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    Clinical Trial Results:
    A PHASE II STUDY OF THE CLINICAL ACTIVITY AND SAFETY OF ACTINOMYCIN D IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA WITH NUCLEOPHOSMIN (NPM1) GENE MUTATION

    Summary
    EudraCT number
    		 2014-000693-18
    Trial protocol
    		 IT  
    Global end of trial date
    19 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Feb 2021
    First version publication date
    06 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ActD-AML-PG01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Perugia, Department of Medicine
    Sponsor organisation address
    Piazzale severi n°1, Perugia, Italy,
    Public contact
    Sezione di Ematologia e Immunologia, University of Perugia, Department of Medicine, +39 0755783190,
    Scientific contact
    Sezione di Ematologia e Immunologia, University of Perugia, Department of Medicine, +39 0755783190,
    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
    06 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the anti-tumor activity of the intravenously administered single agent actinomycin D in AML patients carrying the NPM1 mutations fulfilling the eligibility criteria for enrollment in this study.
    Protection of trial subjects
    Normal clinical practice
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Mar 2014
    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
    Italy: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    6
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 10 patients with relapsed/refractory acute myeloid leukemia with mutated NPM1 were recruited between June 28, 2014 and February 20, 2016. All patients were enrolled and treated at Santa Maria della Misericordia hospital in Perugia, Italy.

    Pre-assignment
    Screening details
    		 All patients meeting the inclusion criteria were sucesfully screened. No screening failure was reported.

    Period 1
    Period 1 title
    Phase II clinical trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Single Arm
    Arm description
    		 10 patients treated with the study drug in a Phase II trial
    Arm type
    		 Experimental

    Investigational medicinal product name
    Actinomycin D
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    15 mcg/Kg/day, single administration, for 5 consecutive days. Dose cap 2 mg/day.

    Number of subjects in period 1
    		Single Arm
    Started
    10
    Completed
    9
    Not completed
    1
         Adverse event, serious fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase II clinical trial
    Reporting group description
    		 -

    Reporting group values
    		 Phase II clinical trial Total
    Number of subjects
    		 10 10
    Age categorical
    Units: Subjects
        Age > 18 years
    		 10 10
    Age continuous
    Units: years
        median (full range (min-max))
    		 66.5 (53 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 4 4
    Subject analysis sets

    Subject analysis set title
    Complete Response Rate
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Four of nine evaluable patients obtained a complete response (including both complete remission and complete remission with incomplete hematological recovery).

    Subject analysis sets values
    		 Complete Response Rate
    Number of subjects
    9
    Age categorical
    Units: Subjects
        Age > 18 years
    9
    Age continuous
    Units: years
        median (full range (min-max))
    66 (53 to 75)
    Gender categorical
    Units: Subjects
        Female
    5
        Male
    4

    End points

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    End points reporting groups
    Reporting group title
    Single Arm
    Reporting group description
    		 10 patients treated with the study drug in a Phase II trial

    Subject analysis set title
    Complete Response Rate
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Four of nine evaluable patients obtained a complete response (including both complete remission and complete remission with incomplete hematological recovery).

    Primary: Complete Response Rate

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    End point title
    		 Complete Response Rate [1]
    End point description
    End point type
    Primary
    End point timeframe
    July 28, 2014 to April 20, 2016. This is the time frame between the response assessment in the first and last patients included in the study.
    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: This phase II pilot study was designed applying the Simon's minimax two-stage model. We calculated a sample size that would be sufficient to accept the alternative hypothesis (CR/CRi rate after one or two induction cycles equals to or higher than 45%) and reject the null hypothesis (CR/CRi rate equals or lower than 10%), with an alfa level of 0.05 and a beta level of 0.2. The study drug was considered Worth of further investigation in CR/CRi was obtained in at least 3 patients.
    End point values
    		 Single Arm Complete Response Rate
    Number of subjects analysed
    9
    9
    Units: % patients
    44
    44
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    June 28, 2014 to July 19, 2016
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    single arm study
    Reporting group description
    		 -

    Serious adverse events
    		 single arm study
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 10 (10.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 single arm study
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    Cardiac disorders
    Electrocardiogram QT interval abnormal
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Syncope
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    3
    fever
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    oral mucositis
         subjects affected / exposed
    8 / 10 (80.00%)
         occurrences all number
    12
    diarrhea
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    nausea
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Hepatobiliary disorders
    Transaminases increased
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    bilirubin increased
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Skin disorder
         subjects affected / exposed
    4 / 10 (40.00%)
         occurrences all number
    6
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    4
    Infections and infestations
    febrile neutropenia
         subjects affected / exposed
    7 / 10 (70.00%)
         occurrences all number
    12
    sepsis
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    3
    Viral infection
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    pneumonia
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2015
    Response assessment to be performed after either one or two induction cycles, instead of after one induction cycle.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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