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    Clinical Trial Results:
    Safety and pharmacokinetics of ODM-207 in patients with selected advanced solid tumours: an open-label, non-randomised, uncontrolled, multicentre, first-in-human study with cohort expansion

    Summary
    EudraCT number
    		 2015-004826-32
    Trial protocol
    		 GB   FI   ES   FR  
    Global end of trial date
    10 May 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Nov 2019
    First version publication date
    27 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3121001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03035591
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Orion Corporation, Orion Pharma
    Sponsor organisation address
    Orionintie 1, Espoo, Finland, 02200
    Public contact
    Clinical Trial Information desk, Orion Corporation, Orion Pharma, +358 104261, clinicaltrials@orionpharma.com
    Scientific contact
    Clinical Trial Information desk, Orion Corporation, Orion Pharma, +358 104261, clinicaltrials@orionpharma.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
    10 May 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1: To evaluate the safety and tolerability, define the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) if possible, and define the recommended doses and dosing schedules of ODM-207 for Part 2 of the study. Part 2: To further evaluate the safety and tolerability, and preliminary antitumour activity of ODM-207 at the dose levels recommended for further clinical studies in patient populations with selected tumour types.
    Protection of trial subjects
    Adequate medical expertise and facilities to handle possible emergency situations were available throughout the study. Study subjects were carefully monitored during the study. The dose escalation for following cohort were decided with a support of the SMB after a minimum of 3 patients had provided evaluable dose limiting toxicity -data.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    France: 7
    Worldwide total number of subjects
    36
    EEA total number of subjects
    36
    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)
    1
    Adults (18-64 years)
    23
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Male and female patients with confirmed advanced solid tumors which were refractory or resistant to therapy or for which no effective standard therapy exists were enrolled into this study.

    Pre-assignment
    Screening details
    		 Male/female subjects with selected locally advanced/metastatic solid tumours refractory or resistant to therapy or with no effective standard therapy and life expectancy >12 weeks at baseline. Subjects >15 years with written informed consent. Adequate haemopoietic, hepatic and renal function. Eastern Cooperative Oncology Group status of 0 or 1.

    Period 1
    Period 1 title
    Part I (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1
    Arm description
    		 A dose of 50 mg of ODM-207 once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    ODM-207
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily as defined by the cohort using 50 mg tablets

    Arm title
    		 Cohort 2
    Arm description
    		 A dose of 100 mg of ODM-207 once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    ODM-207
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily as defined by the cohort using 50 mg tablets

    Arm title
    		 Cohort 3
    Arm description
    		 A dose of 1.5 mg/kg of ODM-207 once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    ODM-207
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily as defined by the cohort using tablets of the following strength: 15, 25 and 50 mg

    Arm title
    		 Cohort 4
    Arm description
    		 A dose of 2.0 mg/kg of ODM-207 once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    ODM-207
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily as defined by the cohort using tablets of the following strength: 15, 25 and 50 mg

    Arm title
    		 Cohort 5
    Arm description
    		 A dose of 1.1 mg/kg of ODM-207 once daily for to study food effect
    Arm type
    		 Experimental

    Investigational medicinal product name
    ODM-207
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily as defined by the cohort using tablets of the following strength: 25 and 50 mg

    Arm title
    		 Cohort 6
    Arm description
    		 A dose of 1.4 mg/kg of ODM-207 once daily to study 72 h elimination
    Arm type
    		 Experimental

    Investigational medicinal product name
    ODM-207
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily as defined by the cohort using tablets of the following strength: 15, 25 and 50 mg

    Number of subjects in period 1
    		Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6
    Started
    3
    7
    6
    6
    10
    4
    Completed
    3
    7
    5
    6
    10
    4
    Not completed
    0
    0
    1
    0
    0
    0
         Did not start study treatment
    -
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part I
    Reporting group description
    		 -

    Reporting group values
    		 Part I Total
    Number of subjects
    		 36 36
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 1 1
        Adults (18-64 years)
    		 23 23
        From 65-84 years
    		 12 12
    Gender categorical
    Units: Subjects
        Female
    		 14 14
        Male
    		 22 22

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 A dose of 50 mg of ODM-207 once daily

    Reporting group title
    Cohort 2
    Reporting group description
    		 A dose of 100 mg of ODM-207 once daily

    Reporting group title
    Cohort 3
    Reporting group description
    		 A dose of 1.5 mg/kg of ODM-207 once daily

    Reporting group title
    Cohort 4
    Reporting group description
    		 A dose of 2.0 mg/kg of ODM-207 once daily

    Reporting group title
    Cohort 5
    Reporting group description
    		 A dose of 1.1 mg/kg of ODM-207 once daily for to study food effect

    Reporting group title
    Cohort 6
    Reporting group description
    		 A dose of 1.4 mg/kg of ODM-207 once daily to study 72 h elimination

    Primary: Frequency of Adverse Events

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    End point title
    		 Frequency of Adverse Events [1]
    End point description
    End point type
    Primary
    End point timeframe
    Treatment emergent adverse events
    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: Descriptive statistics because only part 1 was conducted.
    End point values
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6
    Number of subjects analysed
    3
    7
    5
    6
    10
    4
    Units: Subjects
    3
    7
    5
    6
    10
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 A dose of 50 mg of ODM-207 once daily

    Reporting group title
    Cohort 2
    Reporting group description
    		 A dose of 100 mg of ODM-207 once daily

    Reporting group title
    Cohort 3
    Reporting group description
    		 A dose of 1.5 mg/kg of ODM-207 once daily

    Reporting group title
    Cohort 5
    Reporting group description
    		 A dose of 1.1 mg/kg of ODM-207 once daily for to study food effect

    Reporting group title
    Cohort 6
    Reporting group description
    		 A dose of 1.4 mg/kg of ODM-207 once daily to study 72 h elimination

    Reporting group title
    Cohort 4
    Reporting group description
    		 A dose of 2.0 mg/kg of ODM-207 once daily

    Serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 5 Cohort 6 Cohort 4
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    2 / 5 (40.00%)
    3 / 10 (30.00%)
    4 / 4 (100.00%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    0
    0
    1
    2
    2
    0
         number of deaths resulting from adverse events
    0
    0
    1
    2
    2
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    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
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Spinal cord compression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    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
    Blood and lymphatic system disorders
    B-cell lymphoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    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
    NUT midline carcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    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 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    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
    Tumour pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    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
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    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
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    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
    Intestinal obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    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
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    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
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    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
    Pancreatitis necrotising
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    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
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    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 / 1
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1 Cohort 2 Cohort 3 Cohort 5 Cohort 6 Cohort 4
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    7 / 7 (100.00%)
    5 / 5 (100.00%)
    10 / 10 (100.00%)
    4 / 4 (100.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    0
    0
    1
    0
    2
    Orthostatic hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    1 / 5 (20.00%)
    3 / 10 (30.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    1
    4
    0
    2
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Chills
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    5 / 7 (71.43%)
    2 / 5 (40.00%)
    4 / 10 (40.00%)
    0 / 4 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    1
    10
    2
    6
    0
    4
    Mucosal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Xerosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    0
    2
    1
    1
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    2
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pleuritic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    2
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    2
    0
    1
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    1
    2
    0
    3
    Blood sodium decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    3 / 3 (100.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    3
    1
    0
    2
    0
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    Laceration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Post procedural haematoma
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Tooth fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Wrist fracture
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    1 / 4 (25.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    0
    1
    1
    4
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    5 / 7 (71.43%)
    2 / 5 (40.00%)
    3 / 10 (30.00%)
    0 / 4 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    0
    8
    3
    4
    0
    5
    Hypotonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Myoclonus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    Tremor
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Visual field defect
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    4 / 10 (40.00%)
    0 / 4 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    0
    1
    0
    8
    0
    4
    Gastrointestinal melanoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    0
    2
    1
    Neutrophilia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 7 (57.14%)
    2 / 5 (40.00%)
    6 / 10 (60.00%)
    0 / 4 (0.00%)
    6 / 6 (100.00%)
         occurrences all number
    0
    8
    2
    14
    0
    11
    Tumour pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eye pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Eye swelling
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Optic nerve disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    3 / 10 (30.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    3
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Aptyalism
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    3 / 5 (60.00%)
    3 / 10 (30.00%)
    1 / 4 (25.00%)
    4 / 6 (66.67%)
         occurrences all number
    2
    8
    5
    3
    1
    6
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Gingival bleeding
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 7 (42.86%)
    3 / 5 (60.00%)
    7 / 10 (70.00%)
    4 / 4 (100.00%)
    4 / 6 (66.67%)
         occurrences all number
    4
    7
    3
    9
    4
    7
    Vomiting
         subjects affected / exposed
    3 / 3 (100.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    4 / 10 (40.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    5
    2
    0
    4
    1
    1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Night sweats
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Solar dermatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Urinary retention
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    2 / 4 (50.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    1
    1
    0
    2
    2
    Flank pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Joint stiffness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Muscle contracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    2
    2
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Trismus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Periodontitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 3 (100.00%)
    6 / 7 (85.71%)
    0 / 5 (0.00%)
    3 / 10 (30.00%)
    1 / 4 (25.00%)
    4 / 6 (66.67%)
         occurrences all number
    7
    9
    0
    3
    1
    7
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 5 (20.00%)
    4 / 10 (40.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    1
    6
    0
    3
    Hypomagnesaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    2 / 10 (20.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Feb 2017
    Evaluation of the effect of food on bioavailability of ODM-207 was added to the secondary objectives. 15 mg ODM-207 tablet was added for dose adjustment purpose. It was made possible to report the SAEs electronically in the EDC system. Minor adjustments in timings and instructions for assessments.
    15 May 2017
    Exclusion criterion 4 was modified to allow that 1 of the 3 measurements of BP is above the defined upper limit of eligibility as BP is known to fluctuate significantly within a short period of time. Exclusion criterion 5 was modified to allow concomitant use of fulvestrant if it’s use had been started before the first dose of study treatment and the treatment related AEs were resolved to at least grade 1. Washout period of anticancer therapy in exclusion criterion 5 was reduced from 5 to 4 half-lives to shorten the period the patient needed to be without antineoplastic treatment.
    27 Oct 2017
    Flat dosing (mg) was changed to individual dosing (mg/kg). The lower age limit for eligible patients in Part 1B and Part 2 was reduced from 18 to 15 years in inclusion criterion 2. A 72-h PK cohort was added to Part 1B to study PK elimination. Patients were allowed to continue treatment with ODM-207 as long as it was considered benefical to the patient (as judged by the investigator) instead of until disease progression. A time window (within 4 weeks before the first dose of study treatment) for the requirement to have testosterone level < 50 mg/ml was added to inclusion criterion 12. The QTcF interval of  450 ms was changed to  470 ms in exclusion criterion 4. The list of drugs that cause QT prolongation or Torsades des Pointes was changed to an online ‘QTDrugs list’ in exclusion criterion 4. Prior exposure to BET inhibitors was modified in exclusion criterion 16 to allow patients with prior exposure to BET inhibitors to be considered eligible if they were considered to have a significantly greater likelihood of responding to ODM-207. Exclusion criterion 17 was added to exclude patients with glioma who had received radiotherapy or chemoradio therapy within the last 3 months before the first dose of study treatment or had a history of glioma-related bleeding as detected by MRI. The duration of ODM-207 treatment at the same dose level was changed to last for at least 8 weeks instead of until disease progression. New PK blood sampling timepoints were added to evaluate the long-term exposure and to follow-up compliance. A possibility to collect additional PK blood samples was added for patients who interrupted the ODM-207 treatment. It was possible to collect additional tumour samples if this was part of the clinical management of the patient.
    12 Feb 2018
    Eligibility criteria for patients with glioma were modified in inclusion criterion 6, removing restrictions on subtypes of the disease and providing more accurate definition of eligible patients’ status and history of response. Exclusion criterion 17 for patients with glioma was modified to exclude patients with a more resistant disease who were less likely to respond with treatment. Modifications to schedules of ECG, PK sample and tumour biopsy.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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