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    Clinical Trial Results:
    A phase Ib/II, open label study of siremadlin monotherapy and in combination with donor lymphocyte infusion as a treatment for patients with acute myeloid leukemia postallogeneic stem cell transplantation who are in complete remission but at high risk for relapse.

    Summary
    EudraCT number
    2021-003596-34
    Trial protocol
    ES   DE   IT  
    Global end of trial date
    26 Oct 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Sep 2024
    First version publication date
    21 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CHDM201K12201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT05447663
    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, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, 41 613241111, novartis.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
    26 Oct 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine the dose and schedule of siremadlin monotherapy that are tolerable without unacceptable toxicities (recommended dose for Part 2) [Part 1 - siremadlin monotherapy].
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration 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
    23 Feb 2023
    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
    Germany: 5
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Spain: 1
    Worldwide total number of subjects
    8
    EEA total number of subjects
    8
    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)
    5
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    38 participants were planned to be enrolled; 12 participants in Part 1 and 26 participants in Part 2; however, due to permanent recruitment halt, the enrollment was stopped after the 1st dose escalation meeting. The study was conducted in 6 centers in 3 countries: Germany, Italy and Spain.

    Pre-assignment
    Screening details
    Prior to dosing at Cycle 1 Day 1, participants who fulfilled all the inclusion/exclusion criteria were enrolled via IRT and a treatment number was provided for the study treatment siremadlin.

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

    Arms
    Arm title
    Siremadlin (HDM201) 30mg
    Arm description
    Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1
    Arm type
    Experimental

    Investigational medicinal product name
    Siremadlin
    Investigational medicinal product code
    HDM201
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg, 20mg and 30 mg* (During the study, siremadlin (HDM201) 30mg capsule was included as additional strength which was globally supplied), administered orally (PO).

    Number of subjects in period 1
    Siremadlin (HDM201) 30mg
    Started
    8
    Entered post-treatment follow-up
    7
    Did not enter post-treatment follow -up
    1
    Completed
    0
    Not completed
    8
         Adverse event, serious fatal
    2
         Consent withdrawn by subject
    1
         Study terminated by Sponsor
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Siremadlin (HDM201) 30mg
    Reporting group description
    Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1

    Reporting group values
    Siremadlin (HDM201) 30mg Total
    Number of subjects
    8 8
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    5 5
        From 65-84 years
    3 3
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    52.0 ( 17.96 ) -
    Sex: Female, Male
    Units: Participants
        Female
    3 3
        Male
    5 5
    Race/Ethnicity, Customized
    Units: Subjects
        Not Hispanic or Latino
    7 7
        Hispanic or Latino
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Siremadlin (HDM201) 30mg
    Reporting group description
    Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1

    Subject analysis set title
    Siremadlin (HDM201) 10mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 10mg siremadlin monotherapy in part 1

    Subject analysis set title
    Seremadlin (HDM201) 30mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1

    Subject analysis set title
    Siremadlin (HDM201) 30mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1

    Subject analysis set title
    Siremadlin (HDM201) 10mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 10mg siremadlin monotherapy in part 1

    Subject analysis set title
    Siremadlin (HDM201) 30mg
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy in part 1

    Primary: Rate of Dose Limiting Toxicities (DLTs) with siremadlin monotherapy in part 1 (dose confirmation with siremadlin monotherapy)

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    End point title
    Rate of Dose Limiting Toxicities (DLTs) with siremadlin monotherapy in part 1 (dose confirmation with siremadlin monotherapy) [1]
    End point description
    To determine the dose and schedule of siremadlin monotherapy that are tolerable without unacceptable toxicities as defined by the incidence of DLT during the first cycle of treatment in part 1. 'A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed, by the Investigator, to be at least possibly related to study treatment (siremadlin monotherapy and/or siremadlin in combination with DLI), and as unrelated to disease, disease progression, inter-current illness, or concomitant medications, that occurs during the DLT observation period and meets severity criteria as per protocol.
    End point type
    Primary
    End point timeframe
    from cycle 1 day 1 (C1D1) to end of Cycle 1 (cycle = 28days)
    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 analysis was done for this endpoint
    End point values
    Siremadlin (HDM201) 30mg
    Number of subjects analysed
    7
    Units: Count of Participants
    1
    No statistical analyses for this end point

    Secondary: Participants who are alive and maintained CR or CRi with no evidence of hematologic relapse

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    End point title
    Participants who are alive and maintained CR or CRi with no evidence of hematologic relapse
    End point description
    This involves evaluating the preliminary efficacy of siremadlin monotherapy at the recommended dose for part 2 on prevention of hematologic relapse
    End point type
    Secondary
    End point timeframe
    Over 6 months from start of siremadlin monotherapy (part 1)
    End point values
    Siremadlin (HDM201) 30mg
    Number of subjects analysed
    0 [2]
    Units: Participants
        number (not applicable)
    Notes
    [2] - No participant was analyzed for this endpoint
    No statistical analyses for this end point

    Secondary: Time from start of study treatment to the date of death from any cause

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    End point title
    Time from start of study treatment to the date of death from any cause
    End point description
    Assessment of Overall survival (OS) in part 2
    End point type
    Secondary
    End point timeframe
    From start of study treatment to up to 36 months from last patient first treatment
    End point values
    Siremadlin (HDM201) 30mg
    Number of subjects analysed
    0 [3]
    Units: months
        number (not applicable)
    Notes
    [3] - No participant was analyzed for this endpoint
    No statistical analyses for this end point

    Secondary: Incidence of Graft versus Host Disease (GvHD)

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    End point title
    Incidence of Graft versus Host Disease (GvHD)
    End point description
    Incidence of grade III or IV acute GvHD, and moderate to severe chronic GvHD in part 1 and 2.
    End point type
    Secondary
    End point timeframe
    From start of study treatment to up to 24 months from last patient first treatment
    End point values
    Siremadlin (HDM201) 30mg
    Number of subjects analysed
    0 [4]
    Units: Participants
        number (not applicable)
    Notes
    [4] - No participant was analyzed for this endpoint
    No statistical analyses for this end point

    Secondary: Percentage of participants with permanent study treatment discontinuation due to GvHD or other adverse events

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    End point title
    Percentage of participants with permanent study treatment discontinuation due to GvHD or other adverse events
    End point description
    Percentage of participants with permanent discontinuation of study treatment due to GvHD or other adverse events in part 1 and 2.
    End point type
    Secondary
    End point timeframe
    From start of study treatment to up to 24 months from last patient first treatment
    End point values
    Siremadlin (HDM201) 30mg
    Number of subjects analysed
    8
    Units: Count of Participants
    3
    No statistical analyses for this end point

    Secondary: Time from start of study treatment to the date of first documented occurrence or worsening of treatment emergent grade III or IV acute GvHD, or chronic GvHD requiring initiation of systemic immunosuppressive treatment

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    End point title
    Time from start of study treatment to the date of first documented occurrence or worsening of treatment emergent grade III or IV acute GvHD, or chronic GvHD requiring initiation of systemic immunosuppressive treatment
    End point description
    Assessment of GvHD-free/relapse-free survival (GRFS) in part 1 and 2.
    End point type
    Secondary
    End point timeframe
    From start of treatment to up to 36 months from last patient first treatment
    End point values
    Siremadlin (HDM201) 30mg
    Number of subjects analysed
    0 [5]
    Units: months
        number (not applicable)
    Notes
    [5] - No participant was analyzed for this endpoint
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) characteristic AUC of siremadlin

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    End point title
    Pharmacokinetic (PK) characteristic AUC of siremadlin
    End point description
    AUC is the area under the concentration vs. time curve in part 1. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed.
    End point type
    Secondary
    End point timeframe
    From Cycle 1 Day 1 to Cycle 1 Day 5 in part 1 [each cycle is 28 days for monotherapy]
    End point values
    Siremadlin (HDM201) 10mg Seremadlin (HDM201) 30mg
    Number of subjects analysed
    1
    7
    Units: hr*ng/mL
    geometric mean (geometric coefficient of variation)
        AUClast: Cycle 1 Day 1
    1497 ( 999 )
    3077 ( 39.7 )
        AUC0-8hr: Cycle 1 Day 1
    446 ( 999 )
    1187.1 ( 39.8 )
        AUClast: Cycle 1 Day 5 (n = 0, 6)
    999 ( 999 )
    1880.7 ( 31.2 )
        AUC0-8hr: Cycle 1 Day 5 (n = 0, 6)
    999 ( 999 )
    1894 ( 30.3 )
    No statistical analyses for this end point

    Secondary: Cumulative incidence of AML relapse

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    End point title
    Cumulative incidence of AML relapse
    End point description
    Cumulative incidence of Acute Myeloid Leukemia (AML) relapse at one year and 2 years after the start of study treatment in part 1 and 2. Cumulative incidence of relapse (CIR) is defined as the time from start of study treatment to the date of first documented hematologic relapse. CIR was to be analyzed in the FAS population who initiated priming phase at siremadlin recommended dose (RD) in Part 2 and participants at the RD in Part 1.
    End point type
    Secondary
    End point timeframe
    at 1 year and at 2 years after start of study treatment
    End point values
    Siremadlin (HDM201) 30mg
    Number of subjects analysed
    0 [6]
    Units: Participants
        number (not applicable)
    Notes
    [6] - No participant was analyzed for this endpoint
    No statistical analyses for this end point

    Secondary: PK characteristic Cmax of siremadlin

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    End point title
    PK characteristic Cmax of siremadlin
    End point description
    The maximum (peak) observed plasma, blood, serum or other body fluid drug concentration following drug administration (mass x volume^-1) in part 1. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed.
    End point type
    Secondary
    End point timeframe
    From Cycle 1 Day 1 to Cycle 1 Day 5 in part 1 [each cycle is 28 days for monotherapy]
    End point values
    Siremadlin (HDM201) 10mg Siremadlin (HDM201) 30mg
    Number of subjects analysed
    1
    7
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    73.6 ( 999 )
    207.68 ( 36.2 )
        Cycle 1 Day 5 (n = 0, 6)
    999 ( 999 )
    296.92 ( 30.4 )
    No statistical analyses for this end point

    Secondary: PK characteristic Tmax of siremadlin

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    End point title
    PK characteristic Tmax of siremadlin
    End point description
    The time to reach maximum (peak) plasma, blood, serum or other body fluid drug concentration after drug administration (time) in part 1. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed.
    End point type
    Secondary
    End point timeframe
    From Cycle 1 Day 1 to Cycle 1 Day 5 in part 1 [each cycle is 28 days for monotherapy]
    End point values
    Siremadlin (HDM201) 10mg Siremadlin (HDM201) 30mg
    Number of subjects analysed
    1
    7
    Units: hour (hr)
    median (full range (min-max))
        Cycle 1 Day
    3.00 (3.00 to 3.00)
    5.95 (2.02 to 6.03)
        Cycle 1 Day 5 (n = 0, 6)
    999 (999 to 999)
    4.50 (1.92 to 7.75)
    No statistical analyses for this end point

    Secondary: PK characteristic Ctrough of siremadlin

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    End point title
    PK characteristic Ctrough of siremadlin
    End point description
    Concentration that is just prior to the beginning of, or at the end of a dosing interval; corresponding to the pre-dose concentration in part 1 and 2.
    End point type
    Secondary
    End point timeframe
    From Cycle 1 Day 1 to Cycle 24 Day 1 in part 1 or from Cycle 1 Day 1 safety confirmation to Cycle 21 Day 1 maintenance in part 2; [each cycle is 28 days for monotherapy, and 42 days for combination]
    End point values
    Siremadlin (HDM201) 30mg
    Number of subjects analysed
    0 [7]
    Units: ng/ml
        geometric mean (geometric coefficient of variation)
    ( )
    Notes
    [7] - No participant was analyzed for this endpoint
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment to 30 days after last dose of study treatment (on-treatment). Subjects remaining in the study after endo of treatment (EOT) (responders and non-responders, regardless of when treatment was d
    Adverse event reporting additional description
    Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Deaths in the post treatment survival follow-up are not considered Adverse Events.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    SIREMADLIN 30 mg
    Reporting group description
    SIREMADLIN 30 mg

    Serious adverse events
    SIREMADLIN 30 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    SIREMADLIN 30 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    3
    Mucosal inflammation
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    3
    Immune system disorders
    Chronic graft versus host disease
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Acute graft versus host disease
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    3
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Endometrial thickening
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Weight decreased
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Upper limb fracture
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Fall
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Nervous system disorders
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    4
    Leukopenia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    3
    Neutropenia
         subjects affected / exposed
    6 / 8 (75.00%)
         occurrences all number
    7
    Thrombocytopenia
         subjects affected / exposed
    7 / 8 (87.50%)
         occurrences all number
    9
    Ear and labyrinth disorders
    External ear pain
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Vertigo
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Eye disorders
    Corneal exfoliation
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Dry eye
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Eyelid oedema
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 8 (50.00%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    4 / 8 (50.00%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    3
    Pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Dermatitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Oral herpes
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Clostridium difficile infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    COVID-19
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jul 2022
    As the release of this amendment, no sites had been initiated, and no subject had been screened or had received study treatment in this trial. The main purpose of this amendment was to comply with health authority’s request to modify the protocol as follows: To modify the study design by adding a siremadlin monotherapy dose confirmation part (Part 1) with at least 6 evaluable participants to evaluate the safety and tolerability of siremadlin monotherapy and determine the recommended dose before commencing the treatment strategy part (Part 2), which includes siremadlin/donor lymphocyte infusion (DLI) combination as well as priming and maintenance with siremadlin monotherapy; To specify that after the recommended siremadlin dose was determined in Part 1, enrollment in Part 2 would start after obtaining Health Authority’s approval as applicable. Enrollment in Part 2 would not have been applicable to the participating sites in the United States; To implement a larger dose reduction to 20% of siremadlin (instead of 30%) of the total planned dose when administered concomitantly with strong CYP3A inhibitors in the initial treatment cohort(s). Following the first safety review meeting and based on safety and siremadlin total exposure data, this could have changed to a dose reduction to 30% of the planned siremadlin dose with concomitant use of strong CYP3A inhibitors; To clarify that pre-allo-SCT participants with AML in morphologic complete remission at time of transplant but with evidence of residual leukemia had been removed from inclusion criteria 4. The assessment of this pre-transplant risk factor was based on retrospective test results and could not fulfill regulatory requirements of a MRD assay; To clarify that the decision about DLI administration in eligible participants in Part 2 would have been at the discretion of the treating investigator per the standard of practice.
    18 Nov 2022
    At the time of release of this amendment, no sites had been initiated, and no subject had been screened or received study treatment in this trial. The main purpose of this amendment was to restrict the participation of the German sites to Part 1 of the study. The protocol specified that the participating sites in Germany will enroll patients only in Part 1 with siremadlin monotherapy. The German sites were not permitted to enroll patients in Part 2, which included Donor Lymphocyte Infusion (DLI) in combination with siremadlin.

    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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