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    Clinical Trial Results:
    A Phase I/II study of clofarabine in combination with cytarabine and liposomal daunorubicin in children with relapsed/refractory pediatric AML

    Summary
    EudraCT number
    		 2009-009457-13
    Trial protocol
    		 NL   CZ   AT   FR   DE  
    Global end of trial date
    02 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Sep 2020
    First version publication date
    23 Sep 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    StudyITCC020&I-BFMRelapsedAML
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Nederlands Trial Register: NTR1880
    Sponsors
    Sponsor organisation name
    Erasmus MC
    Sponsor organisation address
    Dr. Molenwaterplein 60, Rotterdam, Netherlands, 3015 GD
    Public contact
    Michel Zwaan, Erasmus MC, 31 107036691, c.m.zwaan@erasmusmc.nl
    Scientific contact
    Michel Zwaan, Erasmus MC, 31 107036691, c.m.zwaan@erasmusmc.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
    12 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To establish the recommended dose of clofarabine in combination with cytarabine and liposomal daunorubicin (DaunoXome®) in children with relapsed/refractory AML. Note: dosages of cytarabine and liposomal daunorubicin should be comparable to those used in the current Relapsed AML 2001/01 study (i.e. in the context of the FLAG/liposomal daunorubicin regimen).
    Protection of trial subjects
    By the informed consent and voluntary participation in the trial. Surgical interventions take place under anaestesia.
    Background therapy
    		 Cytarabine and liposomal daunorubicin
    Evidence for comparator
    		 In this study the cytarabine dose as administered in the FLAG regimen (2 gram/m2 bolus IV for 5 consecutive days) is used – which will allow a fair comparison with the FLAG regimen in later studies.
    Actual start date of recruitment
    10 May 2010
    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
    Netherlands: 13
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 12
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    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)
    6
    Children (2-11 years)
    16
    Adolescents (12-17 years)
    10
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study initiation date/first subject first visit: May 10, 2010 Study completion date/last subject last visit: April 2, 2015 34 subjects enrolled.

    Pre-assignment
    Screening details
    		 Patient eligibility: - <19 years of age with early 1st relapse (within 12 months from initial diagnosis) - refractory 1st relapse (≥20% blasts in the bone marrow after the 1st course of standard re-induction therapy) - with at least a 2nd relapsed AML Only patients with early 1st relapse without prior SCT were eligible for DL5.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose level 1
    Arm description
    		 Clofarabine = 20 mg/m2/day x 5d, DaunoXome = 40 mg/m2/ d 1-3-5, Ara-C = 2 gr/m2/day x 5d
    Arm type
    		 Dose level 1

    Investigational medicinal product name
    Clofarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/m2/day x 5 days

    Investigational medicinal product name
    Daunoxome
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg/m2/day; day 1-3-5

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 gr/m2/d x 5d

    Arm title
    		 Dose level 2
    Arm description
    		 Clofarabine = 30 mg/m2/day x 5d, DaunoXome = 40 mg/m2/ d 1-3-5, Ara-C = 2 gr/m2/day x 5d
    Arm type
    		 Dose level 2

    Investigational medicinal product name
    Clofarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/m2/d x 5d

    Investigational medicinal product name
    DaunoXome
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg/m2/d 1-3-5

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 gr/m2/d x 5d

    Arm title
    		 Dose level 3a
    Arm description
    		 clofarabine = 30 mg/m2/day x 5d, DaunoXome = 60 mg/m2/ d 1-3-5, Ara-C = 2 gr/m2/day x 5d
    Arm type
    		 Dose level 3a

    Investigational medicinal product name
    Clofarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/m2/d x 5 d

    Investigational medicinal product name
    DaunoXome
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    60 mg/m2/d 1-3-5

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 gr/m2/d x 5 d

    Arm title
    		 Dose level 3b
    Arm description
    		 clofarabine = 30 mg/m2/day x 5d, DaunoXome = 60 mg/m2/ d 1-3-5, Ara-C = 2 gr/m2/day x 5d
    Arm type
    		 Dose level 3b

    Investigational medicinal product name
    Clofarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/m2/d x 5 d

    Investigational medicinal product name
    DaunoXome
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    60 mg/m2/d 1-3-5

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 gr/m2/d x 5 d

    Arm title
    		 Dose level 4
    Arm description
    		 clofarabine = 40 mg/m2/day x 5d, DaunoXome = 60 mg/m2/ d 1-3-5, Ara-C = 2 gr/m2/day x 5d
    Arm type
    		 Dose level 4

    Investigational medicinal product name
    Clofarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg/m2/d x 5 d

    Investigational medicinal product name
    DaunoXome
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    60 mg/m2/d 1-3-5

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 gr/m2/d x 5 d

    Arm title
    		 Dose level 5
    Arm description
    		 clofarabine = 40 mg/m2/day x 5d, DaunoXome = 80 mg/m2/ d 1-3-5, Ara-C = 2 gr/m2/day x 5d
    Arm type
    		 Dose level 5

    Investigational medicinal product name
    Clofarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    40 mg/m2/d x 5 d

    Investigational medicinal product name
    DaunoXome
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    80 mg/m2/d 1-3-5

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 gr/m2/d x 5 d

    Number of subjects in period 1
    		Dose level 1 Dose level 2 Dose level 3a Dose level 3b Dose level 4 Dose level 5
    Started
    4
    3
    6
    6
    10
    5
    Completed
    4
    3
    6
    6
    10
    5

    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
    		 34 34
    Age categorical
    paediatric patients
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 6 6
        Children (2-11 years)
    		 16 16
        Adolescents (12-17 years)
    		 10 10
        Adults (18-64 years)
    		 2 2
    Gender categorical
    gender
    Units: Subjects
        Female
    		 14 14
        Male
    		 20 20
    Disease status
    Disease status
    Units: Subjects
        early first relapse
    		 15 15
        refractory first relapse
    		 11 11
        second relapse
    		 7 7
        greater than second relapse
    		 1 1
    FLT3/ITD
    FLT3/ITD mutated
    Units: Subjects
        no
    		 23 23
        yes
    		 4 4
        ND
    		 7 7
    AML/ETO
    AML/ETO mutated
    Units: Subjects
        no
    		 25 25
        yes
    		 0 0
        ND
    		 9 9
    CBFb-MYH11
    CBFb-MYH11 mutated
    Units: Subjects
        no
    		 27 27
        yes
    		 0 0
        ND
    		 7 7
    SCT
    underwent SCT
    Units: Subjects
        no
    		 22 22
        yes, 1 SCT
    		 11 11
        yes, 2 SCT's
    		 1 1
    WBC at initial diagnosis
    WBC at initial diagnosis
    Units: 10^9/L
        arithmetic mean (standard deviation)
    		 58 ± 108 -
    WBC at inclusion
    WBC at inclusion
    Units: 10^9/L
        arithmetic mean (standard deviation)
    		 19 ± 60 -

    End points

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    End points reporting groups
    Reporting group title
    Dose level 1
    Reporting group description
    		 Clofarabine = 20 mg/m2/day x 5d, DaunoXome = 40 mg/m2/ d 1-3-5, Ara-C = 2 gr/m2/day x 5d

    Reporting group title
    Dose level 2
    Reporting group description
    		 Clofarabine = 30 mg/m2/day x 5d, DaunoXome = 40 mg/m2/ d 1-3-5, Ara-C = 2 gr/m2/day x 5d

    Reporting group title
    Dose level 3a
    Reporting group description
    		 clofarabine = 30 mg/m2/day x 5d, DaunoXome = 60 mg/m2/ d 1-3-5, Ara-C = 2 gr/m2/day x 5d

    Reporting group title
    Dose level 3b
    Reporting group description
    		 clofarabine = 30 mg/m2/day x 5d, DaunoXome = 60 mg/m2/ d 1-3-5, Ara-C = 2 gr/m2/day x 5d

    Reporting group title
    Dose level 4
    Reporting group description
    		 clofarabine = 40 mg/m2/day x 5d, DaunoXome = 60 mg/m2/ d 1-3-5, Ara-C = 2 gr/m2/day x 5d

    Reporting group title
    Dose level 5
    Reporting group description
    		 clofarabine = 40 mg/m2/day x 5d, DaunoXome = 80 mg/m2/ d 1-3-5, Ara-C = 2 gr/m2/day x 5d

    Primary: Safety and tolerability

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    End point title
    		 Safety and tolerability [1]
    End point description
    safety/tolerability was investigated by counting the DLT's per dose level
    End point type
    Primary
    End point timeframe
    during first course
    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: Study is phase I with primary endpoint DLT's ; number of DLT's is provided; statistical analysis not applicable.
    End point values
    		 Dose level 1 Dose level 2 Dose level 3a Dose level 3b Dose level 4 Dose level 5
    Number of subjects analysed
    4
    3
    6
    6
    10
    5
    Units: number of DLT's
    1
    0
    4
    1
    1
    2
    No statistical analyses for this end point

    Secondary: OS

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    End point title
    		 OS
    End point description
    OS (overall survival)
    End point type
    Secondary
    End point timeframe
    OS = time from study inclusion to death/DLC
    End point values
    		 Dose level 1 Dose level 2 Dose level 3a Dose level 3b Dose level 4 Dose level 5
    Number of subjects analysed
    4
    3
    6
    6
    10
    5
    Units: months
        alive
    0
    0
    1
    2
    6
    4
        dead
    4
    3
    5
    4
    4
    1
    No statistical analyses for this end point

    Secondary: EFS

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    End point title
    		 EFS
    End point description
    event free survival
    End point type
    Secondary
    End point timeframe
    EFS = time from inclusion in study to treatment failure, relapse or death/DLC
    End point values
    		 Dose level 1 Dose level 2 Dose level 3a Dose level 3b Dose level 4 Dose level 5
    Number of subjects analysed
    4
    3
    6
    6
    10
    5
    Units: months
        EFS
    0
    0
    0
    2
    6
    2
        treat. failure
    3
    1
    4
    0
    1
    1
        relapse
    0
    2
    1
    1
    1
    2
        death
    1
    0
    1
    3
    2
    0
    No statistical analyses for this end point

    Secondary: Response on cycle 1

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    End point title
    		 Response on cycle 1
    End point description
    response on first cycle
    End point type
    Secondary
    End point timeframe
    evaluation of first treatment cycle
    End point values
    		 Dose level 1 Dose level 2 Dose level 3a Dose level 3b Dose level 4 Dose level 5
    Number of subjects analysed
    4
    3
    6
    6
    10
    5
    Units: type respose
        CR
    0
    0
    0
    0
    2
    3
        CRi
    1
    2
    1
    5
    5
    1
        PR
    0
    0
    0
    0
    1
    0
        SD
    1
    0
    3
    0
    1
    1
        PD
    1
    0
    1
    0
    0
    0
        treatment failure
    0
    1
    0
    0
    0
    0
        unknown
    0
    0
    1
    1
    1
    0
    No statistical analyses for this end point

    Secondary: Response on cycle 2

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    End point title
    		 Response on cycle 2
    End point description
    response on second cycle
    End point type
    Secondary
    End point timeframe
    evaluation of second treatment cycle
    End point values
    		 Dose level 1 Dose level 2 Dose level 3a Dose level 3b Dose level 4 Dose level 5
    Number of subjects analysed
    4
    3
    6
    6
    10
    5
    Units: type response
        CR
    0
    0
    0
    0
    0
    0
        CRi
    0
    0
    0
    0
    2
    0
        PR
    0
    0
    0
    0
    0
    0
        SD
    0
    0
    0
    0
    0
    0
        PD
    0
    0
    0
    0
    0
    0
        treatment failure
    0
    0
    0
    0
    0
    0
        unknown
    4
    3
    6
    6
    8
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event assessment from time of signing informed consent until long term follow-up.
    Adverse event reporting additional description
    (S)AEs need to be reported until 30 days after the last administration of study medication, or until another treatment regimen is started, whichever occurs first. However, in the case of AEs occurring later than this deadline but which are considered related to the study medication by the investigator, such AEs still need to be reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    dose level 1-5
    Reporting group description
    		 all patients treated in dose levels 1-5

    Serious adverse events
    		 dose level 1-5
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 34 (76.47%)
         number of deaths (all causes)
    21
         number of deaths resulting from adverse events
    2
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    15 / 34 (44.12%)
         occurrences causally related to treatment / all
    13 / 15
         deaths causally related to treatment / all
    0 / 0
    blood/BM other: progressive leukemia
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    hypoxia
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Skin and subcutaneous tissue disorders
    rash
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Endocrine disorders
    Capillary disorder
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    infection lung
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    6 / 34 (17.65%)
         occurrences causally related to treatment / all
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 dose level 1-5
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 34 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor lysis syndrome
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Vascular disorders
    Capillary leak syndrome
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fever
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Pain bone
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Pain (headache)
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Pain oral cavity
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Pain-legs/feet
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Immune system disorders
    Allergic reaction (abelcet)
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    3
    Pneumonitis
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    2
    Dyspnea
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Investigations
    Hyperbillirubinemia
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Bilirubin
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    ALT
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Glutamyl transpeptidase
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    PTT
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    GGT
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Hypokalaemia
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Cardiac disorders
    Hypotension
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    3
    Hypertension
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Ventricular tachycardia
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Nervous system disorders
    Tremor
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Platelets
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    4 / 34 (11.76%)
         occurrences all number
    9
    Anemia
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    3
    DIC
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Thrombocytopenia
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Neutropenia
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    4 / 34 (11.76%)
         occurrences all number
    4
    Hemoglobin
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    4 / 34 (11.76%)
         occurrences all number
    4
    Leukocytes
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    5
    Edema limb
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Neutrophiles
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Eye disorders
    Dry eye syndrome
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Ocular/other hyposfagma, swelling
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    3 / 34 (8.82%)
         occurrences all number
    3
    Nausea
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    5 / 34 (14.71%)
         occurrences all number
    5
    Diarrhea
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    6 / 34 (17.65%)
         occurrences all number
    6
    Anorexia
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Dehydration
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Abdominal pain
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Ascites
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pruritus
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Rash: Hand - feet skin reaction
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Skin pain (cellulitis)
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Renal and urinary disorders
    Acute renal failure
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    2
    Reduced diuresis
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Infections and infestations
    Infection
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    3
    Febrile neutropenia
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    19 / 34 (55.88%)
         occurrences all number
    36
    Infection with grade 3 or 4 neutrophils (sepsis)
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    2 / 34 (5.88%)
         occurrences all number
    2
    Infection lung
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Fever
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Infection documented clinically blood
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Sepsis Candides non Albicans
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Febrile Aplasia
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Infection (candida)
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Cellulitis infection
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Infection eyes with grade 4 ANC
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Infection - ANC grade 4 (CVAD)
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    AST
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Infection lungs
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Pulmonary infection (aspergillosis)
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Acidosis
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         occurrences all number
    1
    Hypophosphataemia
    Additional description: All grade 3 and grade 4 AE's related to the first treatment cycle
         subjects affected / exposed
    1 / 34 (2.94%)
         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
    05 Nov 2011
    Revision of in- and exclusion criteria of the protocol regarding: - uncontrolled infections: actively excluding patients who may have subclinical fungal infection; - early relapse AML patients are eligible due to closure of the AML 2001-01 study; Revision of the dose escalation schedule; Prolongation of inclusion period; Recalculation of Statistical approach and Sample size.

    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/29773602
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