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    Clinical Trial Results:
    A CCLG/Cancer Research UK Phase I Trial of AT9283 (a selective inhibitor of aurora kinases) given for 72 hours every 21 days via intravenous infusion in children and adolescents with relapsed and refractory solid tumours

    Summary
    EudraCT number
    2008-005542-23
    Trial protocol
    GB  
    Global end of trial date

    Results information
    Results version number
    v1
    This version publication date
    15 Apr 2017
    First version publication date
    15 Apr 2017
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    CR0708-11
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00985868
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Cancer Research UK
    Sponsor organisation address
    407 St John Street, London, United Kingdom, EC1V 4AD
    Public contact
    Centre for Drug Development, Cancer Research UK, +44 02072420200, regquery@cancer.org.uk
    Scientific contact
    Centre for Drug Development, Cancer Research UK, +44 02072420200, regquery@cancer.org.uk
    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
    Interim
    Date of interim/final analysis
    20 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jan 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of AT9283 (given by intravenous [IV] infusion) by characterising the dose limiting toxicities (DLTs) and determining a maximum tolerated dose (MTD) in children and adolescents with relapsed and refractory solid tumours.
    Protection of trial subjects
    None
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Oct 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 33
    Worldwide total number of subjects
    33
    EEA total number of subjects
    33
    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)
    21
    Adolescents (12-17 years)
    10
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    For the overall trial participants were enrolled from 20 October 2009 to 31 December 2012 in five clinical trial centres in the UK.

    Pre-assignment
    Screening details
    Males or females aged 2-18 years with histologically proven solid tumours refractory to conventional treatment, or for which no conventional therapy existed. Patients had to have no prior exposure to an aurora kinase inhibitor, a life expectancy of at least 12 weeks and have a WHO performance status of 0-2 or Lansky Play Performance Scale ≥70%.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1
    Arm description
    AT9283 at 7.0 mg/m2
    Arm type
    Experimental

    Investigational medicinal product name
    AT9283
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AT9283 was administered as an IV infusion over 72 hours by central line. One cycle of treatment was defined as a 72 hour (Days 1-3) IV infusion of AT9283 every 21 days.

    Arm title
    Cohort 2
    Arm description
    AT9283 at 9.0 mg/m2
    Arm type
    Experimental

    Investigational medicinal product name
    AT9283
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AT9283 was administered as an IV infusion over 72 hours by central line. One cycle of treatment was defined as a 72 hour (Days 1-3) IV infusion of AT9283 every 21 days.

    Arm title
    Cohort 3
    Arm description
    AT9283 at 11.5 mg/m2
    Arm type
    Experimental

    Investigational medicinal product name
    AT9283
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AT9283 was administered as an IV infusion over 72 hours by central line. One cycle of treatment was defined as a 72 hour (Days 1-3) IV infusion of AT9283 every 21 days.

    Arm title
    Cohort 4
    Arm description
    AT9283 at 14.5 mg/m2
    Arm type
    Experimental

    Investigational medicinal product name
    AT9283
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AT9283 was administered as an IV infusion over 72 hours by central line. One cycle of treatment was defined as a 72 hour (Days 1-3) IV infusion of AT9283 every 21 days.

    Arm title
    Cohort 5
    Arm description
    AT9283 at 18.5 mg/m2
    Arm type
    Experimental

    Investigational medicinal product name
    AT9283
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AT9283 was administered as an IV infusion over 72 hours by central line. One cycle of treatment was defined as a 72 hour (Days 1-3) IV infusion of AT9283 every 21 days.

    Arm title
    Cohort 6
    Arm description
    AT9283 at 23.0 mg/m2
    Arm type
    Experimental

    Investigational medicinal product name
    AT9283
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AT9283 was administered as an IV infusion over 72 hours by central line. One cycle of treatment was defined as a 72 hour (Days 1-3) IV infusion of AT9283 every 21 days.

    Number of subjects in period 1
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6
    Started
    6
    5
    6
    7
    7
    2
    Completed
    6
    5
    6
    7
    7
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    AT9283 at 7.0 mg/m2

    Reporting group title
    Cohort 2
    Reporting group description
    AT9283 at 9.0 mg/m2

    Reporting group title
    Cohort 3
    Reporting group description
    AT9283 at 11.5 mg/m2

    Reporting group title
    Cohort 4
    Reporting group description
    AT9283 at 14.5 mg/m2

    Reporting group title
    Cohort 5
    Reporting group description
    AT9283 at 18.5 mg/m2

    Reporting group title
    Cohort 6
    Reporting group description
    AT9283 at 23.0 mg/m2

    Reporting group values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Total
    Number of subjects
    6 5 6 7 7 2 33
    Age categorical
    Units: Subjects
        Children (2-11 years)
    4 3 4 6 3 1 21
        Adolescents (12-17 years)
    2 2 2 1 2 1 10
        Adults (18-64 years)
    0 0 0 0 2 0 2
    Gender categorical
    Units: Subjects
        Female
    3 3 5 5 5 1 22
        Male
    3 2 1 2 2 1 11
    Subject analysis sets

    Subject analysis set title
    Overall Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All enrolled patients for the overall trial who received at least one infusion of AT9283.

    Subject analysis set title
    Response Population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All eligible patients who received AT9283, had measureable disease at baseline according to RECIST criteria (or according to the International Neuroblastoma Response Criteria [INRC] for neuroblastoma patients), and had a second radiological tumour assessment.

    Subject analysis set title
    Pharmacokinetic Population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All eligible patients who received at least one infusion of AT9283 and provided pre- and post-infusion pharmacokinetic plasma samples.

    Subject analysis set title
    Pharmacodynamic Population (ELISA)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All eligible patients who received at least one infusion of AT9283 and provided pre- and post-infusion pharmacodynamic blood samples during Cycle 1.

    Subject analysis sets values
    Overall Safety Population Response Population Pharmacokinetic Population Pharmacodynamic Population (ELISA)
    Number of subjects
    33
    22
    32
    32
    Age categorical
    Units: Subjects
        Children (2-11 years)
    21
    11
    20
    20
        Adolescents (12-17 years)
    10
    9
    10
    10
        Adults (18-64 years)
    2
    2
    2
    2
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    22
    14
    22
    22
        Male
    11
    8
    10
    10

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    AT9283 at 7.0 mg/m2

    Reporting group title
    Cohort 2
    Reporting group description
    AT9283 at 9.0 mg/m2

    Reporting group title
    Cohort 3
    Reporting group description
    AT9283 at 11.5 mg/m2

    Reporting group title
    Cohort 4
    Reporting group description
    AT9283 at 14.5 mg/m2

    Reporting group title
    Cohort 5
    Reporting group description
    AT9283 at 18.5 mg/m2

    Reporting group title
    Cohort 6
    Reporting group description
    AT9283 at 23.0 mg/m2

    Subject analysis set title
    Overall Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All enrolled patients for the overall trial who received at least one infusion of AT9283.

    Subject analysis set title
    Response Population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All eligible patients who received AT9283, had measureable disease at baseline according to RECIST criteria (or according to the International Neuroblastoma Response Criteria [INRC] for neuroblastoma patients), and had a second radiological tumour assessment.

    Subject analysis set title
    Pharmacokinetic Population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All eligible patients who received at least one infusion of AT9283 and provided pre- and post-infusion pharmacokinetic plasma samples.

    Subject analysis set title
    Pharmacodynamic Population (ELISA)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All eligible patients who received at least one infusion of AT9283 and provided pre- and post-infusion pharmacodynamic blood samples during Cycle 1.

    Primary: Safety

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    End point title
    Safety [1]
    End point description
    The causality and severity grading of each adverse event (AE) to AT9283, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AEs with a causality of possibly, probably or almost certainly related to AT9283 were considered to indicate relatedness. Dose limiting toxicity was defined as almost certainly or probably related to AT9283 and when one or more of the following occurred: a) CTCAE Grade 3 or higher non-haematological toxicity excluding: - Grade 3 nausea and vomiting in patients who had not received optimal treatment with anti-emetics. - Grade 3 fever in the absence of Grade 3 or 4 neutropenia. - Grade 3 transaminase elevations that reversed to ≤Grade 1 before Day 22. - Grade 3 diarrhoea in patients who had not received optimal treatment with anti-diarrhoeals. b) CTCAE Grade 4 neutropenia lasting ≥7 days. c) CTCAE Grade 3 thrombocytopenia lasting >7 days or any Grade 4 thrombocytopenia.
    End point type
    Primary
    End point timeframe
    From patient consent to 28 days post last administration of AT9283.
    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: All safety data were presented in a descriptive fashion, with AEs presented by CTCAE adverse event term by worst grade observed.
    End point values
    Overall Safety Population
    Number of subjects analysed
    33
    Units: Number of AEs
        All AEs
    591
        Related AEs
    207
        DLT - neutropenia
    3
        DLT - febrile neutropenia
    2
        DLT - suspected bacterial infection
    1
    Attachments
    Untitled (Filename: AT9283 DLT Summary_CSR extract_prepared 30Mar17.pdf)
    No statistical analyses for this end point

    Secondary: Tumour Response

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    End point title
    Tumour Response
    End point description
    All eligible patients who received AT9283, had measurable disease at baseline according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.0 and had a second radiological tumour assessment were evaluable for response. For neuroblastoma patients, response was assessed according to the International Neuroblastoma Response Criteria (INRC). Patients with measureable disease were placed into response categories of complete response (CR), partial response (PR), stable disease (SD), progressive disease and early progression. Very good partial response, mixed response and no response were also included for patients assessed using INRC. For responses of CR and PR, changes in tumour measurements were required to be confirmed by repeat assessments performed no less than four weeks after the response criteria were initially met. For SD, tumour measurements were required to have met the criteria for SD at least once and at a minimum of six weeks after AT9283 was started.
    End point type
    Secondary
    End point timeframe
    From baseline assessment and then after every two cycles until 28 days post last administration of AT9283.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Response Population
    Number of subjects analysed
    4
    3
    4
    4
    5
    2
    22
    Units: Number of patients
    number (not applicable)
        Complete Response
    0
    0
    0
    0
    0
    0
    0
        Partial Response
    0
    0
    0
    0
    1
    0
    1
        Stable Disease
    1
    2
    1
    2
    2
    0
    8
        Progressive Disease
    3
    0
    2
    2
    2
    2
    11
        Early Progression
    0
    0
    0
    0
    0
    0
    0
        Very good Partial Response (INRC)
    0
    0
    0
    0
    0
    0
    0
        Mixed Response (INRC)
    0
    0
    1
    0
    0
    0
    1
        No Response (INRC)
    0
    1
    0
    0
    0
    0
    1
    Attachments
    Untitled (Filename: AT9283 Tumour Marker Summary_CSR extract_prepared 30Mar17.pdf)
    No statistical analyses for this end point

    Secondary: AT9283 Pharmacokinetic Profile

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    End point title
    AT9283 Pharmacokinetic Profile
    End point description
    Pharmacokinetic parameters estimated included area under the plasma concentration-time curve (AUC); maximum concentration achieved (Cmax); time to maximum concentration (Tmax); elimination half-life (T1/2); clearance (Cl) and volume of distribution at steady state (Vss) for AT9283.
    End point type
    Secondary
    End point timeframe
    Pre-treatment (during screening within one week prior to first AT9283 administration), 4, 24, 48, 70, 73, 76 and 96 hours post infusion in Cycle 1 only.
    End point values
    Pharmacokinetic Population
    Number of subjects analysed
    32
    Units: Number of patients
    number (not applicable)
        Dose Level 7.0 mg/m2
    5
        Dose Level 9.0 mg/m2
    5
        Dose Level 11.5 mg/m2
    6
        Dose Level 14.5 mg/m2
    7
        Dose Level 18.5 mg/m2
    7
        Dose Level 23.0 mg/m2
    2
    Attachments
    Untitled (Filename: AT9283 PK Summary_CSR extract_prepared 30Mar17.pdf)
    No statistical analyses for this end point

    Secondary: Pharmacodynamic Activity of AT9283

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    End point title
    Pharmacodynamic Activity of AT9283
    End point description
    Investigation of the pharmacodynamic behaviour of AT9283 using enzyme linked immunosorbent assays to analyse levels of circulating cytokeratin 18 (M65 ELISA) and caspase 3 cleaved cytokeratin 18 (M30 ELISA) in plasma as surrogate markers for cell death and apoptosis respectively.
    End point type
    Secondary
    End point timeframe
    Pre-treatment (within one week prior to first AT9283 administration), then at 24 hours, 48 hours, 70 hours and 8 days post-infusion during Cycle 1 only.
    End point values
    Pharmacodynamic Population (ELISA)
    Number of subjects analysed
    32
    Units: Number of patients
    number (not applicable)
        Dose Level 7.0 mg/m2
    5
        Dose Level 9.0 mg/m2
    5
        Dose Level 11.5 mg/m2
    6
        Dose Level 14.5 mg/m2
    7
        Dose Level 18.5 mg/m2
    7
        Dose Level 23.0 mg/m2
    2
    Attachments
    Untitled (Filename: AT9283 PD Summary_CSR extract_prepared 30Mar17.pdf)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of consent until 28 days post final administration of AT9283. Any AT9283-related AEs still present at that time, were followed up monthly until the AE resolved, stabilised or the patient commenced another anti-cancer therapy.
    Adverse event reporting additional description
    All eligible patients who received at least one infusion of AT9283 were included in the safety analysis. NCI CTCAE Version 3.0 was used to code AEs and grade their severity.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Overall Safety Population
    Reporting group description
    -

    Reporting group title
    Cohort 1
    Reporting group description
    Dose Level 7.0 mg/m2

    Reporting group title
    Cohort 2
    Reporting group description
    Dose Level 9.0 mg/m2

    Reporting group title
    Cohort 3
    Reporting group description
    Dose Level 11.5 mg/m2

    Reporting group title
    Cohort 4
    Reporting group description
    Dose Level 14.5 mg/m2

    Reporting group title
    Cohort 5
    Reporting group description
    Dose Level 18.5 mg/m2

    Reporting group title
    Cohort 6
    Reporting group description
    Dose Level 23.0 mg/m2

    Serious adverse events
    Overall Safety Population Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 33 (60.61%)
    6 / 6 (100.00%)
    2 / 5 (40.00%)
    4 / 6 (66.67%)
    1 / 7 (14.29%)
    5 / 7 (71.43%)
    2 / 2 (100.00%)
         number of deaths (all causes)
    3
    0
    1
    1
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Haemorrhage - other
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophils
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    6 / 33 (18.18%)
    3 / 6 (50.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 3
    0 / 0
    0 / 2
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    4 / 33 (12.12%)
    3 / 6 (50.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurology - other
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain - head/headache
         subjects affected / exposed
    4 / 33 (12.12%)
    2 / 6 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    6 / 33 (18.18%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    2 / 8
    1 / 1
    0 / 3
    0 / 1
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death - disease progression
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Pain - other
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection site reaction
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage GI - oral cavity
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Reproductive system - other (infertility/sterility)
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Hand-foot
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle weakness left-sided
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle weakness right-sided
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain - back
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain - bone
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain - joint
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain - chest wall
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infection - other
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection normal ANC - soft tissue NOS
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Overall Safety Population Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 33 (96.97%)
    6 / 6 (100.00%)
    5 / 5 (100.00%)
    5 / 6 (83.33%)
    7 / 7 (100.00%)
    7 / 7 (100.00%)
    2 / 2 (100.00%)
    Vascular disorders
    Vascular - other
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 33 (36.36%)
    1 / 6 (16.67%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    4 / 7 (57.14%)
    3 / 7 (42.86%)
    1 / 2 (50.00%)
         occurrences all number
    14
    1
    3
    1
    4
    4
    1
    Sweating
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Fever
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 2 (50.00%)
         occurrences all number
    5
    0
    0
    0
    1
    3
    1
    Rigors/chills
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Oedema: head and neck
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    1
    0
    0
    0
    Oedema: limb
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    4
    1
    1
    0
    0
    2
    0
    Pain - chest/thorax NOS
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    2
    0
    Pain - other
         subjects affected / exposed
    5 / 33 (15.15%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    0 / 2 (0.00%)
         occurrences all number
    6
    0
    0
    2
    2
    2
    0
    Flu-like syndrome
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    6
    0
    0
    0
    0
    6
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Mood - anxiety
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    0
    Mood - agitation
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    0
    Confusion
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Sexual - other
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Intraop injury - other
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Investigations
    Weight loss
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    1
    0
    2
    0
    0
    Weight gain
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    1
    1
    1
    0
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    0
    Hypotension
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Supr - sinus bradycardia
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Cardiac general - other
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Neutrophils
         subjects affected / exposed
    12 / 33 (36.36%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    3 / 7 (42.86%)
    4 / 7 (57.14%)
    2 / 2 (100.00%)
         occurrences all number
    31
    3
    1
    2
    3
    19
    3
    Leucocytes
         subjects affected / exposed
    8 / 33 (24.24%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    3 / 6 (50.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    1 / 2 (50.00%)
         occurrences all number
    25
    2
    0
    4
    3
    14
    2
    Platelets
         subjects affected / exposed
    9 / 33 (27.27%)
    2 / 6 (33.33%)
    1 / 5 (20.00%)
    3 / 6 (50.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    1 / 2 (50.00%)
         occurrences all number
    13
    2
    2
    5
    0
    3
    1
    Haemoglobin
         subjects affected / exposed
    9 / 33 (27.27%)
    0 / 6 (0.00%)
    3 / 5 (60.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    2 / 2 (100.00%)
         occurrences all number
    19
    0
    4
    3
    0
    10
    2
    Lymphopenia
         subjects affected / exposed
    8 / 33 (24.24%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    3 / 7 (42.86%)
    1 / 2 (50.00%)
         occurrences all number
    31
    0
    0
    3
    3
    23
    2
    Blood - other
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Haemorrhage - other
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Haemorrhage pulmonary upper respiratory - nose
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Pain - throat/pharynx/larynx
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    8
    0
    0
    0
    2
    6
    0
    Pulmonary - other
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    4
    1
    1
    0
    1
    1
    0
    Cough
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    4
    0
    1
    0
    2
    1
    0
    Voice changes
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    1
    2
    0
    0
    Dyspnoea
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    0
    Nervous system disorders
    Neuropathy - sensory
         subjects affected / exposed
    6 / 33 (18.18%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    3 / 7 (42.86%)
    0 / 2 (0.00%)
         occurrences all number
    6
    1
    1
    1
    0
    3
    0
    Neurology - other
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    6
    2
    0
    1
    1
    2
    0
    Tremor
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    0
    Ataxia
         subjects affected / exposed
    6 / 33 (18.18%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    2 / 2 (100.00%)
         occurrences all number
    6
    0
    0
    1
    2
    1
    2
    Dizziness
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 2 (50.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    1
    Somnolence
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Neuropathy - CN VII motor-face; sensory-taste
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Seizure
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    5
    0
    0
    0
    1
    4
    0
    Memory impairment
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Neuropathy - motor
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Pyramidal tract dysfunction
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Pain - head/headache
         subjects affected / exposed
    15 / 33 (45.45%)
    2 / 6 (33.33%)
    1 / 5 (20.00%)
    2 / 6 (33.33%)
    3 / 7 (42.86%)
    5 / 7 (71.43%)
    2 / 2 (100.00%)
         occurrences all number
    35
    3
    2
    4
    7
    15
    4
    Pain - neuralgia/peripheral nerve
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    0
    Ocular - other
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    3
    2
    0
    0
    0
    0
    1
    Diplopia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Nystagmus
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Optic disc oedema
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Blurred vision
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Eyelid dysfunction
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    10 / 33 (30.30%)
    3 / 6 (50.00%)
    2 / 5 (40.00%)
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    1 / 2 (50.00%)
         occurrences all number
    13
    4
    2
    2
    0
    4
    1
    Dehydration
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    3
    1
    0
    1
    0
    0
    1
    Mucositis (functional/symptomatic) - oral cavity
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    1
    Mucositis (clinical exam) - oral cavity
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    8 / 33 (24.24%)
    2 / 6 (33.33%)
    2 / 5 (40.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    0 / 2 (0.00%)
         occurrences all number
    8
    2
    2
    1
    1
    2
    0
    Vomiting
         subjects affected / exposed
    15 / 33 (45.45%)
    4 / 6 (66.67%)
    3 / 5 (60.00%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    3 / 7 (42.86%)
    2 / 2 (100.00%)
         occurrences all number
    23
    6
    4
    4
    1
    3
    5
    Anorexia
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 2 (0.00%)
         occurrences all number
    4
    0
    1
    1
    0
    2
    0
    Diarrhoea
         subjects affected / exposed
    6 / 33 (18.18%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    3 / 7 (42.86%)
    1 / 2 (50.00%)
         occurrences all number
    10
    0
    0
    1
    1
    7
    1
    Distension
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Dysphagia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    0
    Taste alteration
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Heartburn
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Pain - abdomen NOS
         subjects affected / exposed
    6 / 33 (18.18%)
    2 / 6 (33.33%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    13
    3
    0
    1
    2
    7
    0
    Pain - dental/teeth/peridontal
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    1
    0
    Pain - stomach
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Pain - oral cavity
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Incontinence urinary
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Urinary retention
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Hepatobiliary disorders
    Hepatic - other
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    7 / 33 (21.21%)
    2 / 6 (33.33%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    4 / 7 (57.14%)
    1 / 2 (50.00%)
         occurrences all number
    11
    3
    0
    0
    0
    7
    1
    Alopecia
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    1 / 2 (50.00%)
         occurrences all number
    4
    0
    0
    0
    1
    2
    1
    Striae
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    1
    0
    Dermatology - other
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    0
    Bruising
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    0
    Cheilitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    0
    Injection site reaction
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain - joint
         subjects affected / exposed
    7 / 33 (21.21%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    3 / 7 (42.86%)
    0 / 2 (0.00%)
         occurrences all number
    8
    1
    0
    1
    2
    4
    0
    Pain - back
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    6
    0
    1
    0
    3
    2
    0
    Pain - extremity-limb
         subjects affected / exposed
    5 / 33 (15.15%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    0 / 2 (0.00%)
         occurrences all number
    10
    0
    5
    0
    2
    3
    0
    Pain - bone
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    0
    0
    Pain - muscle
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Pain - neck
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    0
    Muscle weakness - extremity-upper
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Muscle weakness - left-sided
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Muscle weakness - facial
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Musculoskeletal - other
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    2
    0
    Endocrine disorders
    Endocrine - other
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Cushingoid
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    1
    1
    0
    0
    Adrenal insufficiency
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Hot flashes
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    1 / 2 (50.00%)
         occurrences all number
    11
    1
    0
    0
    0
    9
    1
    ALT
         subjects affected / exposed
    5 / 33 (15.15%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    0 / 2 (0.00%)
         occurrences all number
    8
    0
    1
    4
    1
    2
    0
    Bilirubin
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    1
    0
    GGT
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    4
    0
    3
    0
    0
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    4
    0
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 2 (50.00%)
         occurrences all number
    5
    0
    0
    1
    0
    3
    1
    Hypocalcaemia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 2 (50.00%)
         occurrences all number
    3
    0
    0
    0
    0
    2
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    6
    0
    0
    3
    2
    0
    1
    Hyponatraemia
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 2 (50.00%)
         occurrences all number
    5
    0
    0
    1
    0
    1
    3
    Alkaline phosphatase
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    2
    AST
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    0
    0
    3
    0
    0
    0
    Metabolic/lab - other
         subjects affected / exposed
    4 / 33 (12.12%)
    0 / 6 (0.00%)
    3 / 5 (60.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    5
    0
    3
    2
    0
    0
    0
    Infections and infestations
    Infection normal ANC - upper airway NOS
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Infection - other
         subjects affected / exposed
    12 / 33 (36.36%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    2 / 6 (33.33%)
    4 / 7 (57.14%)
    4 / 7 (57.14%)
    1 / 2 (50.00%)
         occurrences all number
    19
    1
    0
    2
    4
    10
    2
    Infection normal ANC - catheter-related
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    Infection documented clinically - wound
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Infection unknown ANC - trachea
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Infection documented clinically - upper airway NOS
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2010
    Clarification of the required delay between dosing the first and second patients at any given dose level. Permission for 50 mL AT9283 infusion volume to be used for patients where necessary. Clarification that the total 72 hour infusion was to be achieved by means of three 24 hour infusions. Addition of the correct method for collecting bone marrow aspirate. Addition of details of the labelling requirements for the reconstituted investigational medicinal product (IMP). Addition of two new informed consent documents to allow for patient assent for optional biopsies. Clarification of the AE reporting period.
    20 Aug 2010
    Clarification of exclusion criterion regarding allergy/auto-immune disease. Clarification of timelines for IMP reconstitution. Update to information concerning blood sampling. Timing of the baseline echocardiogram changed from one week to two weeks prior to first administration of IMP.
    08 Apr 2011
    Restart to the trial on 08 April 2011 following a temporary halt. Updates to the inclusion criteria to allow patients with diffuse intrinsic pontine gliomas that had progressed or relapsed after first line therapy to be included without histological verification, and to clarify the minimum Lansky Play Scale Score required. Addition of a new exclusion criterion to exclude patients experiencing uncontrolled hypertension during the screening period. Amendment to the timing of urinalysis tests. Update to the collection of samples for pharmacodynamics analysis so that skin punch biopsies became mandatory. Change to Sponsor contact details.
    18 Jun 2014
    Reduction in the frequency of radiological disease assessments, echocardiogram and urinalysis evaluations from every two cycles of AT9283 to every four cycles for the one remaining patient on trial.
    31 Mar 2016
    Removal of requirement for echocardiogram evaluation. Increase in trial duration and clarification that final analysis could be conducted due to all patients completing their final visit (with the exception of one patient continuing to benefit from treatment). Clarification of data collection methods for one remaining patient on trial.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Sep 2010
    Recruitment to the trial was temporarily halted on 20 September 2010. This was as a direct result of the review of safety data from adult leukaemia studies with AT9283 and preliminary evidence of drug-related cardiac toxicity. Protocol Version 04 and 05 were not issued to trial sites as a result of the halt to the trial.
    08 Apr 2011

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    At the data cut-off date for the interim analysis (25 January 2016), one patient was continuing on trial in accordance with the protocol, as the Chief Investigator and Sponsor considered the patient would benefit from continued treatment.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/25370467
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