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    Clinical Trial Results:
    A phase IB/II study to evaluate the safety and efficacy of vismodegib in relapsed/refractory acute myelogenous leukemia (AML) and relapsed/refractory high-risk myelodysplastic syndrome (MDS).

    Summary
    EudraCT number
    		 2013-001570-14
    Trial protocol
    		 DE  
    Global end of trial date
    03 Nov 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Feb 2016
    First version publication date
    17 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GO28852
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01880437
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F.Hoffmann-LaRocheAG
    Sponsor organisation address
    Grenzacherstrasse124, Basel, CH-4070, Switzerland,
    Public contact
    RocheTrialInformationHotline, F.Hoffmann-LaRocheAG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    RocheTrialInformationHotline, F.Hoffmann-LaRocheAG, +41 616878333, global.trial_information@roche.com
    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
    30 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Nov 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study was a single-arm, open-label study to assess the overall response rate and safety of single-agent vismodegib in participants with relapsed/refractory acute myeloid leukemia (AML) or relapsed/refractory high-risk myelodysplastic syndrome (MDS). There were two planned stages in this study: (1) efficacy and safety assessment of single-agent vismodegib (Cohort 1), and (2) efficacy and safety assessment of vismodegib in combination with cytarabine (Cohort 2). Cohort 2 was only to occur if efficacy was observed in Cohort 1.
    Protection of trial subjects
    This study was conducted in full conformance with the International Conference on Harmonisation (ICH) E6 guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki or the laws and regulations of the country in which the research is conducted, whichever afforded the greater protection to the individual. Study conducted in the United States (US) or under a U.S. Investigational New Drug (IND) application complied with U.S. Food and Drug Administration (FDA) regulations and applicable local, state, and federal laws. The study complied with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting) and also with the European Union (EU) Clinical Trial Directive (2001/20/EC).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Sep 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 19
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Germany: 13
    Worldwide total number of subjects
    38
    EEA total number of subjects
    13
    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)
    18
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 47 participants were screened; of which, 7 participants failed screening and 2 participants were erroneously entered but did not receive study drug. A total of 38 participants were enrolled and treated in Cohort 1. Cohort 2 was planned but no participants were enrolled.

    Pre-assignment
    Screening details
    		 Based on lower-than-expected efficacy observed in interim data review, study was terminated prior to initiation of Cohort 2. Results are reported as per subgroups of Cohort 1: "Poor Risk Cytogenetics", "FLT-3 Mutation Positive", "Neither Poor Risk Cytogenetics Nor FLT-3", unless otherwise specified.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Poor Risk Cytogenetics
    Arm description
    		 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'poor risk cytogenetics' subgroup received oral 150 milligrams (mg) dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vismodegib
    Investigational medicinal product code
    RO5450815
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vismodegib at a dose of 150 mg once daily with at least 4 ounces of water.

    Arm title
    		 FLT-3 Mutation Positive
    Arm description
    		 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vismodegib
    Investigational medicinal product code
    RO5450815
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vismodegib at a dose of 150 mg once daily with at least 4 ounces of water.

    Arm title
    		 Neither Poor Risk Cytogenetics Nor FLT-3
    Arm description
    		 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vismodegib
    Investigational medicinal product code
    RO5450815
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vismodegib at a dose of 150 mg once daily with at least 4 ounces of water.

    Number of subjects in period 1
    		Poor Risk Cytogenetics FLT-3 Mutation Positive Neither Poor Risk Cytogenetics Nor FLT-3
    Started
    15
    4
    19
    Completed
    0
    0
    0
    Not completed
    15
    4
    19
         Study terminated by Sponsor
    3
    -
    2
         Death
    12
    4
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Poor Risk Cytogenetics
    Reporting group description
    		 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'poor risk cytogenetics' subgroup received oral 150 milligrams (mg) dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.

    Reporting group title
    FLT-3 Mutation Positive
    Reporting group description
    		 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.

    Reporting group title
    Neither Poor Risk Cytogenetics Nor FLT-3
    Reporting group description
    		 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.

    Reporting group values
    		 Poor Risk Cytogenetics FLT-3 Mutation Positive Neither Poor Risk Cytogenetics Nor FLT-3 Total
    Number of subjects
    		 15 4 19 38
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.5 ( 20.7 ) 54.5 ( 5.9 ) 66.2 ( 14.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 2 9 17
        Male
    		 9 2 10 21

    End points

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    End points reporting groups
    Reporting group title
    Poor Risk Cytogenetics
    Reporting group description
    		 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'poor risk cytogenetics' subgroup received oral 150 milligrams (mg) dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.

    Reporting group title
    FLT-3 Mutation Positive
    Reporting group description
    		 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.

    Reporting group title
    Neither Poor Risk Cytogenetics Nor FLT-3
    Reporting group description
    		 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.

    Primary: Percentage of Participants With a Complete Response (CR) or CR With Incomplete Blood Count Recovery (CRi) or Morphologic Leukemia Free State (MLFS) or Partial Response (PR) at Week 8

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    End point title
    		 Percentage of Participants With a Complete Response (CR) or CR With Incomplete Blood Count Recovery (CRi) or Morphologic Leukemia Free State (MLFS) or Partial Response (PR) at Week 8 [1]
    End point description
    CR: defined as achieved if the neutrophils count was greater than (>) 1000 cells per microliter (µL), platelets count >100000/µL, bone marrow blasts (BMB) percent (%) less than (<) 5, no Auer rods (clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts), no transfusion requirements and no signs of extra medullary disease (EMD). CRi: defined if either of the cell (neutrophil or platelet) lineage was not recovered (neutrophils >1000 cells/µL or Not applicable [NA] or platelets count >100000/µL or NA), BMB <5% with no Auer rods and confirmed by flow cytometry with no signs of EMD. MLFS (neutrophil and platelet criteria were NA): defined as BMB <5% with no Auer rods and confirmed by flow cytometry with no signs of EMD. PR: defined as neutrophils count >1000 cells/µL, platelets count >100000/µL, and >50% decrease from baseline to a range of 5-25% of BMB or BMB <5% with Auer rods.
    End point type
    Primary
    End point timeframe
    Week 8
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this end point.
    End point values
    		 Poor Risk Cytogenetics FLT-3 Mutation Positive Neither Poor Risk Cytogenetics Nor FLT-3
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: percentage of participants
        number (not applicable)
    Notes
    [2] - No participants analyzed as the study was terminated before Week 8 based on interim analysis.
    [3] - No participants analyzed as the study was terminated before Week 8 based on interim analysis.
    [4] - No participants analyzed as the study was terminated before Week 8 based on interim analysis.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment

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    End point title
    		 Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment
    End point description
    CR: defined as achieved if the neutrophils count >1000 cells/µL, platelets count >100000/µL, BMB <5%, no Auer rods (clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts), no transfusion requirements and no signs of EMD. CRi: defined if either of the cell (neutrophil or platelet) lineage was not recovered (neutrophils > 1000 cells/µL or NA or platelets count >100000/µL or NA, BMB <5% with no Auer rods and confirmed by flow cytometry with no signs of EMD. MLFS (neutrophil and platelet criteria were NA): defined as BMB <5% with no Auer rods and confirmed by flow cytometry with no signs of EMD. PR: defined as neutrophils count >1000 cells/µL, platelets count >100000/µL, and >50% decrease from baseline to a range of 5-25% of BMB or BMB <5% with Auer rods. Efficacy analysis population included all enrolled participants. "Number of subjects analyzed" = participants who were evaluable for tumor response at anytime during the study.
    End point type
    Secondary
    End point timeframe
    Up to 30 days of last dose of study drug (maximum treatment duration = 225 days)
    End point values
    		 Poor Risk Cytogenetics FLT-3 Mutation Positive Neither Poor Risk Cytogenetics Nor FLT-3
    Number of subjects analysed
    13
    4
    16
    Units: percentage of participants
    number (confidence interval 95%)
        CR
    0 (0 to 22.51)
    0 (0 to 52.71)
    0 (0 to 19.75)
        CRi
    0 (0 to 22.51)
    0 (0 to 52.71)
    6.3 (0.32 to 29.88)
        MLFS
    0 (0 to 22.51)
    0 (0 to 52.71)
    0 (0 to 19.75)
        PR
    0 (0 to 22.51)
    0 (0 to 52.71)
    6.3 (0.32 to 29.88)
    No statistical analyses for this end point

    Secondary: Duration of Overall Response (DOR)

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    End point title
    		 Duration of Overall Response (DOR)
    End point description
    DOR is defined as the time from the first occurrence of a documented overall response to the time of relapse, as determined by the investigator using International Working Group (IWG) criteria (Participants not falling under any of the response criteria [CR or CRi or MLFS or PR] described under outcome measure 1 were considered as non-responders) or death from any cause during the study (defined as death within 30 days after the last dose of study drug). Efficacy population included participants who were considered as responders. The 95% confidence interval was not estimable as only 1 participant was evaluable and reported as -99999 to 99999.
    End point type
    Secondary
    End point timeframe
    Up to 30 days of last dose of study drug (maximum treatment duration = 225 days)
    End point values
    		 Poor Risk Cytogenetics FLT-3 Mutation Positive Neither Poor Risk Cytogenetics Nor FLT-3
    Number of subjects analysed
    0 [5]
    0 [6]
    2
    Units: weeks
    number (confidence interval 95%)
        DOR of participants with CRi (n=0,0,1)
    ( to )
    ( to )
    13 (-99999 to 99999)
        DOR of participants with PR (n=0,0,1)
    ( to )
    ( to )
    6.1 (-99999 to 99999)
    Notes
    [5] - No Responders were present in this group.
    [6] - No Responders were present in this group.
    No statistical analyses for this end point

    Secondary: Median Overall Survival (OS) Time

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    End point title
    		 Median Overall Survival (OS) Time
    End point description
    OS was defined as the time from start of study drug to death from any cause. OS was estimated using Kaplan-Meier analysis. Participants alive at the last date known to be alive were censored for the analysis. Efficacy analysis population was considered for analysis of this end point.
    End point type
    Secondary
    End point timeframe
    Up to death or 30 days of last dose of study drug (maximum treatment duration = 225 days)
    End point values
    		 Poor Risk Cytogenetics FLT-3 Mutation Positive Neither Poor Risk Cytogenetics Nor FLT-3
    Number of subjects analysed
    15
    4
    19
    Units: months
        median (confidence interval 95%)
    3.38 (2.37 to 4.83)
    1.43 (0.33 to 3.94)
    3.65 (1.94 to 5.36)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With an Event of Death During the Study

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    End point title
    		 Percentage of Participants With an Event of Death During the Study
    End point description
    Efficacy analysis population was considered for analysis of this end point.
    End point type
    Secondary
    End point timeframe
    Up to death or 30 days of last dose of study drug (maximum treatment duration = 225 days)
    End point values
    		 Poor Risk Cytogenetics FLT-3 Mutation Positive Neither Poor Risk Cytogenetics Nor FLT-3
    Number of subjects analysed
    15
    4
    19
    Units: percentage of participants
        number (not applicable)
    80
    100
    89.5
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Steady-state Plasma Concentration of Vismodegib

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    End point title
    		 Pharmacokinetics (PK): Steady-state Plasma Concentration of Vismodegib
    End point description
    PK data was planned to be reported only if the results of Cohort 2 are available. As the study was terminated prior to Cohort 2 enrollment, PK analysis could not be performed, as planned.
    End point type
    Secondary
    End point timeframe
    Predose (0 hour) on Days 8, 29 and 57 or unplanned early termination visit for participants who terminate early
    End point values
    		 Poor Risk Cytogenetics FLT-3 Mutation Positive Neither Poor Risk Cytogenetics Nor FLT-3
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    Units: nanograms per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [7] - No participants were analyzed.
    [8] - No participants were analyzed.
    [9] - No participants were analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening until study completion or early termination visit (Up to 14 months)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Poor Risk Cytogenetics
    Reporting group description
    		 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'poor risk cytogenetics' subgroup received oral 150 mg dose of vismodegib once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.

    Reporting group title
    FLT-3 Mutation Positive
    Reporting group description
    		 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.

    Reporting group title
    Neither Poor Risk Cytogenetics nor FLT-3
    Reporting group description
    		 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent.

    Serious adverse events
    		 Poor Risk Cytogenetics FLT-3 Mutation Positive Neither Poor Risk Cytogenetics nor FLT-3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 15 (66.67%)
    3 / 4 (75.00%)
    13 / 19 (68.42%)
         number of deaths (all causes)
    12
    4
    17
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Central venous catheterisation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 4 (25.00%)
    4 / 19 (21.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    6 / 19 (31.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Graft versus host disease
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vaginal abscess
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Poor Risk Cytogenetics FLT-3 Mutation Positive Neither Poor Risk Cytogenetics nor FLT-3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 15 (86.67%)
    4 / 4 (100.00%)
    19 / 19 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acrochordon
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Chloroma
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Renal cell carcinoma
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    3
    Hypertension
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    3
    Hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    1
    0
    4
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Vasculitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Catheter site pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Chest discomfort
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Chills
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    1
    2
    Early satiety
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 4 (50.00%)
    5 / 19 (26.32%)
         occurrences all number
    1
    2
    8
    Feeling cold
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Localised oedema
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Malaise
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Mucosal dryness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Mucosal inflammation
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Multi-organ failure
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    Oedema
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    4 / 15 (26.67%)
    0 / 4 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    4
    0
    4
    Pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    1
    0
    3
    Peripheral swelling
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    3
    0
    1
    Pyrexia
         subjects affected / exposed
    3 / 15 (20.00%)
    3 / 4 (75.00%)
    5 / 19 (26.32%)
         occurrences all number
    6
    3
    5
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Vulval ulceration
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Vulvovaginal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    1
    0
    3
    Dysphonia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    4
    0
    3
    Dyspnoea exertional
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    2
    Epistaxis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    8 / 19 (42.11%)
         occurrences all number
    2
    0
    9
    Hypoxia
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    3
    1
    1
    Nasal congestion
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    1
    3
    Pleural effusion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Productive cough
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Pulmonary oedema
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory failure
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    1
    2
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Snoring
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Wheezing
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Disorientation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    4
    Mental status changes
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Restlessness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Blood bilirubin increased
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    Blood creatine increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Cardiac murmur
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Liver function test abnormal
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    3
    Platelet count decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Weight decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Contusion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Fall
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Laceration
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    Ligament sprain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Scratch
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Skin abrasion
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Pericardial effusion
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    6 / 19 (31.58%)
         occurrences all number
    2
    0
    6
    Dysgeusia
         subjects affected / exposed
    4 / 15 (26.67%)
    1 / 4 (25.00%)
    7 / 19 (36.84%)
         occurrences all number
    5
    1
    9
    Headache
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    2
    1
    Hyperaesthesia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Orthostatic intolerance
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Radicular pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Sinus headache
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Somnolence
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 4 (25.00%)
    4 / 19 (21.05%)
         occurrences all number
    2
    1
    12
    Febrile neutropenia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    1
    0
    Haemoglobinaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Leukocytosis
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 4 (50.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    2
    Leukopenia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    0
    5
    Neutropenia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    2
    0
    3
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Hearing impaired
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Hypoacusis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Eye pruritus
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Scleral discolouration
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 15 (26.67%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    4
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    1
    2
    Anal fissure
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Aphthous stomatitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Breath odour
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Cheilitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    4 / 15 (26.67%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    4
    0
    2
    Dental caries
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    6 / 19 (31.58%)
         occurrences all number
    1
    0
    6
    Dry mouth
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Faecal incontinence
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Gingival bleeding
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Haematochezia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    2
    Haemorrhoids
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Melaena
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    4 / 15 (26.67%)
    0 / 4 (0.00%)
    10 / 19 (52.63%)
         occurrences all number
    4
    0
    13
    Oesophageal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Oesophagitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Oral pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Toothache
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 4 (25.00%)
    4 / 19 (21.05%)
         occurrences all number
    2
    1
    6
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Decubitus ulcer
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Dermatitis acneiform
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Drug eruption
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Dry skin
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    1
    Ecchymosis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    1
    Night sweats
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Petechiae
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    1
    Pruritus
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Rash
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    2
    0
    2
    Back pain
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    1
    Bone pain
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    2
    Flank pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Joint swelling
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    0
    Muscle spasms
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 4 (25.00%)
    5 / 19 (26.32%)
         occurrences all number
    4
    1
    6
    Muscular weakness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    2
    Neck pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    2
    0
    3
    Infections and infestations
    Candida
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Catheter site infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Cellulitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Clostridium difficile infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Enterococcal infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Erysipelas
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Herpes simplex
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Liver abscess
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Localised infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Mucosal infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Oral fungal infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Oral herpes
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Post procedural infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Staphylococcal infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    2
    Tooth infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 15 (26.67%)
    1 / 4 (25.00%)
    4 / 19 (21.05%)
         occurrences all number
    4
    1
    4
    Dehydration
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    3
    0
    2
    Electrolyte imbalance
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Failure to thrive
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    1
    Hyperalbuminaemia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 4 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 4 (25.00%)
    6 / 19 (31.58%)
         occurrences all number
    1
    1
    7
    Hypomagnesaemia
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 4 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    3
    0
    3
    Hyponatraemia
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 4 (25.00%)
    2 / 19 (10.53%)
         occurrences all number
    3
    1
    2
    Hypophosphataemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 4 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 May 2013
    Clarified the number of participants with poor-risk cytogenetics and FLT3-positive disease to be enrolled, added interim safety review 8 weeks after the first 12 participants were enrolled, added early stopping rules for lack of efficacy (futility).Changed sperm donation period following the last dose of vismodegib to 2 months for consistency with other vismodegib protocols and clarified that if bone marrow aspirate and biopsy, whole blood samples, and plasma samples were required at early termination, they were to be performed within 5 days of stopping study drug.
    24 Jun 2014
    Removed cytarabine PK sampling and added additional bone marrow aspirations and biopsies at Weeks 24 and 48 for participants who remained on treatment after Week 8.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    03 Nov 2014
    This study was prematurely terminated because of lower-than-expected efficacy observed in interim data analyses.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Study was prematurely terminated due to lower-than-expected efficacy observed in interim data analyses. The end point related to Cohort 2, "Area Under the Concentration-time Curve of Cytarabine" was not reported as Cohort 2 was not initiated.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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