venetoclax
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Venetoclax was provided in the form of 10 mg, 50 mg and 100 mg tablets. Subjects were dosed at 400 mg dose per day.

    Number of subjects in period 1
    		Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Started
    6
    8
    Did not enter post-treatment follow-up
    4
    6
    Entered post-treatment f/u, discont.
    2
    1
    Safety Set
    6
    8
    Full Analysis Set (FAS)
    6
    7
    Excluded from FAS due to TP53
    0
    1
    Completed
    0
    0
    Not completed
    6
    8
         Adverse event, serious fatal
    3
    7
         Subject Decision
    1
    -
         Excluded from FAS due to TP53 & died
    -
    1
         Study Terminated by Sponsor
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1: Adult participants with unfit AML
    Reporting group description
    		 Adult participants with unfit AML who responded sub-optimally to at least 2 and not more than 4 cycles of first-line venetoclax plus azacitidine therapy. Siremadlin was administered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m^2.

    Reporting group title
    Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Reporting group description
    		 Adult participants with unfit AML who were newly diagnosed and presenting with high-risk clinical features (which related to factors conferring to a low likelihood of response to venetoclax plus azacitidine) and with adverse genetic risk stratification (according to ELN 2022) (Except TP53 mutation positive participants). Siremadlin was administered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m^2.

    Reporting group values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats Total
    Number of subjects
    		 6 8 14
    Age Categorical
    Units: Participants
        < 65 years
    		 1 0 1
        >= 65 years
    		 5 8 13
    Sex: Female, Male
    Units: participants
        Female
    		 4 3 7
        Male
    		 2 5 7
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 6 4 10
        Asian
    		 0 4 4

    End points

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    End points reporting groups
    Reporting group title
    Arm 1: Adult participants with unfit AML
    Reporting group description
    		 Adult participants with unfit AML who responded sub-optimally to at least 2 and not more than 4 cycles of first-line venetoclax plus azacitidine therapy. Siremadlin was administered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m^2.

    Reporting group title
    Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Reporting group description
    		 Adult participants with unfit AML who were newly diagnosed and presenting with high-risk clinical features (which related to factors conferring to a low likelihood of response to venetoclax plus azacitidine) and with adverse genetic risk stratification (according to ELN 2022) (Except TP53 mutation positive participants). Siremadlin was administered at a dose of 20 mg QD which could be increased based on toxicities; venetoclax was administered at 400 mg once daily and azacitidine was administered at 75 mg/m^2.

    Primary: Percentage of participants with Dose Limiting Toxicities (DLTs) as per investigator assessment reported during the first cycle (Part 1: Safety run-in part)

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    End point title
    		 Percentage of participants with Dose Limiting Toxicities (DLTs) as per investigator assessment reported during the first cycle (Part 1: Safety run-in part) [1]
    End point description
    A dose-limiting toxicity (DLT) is defined as an adverse event (AE) or abnormal laboratory value considered by the Investigator to be at least possibly related to siremadlin as a single contributor or in combination with other component(s) of study treatment that occurs beginning the first day of siremadlin dosing in the study until end of cycle 1.
    End point type
    Primary
    End point timeframe
    From Cycle 1 Day 1 to Cycle 1 Day 28; Cycle = 28 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical analysis was done.
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    3
    7
    Units: Percentage of Participants
        number (not applicable)
    0.0
    14.29
    No statistical analyses for this end point

    Primary: Percentage of participants achieving a complete remission (CR) rate as per investigator assessment (Arm 1 only: Safety run-in part)

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    End point title
    		 Percentage of participants achieving a complete remission (CR) rate as per investigator assessment (Arm 1 only: Safety run-in part) [2] [3]
    End point description
    Assessed by CR rate. CR rate is defined as the percentage of participants with best overall response of complete remission (CR) as per investigator assessment using the international guidelines for assessment of response in AML (IWG ELN criteria 2027 and 2022).
    End point type
    Primary
    End point timeframe
    Day 14, Day 28, Day 56 and then every 84 days; end of treatment; estimated median time on follow-up was 57 days
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No Statistical analysis was done.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No Statistical analysis was done.
    End point values
    		 Arm 1: Adult participants with unfit AML
    Number of subjects analysed
    6
    Units: Percentage of participants
        number (not applicable)
    16.67
    No statistical analyses for this end point

    Secondary: Time from date of the first documented CR to the date of the first documented relapse or death due to any cause, whichever occurs first (Part 2: Expansion phase)

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    End point title
    		 Time from date of the first documented CR to the date of the first documented relapse or death due to any cause, whichever occurs first (Part 2: Expansion phase)
    End point description
    Duration of CR is defined as time from the date of the first documented CR to the date of first documented relapse or death due to any cause, whichever occurs first. Assessment of duration of CR in participants who achieved a CR. This endpoint was not analyzed because Part 2 was not conducted.
    End point type
    Secondary
    End point timeframe
    Day 14, Day 28, Day 56 and then every 84 days; end of treatment
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [4] - No subjects were analyzed for this endpoint as the study was terminated.
    [5] - No subjects were analyzed for this endpoint as the study was terminated.
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving complete remission (CR) as per Investigator assessment - Arm 2 only (Part 1: Safety run-in part)

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    End point title
    		 Percentage of participants achieving complete remission (CR) as per Investigator assessment - Arm 2 only (Part 1: Safety run-in part) [6]
    End point description
    Assessed by CR rate. CR rate is defined as the percentage of participants with best overall response of complete remission (CR) as per investigator assessment using the international guidelines for assessment of response in AML (IWG ELN criteria 2027 and 2022).
    End point type
    Secondary
    End point timeframe
    Day 14, Day 28, Day 56 and then every 84 days; end of treatment; estimated median time on follow-up was 66 days
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No Statistical analysis was done.
    End point values
    		 Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    7
    Units: Percentage of participants
        number (not applicable)
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving CR or complete remission with partial hematological recovery (CRh) (Part 1: Safety run-in part)

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    End point title
    		 Percentage of participants achieving CR or complete remission with partial hematological recovery (CRh) (Part 1: Safety run-in part)
    End point description
    Assessed by CR/CRh rate. CR/CRh rate is defined as the percentage of participants with best overall response of either complete remission or complete remission with partial hematological recovery (CR/CRh) as per investigator assessment using the international guidelines for assessment of response in AML (IWG ELN criteria 2027 and 2022).
    End point type
    Secondary
    End point timeframe
    Day 14, Day 28, Day 56 and then every 84 days; end of treatment; estimated median time on follow-up was 57 days for Arm 1; estimated median time on follow-up was 66 days for Arm 2
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    6
    7
    Units: Percentage of participants
        number (not applicable)
    16.67
    42.86
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving complete remission (CR) or complete remission with incomplete hematological recovery (CRi) (Part 1: Safety run-in part)

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    End point title
    		 Percentage of participants achieving complete remission (CR) or complete remission with incomplete hematological recovery (CRi) (Part 1: Safety run-in part)
    End point description
    Assessed by CR/CRi rate. CR/CRi rate is defined as the percentage of participants with best overall response of either complete remission or complete remission with incomplete hematological recovery (CR/CRi) as per investigator assessment using the international guidelines for assessment of response in AML (IWG ELN criteria 2027 and 2022).
    End point type
    Secondary
    End point timeframe
    Day 14, Day 28, Day 56 and then every 84 days; end of treatment; estimated median time on follow-up was 57 days for Arm 1; estimated median time on follow-up was 66 days for Arm 2
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    6
    7
    Units: Percentage of participants
        number (not applicable)
    16.67
    14.29
    No statistical analyses for this end point

    Secondary: Time from the date of the first documented CR/CRh to the date of first documented relapse or death due to any cause, whichever occurs first (Part 2: Expansion phase)

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    End point title
    		 Time from the date of the first documented CR/CRh to the date of first documented relapse or death due to any cause, whichever occurs first (Part 2: Expansion phase)
    End point description
    Assessed by duration of CR/CRh. Duration of CR/CRh is defined as time from the date of the first documented CR/CRh to the date of first documented relapse or death due to any cause, whichever occurs first. This endpoint was not analyzed because Part 2 was not conducted.
    End point type
    Secondary
    End point timeframe
    Day 14, Day 28, Day 56 and then every 84 days; end of treatment
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: Months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [7] - No subjects were analyzed for this endpoint as the study was terminated.
    [8] - No subjects were analyzed for this endpoint as the study was terminated.
    No statistical analyses for this end point

    Secondary: Time from the date of the first documented CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first (Part 2: Expansion phase)

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    End point title
    		 Time from the date of the first documented CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first (Part 2: Expansion phase)
    End point description
    Assessed by duration of CR/CRi. Duration of CR/CRi is defined as time from the date of the first documented CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first. This endpoint was not analyzed because Part 2 was not conducted.
    End point type
    Secondary
    End point timeframe
    Day 14, Day 28, Day 56 and then every 84 days; end of treatment
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: Months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [9] - No subjects were analyzed for this endpoint as the study was terminated.
    [10] - No subjects were analyzed for this endpoint as the study was terminated.
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) (Part 1: Safety run-in part and Part 2: Expansion phase)

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    End point title
    		 Overall Survival (OS) (Part 1: Safety run-in part and Part 2: Expansion phase)
    End point description
    OS is the time from start of treatment to death due to any cause.
    End point type
    Secondary
    End point timeframe
    Every 3 months after end of treatment. Estimated median survival follow-up: 186 Days for Arm 1 (part 1), 91 Days for Arm 2 (Part 1)
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: Months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [11] - No subjects were analyzed for this endpoint as the study was terminated.
    [12] - No subjects were analyzed for this endpoint as the study was terminated.
    No statistical analyses for this end point

    Secondary: Early mortality (Arm 1 & 2 in Part 1: Safety run-in part)

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    End point title
    		 Early mortality (Arm 1 & 2 in Part 1: Safety run-in part)
    End point description
    Early mortality was defined as the percentage of participants who died from any cause within 30- and 60-day of starting treatment. This was calculated as the ratio of deaths to the total number of participants at Day 30 and Day 60.
    End point type
    Secondary
    End point timeframe
    30 days & 60 days from start of study treatment
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    6
    7
    Units: Percentage of participants
    number (not applicable)
        Death in first 30 days from treatment start
    0.0
    14.29
        Death in first 60 days from treatment start
    33.33
    28.57
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameters: AUC0-24h and AUClast of siremadlin and venetoclax (Part 1: Safety run-in part)

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    End point title
    		 Pharmacokinetic (PK) parameters: AUC0-24h and AUClast of siremadlin and venetoclax (Part 1: Safety run-in part)
    End point description
    AUC0-24h: The area under the concentration vs. time Curve (AUC) from time zero to specified time point: 24h. AUClast is the AUC from time zero to the last quantifiable concentration point (last) (mass x time x volume -1).
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5 hour (h), 1h, 2h, 3h, 6h, 8h and 12h, 24h post-dose, Days 1 & 5 of Cycles 1 & 5; Cycle = 28 Days
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    6
    8
    Units: h*ng/mL
    geometric mean (geometric coefficient of variation)
        AUC0-24h: Siremadlin Cycle (C)1 Day (D)1
    2542 ( 52.9 )
    2626 ( 34.8 )
        AUC0-24h: Siremadlin C1D5
    2223 ( 28.4 )
    3556 ( 74.7 )
        AUC0-24h: Siremadlin C5D1 (n = 1, 1)
    6405 ( 0 )
    1689 ( 0 )
        AUC0-24h: Siremadlin C5D5 (n = 0, 1)
    0 ( 0 )
    1466 ( 0 )
        AUClast: Siremadlin C1D1
    2555 ( 52.6 )
    2636 ( 34.4 )
        AUClast: Siremadlin C1D5
    2226 ( 28.3 )
    3569 ( 74.4 )
        AUClast: Siremadlin C5D1 (n = 1, 1)
    6602 ( 0 )
    1755 ( 0 )
        AUClast: Siremadlin C5D5 (n = 0, 1)
    0 ( 0 )
    1495 ( 0 )
        AUC0-24h: Venetoclax C1D1 (n = 5, 6)
    11165 ( 114.1 )
    7792 ( 91.7 )
        AUC0-24h: Venetoclax C1D5 (n = 4, 3)
    15913 ( 164.6 )
    60251 ( 62.3 )
        AUC0-24h: Venetoclax C5D1(n = 1, 1)
    44472 ( 0 )
    6503 ( 0 )
        AUClast: Venetoclax C1D1 (n = 5 ,8)
    11207 ( 111.5 )
    6602 ( 103.5 )
        AUClast: Venetoclax C1D5 (n = 5, 7)
    17738 ( 136.2 )
    55722 ( 48.2 )
        AUClast: Venetoclax C5D1 (n = 1, 1)
    43942 ( 0 )
    6557 ( 0 )
        AUClast: Venetoclax C5D5 (n = 0, 1)
    0 ( 0 )
    50109 ( 0 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) parameters: AUC of azacitidine (Part 1: Safety run-in part)

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    End point title
    		 Pharmacokinetic (PK) parameters: AUC of azacitidine (Part 1: Safety run-in part)
    End point description
    AUC0-3h and 6h: The area under the concentration vs. time Curve (AUC) from time zero to specified time point.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and 5 at Day 1 pre-dose, 0.5 h, 1 h, 2 h, 3 h, 6 h; Cycle = 28 Days
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    4
    8
    Units: h*ng/mL
    geometric mean (geometric coefficient of variation)
        AUC0-3h: C1D1(n = 3, 8)
    1162 ( 79.0 )
    621 ( 155.0 )
        AUC0-3h: C5D1 (n = 0, 1)
    0 ( 0 )
    694 ( 0 )
        AUC0-6h: C1D1 (n = 3, 6)
    1302 ( 69.2 )
    1042 ( 39.1 )
        AUC0-6h: C5D1 (n = 0, 1),
    0 ( 0 )
    951 ( 0 )
        AUClast: C1D1 (n = 4, 8)
    979 ( 83.2 )
    587 ( 179.5 )
        AUClast: C5D1 (n = 0, 1)
    0 ( 0 )
    951 ( 0 )
    No statistical analyses for this end point

    Secondary: PK parameter: Cmax of siremadlin and venetoclax (Part 1: Safety run-in part)

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    End point title
    		 PK parameter: Cmax of siremadlin and venetoclax (Part 1: Safety run-in part)
    End point description
    Cmax is the maximum (peak) observed plasma, blood, serum or other body fluid drug concentration following drug administration (mass x volume -1)
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5 hour (h), 1h, 2h, 3h, 6h, 8h and 12h, 24h post-dose, Days 1 & 5 of Cycles 1 & 5; Cycle = 28 Days
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    6
    8
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Siremadlin: C1D1
    179 ( 62.6 )
    177 ( 35.6 )
        Siremadlin: C1D5
    163 ( 30.8 )
    229 ( 67.5 )
        Siremadlin: C5D1 (n = 1, 1)
    397 ( 0 )
    100 ( 0 )
        Siremadlin: C5D5 (n = 0, 1)
    0 ( 0 )
    80 ( 0 )
        Venetoclax: C1D1 (n = 5, 8)
    923 ( 82.6 )
    441 ( 129.8 )
        Venetoclax: C1D5 (n = 5, 7)
    1181 ( 98.6 )
    3387 ( 40.0 )
        Venetoclax: C5D1 (n = 1, 1)
    2900 ( 0 )
    358 ( 0 )
        Venetoclax: C5D5 (n = 0, 1)
    0 ( 0 )
    2840 ( 0 )
    No statistical analyses for this end point

    Secondary: PK parameter: Cmax of azacitidine (Part 1: Safety run-in part)

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    End point title
    		 PK parameter: Cmax of azacitidine (Part 1: Safety run-in part)
    End point description
    Cmax is the maximum (peak) observed plasma, blood, serum or other body fluid drug concentration following drug administration (mass x volume -1)
    End point type
    Secondary
    End point timeframe
    Cycle 1 and 5 at Day 1 pre-dose, 0.5 h, 1 h, 2 h, 3 h, 6 h; Cycle = 28 Days
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    4
    8
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        C1D1 (n = 4, 8)
    787 ( 70.2 )
    543 ( 114.9 )
        C5D1 (n = 0, 1)
    0 ( 0 )
    541 ( 0 )
    No statistical analyses for this end point

    Secondary: PK parameter: Tmax of siremadlin and venetoclax (Part 1: Safety run-in part)

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    End point title
    		 PK parameter: Tmax of siremadlin and venetoclax (Part 1: Safety run-in part)
    End point description
    Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after drug administration (time). Actual sampling times were taken into consideration for the calculation of Tmax.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5 hour (h), 1h, 2h, 3h, 6h, 8h and 12h, 24h post-dose, Days 1 & 5 of Cycles 1 & 5; Cycle = 28 Days
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    6
    8
    Units: hours
    median (full range (min-max))
        Siremadlin: C1D1
    4.46 (2.0 to 24.0)
    2.70 (1.1 to 24.0)
        Siremadlin: C1D5
    3.08 (2.1 to 12.0)
    2.0 (1.0 to 5.9)
        Siremadlin: C5D1 (n = 1, 1)
    24.5 (24.5 to 24.5)
    2.0 (2.0 to 2.0)
        Siremadlin: C5D5 (n = 0, 1)
    0 (0 to 0)
    2.0 (2.0 to 2.0)
        Venetoclax: C1D1 (n = 5, 8)
    6.0 (5.9 to 25.1)
    7.0 (5.8 to 24.0)
        Venetoclax: C1D5 (n = 5, 7)
    6.0 (3.0 to 23.1)
    7.92 (6.0 to 12.0)
        Venetoclax: C5D1(n = 1, 1)
    6.0 (6.0 to 6.0)
    7.5 (7.5 to 7.5)
        Venetoclax: C5D5(n = 0, 1)
    0 (0 to 0)
    10.0 (10.0 to 10.0)
    No statistical analyses for this end point

    Secondary: PK parameter: Tmax of azactidine (Part 1 (Safety run-in))

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    End point title
    		 PK parameter: Tmax of azactidine (Part 1 (Safety run-in))
    End point description
    Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after drug administration (time). Actual sampling times were taken into consideration for the calculation of Tmax.
    End point type
    Secondary
    End point timeframe
    Cycle 1 and 5 at Day 1 pre-dose, 0.5 h, 1 h, 2 h, 3 h, 6 h; Cycle = 28 Days
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    4
    8
    Units: hours
    median (full range (min-max))
        C1D1
    0.62 (0.4 to 1.0)
    0.5 (0.3 to 2.0)
        C5D1 (n = 0, 1)
    0 (0 to 0)
    0.5 (0.5 to 0.5)
    No statistical analyses for this end point

    Secondary: Percentage of CR- Measurable Residual Disease (MRD) negative overall and in participants achieving a CR, CR/CRh, and CR/CRi (Part 1: Safety run-in part)

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    End point title
    		 Percentage of CR- Measurable Residual Disease (MRD) negative overall and in participants achieving a CR, CR/CRh, and CR/CRi (Part 1: Safety run-in part)
    End point description
    Assessed by MRD-negativity rate. MRD negativity is defined as an MRD negative sample (frequency of LAIP below 0.1%, as determined by an MFC-AML MRD) assay at Central Lab) in participants with a CR, CRh or CRi as per investigator assessment.
    End point type
    Secondary
    End point timeframe
    At Screening, Cycle 1 Day 14, Cycle 2 Day 1, end of treatment, every 3 cycles until disease progression; estimated median time on follow-up was 57 days for Arm 1; estimated median time on follow-up was 66 days for Arm 2; Cycle = 28 Days
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    6
    7
    Units: Percentage of participants
        number (not applicable)
    0.0
    0.0
    No statistical analyses for this end point

    Post-hoc: All Collected Deaths

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    End point title
    		 All Collected Deaths
    End point description
    Adverse events and on-treatment deaths were collected from the first dose of study treatment until 30 days after last administration of study treatment, for a maximum duration of 7.3 months. Post-treatment survival follow-up deaths were collected 31 days after last dose of study medication until the end of the study, up to approx. 23 months.
    End point type
    Post-hoc
    End point timeframe
    AEs & On-treatment deaths: Up to approx. 7.3 months, Post-treatment survival follow-up deaths: Up to approx. 23 months after the end of treatment
    End point values
    		 Arm 1: Adult participants with unfit AML Arm2:Adult parts wth newly diag unfit AML/high-risk clin feats
    Number of subjects analysed
    6
    8
    Units: Participants
        Total Deaths
    3
    8
        On-treatment deaths
    1
    4
        Post-treatment deaths
    2
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from first dosing (Day 1) until 30 days after the date of last actual administration of study treatment, maximum treatment duration: approx. 9.3 months for Arm 1 and approx. 7.4 months for Arm 2.
    Adverse event reporting additional description
    An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Arm 2@HDM201+AZA+VEN
    Reporting group description
    		 Arm 2@HDM201+AZA+VEN

    Reporting group title
    Arm 1@HDM201+AZA+VEN
    Reporting group description
    		 Arm 1@HDM201+AZA+VEN

    Serious adverse events
    		 Arm 2@HDM201+AZA+VEN Arm 1@HDM201+AZA+VEN
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 8 (87.50%)
    6 / 6 (100.00%)
         number of deaths (all causes)
    4
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         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
    Febrile neutropenia
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (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 / 8 (0.00%)
    1 / 6 (16.67%)
         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
    		 Arm 2@HDM201+AZA+VEN Arm 1@HDM201+AZA+VEN
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    5 / 6 (83.33%)
    Vascular disorders
    Subclavian vein occlusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Thrombophlebitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    2
    Chills
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Fat necrosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Injection site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Delirium
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Antithrombin III decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Enterococcus test positive
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Platelet count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
         occurrences all number
    1
    6
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Injury, poisoning and procedural complications
    Jaw fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Lip injury
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Skin laceration
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    Palpitations
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Bundle branch block left
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 6 (33.33%)
         occurrences all number
    5
    2
    Cytopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pancytopenia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Neutropenia
         subjects affected / exposed
    5 / 8 (62.50%)
    2 / 6 (33.33%)
         occurrences all number
    19
    6
    Leukopenia
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Febrile neutropenia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Thrombocytopenia
         subjects affected / exposed
    6 / 8 (75.00%)
    1 / 6 (16.67%)
         occurrences all number
    15
    1
    Eye disorders
    Retinal haemorrhage
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Paraesthesia oral
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 6 (16.67%)
         occurrences all number
    5
    1
    Oesophageal spasm
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    3 / 8 (37.50%)
    3 / 6 (50.00%)
         occurrences all number
    3
    3
    Flatulence
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 6 (50.00%)
         occurrences all number
    3
    3
    Aphthous ulcer
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Anal haemorrhage
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Anal fistula
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Ecchymosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Purpura
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pneumonia fungal
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Sinusitis fungal
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    Hyperphosphataemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Hypokalaemia
         subjects affected / exposed
    4 / 8 (50.00%)
    1 / 6 (16.67%)
         occurrences all number
    8
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2021
    In response to the request from Health Authorities, the inclusion criteria were revised. The amendment included: Clarification on inclusion criterion 4 regarding ineligibility of participants for standard induction chemotherapy, to be determined for both arms’ participant population prior to initiation of standard of care venetoclax plus azacitidine treatment; particularly for Arm 1 participants, who received first line venetoclax plus azacitidine treatment prior to study entry. Inclusion criterion 9 was amended to specify that participants with an estimated glomerular filtration rate (eGFR)≥ 60 mL/min/1.73 m2, were eligible for the study. Amendment also specified that siremadlin would be discontinued in case of Grade 4 hyperbilirubinemia in the guidance for dose modification. Clarification regarding Tumor Lysis Syndrome (TLS) prophylactic treatments options were added. Additional, ECHO (or MUGA scan) was added at screening visit (and during treatment, if clinically indicated) for the evaluation of cardiac function.
    03 Aug 2022
    Protocol was amended to update the dose modifications guidelines of the study treatment based on participant’s efficacy response and associated hematological toxicities. The amendment adopted 2022 European Leukemia Net (ELN) 2022 genetic risk classification and AML response criteria (Döhner et al 2022). Dose modification guidelines for hepatic adverse reaction were updated, and the follow-up for participants with QTcF prolongations was clarified.
    28 Apr 2023
    The protocol was amended on February 24, 2023, to implement Urgent Safety Measures addressing severe neutropenia and thrombocytopenia. Changes included dose modification and early treatment interruption starting from Cycle 1, along with a mandatory bone marrow assessment at C1D14 for all participants. Guidance was provided on prophylactic anti-infective therapy and G-CSF use. Venetoclax dose modification was updated, considering a minimum exposure criterion at Cycle 1 for the Dose Determining Set, with the planned dose reduced from 75% to 50%. Clarifications were made regarding the prior use of Hypomethylating agents (HMA) for treating primary MDS, excluding participants with an antecedent diagnosis of myelofibrosis during the safety-run and enrolling them only in the expansion part of the study. Participants previously treated with FLT-3 inhibitors and checkpoint inhibitors were excluded. Flexibility for PK sample collection was adjusted to +/- 2 hours for the 12-hour and 24-hour post-dose timepoints in the safety run-in phase. Emphasis was placed on caution or action against the use of strong or moderate CYP3A inhibitors or P-gp inhibitors. The azacitidine SmPC was updated to extend the mandatory contraception period for female participants from 3 to 6 months. Clear guidance was provided on overdose management and dose modification for isolated Grade 2 bilirubin increases.

    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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