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    Clinical Trial Results:
    A phase I/randomised phase II trial of abiraterone acetate or enzalutamide with or without idasanutlin (RO5503781) in patients with metastatic castration resistant prostate cancer who have not previously received docetaxel.

    Summary
    EudraCT number
    		 2013-002014-13
    Trial protocol
    		 GB  
    Global end of trial date
    09 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Dec 2020
    First version publication date
    25 Dec 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MAdCaP2013
    Additional study identifiers
    ISRCTN number
    		 ISRCTN38949950
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    NHS Greater Glasgow & Clyde
    Sponsor organisation address
    Ward 11, Dykebar Hospital, Paisley, United Kingdom, PA2 7DE
    Public contact
    Lorna Sweeting, CRUK Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Glasgow, G12 0YN, 44 0141 301 7194, lorna.sweeting@glasgow.ac.uk
    Scientific contact
    Lorna Sweeting, CRUK Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Glasgow, G12 0YN, 44 0141 301 7194, lorna.sweeting@glasgow.ac.uk
    Sponsor organisation name
    University of Glasgow
    Sponsor organisation address
    Room 327, Wolfson Medical School Building, Glasgow, United Kingdom, G12 8QQ
    Public contact
    Lorna Sweeting, CRUK Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Glasgow, G12 0YN, 44 0141 301 7194, lorna.sweeting@glasgow.ac.uk
    Scientific contact
    Lorna Sweeting, CRUK Clinical Trials Unit, Beatson West of Scotland Cancer Centre, Glasgow, G12 0YN, 44 0141 301 7194, lorna.sweeting@glasgow.ac.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
    Final
    Date of interim/final analysis
    09 Dec 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective (phase I): To establish a safe and tolerable dose for RO5503781 given in combination with abiraterone or enzalutamide. Primary objective (phase II): To establish whether the efficacy of the combination of RO5503781 with abiraterone and prednisolone or enzalutamide merits further study in patients with mCRPC. The primary endpoint will be radiological progression free survival (please note, our commercial partner Roche decided not to provide support for the planned Phase II component of the study and therefore this did not proceed).
    Protection of trial subjects
    Patients were required to attend for visits and investigations that were considered to be additional to standard of care. The number and types of visits and assessments were fully explained verbally and in a Patient Information Sheet which patients were given time to read and discuss with family, and the research team, prior to consent. All staff involved in delivering the study were fully GCP trained. In the dose escalation phase (phase I), patients were reviewed weekly for Dose Limiting Toxicities and a Safety Review Committee met at the completion of each dose cohort to review the patient details and confirm the escalation to the next dose level where appropriate.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 22
    Worldwide total number of subjects
    22
    EEA total number of subjects
    22
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    16
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Phase I: Open to recruitment between 31st March 2014 and 3rd July 2017 with 22 patients recruited over 6 cohorts. Phase II: Roche, our commercial partner, decided not to provide support for the Phase II component of the study, therefore this did not proceed and no patients were recruited.

    Pre-assignment
    Screening details
    		 Following consent, all patients underwent screening to determine eligibility, including confirmation of disease progressions, physical exam, blood tests (including testosterone), review of prior treatment (prior cytotoxic chemotherapy excluded, no other anticancer therapy (apart from LHRH agonist/antagonist) within 4 weeks.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort -1
    Arm description
    		 RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, a single dose given orally on day -7, then 200mg orally once daily on days 1-3 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idasanutlin
    Investigational medicinal product code
    RO5503781
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, a single dose given orally on day -7, then 200mg orally once daily on days 1-3 of a 28 day cycle

    Investigational medicinal product name
    Abiraterone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000mg orally once a day continuously

    Arm title
    		 Cohort 1
    Arm description
    		 RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, a single dose given orally on day -7, then 200mg orally once daily on days 1-5 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idasanutlin
    Investigational medicinal product code
    RO5503781
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, a single dose given orally on day -7, then 200mg orally once daily on days 1-5 of a 28 day cycle

    Investigational medicinal product name
    Abiraterone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000mg orally once a day continuously

    Arm title
    		 Cohort 1*
    Arm description
    		 RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation 200mg orally once daily on days 1-5 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idasanutlin
    Investigational medicinal product code
    RO5503781
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, 200mg orally once daily on days 1-5 of a 28 day cycle

    Investigational medicinal product name
    Abiraterone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000mg orally once a day continuously

    Arm title
    		 Cohort 2
    Arm description
    		 RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, 400mg orally once daily on days 1-5 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idasanutlin
    Investigational medicinal product code
    RO5503781
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, 400mg orally once daily on days 1-5 of a 28 day cycle

    Investigational medicinal product name
    Abiraterone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000mg orally once a day continuously

    Arm title
    		 Cohort 3B
    Arm description
    		 RO5503781 (Idasanutlin) SDP (spray-dried powder) tablet formulation, 250mg orally once daily on days 1-5 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idasanutlin
    Investigational medicinal product code
    RO5503781
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RO5503781 (Idasanutlin) SDP (spray-dried powder) tablet formulation, 250mg orally once daily on days 1-5 of a 28 day cycle

    Investigational medicinal product name
    Abiraterone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000mg orally once a day continuously

    Arm title
    		 Cohort 1E
    Arm description
    		 RO5503781 (Idasanutlin) SDP (spray-dried powder) tablet formulation, 250mg orally once daily on days 1-5 of a 28 day cycle with enzalutamide orally 160mg once daily. This was repeated every 28 days until progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idasanutlin
    Investigational medicinal product code
    RO5503781
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RO5503781 (Idasanutlin) SDP (spray-dried powder) tablet formulation, 250mg orally once daily on days 1-5 of a 28 day cycle

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    enzalutamide 160mg once daily continuously

    Number of subjects in period 1
    		Cohort -1 Cohort 1 Cohort 1* Cohort 2 Cohort 3B Cohort 1E
    Started
    3
    3
    3
    3
    7
    3
    Completed
    3
    3
    3
    3
    7
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort -1
    Reporting group description
    		 RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, a single dose given orally on day -7, then 200mg orally once daily on days 1-3 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.

    Reporting group title
    Cohort 1
    Reporting group description
    		 RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, a single dose given orally on day -7, then 200mg orally once daily on days 1-5 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.

    Reporting group title
    Cohort 1*
    Reporting group description
    		 RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation 200mg orally once daily on days 1-5 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.

    Reporting group title
    Cohort 2
    Reporting group description
    		 RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, 400mg orally once daily on days 1-5 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.

    Reporting group title
    Cohort 3B
    Reporting group description
    		 RO5503781 (Idasanutlin) SDP (spray-dried powder) tablet formulation, 250mg orally once daily on days 1-5 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.

    Reporting group title
    Cohort 1E
    Reporting group description
    		 RO5503781 (Idasanutlin) SDP (spray-dried powder) tablet formulation, 250mg orally once daily on days 1-5 of a 28 day cycle with enzalutamide orally 160mg once daily. This was repeated every 28 days until progression.

    Reporting group values
    		 Cohort -1 Cohort 1 Cohort 1* Cohort 2 Cohort 3B Cohort 1E Total
    Number of subjects
    		 3 3 3 3 7 3 22
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 1 3 2 3 4 3 16
        From 65-84 years
    		 2 0 1 0 3 0 6
        85 years and over
    		 0 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0 0 0 0
        Male
    		 3 3 3 3 7 3 22
    Subject analysis sets

    Subject analysis set title
    Phase I Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Phase I patients with one or more dose of study medication

    Subject analysis set title
    Phase I Evaluable Study Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    • Any patient who has experienced a DLT • Any patient who has received 5 consecutive days of treatment with RO5503781 within the first 21 days of combination therapy • Any patient who has received at least 80% of planned doses of abiraterone or enzalutamide within the first 21 days of combination therapy Any patient who has dose modifications not permitted by study protocol within the first 21 days will NOT be evauable unless they experience a DLT

    Subject analysis sets values
    		 Phase I Safety Population Phase I Evaluable Study Population
    Number of subjects
    22
    21
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    16
    15
        From 65-84 years
    6
    6
        85 years and over
    0
    0
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    0
    0
        Male
    22
    21

    End points

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    End points reporting groups
    Reporting group title
    Cohort -1
    Reporting group description
    		 RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, a single dose given orally on day -7, then 200mg orally once daily on days 1-3 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.

    Reporting group title
    Cohort 1
    Reporting group description
    		 RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, a single dose given orally on day -7, then 200mg orally once daily on days 1-5 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.

    Reporting group title
    Cohort 1*
    Reporting group description
    		 RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation 200mg orally once daily on days 1-5 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.

    Reporting group title
    Cohort 2
    Reporting group description
    		 RO5503781 (Idasanutlin) MBP (microprecipitated bulk powder) tablet formulation, 400mg orally once daily on days 1-5 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.

    Reporting group title
    Cohort 3B
    Reporting group description
    		 RO5503781 (Idasanutlin) SDP (spray-dried powder) tablet formulation, 250mg orally once daily on days 1-5 of a 28 day cycle with abiraterone orally 1000mg once daily and prednisolone orally 5mg twice a day. This was repeated every 28 days until progression.

    Reporting group title
    Cohort 1E
    Reporting group description
    		 RO5503781 (Idasanutlin) SDP (spray-dried powder) tablet formulation, 250mg orally once daily on days 1-5 of a 28 day cycle with enzalutamide orally 160mg once daily. This was repeated every 28 days until progression.

    Subject analysis set title
    Phase I Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Phase I patients with one or more dose of study medication

    Subject analysis set title
    Phase I Evaluable Study Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    • Any patient who has experienced a DLT • Any patient who has received 5 consecutive days of treatment with RO5503781 within the first 21 days of combination therapy • Any patient who has received at least 80% of planned doses of abiraterone or enzalutamide within the first 21 days of combination therapy Any patient who has dose modifications not permitted by study protocol within the first 21 days will NOT be evauable unless they experience a DLT

    Primary: Incidence of dose-limiting toxicities

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    End point title
    		 Incidence of dose-limiting toxicities [1]
    End point description
    Any of the following events beginning between the first administration of RO and 21 days after starting combination therapy if, in the opinion of the investigator, the event is due to the combination of abiraterone/enzalutamide, RO and prednisolone (if applicable) will be considered a dose limiting toxicity (DLT): * Grade 4 neutropenia >= 7 days duration * Grade 3–4 neutropenia associated with an oral temperature >=38.5oC * Grade 3–4 neutropenia associated with bacteriologically proven sepsis * Any grade 4 thrombocytopenia * Grade 3 thrombocytopenia associated with non-traumatic bleeding (except where this can be explained by therapeutic anticoagulation) * Any other clinically significant grade 3 or above toxicity except suboptimally-treated nausea or vomiting
    End point type
    Primary
    End point timeframe
    Between the first administration of RO and 21 days after starting combination therapy
    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: The Phase I part of the trial was to determine the maximum tolerated dose based on descriptive data only and not statistical analysis
    End point values
    		 Cohort -1 Cohort 1 Cohort 1* Cohort 2 Cohort 3B Cohort 1E Phase I Evaluable Study Population
    Number of subjects analysed
    3
    3
    3
    3
    6
    3
    21
    Units: Patients
    0
    0
    0
    0
    1
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From consent until resolution, or for at least 30 days after discontinuation of study medication, whichever comes first or until toxicity has resolved to baseline or < Grade 1, or until the toxicity is considered to be irreversible.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Cohort -1
    Reporting group description
    		 -

    Reporting group title
    Cohort 1
    Reporting group description
    		 -

    Reporting group title
    Cohort 1*
    Reporting group description
    		 -

    Reporting group title
    Cohort 1E
    Reporting group description
    		 -

    Reporting group title
    Cohort 2
    Reporting group description
    		 -

    Reporting group title
    Cohort 3B
    Reporting group description
    		 -

    Serious adverse events
    		 Cohort -1 Cohort 1 Cohort 1* Cohort 1E Cohort 2 Cohort 3B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    6 / 7 (85.71%)
         number of deaths (all causes)
    1
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    MYELODYSPLASTIC SYNDROME
    Additional description: MYELODYSPLASTIC SYNDROME
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         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
    NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - OTHER, SPECIFY
    Additional description: NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TUMOR PAIN
    Additional description: TUMOR PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Vascular disorders
    THROMBOEMBOLIC EVENT
    Additional description: THROMBOEMBOLIC EVENT
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    SURGICAL AND MEDICAL PROCEDURES - OTHER, SPECIFY
    Additional description: SURGICAL AND MEDICAL PROCEDURES - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    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
    General disorders and administration site conditions
    EDEMA LIMBS
    Additional description: EDEMA LIMBS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    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
    PAIN
    Additional description: PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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
    Reproductive system and breast disorders
    GENITAL EDEMA
    Additional description: GENITAL EDEMA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    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
    Respiratory, thoracic and mediastinal disorders
    PRODUCTIVE COUGH
    Additional description: PRODUCTIVE COUGH
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Psychiatric disorders
    DEPRESSION
    Additional description: DEPRESSION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    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
    Investigations
    CREATININE INCREASED
    Additional description: CREATININE INCREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         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
    INVESTIGATIONS - OTHER, SPECIFY
    Additional description: INVESTIGATIONS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
    Additional description: PLATELET COUNT DECREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
    Additional description: ATRIAL FIBRILLATION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    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
    MYOCARDIAL INFARCTION
    Additional description: MYOCARDIAL INFARCTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Nervous system disorders
    TRANSIENT ISCHEMIC ATTACKS
    Additional description: TRANSIENT ISCHEMIC ATTACKS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Blood and lymphatic system disorders
    ANEMIA
    Additional description: ANEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    COLITIS
    Additional description: COLITIS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (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
    COLONIC OBSTRUCTION
    Additional description: COLONIC OBSTRUCTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         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
    DIARRHEA
    Additional description: DIARRHEA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NAUSEA
    Additional description: NAUSEA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         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
    VOMITING
    Additional description: VOMITING
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    HEMATURIA
    Additional description: HEMATURIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    URINARY RETENTION
    Additional description: URINARY RETENTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Musculoskeletal and connective tissue disorders
    BACK PAIN
    Additional description: BACK PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Infections and infestations
    BRONCHIAL INFECTION
    Additional description: BRONCHIAL INFECTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         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
    LUNG INFECTION
    Additional description: LUNG INFECTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
    Additional description: URINARY TRACT INFECTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (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
    Metabolism and nutrition disorders
    HYPERCALCEMIA
    Additional description: HYPERCALCEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    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
    HYPERGLYCEMIA
    Additional description: HYPERGLYCEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         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
    HYPOKALEMIA
    Additional description: HYPOKALEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         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
    HYPOPHOSPHATEMIA
    Additional description: HYPOPHOSPHATEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         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 1 Cohort 1* Cohort 1E Cohort 2 Cohort 3B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    7 / 7 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - OTHER, SPECIFY
    Additional description: NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Vascular disorders
    FLUSHING
    Additional description: FLUSHING
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    HOT FLASHES
    Additional description: HOT FLASHES
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    15
    0
    0
    0
    0
    HYPERTENSION
    Additional description: HYPERTENSION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    2
    1
    0
    0
    2
    HYPOTENSION
    Additional description: HYPOTENSION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    PHLEBITIS
    Additional description: PHLEBITIS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    THROMBOEMBOLIC EVENT
    Additional description: THROMBOEMBOLIC EVENT
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    EDEMA FACE
    Additional description: EDEMA FACE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    EDEMA LIMBS
    Additional description: EDEMA LIMBS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    FATIGUE
    Additional description: FATIGUE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    1 / 3 (33.33%)
    5 / 7 (71.43%)
         occurrences all number
    0
    7
    20
    18
    1
    21
    FEVER
    Additional description: FEVER
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    FLU LIKE SYMPTOMS
    Additional description: FLU LIKE SYMPTOMS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    2
    2
    1
    GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, SPECIFY
    Additional description: GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    3
    1
    1
    2
    0
    4
    HYPOTHERMIA
    Additional description: HYPOTHERMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    MALAISE
    Additional description: MALAISE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    0
    0
    0
    9
    0
    6
    NON-CARDIAC CHEST PAIN
    Additional description: NON-CARDIAC CHEST PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    PAIN
    Additional description: PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 3 (100.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    1 / 3 (33.33%)
    4 / 7 (57.14%)
         occurrences all number
    5
    12
    2
    6
    3
    7
    Immune system disorders
    ALLERGIC REACTION
    Additional description: ALLERGIC REACTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    GYNECOMASTIA
    Additional description: GYNECOMASTIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    PELVIC PAIN
    Additional description: PELVIC PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    REPRODUCTIVE SYSTEM AND BREAST DISORDERS - OTHER, SPECIFY
    Additional description: REPRODUCTIVE SYSTEM AND BREAST DISORDERS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    COUGH
    Additional description: COUGH
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    0
    3
    0
    3
    DYSPNEA
    Additional description: DYSPNEA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    4 / 7 (57.14%)
         occurrences all number
    0
    3
    1
    1
    0
    6
    EPISTAXIS
    Additional description: EPISTAXIS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    LARYNGEAL INFLAMMATION
    Additional description: LARYNGEAL INFLAMMATION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER, SPECIFY
    Additional description: RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    0
    0
    2
    0
    2
    SLEEP APNEA
    Additional description: SLEEP APNEA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    WHEEZING
    Additional description: WHEEZING
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Psychiatric disorders
    ANXIETY
    Additional description: ANXIETY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    CONFUSION
    Additional description: CONFUSION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    DEPRESSION
    Additional description: DEPRESSION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    PSYCHIATRIC DISORDERS - OTHER, SPECIFY
    Additional description: PSYCHIATRIC DISORDERS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Investigations
    ACTIVATED PARTIAL THROMBOPLASTIN TIME PROLONGED
    Additional description: ACTIVATED PARTIAL THROMBOPLASTIN TIME PROLONGED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    INVESTIGATIONS - OTHER, SPECIFY
    Additional description: INVESTIGATIONS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 3 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    NEUTROPHIL COUNT DECREASED
    Additional description: NEUTROPHIL COUNT DECREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    4 / 7 (57.14%)
         occurrences all number
    0
    2
    0
    1
    1
    6
    PLATELET COUNT DECREASED
    Additional description: PLATELET COUNT DECREASED
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    4 / 7 (57.14%)
         occurrences all number
    0
    1
    0
    0
    2
    6
    WEIGHT GAIN
    Additional description: WEIGHT GAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    WEIGHT LOSS
    Additional description: WEIGHT LOSS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    BRUISING
    Additional description: BRUISING
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    7
    0
    0
    0
    2
    FALL
    Additional description: FALL
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    2
    0
    0
    1
    FRACTURE
    Additional description: FRACTURE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    INJURY TO SUPERIOR VENA CAVA
    Additional description: INJURY TO SUPERIOR VENA CAVA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    INJURY, POISONING AND PROCEDURAL COMPLICATIONS - OTHER, SPECIFY
    Additional description: INJURY, POISONING AND PROCEDURAL COMPLICATIONS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
         occurrences all number
    2
    0
    0
    1
    1
    2
    Cardiac disorders
    ATRIAL FIBRILLATION
    Additional description: ATRIAL FIBRILLATION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    CHEST PAIN - CARDIAC
    Additional description: CHEST PAIN - CARDIAC
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nervous system disorders
    DIZZINESS
    Additional description: DIZZINESS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    3 / 7 (42.86%)
         occurrences all number
    0
    0
    0
    0
    1
    5
    HEADACHE
    Additional description: HEADACHE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    3 / 7 (42.86%)
         occurrences all number
    1
    0
    0
    2
    4
    3
    LETHARGY
    Additional description: LETHARGY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    MEMORY IMPAIRMENT
    Additional description: MEMORY IMPAIRMENT
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    MOVEMENTS INVOLUNTARY
    Additional description: MOVEMENTS INVOLUNTARY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    NERVOUS SYSTEM DISORDERS - OTHER, SPECIFY
    Additional description: NERVOUS SYSTEM DISORDERS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    2 / 7 (28.57%)
         occurrences all number
    1
    0
    0
    2
    2
    4
    NEURALGIA
    Additional description: NEURALGIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    OLFACTORY NERVE DISORDER
    Additional description: OLFACTORY NERVE DISORDER
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    ANEMIA
    Additional description: ANEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 7 (42.86%)
         occurrences all number
    0
    0
    0
    1
    0
    4
    THROMBOTIC THROMBOCYTOPENIC PURPURA
    Additional description: THROMBOTIC THROMBOCYTOPENIC PURPURA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    3 / 7 (42.86%)
         occurrences all number
    0
    0
    0
    1
    2
    4
    Ear and labyrinth disorders
    EAR AND LABYRINTH DISORDERS - OTHER, SPECIFY
    Additional description: EAR AND LABYRINTH DISORDERS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    EAR PAIN
    Additional description: EAR PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Eye disorders
    BLURRED VISION
    Additional description: BLURRED VISION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    EYE DISORDERS - OTHER, SPECIFY
    Additional description: EYE DISORDERS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    ABDOMINAL PAIN
    Additional description: ABDOMINAL PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    BLOATING
    Additional description: BLOATING
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    CONSTIPATION
    Additional description: CONSTIPATION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 3 (100.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
         occurrences all number
    5
    3
    1
    1
    1
    8
    DIARRHEA
    Additional description: DIARRHEA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    6 / 7 (85.71%)
         occurrences all number
    8
    6
    20
    44
    6
    28
    DYSPEPSIA
    Additional description: DYSPEPSIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    GASTROINTESTINAL DISORDERS - OTHER, SPECIFY
    Additional description: GASTROINTESTINAL DISORDERS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    0
    3
    1
    GASTROINTESTINAL PAIN
    Additional description: GASTROINTESTINAL PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    MUCOSITIS ORAL
    Additional description: MUCOSITIS ORAL
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    NAUSEA
    Additional description: NAUSEA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    2 / 3 (66.67%)
    3 / 3 (100.00%)
    2 / 3 (66.67%)
    6 / 7 (85.71%)
         occurrences all number
    8
    7
    36
    30
    3
    32
    ORAL PAIN
    Additional description: ORAL PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    SALIVARY DUCT INFLAMMATION
    Additional description: SALIVARY DUCT INFLAMMATION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    STOMACH PAIN
    Additional description: STOMACH PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    VOMITING
    Additional description: VOMITING
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    5 / 7 (71.43%)
         occurrences all number
    2
    2
    13
    1
    2
    8
    Skin and subcutaneous tissue disorders
    DRY SKIN
    Additional description: DRY SKIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    RASH MACULO-PAPULAR
    Additional description: RASH MACULO-PAPULAR
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    SCALP PAIN
    Additional description: SCALP PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, SPECIFY
    Additional description: SKIN AND SUBCUTANEOUS TISSUE DISORDERS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
         occurrences all number
    5
    2
    0
    0
    3
    2
    Renal and urinary disorders
    CYSTITIS NONINFECTIVE
    Additional description: CYSTITIS NONINFECTIVE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    5
    2
    0
    3
    HEMATURIA
    Additional description: HEMATURIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    5
    0
    1
    RENAL AND URINARY DISORDERS - OTHER, SPECIFY
    Additional description: RENAL AND URINARY DISORDERS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    3
    1
    0
    0
    2
    URINARY FREQUENCY
    Additional description: URINARY FREQUENCY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    1
    1
    0
    0
    0
    2
    URINARY RETENTION
    Additional description: URINARY RETENTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    BACK PAIN
    Additional description: BACK PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    3 / 7 (42.86%)
         occurrences all number
    0
    2
    1
    0
    2
    4
    BONE PAIN
    Additional description: BONE PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    3
    0
    1
    1
    BUTTOCK PAIN
    Additional description: BUTTOCK PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    CHEST WALL PAIN
    Additional description: CHEST WALL PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    FLANK PAIN
    Additional description: FLANK PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    MUSCLE WEAKNESS LOWER LIMB
    Additional description: MUSCLE WEAKNESS LOWER LIMB
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER - OTHER, SPECIFY
    Additional description: MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDER - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
         occurrences all number
    2
    0
    0
    1
    6
    3
    NECK PAIN
    Additional description: NECK PAIN
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Infections and infestations
    BLADDER INFECTION
    Additional description: BLADDER INFECTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    INFECTIONS AND INFESTATIONS - OTHER, SPECIFY
    Additional description: INFECTIONS AND INFESTATIONS - OTHER, SPECIFY
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    2 / 7 (28.57%)
         occurrences all number
    2
    0
    2
    6
    4
    2
    LARYNGITIS
    Additional description: LARYNGITIS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    LUNG INFECTION
    Additional description: LUNG INFECTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    PENILE INFECTION
    Additional description: PENILE INFECTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    PHARYNGITIS
    Additional description: PHARYNGITIS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    RHINITIS INFECTIVE
    Additional description: RHINITIS INFECTIVE
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    6
    0
    0
    SINUSITIS
    Additional description: SINUSITIS
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    SKIN INFECTION
    Additional description: SKIN INFECTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    SOFT TISSUE INFECTION
    Additional description: SOFT TISSUE INFECTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    UPPER RESPIRATORY INFECTION
    Additional description: UPPER RESPIRATORY INFECTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    2
    0
    1
    URINARY TRACT INFECTION
    Additional description: URINARY TRACT INFECTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    UTERINE INFECTION
    Additional description: UTERINE INFECTION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Metabolism and nutrition disorders
    ANOREXIA
    Additional description: ANOREXIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
         occurrences all number
    2
    0
    28
    8
    2
    7
    DEHYDRATION
    Additional description: DEHYDRATION
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    HYPERGLYCEMIA
    Additional description: HYPERGLYCEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    HYPOCALCEMIA
    Additional description: HYPOCALCEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    1
    0
    1
    2
    HYPOGLYCEMIA
    Additional description: HYPOGLYCEMIA
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Apr 2015
    Protocol updated with details of intermediate dose levels to be explored, if required, during the Phase I component of the study. Clarification of the PK requirements for Phase I patients, including timings and the removal of the Day -7 single dose for PK testing from cohort 1* onwards.
    04 Apr 2016
    Protocol updated with the addition of enzalutamide as an IMP for the study. As a result of this update, an additional Phase I cohort exploring the combination of idasanutlin (RO5503781) and enzalutamide included in the study protocol.
    26 Jun 2017
    Notification that the Phase II component of the study no longer supported by our partner and therefore would not be proceeding. Additionally, clarification provided around the allowed window for study assessments and visits.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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