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    Clinical Trial Results:
    A Phase 2 Open-label, AC220 Monotherapy Efficacy (ACE) Study in Patients with Acute Myeloid Leukemia (AML) with and without FLT3-ITD Activating Mutations

    Summary
    EudraCT number
    2009-013093-41
    Trial protocol
    FR   DE   ES   NL   PL   IT   GB  
    Global end of trial date
    31 Dec 2014

    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
    AC220-002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00989261
    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
    Global Clinical Leader, Daiichi Sankyo, Inc., 1 9089926400,
    Scientific contact
    Global Clinical Leader, Daiichi Sankyo, Inc., 1 9089926400,
    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
    28 Sep 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Sep 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determination of: •Overall complete remission rate, defined as the confirmed rate of complete remission (CR) plus complete remission with incomplete platelet (CRp) or incomplete hematological recovery (CRi) ( ie, CR + CRp + CRi) •Complete remission rate, defined as the confirmed rate of CR The basic results in the Clinical Study Report reflected here, focus on the combined data across both the Exploratory and Confirmatory Stages, as the results were able to be integrated and, in doing so, provide a more robust perspective on the objectives. All combination data tables were reprogrammed based on the original data and the results were validated. Of note, the SAP was not modified to reflect the presentation of the combination output. The key analyses for all disease assessment-related endpoints were carried out on the derived response rate based on local morphology using the Safety Analysis Set, equivalent to a traditional Intent-To-Treat Analysis Set.
    Protection of trial subjects
    This trial was conducted under ICH E6 Good Clinical Practices, which has its foundation in the Declaration of Helsinki. Subjects were allowed to continue taking the compound after trial completion, as long as it was providing benefit (compassionate use). A single scheduled review of efficacy data was conducted by an independent Data Monitoring Committee (DMC) for recommendation whether to continue the study from the Exploratory Stage into the Confirmatory Stage. The DMC reviewed trial safety data in an ongoing fashion as detailed below. The DMC was responsible for safeguarding the interests of study subjects, assessing the safety and efficacy of the interventions during the study, and for monitoring the overall conduct of the clinical study. The DMC was tasked with providing recommendations about stopping or continuing the study. The DMC was responsible for confirming the safety and related parameters including corrected QT interval (QTc) prolongation interval and primary response data to be monitored, as defined in the protocol, and discussed the frequency of DMC meetings and criteria for making recommendations to the Sponsor. Safety/study integrity reviews were held during protocol enrollment and follow-up, to review safety information, response data and factors relating to quality of study conduct. Because this was an open-label study, the DMC members were not blinded to a subject’s or a group’s treatment. The DMC was advisory to the Sponsor. The Sponsor had the responsibility to promptly review the DMC recommendations, to decide whether to continue, modify or terminate the study, and to determine whether amendments to the protocol or changes in study conduct were required.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Nov 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Ethical reason
    Long term follow-up duration
    4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    France: 53
    Country: Number of subjects enrolled
    Germany: 64
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    United States: 145
    Country: Number of subjects enrolled
    Canada: 4
    Worldwide total number of subjects
    333
    EEA total number of subjects
    184
    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)
    186
    From 65 to 84 years
    145
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Of all potential participants screened, a total of 333 patients were enrolled in nine countries.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1
    Arm description
    Cohort 1 was to include subjects 60 years of age or older who relapsed within 1 year after first line chemotherapy regimen, with or without consolidation, or were primary refractory to first line chemotherapy. - Exploratory (N=24): FLT3-ITD(+): n=22; FLT-ITD(-): n=2; unknown: n=0 - Confirmatory (N=133): FLT3-ITD(+): n=90; FLT-ITD(-): n=42; unknown: n=1 - Total (N=157): FLT3-ITD(+): n=112; FLT-ITD(-): n=44; unknown: n=1
    Arm type
    Experimental

    Investigational medicinal product name
    Quizartinib
    Investigational medicinal product code
    Other name
    Compound AC220
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Quizartinib administered as a once daily oral solution given continuously as 28-day treatment cycles, without any rest periods, until disease progression, relapse, intolerance to the drug, or elective allogeneic hematopoietic stem cell transplantation (HSCT)

    Arm title
    Cohort 2
    Arm description
    Cohort 2 was to include subjects 18 years of age or older, including those 60 years of age or older, who were relapsed or refractory after 1 second line (salvage) regimen, or after hematopoietic stem cell transplant (HSCT). - Exploratory (N=38): FLT3-ITD(+): n=36; FLT-ITD(-): n=2; unknown: n=0 - Confirmatory (N=138): FLT3-ITD(+): n=100; FLT-ITD(-): n=38; unknown: n=0 - Total (N=176): FLT3-ITD(+): n=136; FLT-ITD(-): n=40; unknown: n=0
    Arm type
    Experimental

    Investigational medicinal product name
    Quizartinib
    Investigational medicinal product code
    Other name
    Compound AC220
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Quizartinib administered as a once daily oral solution given continuously as 28-day treatment cycles, without any rest periods, until disease progression, relapse, intolerance to the drug, or elective allogeneic hematopoietic stem cell transplantation (HSCT)

    Number of subjects in period 1
    Cohort 1 Cohort 2
    Started
    157
    176
    Study Treatment Discontinued
    155
    174
    Completed
    142
    154
    Not completed
    15
    22
         Still in Follow-up
    12
    21
         Consent withdrawn by subject
    -
    1
         Lost to follow-up
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Cohort 1 was to include subjects 60 years of age or older who relapsed within 1 year after first line chemotherapy regimen, with or without consolidation, or were primary refractory to first line chemotherapy. - Exploratory (N=24): FLT3-ITD(+): n=22; FLT-ITD(-): n=2; unknown: n=0 - Confirmatory (N=133): FLT3-ITD(+): n=90; FLT-ITD(-): n=42; unknown: n=1 - Total (N=157): FLT3-ITD(+): n=112; FLT-ITD(-): n=44; unknown: n=1

    Reporting group title
    Cohort 2
    Reporting group description
    Cohort 2 was to include subjects 18 years of age or older, including those 60 years of age or older, who were relapsed or refractory after 1 second line (salvage) regimen, or after hematopoietic stem cell transplant (HSCT). - Exploratory (N=38): FLT3-ITD(+): n=36; FLT-ITD(-): n=2; unknown: n=0 - Confirmatory (N=138): FLT3-ITD(+): n=100; FLT-ITD(-): n=38; unknown: n=0 - Total (N=176): FLT3-ITD(+): n=136; FLT-ITD(-): n=40; unknown: n=0

    Reporting group values
    Cohort 1 Cohort 2 Total
    Number of subjects
    157 176 333
    Age categorical
    Units: Subjects
        less than 60 years
    2 132 134
        at least 60 years
    155 44 199
    Age continuous
    Units: years
        median (full range (min-max))
    69.0 (32 to 86) 51.0 (19 to 77) -
    Gender categorical
    Units: Subjects
        Female
    80 83 163
        Male
    77 93 170
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    2 5 7
        Black or African American
    5 5 10
        Native Hawaiian or Other Pacific Islander
    1 0 1
        White
    135 156 291
        Not Provided
    12 4 16
        Other
    2 6 8
    Ethnicity
    Units: Subjects
        Hispanic
    4 6 10
        Not Hispanic
    126 150 276
        Not allowed to ask per local regulations
    27 20 47
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    74.66 ± 14.75 74.76 ± 19.41 -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Cohort 1 was to include subjects 60 years of age or older who relapsed within 1 year after first line chemotherapy regimen, with or without consolidation, or were primary refractory to first line chemotherapy. - Exploratory (N=24): FLT3-ITD(+): n=22; FLT-ITD(-): n=2; unknown: n=0 - Confirmatory (N=133): FLT3-ITD(+): n=90; FLT-ITD(-): n=42; unknown: n=1 - Total (N=157): FLT3-ITD(+): n=112; FLT-ITD(-): n=44; unknown: n=1

    Reporting group title
    Cohort 2
    Reporting group description
    Cohort 2 was to include subjects 18 years of age or older, including those 60 years of age or older, who were relapsed or refractory after 1 second line (salvage) regimen, or after hematopoietic stem cell transplant (HSCT). - Exploratory (N=38): FLT3-ITD(+): n=36; FLT-ITD(-): n=2; unknown: n=0 - Confirmatory (N=138): FLT3-ITD(+): n=100; FLT-ITD(-): n=38; unknown: n=0 - Total (N=176): FLT3-ITD(+): n=136; FLT-ITD(-): n=40; unknown: n=0

    Primary: Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD (+) Subjects)

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    End point title
    Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD (+) Subjects) [1]
    End point description
    Derived disease assessment based on local morphology of bone marrow disease performed by each local site pathologist, including all on-treatment data (Safety Population, FLT3-ITD(+) Patients) Modified from Cheson et al, abbreviations used include the following: CR = complete remission; CRc = composite complete remission (CR + CRp + CRi); CRi = complete remission with incomplete hematological recovery, includes subjects who met CRia criteria plus subjects who met CRib criteria; CRia = all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia <1 × 109/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib = All criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion; CRp = complete remission with incomplete platelet recovery; NR = no response; PR = partial remission.
    End point type
    Primary
    End point timeframe
    Within the first 3 cycles of treatment (84 days)
    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 Cohort 2
    Number of subjects analysed
    112
    136
    Units: Patients
        CRc
    63
    62
        CR
    3
    5
        CRp
    4
    2
        CRi
    56
    55
        PR
    23
    39
        NR
    20
    24
        UNK
    6
    11
    No statistical analyses for this end point

    Primary: Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD (-) Subjects)

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    End point title
    Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD (-) Subjects) [2]
    End point description
    Derived disease assessment based on local morphology of bone marrow disease performed by each local site pathologist, including all on-treatment data. Modified from Cheson et al, abbreviations used include the following: CR = complete remission; CRc = composite complete remission (CR + CRp + CRi); CRi = complete remission with incomplete hematological recovery, includes subjects who met CRia criteria plus subjects who met CRib criteria; CRia = all criteria specified for CR are met, except for incomplete hematological recovery with residual neutropenia <1 × 109/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib = All criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion; NR = no response; PR = partial remission; UNK = unknown
    End point type
    Primary
    End point timeframe
    Within the first 3 cycles of treatment (84 days)
    Notes
    [2] - 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 Cohort 2
    Number of subjects analysed
    44
    40
    Units: Patients
        CRc
    16
    12
        CR
    2
    1
        CRp
    1
    1
        CRi
    13
    10
        PR
    4
    6
        NR
    17
    16
        UNK
    7
    6
    No statistical analyses for this end point

    Primary: Number of patients with composite complete remission (CRc), categorised by FLT3-ITD status

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    End point title
    Number of patients with composite complete remission (CRc), categorised by FLT3-ITD status [3]
    End point description
    CRc is defined as composite complete remission (CR + CRp + CRi) - CR = complete remission; CRp = complete remission with incomplete platelet recovery; CRi = complete remission with incomplete hematological recovery, includes subjects who met CRia criteria plus subjects who met CRib criteria; CRia = all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia <1 × 109/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib = All criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion
    End point type
    Primary
    End point timeframe
    within 28 months
    Notes
    [3] - 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 Cohort 2
    Number of subjects analysed
    157
    176
    Units: Patients
        FLT3-ITD (+)
    63
    62
        FLT3-ITD (-)
    16
    12
    No statistical analyses for this end point

    Secondary: Duration of Composite Complete Remission in Subjects who Achieved CRc Based on All On-Treatment Data

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    End point title
    Duration of Composite Complete Remission in Subjects who Achieved CRc Based on All On-Treatment Data
    End point description
    Kaplan-Meier analysis of duration of composite complete remission derived based on local morphology including all on-treatment data (Safety Population) The definition of relapse at CRc includes an evaluation of blasts in the peripheral blood of >1%. Though not specified in the protocol, the addition of these criteria was deemed necessary for consistency with the Cheson criteria.
    End point type
    Secondary
    End point timeframe
    Within first 3 cycles of treatment (84 days)
    End point values
    Cohort 1 Cohort 2
    Number of subjects analysed
    63 [4]
    62 [5]
    Units: Weeks
    median (confidence interval 95%)
        FLT3-ITD(+) Patients
    12.1 (6.3 to 15.7)
    10.6 (8.1 to 16.1)
        FLT3-ITD(-) Patients
    16.4 (8.1 to 30.4)
    7.0 (4.1 to 8.1)
    Notes
    [4] - Note: N=63 for FLTE-ITD (+) subjects and N=16 for FLT3-ITD(-) subjects
    [5] - Note: N=62 for FLTE-ITD (+) subjects and N=12 for FLT3-ITD(-) subjects
    No statistical analyses for this end point

    Secondary: Duration of Any Response

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    End point title
    Duration of Any Response
    End point description
    Kaplan-Meier analysis of duration of any response (CR, CRp, CRi, or PR), derived based on local morphology for subjects who achieved a response during the first 3 cycles of treatment (Safety Population)
    End point type
    Secondary
    End point timeframe
    Within the first 3 cycles of treatment (84 days)
    End point values
    Cohort 1 Cohort 2
    Number of subjects analysed
    83 [6]
    99 [7]
    Units: Weeks
    median (confidence interval 95%)
        FLT3-ITD(+) Patients
    15.1 (12.1 to 18.4)
    12.1 (10.0 to 18.4)
        FLT3-ITD(-) Patients
    12.4 (8.3 to 30.4)
    7.9 (6.3 to 12.1)
    Notes
    [6] - Note: N=83 for FLTE-ITD (+) subjects and N=20 for FLT3-ITD(-) subjects
    [7] - Note: N=99 for FLTE-ITD (+) subjects and N=18 for FLT3-ITD(-) subjects
    No statistical analyses for this end point

    Secondary: Median Duration of Leukemia-Free Survival

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    End point title
    Median Duration of Leukemia-Free Survival
    End point description
    Kaplan-Meier analysis of leukemia-free survival in patients who achieved a CRc in the first three cycles of treatment derived based on local morphology (Safety Population)
    End point type
    Secondary
    End point timeframe
    Within first 3 cycles of treatment (84 days)
    End point values
    Cohort 1 Cohort 2
    Number of subjects analysed
    61 [8]
    61 [9]
    Units: Weeks
    median (confidence interval 95%)
        FLT3-ITD(+) Patients
    12.1 (6.1 to 14.3)
    12.9 (9.4 to 19.1)
        FLT3-ITD(-) Patients
    20.4 (8.1 to 26.1)
    7.0 (5.0 to 8.1)
    Notes
    [8] - Note: N=61 for FLTE-ITD (+) subjects and N=13 for FLT3-ITD(-) subjects
    [9] - Note: N=61 for FLTE-ITD (+) subjects and N=11 for FLT3-ITD(-) subjects
    No statistical analyses for this end point

    Secondary: Median Duration of Overall Survival

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    End point title
    Median Duration of Overall Survival
    End point description
    Kaplan-Meier analysis of overall survival (Safety population)
    End point type
    Secondary
    End point timeframe
    Within first 3 cycles of treatment (84 days)
    End point values
    Cohort 1 Cohort 2
    Number of subjects analysed
    112 [10]
    136 [11]
    Units: weeks
    number (confidence interval 95%)
        FLTE-ITD (+) Subjects
    25.4 (21.3 to 29.7)
    24.0 (21.1 to 27.1)
        FLTE-ITD (-) Subjects
    19.1 (12.0 to 29.4)
    25.1 (18.1 to 37.0)
    Notes
    [10] - Note: N=112 for FLTE-ITD (+) subjects and N=44 for FLT3-ITD(-) subjects
    [11] - Note: N=136 for FLTE-ITD (+) subjects and N=40 for FLT3-ITD(-) subjects
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the trial plus 30 days
    Adverse event reporting additional description
    Of note, AML disease progression (which includes the verbatim terms of progressive disease, disease progression, and relapsed AML) 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 subject population under study and is not further discussed.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    -

    Reporting group title
    Cohort 2
    Reporting group description
    -

    Serious adverse events
    Cohort 1 Cohort 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    134 / 157 (85.35%)
    135 / 176 (76.70%)
         number of deaths (all causes)
    71
    60
         number of deaths resulting from adverse events
    10
    8
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 157 (0.64%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hypotension
         subjects affected / exposed
    3 / 157 (1.91%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    37 / 157 (23.57%)
    36 / 176 (20.45%)
         occurrences causally related to treatment / all
    0 / 37
    0 / 36
         deaths causally related to treatment / all
    0 / 35
    0 / 32
    Leukaemic infiltration brain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphohistiocytosis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelofibrosis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Graft versus host disease in skin
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 157 (1.27%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Localised oedema
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Oedema peripheral
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    10 / 157 (6.37%)
    8 / 176 (4.55%)
         occurrences causally related to treatment / all
    5 / 10
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Secretion discharge
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    3 / 157 (1.91%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         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 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental poisoning
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endotracheal intubation complication
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    3 / 157 (1.91%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (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
    1 / 157 (0.64%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 157 (0.64%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood potassium decreased
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    17 / 157 (10.83%)
    16 / 176 (9.09%)
         occurrences causally related to treatment / all
    17 / 17
    15 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin T increased
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    8 / 157 (5.10%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    6 / 8
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Cardiac failure
         subjects affected / exposed
    3 / 157 (1.91%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute promyelocytic leukaemia differentiation syndrome
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 157 (0.64%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 157 (1.27%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 157 (4.46%)
    6 / 176 (3.41%)
         occurrences causally related to treatment / all
    5 / 7
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Febrile bone marrow aplasia
         subjects affected / exposed
    4 / 157 (2.55%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Febrile neutropenia
         subjects affected / exposed
    60 / 157 (38.22%)
    66 / 176 (37.50%)
         occurrences causally related to treatment / all
    34 / 60
    42 / 66
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pancytopenia
         subjects affected / exposed
    1 / 157 (0.64%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Thrombocytopenia
         subjects affected / exposed
    4 / 157 (2.55%)
    6 / 176 (3.41%)
         occurrences causally related to treatment / all
    3 / 4
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 157 (0.00%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    4 / 157 (2.55%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Memory impairment
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postictal state
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 157 (1.27%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Barrett's oesophagus
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 157 (1.91%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecal incontinence
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 157 (2.55%)
    7 / 176 (3.98%)
         occurrences causally related to treatment / all
    1 / 4
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroesophageal reflux disease
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Large intestine perforation
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (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
    1 / 157 (0.64%)
    5 / 176 (2.84%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 157 (2.55%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 157 (1.27%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    1 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 157 (1.91%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal tubular disorder
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    1 / 157 (0.64%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Petechiae
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint effusion
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    5 / 157 (3.18%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (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 neck
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acinetobacter bacteraemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    6 / 157 (3.82%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    2 / 157 (1.27%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Breast cellulitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Candidiasis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    5 / 157 (3.18%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cellulitis orbital
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    0 / 157 (0.00%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 157 (0.64%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter bacteraemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingival infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Influenza
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection fungal
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 157 (0.64%)
    6 / 176 (3.41%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mucosal infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericoronitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    24 / 157 (15.29%)
    16 / 176 (9.09%)
         occurrences causally related to treatment / all
    7 / 24
    7 / 16
         deaths causally related to treatment / all
    2 / 6
    0 / 1
    Pneumonia fungal
         subjects affected / exposed
    1 / 157 (0.64%)
    7 / 176 (3.98%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection fungal
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rhinovirus infection
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    12 / 157 (7.64%)
    13 / 176 (7.39%)
         occurrences causally related to treatment / all
    5 / 12
    3 / 13
         deaths causally related to treatment / all
    1 / 3
    1 / 6
    Sepsis syndrome
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 157 (1.91%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 3
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Serratia bacteraemia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis fungal
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    2 / 157 (1.27%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         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
    6 / 157 (3.82%)
    6 / 176 (3.41%)
         occurrences causally related to treatment / all
    1 / 6
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval cellulitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 176 (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 Cohort 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    151 / 157 (96.18%)
    175 / 176 (99.43%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    17 / 157 (10.83%)
    12 / 176 (6.82%)
         occurrences all number
    17
    12
    Hypotension
         subjects affected / exposed
    17 / 157 (10.83%)
    13 / 176 (7.39%)
         occurrences all number
    17
    13
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    33 / 157 (21.02%)
    32 / 176 (18.18%)
         occurrences all number
    33
    32
    Chest pain
         subjects affected / exposed
    10 / 157 (6.37%)
    13 / 176 (7.39%)
         occurrences all number
    10
    13
    Chills
         subjects affected / exposed
    13 / 157 (8.28%)
    14 / 176 (7.95%)
         occurrences all number
    13
    14
    Fatigue
         subjects affected / exposed
    62 / 157 (39.49%)
    49 / 176 (27.84%)
         occurrences all number
    62
    49
    Mucosal inflammation
         subjects affected / exposed
    8 / 157 (5.10%)
    15 / 176 (8.52%)
         occurrences all number
    8
    15
    Oedema peripheral
         subjects affected / exposed
    46 / 157 (29.30%)
    45 / 176 (25.57%)
         occurrences all number
    46
    45
    Pyrexia
         subjects affected / exposed
    47 / 157 (29.94%)
    49 / 176 (27.84%)
         occurrences all number
    47
    49
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    8 / 157 (5.10%)
    2 / 176 (1.14%)
         occurrences all number
    8
    2
    Depression
         subjects affected / exposed
    12 / 157 (7.64%)
    10 / 176 (5.68%)
         occurrences all number
    12
    10
    Insomnia
         subjects affected / exposed
    11 / 157 (7.01%)
    15 / 176 (8.52%)
         occurrences all number
    11
    15
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    14 / 157 (8.92%)
    6 / 176 (3.41%)
         occurrences all number
    14
    6
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 157 (5.73%)
    15 / 176 (8.52%)
         occurrences all number
    9
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 157 (5.10%)
    7 / 176 (3.98%)
         occurrences all number
    8
    7
    Electrocardiogram QT prolonged
         subjects affected / exposed
    31 / 157 (19.75%)
    48 / 176 (27.27%)
         occurrences all number
    31
    48
    Neutrophil count decreased
         subjects affected / exposed
    8 / 157 (5.10%)
    6 / 176 (3.41%)
         occurrences all number
    8
    6
    Platelet count decreased
         subjects affected / exposed
    17 / 157 (10.83%)
    12 / 176 (6.82%)
         occurrences all number
    17
    12
    Weight decreased
         subjects affected / exposed
    10 / 157 (6.37%)
    11 / 176 (6.25%)
         occurrences all number
    10
    11
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    10 / 157 (6.37%)
    10 / 176 (5.68%)
         occurrences all number
    10
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    44 / 157 (28.03%)
    48 / 176 (27.27%)
         occurrences all number
    44
    48
    Febrile neutropenia
         subjects affected / exposed
    12 / 157 (7.64%)
    14 / 176 (7.95%)
         occurrences all number
    12
    14
    Leukopenia
         subjects affected / exposed
    10 / 157 (6.37%)
    18 / 176 (10.23%)
         occurrences all number
    10
    18
    Neutropenia
         subjects affected / exposed
    15 / 157 (9.55%)
    20 / 176 (11.36%)
         occurrences all number
    15
    20
    Pancytopenia
         subjects affected / exposed
    9 / 157 (5.73%)
    2 / 176 (1.14%)
         occurrences all number
    9
    2
    Thrombocytopenia
         subjects affected / exposed
    22 / 157 (14.01%)
    25 / 176 (14.20%)
         occurrences all number
    22
    25
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 157 (16.56%)
    37 / 176 (21.02%)
         occurrences all number
    26
    37
    Dyspnoea
         subjects affected / exposed
    28 / 157 (17.83%)
    26 / 176 (14.77%)
         occurrences all number
    28
    26
    Dyspnoea exertional
         subjects affected / exposed
    8 / 157 (5.10%)
    2 / 176 (1.14%)
         occurrences all number
    8
    2
    Epistaxis
         subjects affected / exposed
    29 / 157 (18.47%)
    27 / 176 (15.34%)
         occurrences all number
    29
    27
    Oropharyngeal pain
         subjects affected / exposed
    8 / 157 (5.10%)
    10 / 176 (5.68%)
         occurrences all number
    8
    10
    Pleural effusion
         subjects affected / exposed
    8 / 157 (5.10%)
    12 / 176 (6.82%)
         occurrences all number
    8
    12
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    27 / 157 (17.20%)
    18 / 176 (10.23%)
         occurrences all number
    27
    18
    Dysgeusia
         subjects affected / exposed
    44 / 157 (28.03%)
    34 / 176 (19.32%)
         occurrences all number
    44
    34
    Headache
         subjects affected / exposed
    19 / 157 (12.10%)
    24 / 176 (13.64%)
         occurrences all number
    19
    24
    Paraesthesia
         subjects affected / exposed
    13 / 157 (8.28%)
    5 / 176 (2.84%)
         occurrences all number
    13
    5
    Tremor
         subjects affected / exposed
    10 / 157 (6.37%)
    2 / 176 (1.14%)
         occurrences all number
    10
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    19 / 157 (12.10%)
    23 / 176 (13.07%)
         occurrences all number
    19
    23
    Abdominal pain upper
         subjects affected / exposed
    24 / 157 (15.29%)
    3 / 176 (1.70%)
         occurrences all number
    24
    3
    Constipation
         subjects affected / exposed
    35 / 157 (22.29%)
    36 / 176 (20.45%)
         occurrences all number
    35
    36
    Diarrhoea
         subjects affected / exposed
    65 / 157 (41.40%)
    67 / 176 (38.07%)
         occurrences all number
    65
    67
    Dry mouth
         subjects affected / exposed
    8 / 157 (5.10%)
    2 / 176 (1.14%)
         occurrences all number
    8
    2
    Dyspepsia
         subjects affected / exposed
    29 / 157 (18.47%)
    25 / 176 (14.20%)
         occurrences all number
    29
    25
    Gastrooesophageal reflux disease
         subjects affected / exposed
    16 / 157 (10.19%)
    9 / 176 (5.11%)
         occurrences all number
    16
    9
    Gingival bleeding
         subjects affected / exposed
    6 / 157 (3.82%)
    9 / 176 (5.11%)
         occurrences all number
    6
    9
    Haemorrhoids
         subjects affected / exposed
    10 / 157 (6.37%)
    9 / 176 (5.11%)
         occurrences all number
    10
    9
    Mouth haemorrhage
         subjects affected / exposed
    12 / 157 (7.64%)
    10 / 176 (5.68%)
         occurrences all number
    12
    10
    Nausea
         subjects affected / exposed
    85 / 157 (54.14%)
    89 / 176 (50.57%)
         occurrences all number
    85
    89
    Stomatitis
         subjects affected / exposed
    9 / 157 (5.73%)
    7 / 176 (3.98%)
         occurrences all number
    9
    7
    Vomiting
         subjects affected / exposed
    57 / 157 (36.31%)
    70 / 176 (39.77%)
         occurrences all number
    57
    70
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    10 / 157 (6.37%)
    9 / 176 (5.11%)
         occurrences all number
    10
    9
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    8 / 157 (5.10%)
    9 / 176 (5.11%)
         occurrences all number
    8
    9
    Erythema
         subjects affected / exposed
    11 / 157 (7.01%)
    14 / 176 (7.95%)
         occurrences all number
    11
    14
    Hair colour changes
         subjects affected / exposed
    3 / 157 (1.91%)
    9 / 176 (5.11%)
         occurrences all number
    3
    9
    Petechiae
         subjects affected / exposed
    32 / 157 (20.38%)
    29 / 176 (16.48%)
         occurrences all number
    32
    29
    Pruritus
         subjects affected / exposed
    8 / 157 (5.10%)
    9 / 176 (5.11%)
         occurrences all number
    8
    9
    Rash
         subjects affected / exposed
    22 / 157 (14.01%)
    24 / 176 (13.64%)
         occurrences all number
    22
    24
    Skin lesion
         subjects affected / exposed
    7 / 157 (4.46%)
    12 / 176 (6.82%)
         occurrences all number
    7
    12
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 157 (8.92%)
    8 / 176 (4.55%)
         occurrences all number
    14
    8
    Back pain
         subjects affected / exposed
    19 / 157 (12.10%)
    17 / 176 (9.66%)
         occurrences all number
    19
    17
    Bone pain
         subjects affected / exposed
    11 / 157 (7.01%)
    4 / 176 (2.27%)
         occurrences all number
    11
    4
    Muscle spasms
         subjects affected / exposed
    16 / 157 (10.19%)
    10 / 176 (5.68%)
         occurrences all number
    16
    10
    Musculoskeletal pain
         subjects affected / exposed
    12 / 157 (7.64%)
    12 / 176 (6.82%)
         occurrences all number
    12
    12
    Myalgia
         subjects affected / exposed
    7 / 157 (4.46%)
    14 / 176 (7.95%)
         occurrences all number
    7
    14
    Neck pain
         subjects affected / exposed
    10 / 157 (6.37%)
    4 / 176 (2.27%)
         occurrences all number
    10
    4
    Pain in extremity
         subjects affected / exposed
    17 / 157 (10.83%)
    22 / 176 (12.50%)
         occurrences all number
    17
    22
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    46 / 157 (29.30%)
    43 / 176 (24.43%)
         occurrences all number
    46
    43
    Hyperglycaemia
         subjects affected / exposed
    13 / 157 (8.28%)
    11 / 176 (6.25%)
         occurrences all number
    13
    11
    Hypocalcaemia
         subjects affected / exposed
    15 / 157 (9.55%)
    18 / 176 (10.23%)
         occurrences all number
    15
    18
    Hypokalaemia
         subjects affected / exposed
    27 / 157 (17.20%)
    33 / 176 (18.75%)
         occurrences all number
    27
    33
    Hypomagnesaemia
         subjects affected / exposed
    17 / 157 (10.83%)
    19 / 176 (10.80%)
         occurrences all number
    17
    19
    Hyponatraemia
         subjects affected / exposed
    7 / 157 (4.46%)
    9 / 176 (5.11%)
         occurrences all number
    7
    9
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    9 / 157 (5.73%)
    10 / 176 (5.68%)
         occurrences all number
    9
    10
    Oral herpes
         subjects affected / exposed
    12 / 157 (7.64%)
    9 / 176 (5.11%)
         occurrences all number
    12
    9
    Pneumonia
         subjects affected / exposed
    2 / 157 (1.27%)
    15 / 176 (8.52%)
         occurrences all number
    2
    15
    Sinusitis
         subjects affected / exposed
    3 / 157 (1.91%)
    9 / 176 (5.11%)
         occurrences all number
    3
    9
    Urinary tract infection
         subjects affected / exposed
    9 / 157 (5.73%)
    8 / 176 (4.55%)
         occurrences all number
    9
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jul 2009
    No patients were enrolled under the original protocol nor this first amendment. The reasons for this amendment were to: - Delete limitation on Second Complete Remission duration for inclusion of subjects in second relapse - Clarify dosing adjustments for subjects with nonhaematological toxicities - Clarify pharmacokinetic (PK) and pharmacodynamic (PD) sampling
    22 Jul 2009
    This amendment was written to: - Exclude subjects with other cancers (except treated Stage 1 cervix or nonmelanotic skin cancer) with the possible exception of subjects in complete remission - Include subjects with controlled CNS leukemia receiving IT therapy - Clarify that the use of other chemotherapeutic or antileukemic agents is not permitted during the study with the exception of hydroxyurea and possible exception of IT therapy (based on investigator discretion and Sponsor agreement). - Add multigated acquisition scan (MUGA) for assessment of left ventricular ejection fraction (LVEF), change the requirement of assessment of LVEF from 3 months to 1 month before study screening to enhance subject safety. - Clarify the role of the independent DMC to include assessment of risk versus benefit and recommend any changes warranted to the study design. - Add 30-day and 3-month telephone follow-up after end of study for safety assessments, further therapies, outcomes and survival in order to record protocol-specified data - Add other genotyping and mRNA analyses to the blood and bone marrow assessments in order to ensure all such assessments are properly described in the protocol.
    16 Nov 2009
    • Increase the maximum number of study sites from ~80 to ~100. • Add “Time to treatment response” as another secondary objective. • Predefined a mutant ratio of >10% FLT3-ITD mutant alleles as a criteria for inclusion in the study. • Require that appropriate samples of bone marrow taken for diagnosis before the subject signs consent and within 14 days prior to first dose of study drug be sent to the Sponsor’s designated laboratory for later morphological confirmation of the AML diagnosis if the bone marrow testing is not repeated during screening. • Specify that bone marrow aspirates and biopsies are preferred, but biopsies may be omitted at the discretion of the Investigator if an adequate aspirate is obtained. • Specify that screening procedures are to be performed ≤14 days from Cycle 1Day 1. • Specify that donor lymphocyte infusion is not permitted during study or 30 days prior to study entry. • Specify the option of a further dose reduction to 90 mg as appropriate. • Specify replacement criteria for subjects erroneously entered into the study. • Allow for MUGA or ECHO at the Screening visit for subjects with current or history of congestive heart failure NYHA class 3 or 4, unless an ECHO or MUGA performed either within 1 month prior to study screening or during screening results in a LVEF that is ≥45% (or institutional lower limit of normal value). • Add language to make the ECG and PK blood draw sequence less restrictive • Add phosphate to clinical laboratory tests. • Add provision for the possibility of stopping for futility based on efficacy at interim timepoints as incorporated in the DMC Charter. • Amend language; reference to disease progression and progressive disease were changed to relapse or deleted if relapse was already stated.
    20 Apr 2010
    In Study AC220-002, the co-primary objectives are to determine complete remission (CR) rate and composite complete remission (CRc) rate, which is the sum of CR, CR with incomplete platelet response (CRp), and CR with incomplete hematological response (CRi). The original intent of the protocol was to use a modified set of Cheson criteria for the assessment of clinical response for efficacy. Specifically, the need for red blood cell (RBC) or platelet transfusions was not to be taken into account for declaring responses of CRi. All of the other Cheson criteria for defining CR, CRp, and CRi were to remain unchanged [34]. This modification was to be implemented in order to fully describe the antileukemic activity of AC220, which is given as a continuous therapy and is myelosuppressive. Previous versions of the protocol erroneously omitted this modification; therefore, Protocol Amendment 7 has been written to clarify the use of the modified Cheson criteria and specify that patients do not need to be RBC or platelet transfusion independent in order for their response to be classified as CRi. An additional change to the protocol has been made for the evaluation of best response. Previous versions of the protocol indicated that best response will be measured up to Day 84 (after 3 cycles of therapy), or at time off study for those patients discontinuing treatment before Day 84. As described in Protocol Amendment 7, best response will also be evaluated for the full treatment period using all assessments up to and including treatment discontinuation.
    05 Nov 2010
    The primary reason for Protocol Amendment 5 is to provide dose modification guidelines for patients who experience complete remission (CR) with incomplete platelet recovery (CRp) or incomplete neutrophil recovery, with or without complete platelet recovery (CRi). Patients experiencing prolonged CRi or CRp may be dose reduced at the discretion of the Investigator and with agreement of the Sponsor. The following criteria must be met: < 100 x 109/L platelets and/or ≤ 1 x 109/L absolute neutrophil count (ANC); marrow blasts < 5%; and the patient has received at least 2 cycles of study treatment. Dose reduction will proceed in a stepwise fashion to a minimum of 60 mg/day (ie, 200 mg/day to 135 mg/day to 90 mg/day to 60 mg/day) if myelosuppression persists and there is no evidence of AML relapse. After any dose reduction, patients should receive at least one complete cycle (28 days) of the reduced dose before further dose reduction is implemented. Patients who subsequently lose response (ie, relapse) may be dose escalated as described in the protocol.
    08 Jan 2011
    Introduction was updated and secondary objectives were changed as follows: Changed from: • Pharmacogenetic analysis of FLT3-ITD mutation • Correlation of remission with FLT3-ITD allelic ratio and other parameters using other assays Changed to: • Pharmacogenetic analysis of FLT3-ITD mutation • For all patients with detectable FLT3-ITD mutation, correlation of remission with FLT3-ITD allelic ratio and other parameters using other assays • For all patients, summaries of non-ITD mutations identified, the percent mutant allelic ratio (normalized for blasts), and correlational analyses.
    15 Jul 2011
    In Study AC220-002, the co-primary objectives are to determine complete remission (CR) rate and composite complete remission (CRc) rate, which is the sum of CR, CR with incomplete platelet response (CRp), and CR with incomplete hematological response (CRi). The original intent of the protocol was to use a modified set of Cheson criteria for the assessment of clinical response for efficacy. Specifically, the need for red blood cell (RBC) or platelet transfusions was not to be taken into account for declaring responses of CRi. All of the other Cheson criteria for defining CR, CRp, and CRi were to remain unchanged [34]. This modification was to be implemented in order to fully describe the antileukemic activity of AC220, which is given as a continuous therapy and is myelosuppressive. Previous versions of the protocol erroneously omitted this modification; therefore, Protocol Amendment 7 has been written to clarify the use of the modified Cheson criteria and specify that patients do not need to be RBC or platelet transfusion independent in order for their response to be classified as CRi. An additional change to the protocol has been made for the evaluation of best response. Previous versions of the protocol indicated that best response will be measured up to Day 84 (after 3 cycles of therapy), or at time off study for those patients discontinuing treatment before Day 84. As described in Protocol Amendment 7, best response will also be evaluated for the full treatment period using all assessments up to and including treatment discontinuation.

    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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