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    Clinical Trial Results:
    10-day decitabine, fludarabine and 2 Gray TBI as conditioning strategy for poor and very poor risk AML in CR1

    Summary
    EudraCT number
    		 2014-000400-99
    Trial protocol
    		 NL   BE  
    Global end of trial date
    01 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2022
    First version publication date
    01 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PLMA34
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02252107
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboud university medical center
    Sponsor organisation address
    P.O. Box 9101, Nijmegen, Netherlands, 6500 HB
    Public contact
    Afdeling Hematologie Trialcoördinat, Radboud university medical center, Datacentrum@HEMAT.umcn.nl
    Scientific contact
    Afdeling Hematologie Trialcoördinat, Radboud university medical center, Datacentrum@HEMAT.umcn.nl
    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
    01 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the feasibility (safety and efficacy) of addition of 10-day decitabine to the standard Seattle non-myeloablative conditioning regimen (3 days fludarabine 30 mg/m2 + 2 Gray TBI) prior to allogeneic HCT in poor and very poor risk AML patients in CR1. Safety will be assessed by adverse events and laboratory parameters; efficacy will be assessed by (decrease of) relapse rate at 12 months (fixed time point) after last-patient-in.
    Protection of trial subjects
    We closely monitored for adverse events and also installed a data and safety management board (DSMB)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 43
    Country: Number of subjects enrolled
    Belgium: 3
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    33
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Initially, 56 patients were included. There were 10 screening failures, resulting in 46 patients starting and completing the study.

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

    Arms
    Arm title
    		 9/10 and 10/10 matched donor
    Arm description
    		 Patients with a 10/10 matched donor received only decitabine, fludarabine and TBI. Patients with a 9/10 mismatched donor received all products indicated below in the arm specification
    Arm type
    		 Experimental

    Investigational medicinal product name
    Decitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Decitabine to be dissolved in 100 ml NaCl 0.9%. Dose/day is 20 mg/m2. Infusion for 1 hour on days -11 through -2.

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Fludarabine to be dissolved in 50 ml NaCl 0.9%. Dose/day is 30 mg/m2. Infusion for 0.5 hour on days -4, -3 and -2.

    Investigational medicinal product name
    Total body irradiation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solvent for...
    Routes of administration
    Other use
    Dosage and administration details
    2 gray on day -1.

    Investigational medicinal product name
    Anti Thymocyte Globulin ATG (rabbit)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    ATG (rabbit) to be dissolved in 500 ml NaCl 0.9%. Dose/day is 2 mg/kg. Infusion for 10 hours on days -8, -7, -6 and -5.

    Investigational medicinal product name
    Methylprednison
    Investigational medicinal product code
    Other name
    Solumedrol
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Methylprednison dissolved in 250 ml NaCl 0.9%. Dose/day is 2 mg/kg. Infusion for 0.5 hours on days -8, -7, -6 and -5.

    Investigational medicinal product name
    Clemastine
    Investigational medicinal product code
    Other name
    Tavegil
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg on days -8, -7, -6 and -5.

    Number of subjects in period 1
    		9/10 and 10/10 matched donor
    Started
    46
    Completed
    46

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 46 46
    Age categorical
    Units: Subjects
    Age continuous
    all adult patients (18 years or older)
    Units: years
        median (full range (min-max))
    		 60 (23 to 74) -
    Gender categorical
    both male and female allowed
    Units: Subjects
        Female
    		 22 22
        Male
    		 24 24
    Type of disease
    Units: Subjects
        De novo AML
    		 41 41
        Secondary AML
    		 5 5
    WHO classification 2008
    Units: Subjects
        AML with recurrent genetic abnormalities
    		 4 4
        AML with myelodysplasia related changes
    		 15 15
        Therapy-related myeloid neoplasms
    		 4 4
        AML, not otherwise specified
    		 22 22
        Myeloid sarcoma
    		 1 1
    Disease status at start of conditioning
    Units: Subjects
        Complete remission (CR)
    		 29 29
        Incomplete remission (CRi)
    		 17 17
    Donor type
    Units: Subjects
        Matched 10/10
    		 43 43
        Mismatched 9/10
    		 3 3

    End points

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    End points reporting groups
    Reporting group title
    9/10 and 10/10 matched donor
    Reporting group description
    		 Patients with a 10/10 matched donor received only decitabine, fludarabine and TBI. Patients with a 9/10 mismatched donor received all products indicated below in the arm specification

    Primary: Relapse at 1-year after the transplantation procedure

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    End point title
    		 Relapse at 1-year after the transplantation procedure [1]
    End point description
    End point type
    Primary
    End point timeframe
    1-year after the transplantation procedure
    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 comparison was made. A 1-sided alfa of 5% was used.
    End point values
    		 9/10 and 10/10 matched donor
    Number of subjects analysed
    46
    Units: percentage
    23
    No statistical analyses for this end point

    Secondary: Non-relapse mortality

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    End point title
    		 Non-relapse mortality
    End point description
    Time to death in CR or non-relapse related mortality (NRM) is defined as the time between the date of complete remission and the date of death in CR (i.e. without a documentation of relapse). For subjects who remain alive and did not relapse, NRM will be censored on the date of last visit/contact with disease assessments. The follow-up of patients who relapsed will be censored at the date of relapse. For the computation of the cumulative incidence of death without relapse, relapse will be considered as a competing risk. Defined according to ELN criteria.
    End point type
    Secondary
    End point timeframe
    Within the first year post allo HCT
    End point values
    		 9/10 and 10/10 matched donor
    Number of subjects analysed
    46
    Units: percentage
    11
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Defined according to ELN criteria
    End point type
    Secondary
    End point timeframe
    One year
    End point values
    		 9/10 and 10/10 matched donor
    Number of subjects analysed
    46
    Units: Percentage
    70
    No statistical analyses for this end point

    Secondary: Relapse-free survival (RFS)

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    End point title
    		 Relapse-free survival (RFS)
    End point description
    Defined according to ELN criteria.
    End point type
    Secondary
    End point timeframe
    One year
    End point values
    		 9/10 and 10/10 matched donor
    Number of subjects analysed
    46
    Units: Percentage
    66
    No statistical analyses for this end point

    Secondary: GVHD-free survival (GRFS)

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    End point title
    		 GVHD-free survival (GRFS)
    End point description
    GRFS was defined as surviving the first 12 months after allo HCT without relapse and without grade III-IV aGVHD and/or severe cGVHD.
    End point type
    Secondary
    End point timeframe
    One year
    End point values
    		 9/10 and 10/10 matched donor
    Number of subjects analysed
    46
    Units: Percentage
    45
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date first included patient, untill 1 year after the last included patient
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    9/10 and 10/10 matched donor
    Reporting group description
    		 Patients with a 10/10 matched donor received only decitabine, fludarabine and TBI. Patients with a 9/10 mismatched donor received all products indicated below in the arm specification

    Serious adverse events
    		 9/10 and 10/10 matched donor
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 46 (26.09%)
         number of deaths (all causes)
    18
         number of deaths resulting from adverse events
    2
    Nervous system disorders
    Vasovagal reaction
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Graft versus host disease in gastrointestinal tract
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Nausea and vomiting
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Thoracic pain
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Septic shock
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Encephalitis
         subjects affected / exposed
    1 / 46 (2.17%)
         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
    		 9/10 and 10/10 matched donor
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 46 (26.09%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    General disorders and administration site conditions
    Insomnia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Immune system disorders
    Febrile neutropenia
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Graft versus host disease
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    2
    Pain at right flank
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Hepatobiliary disorders
    Blood bilirubin increased
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    2
    ALT increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    AST increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Idiopathic pneumonia syndrome
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Renal and urinary disorders
    Creatinine increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Product issues
    Take failure
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Infections and infestations
    Upper respiratory tract infection
    Additional description: RS virus
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Anorexia nervosa
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33824442
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