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    Clinical Trial Results:
    A Phase 2, Randomized, Open-Label Study of the Safety and Efficacy of Two Doses of Quizartinib (AC220; ASP2689) in Subjects with FLT3-ITD Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)

    Summary
    EudraCT number
    2011-005408-13
    Trial protocol
    GB   IT  
    Global end of trial date
    09 Mar 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Dec 2018
    First version publication date
    23 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2689-CL-2004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01565668
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mt. Airy Road, Basking Ridge, United States, 07920
    Public contact
    Study Director, Daiichi Sankyo, Inc., 1 908-992-6400,
    Scientific contact
    Study Director, Daiichi Sankyo, Inc., 1 908-992-6400,
    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
    10 Nov 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives are to evaluate the rate of Grade 2 or higher QTcF prolongation and to evaluate the composite complete remission rate (CRc), defined as the confirmed rate of complete remission (CR) plus complete remission with incomplete platelet recovery (CRp) or incomplete hematological recovery (CRi) at different doses of AC220.
    Protection of trial subjects
    This trial was conducted in accordance with the ethical principles of Good Clinical Practice, according to the ICH Harmonized Tripartite Guideline.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Apr 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 58
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    76
    EEA total number of subjects
    18
    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)
    56
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Approximately 70 subjects were to be randomized equally between 2 treatment arms of quizartinib (at approximately 50 centers in North America and Europe), to receive daily doses of 30 mg or 60 mg. This was to provide, at the minimum, 32 centrally tested FLT3-ITD (+) AML subjects.

    Pre-assignment
    Screening details
    Of the subjects screened, 76 were enrolled into the intention to treat (ITT) analysis set. Two patients who were randomized to quizartinib (60 mg/day) did not receive study drug, so are not included in the data.

    Pre-assignment period milestones
    Number of subjects started
    76
    Number of subjects completed
    76

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Open label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1 30 mg
    Arm description
    Patients were randomized to receive 30 mg quizartinib once daily
    Arm type
    Experimental

    Investigational medicinal product name
    Quizartinib
    Investigational medicinal product code
    Other name
    AC220, ASP2689
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Once-daily dose of oral solution for continuous 28-day cycles until deemed no longer beneficial by investigator

    Arm title
    Cohort 2 60 mg
    Arm description
    Patients were randomized to receive 60 mg quizartinib once daily
    Arm type
    Experimental

    Investigational medicinal product name
    Quizartinib
    Investigational medicinal product code
    Other name
    AC220, ASP2689
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Once-daily dose of oral solution for continuous 28-day cycles until deemed no longer beneficial by investigator

    Number of subjects in period 1
    Cohort 1 30 mg Cohort 2 60 mg
    Started
    38
    38
    Started treatment
    38
    38
    Completed treatment per protocol
    0
    0
    Started 30-day follow-up
    37
    37
    Completed 30-day follow-up
    11
    5
    Started long-term follow-up
    36
    33
    Completed long-term follow-up
    0
    0
    Completed
    0
    0
    Not completed
    38
    38
         Death
    2
    1
         Lack of efficacy
    4
    2
         Patient went on Hospice Care
    1
    -
         Adverse event, non-fatal
    6
    1
         Randomized But Never Received Study Drug
    -
    2
         Progressive Disease
    13
    14
         Consent withdrawn by subject
    1
    3
         HSCT Transplant
    11
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    -

    Reporting group values
    Overall Study Total
    Number of subjects
    76 76
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    56 56
        From 65-84 years
    20 20
    Age continuous
    Units: years
        median (full range (min-max))
    54.5 (19 to 77) -
    Gender categorical
    Units: Subjects
        Female
    32 32
        Male
    44 44

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 30 mg
    Reporting group description
    Patients were randomized to receive 30 mg quizartinib once daily

    Reporting group title
    Cohort 2 60 mg
    Reporting group description
    Patients were randomized to receive 60 mg quizartinib once daily

    Primary: Number of Subjects Who Achieved Composite Complete Remission (CRc)

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    End point title
    Number of Subjects Who Achieved Composite Complete Remission (CRc) [1]
    End point description
    CRc is defined as Complete remission (CR) + Complete remission with incomplete platelet recovery (CRp) + Complete remission with incomplete hematological recovery (CRi)
    End point type
    Primary
    End point timeframe
    After two 28-day cycles
    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: Comparisons between cohorts were not made.
    End point values
    Cohort 1 30 mg Cohort 2 60 mg
    Number of subjects analysed
    38
    38
    Units: Patients
    18
    18
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Achieved Complete Remission (CR)

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    End point title
    Number of Subjects Who Achieved Complete Remission (CR)
    End point description
    Patient must have bone marrow regenerating normal hematopoietic cells and achieve a morphologic leukemia-free state (< 5% bone marrow blasts in bone marrow, no blasts with Auer rods and no persistence of extramedullary disease) and must have an absolute neutrophil count (ANC) ≥ 1x109/L and platelet count ≥ 100 x 109/L and they will be red blood cell (RBC) and platelet transfusion independent (defined as 4 weeks without RBC transfusions and 1 week without platelet transfusion).
    End point type
    Secondary
    End point timeframe
    After two complete 28-day cycles
    End point values
    Cohort 1 30 mg Cohort 2 60 mg
    Number of subjects analysed
    38
    38
    Units: Patients
    2
    0
    No statistical analyses for this end point

    Secondary: Duration of Response In Subjects Who Achieved CRc or PR

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    End point title
    Duration of Response In Subjects Who Achieved CRc or PR
    End point description
    Duration of response (DOR) was defined as the time from either the first CRc or PR until the date of relapse (any type) for subjects who achieved CRc or PR (relapse date - first CRc or PR disease assessment date + 1). DOR was measured in weeks and categorized by quartiles; the 50% quartile is presented.
    End point type
    Secondary
    End point timeframe
    Time from first CRc or PR until date of relapse
    End point values
    Cohort 1 30 mg Cohort 2 60 mg
    Number of subjects analysed
    23
    27
    Units: Weeks
    number (confidence interval 95%)
        DOR; 50% quartile
    7.3 (4.1 to 11.9)
    9.1 (5.6 to 21.0)
    No statistical analyses for this end point

    Secondary: Time to CRc in Subjects Who Achieved CRc

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    End point title
    Time to CRc in Subjects Who Achieved CRc
    End point description
    Time to CRc was defined as the time from the date of randomization until the first disease assessment of CRc (first CRc disease assessment date - randomization date +1). Time to CRc was only assessed who achieved CRc. Time to CRc was measured in weeks and categorized by quartiles; the 50% quartile is presented.
    End point type
    Secondary
    End point timeframe
    Time from the date of randomization until the first disease assessment of CRc
    End point values
    Cohort 1 30 mg Cohort 2 60 mg
    Number of subjects analysed
    18
    18
    Units: weeks
    number (confidence interval 95%)
        Time to CRc; 50% quartile
    4.4 (4.1 to 7.7)
    4.6 (4.1 to 8.0)
    No statistical analyses for this end point

    Other pre-specified: Maximum QTcF Value in Subjects Who Received Quizartinib

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    End point title
    Maximum QTcF Value in Subjects Who Received Quizartinib
    End point description
    The number of patients with maximum corrected for heart rate using Fridericia's factor (QTcF) value (msec) on study is presented. Grade 2 or higher prolongation is defined as QTcF >480 msec.
    End point type
    Other pre-specified
    End point timeframe
    After 2 continuous 28-day cycles
    End point values
    Cohort 1 30 mg Cohort 2 60 mg
    Number of subjects analysed
    38
    36
    Units: Subjects
    number (not applicable)
        <450
    18
    13
        ≥450 and ≤480
    16
    17
        >480 and ≤500
    2
    5
        >500
    2
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the trial for adverse events, plus 30 days for serious AEs
    Adverse event reporting additional description
    Of note, AML disease progression (including the MedDRA verbatim terms of AML progression and disease progression, malignant neoplasm progression, and leukocytosis) is reported as an AE in the data output and in the in-text tables; however, it is not considered an AE because of the patient population under study and is not further discussed.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Cohort 1 30 mg
    Reporting group description
    -

    Reporting group title
    Cohort 2 60 mg
    Reporting group description
    -

    Serious adverse events
    Cohort 1 30 mg Cohort 2 60 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 38 (65.79%)
    25 / 36 (69.44%)
         number of deaths (all causes)
    9
    13
         number of deaths resulting from adverse events
    1
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive disease
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    5 / 38 (13.16%)
    7 / 36 (19.44%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 5
    0 / 6
    Lung neoplasm
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 38 (7.89%)
    5 / 36 (13.89%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical observation
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    7 / 38 (18.42%)
    6 / 36 (16.67%)
         occurrences causally related to treatment / all
    3 / 7
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Arachnoiditis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Caecitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal infarction
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary retention
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess intestinal
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis fungal
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candidiasis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile sepsis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Device related infection
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 38 (7.89%)
    6 / 36 (16.67%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia fungal
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinusitis aspergillus
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort 1 30 mg Cohort 2 60 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 38 (97.37%)
    36 / 36 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Hypotension
         subjects affected / exposed
    5 / 38 (13.16%)
    4 / 36 (11.11%)
         occurrences all number
    5
    4
    Thrombophlebitis superficial
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 36 (5.56%)
         occurrences all number
    3
    2
    Catheter site erythema
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Catheter site pain
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Chest discomfort
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Chills
         subjects affected / exposed
    5 / 38 (13.16%)
    3 / 36 (8.33%)
         occurrences all number
    5
    3
    Fatigue
         subjects affected / exposed
    13 / 38 (34.21%)
    8 / 36 (22.22%)
         occurrences all number
    13
    8
    Malaise
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Mucosal inflammation
         subjects affected / exposed
    6 / 38 (15.79%)
    5 / 36 (13.89%)
         occurrences all number
    6
    5
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    0
    4
    Oedema
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Oedema peripheral
         subjects affected / exposed
    8 / 38 (21.05%)
    6 / 36 (16.67%)
         occurrences all number
    8
    6
    Pain
         subjects affected / exposed
    2 / 38 (5.26%)
    4 / 36 (11.11%)
         occurrences all number
    2
    4
    Pyrexia
         subjects affected / exposed
    10 / 38 (26.32%)
    10 / 36 (27.78%)
         occurrences all number
    10
    10
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 38 (2.63%)
    5 / 36 (13.89%)
         occurrences all number
    1
    5
    Confusional state
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Insomnia
         subjects affected / exposed
    2 / 38 (5.26%)
    5 / 36 (13.89%)
         occurrences all number
    2
    5
    Hallucination, visual
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    Fall
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Procedural pain
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Transfusion reaction
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 36 (8.33%)
         occurrences all number
    3
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Blood bilirubin increased
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 36 (8.33%)
         occurrences all number
    3
    3
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 38 (5.26%)
    5 / 36 (13.89%)
         occurrences all number
    2
    5
    Platelet count decreased
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    White blood cell count decreased
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Tachycardia
         subjects affected / exposed
    3 / 38 (7.89%)
    6 / 36 (16.67%)
         occurrences all number
    3
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 38 (21.05%)
    9 / 36 (25.00%)
         occurrences all number
    8
    9
    Dyspnoea
         subjects affected / exposed
    8 / 38 (21.05%)
    5 / 36 (13.89%)
         occurrences all number
    8
    5
    Dyspnoea exertional
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Epistaxis
         subjects affected / exposed
    6 / 38 (15.79%)
    4 / 36 (11.11%)
         occurrences all number
    6
    4
    Nasal congestion
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Oropharyngeal pain
         subjects affected / exposed
    5 / 38 (13.16%)
    6 / 36 (16.67%)
         occurrences all number
    5
    6
    Pleural effusion
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    Productive cough
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Rhinorrhoea
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Sinus congestion
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 38 (44.74%)
    9 / 36 (25.00%)
         occurrences all number
    17
    9
    Febrile neutropenia
         subjects affected / exposed
    5 / 38 (13.16%)
    7 / 36 (19.44%)
         occurrences all number
    5
    7
    Leukocytosis
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Neutropenia
         subjects affected / exposed
    1 / 38 (2.63%)
    5 / 36 (13.89%)
         occurrences all number
    1
    5
    Thrombocytopenia
         subjects affected / exposed
    8 / 38 (21.05%)
    7 / 36 (19.44%)
         occurrences all number
    8
    7
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Dizziness
         subjects affected / exposed
    3 / 38 (7.89%)
    4 / 36 (11.11%)
         occurrences all number
    3
    4
    Dysgeusia
         subjects affected / exposed
    6 / 38 (15.79%)
    2 / 36 (5.56%)
         occurrences all number
    6
    2
    Headache
         subjects affected / exposed
    4 / 38 (10.53%)
    9 / 36 (25.00%)
         occurrences all number
    4
    9
    Paraesthesia
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Tremor
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Abdominal pain
         subjects affected / exposed
    6 / 38 (15.79%)
    11 / 36 (30.56%)
         occurrences all number
    6
    11
    Abdominal pain upper
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    6 / 38 (15.79%)
    3 / 36 (8.33%)
         occurrences all number
    6
    3
    Diarrhoea
         subjects affected / exposed
    10 / 38 (26.32%)
    12 / 36 (33.33%)
         occurrences all number
    10
    12
    Dyspepsia
         subjects affected / exposed
    6 / 38 (15.79%)
    2 / 36 (5.56%)
         occurrences all number
    6
    2
    Eructation
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Haematemesis
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Haemorrhoids
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    Mouth haemorrhage
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    10 / 38 (26.32%)
    16 / 36 (44.44%)
         occurrences all number
    10
    16
    Proctalgia
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Toothache
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Vomiting
         subjects affected / exposed
    11 / 38 (28.95%)
    12 / 36 (33.33%)
         occurrences all number
    11
    12
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Urinary hesitation
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Urinary incontinence
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    Erythema
         subjects affected / exposed
    0 / 38 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    0
    4
    Night sweats
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Petechiae
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Pruritus
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Rash
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Rash erythematous
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Rash maculo-papular
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Skin lesion
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 36 (5.56%)
         occurrences all number
    3
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 36 (5.56%)
         occurrences all number
    3
    2
    Back pain
         subjects affected / exposed
    5 / 38 (13.16%)
    3 / 36 (8.33%)
         occurrences all number
    5
    3
    Muscular weakness
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 38 (5.26%)
    6 / 36 (16.67%)
         occurrences all number
    2
    6
    Myalgia
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 36 (2.78%)
         occurrences all number
    4
    1
    Neck pain
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 36 (11.11%)
         occurrences all number
    1
    4
    Pain in extremity
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 36 (8.33%)
         occurrences all number
    3
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 38 (13.16%)
    6 / 36 (16.67%)
         occurrences all number
    5
    6
    Hyperglycaemia
         subjects affected / exposed
    4 / 38 (10.53%)
    3 / 36 (8.33%)
         occurrences all number
    4
    3
    Hyperkalaemia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 38 (0.00%)
    6 / 36 (16.67%)
         occurrences all number
    0
    6
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 36 (5.56%)
         occurrences all number
    4
    2
    Hypocalcaemia
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 36 (5.56%)
         occurrences all number
    4
    2
    Hypokalaemia
         subjects affected / exposed
    9 / 38 (23.68%)
    6 / 36 (16.67%)
         occurrences all number
    9
    6
    Hypomagnesaemia
         subjects affected / exposed
    5 / 38 (13.16%)
    4 / 36 (11.11%)
         occurrences all number
    5
    4
    Hyponatraemia
         subjects affected / exposed
    4 / 38 (10.53%)
    2 / 36 (5.56%)
         occurrences all number
    4
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 38 (2.63%)
    5 / 36 (13.89%)
         occurrences all number
    1
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Clostridial infection
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Herpes simplex
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Pneumonia
         subjects affected / exposed
    0 / 38 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    0
    5
    Pneumonia fungal
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Rhinitis
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Vaginal infection
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 May 2012
    • Updated the Sponsor address. • Updated contact details of key Sponsor's personnel. • Corrected the compound code for the active metabolite of AC220. • Revised inclusion criteria. • Updated and clarified exclusion criteria. • Revised significance level in statistics section. • Updated stopping table in statistics section. • Updated Table 1 and footnotes. • Updated Table 2 and footnotes. • Clarifies that MUGA or ECHO is allowed at Screening. • Updated the formulation of the investigational drug is supplied as 90 mg of AC220. • Updated the storage temperature of AC220. • Updated the time of stability for reconstituted AC220. • Defined AE reporting time. • Clarified the requirements on when to include height and weight during physical exams. • Updated the title of sections 5.7.1.2 and 5.7.1.3. • Updated the total amount of blood required for the study. • Updated Appendix 12.10. • Included other minor administrative-type corrections, eg, consistency, format, typos, etc.
    22 Oct 2012
    • Updated the List of Abbreviations. • Updated secondary objectives. • Revised sample size. • Clarified that MUGA or ECHO is allowed at Screening. • Clarified the screening assessments that require bone marrow samples. • Revised inclusion criteria. • Revised exclusion criteria. • Clarified CR definition. • Clarified and corrected QTcF grading definition. • Updated and clarified exploratory variables. • Clarified efficacy analysis based on central versus local FLT3-ITD testing. • Added central morphological review of bone marrow samples. • Revised language in efficacy, safety and PK analysis sections. • Updated footnote in Table 1. • Updated clinical information from AC220-002 clinical study. • Clarified AC220 dose re-escalation language. • Updated concomitant medication section. • Added instructions to be followed in the case of a missed dosage. • Clarified criteria for continuation of treatment. • Added text describing secondary efficacy objectives. • Added text on disease history and extent of exposure. • Updated language about secondary safety analysis. • Added text on previous and concomitant transfusions. • Updated pharmacodynamic analyses section. • Included information on protocol deviations. • Clarified use of a Data Monitoring Committee. • Added missing CYP3A4 inhibitors to the list of excluded concomitant medication. • Clarified lines of therapy and add tools for patient eligibility determination. • Included other minor administrative-type corrections, eg, consistency, format, typos, etc.
    28 Aug 2013
    • Changed headers and footers. • Changed title page format. • Changed IND and EudraCT numbers. • Removed Astellas terminology. • Removed reference to Astellas. • Removed reference to Astellas personnel.
    04 Oct 2014
    • EudraCT number was corrected. • Contact details of key Sponsor personnel were updated (Section II). • Planned study period was updated (Section IV). • Description of study drug was updated to include both powder and tablet formulations.

    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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