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    Clinical Trial Results:
    A Phase I, Open Label, Multi-centre Study of AZD2281 Administered Orally in Combination with Cisplatin, to Assess the Safety and Tolerability in Patients with Advanced Solid Tumours

    Summary
    EudraCT number
    		 2008-000062-24
    Trial protocol
    		 ES  
    Global end of trial date
    07 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Dec 2024
    First version publication date
    25 Dec 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D0810C00021
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00782574
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    151 85, Sodertalje, Sweden,
    Public contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.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
    01 Feb 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to determine the safety and tolerability of twice daily oral doses of AZD2281 when administered in combination with cisplatin to participants with advanced solid tumours.
    Protection of trial subjects
    The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Participants signed an informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Nov 2008
    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: 22
    Country: Number of subjects enrolled
    United States: 32
    Worldwide total number of subjects
    54
    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)
    48
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 4 sites in 2 countries (the United States and Spain).

    Pre-assignment
    Screening details
    		 A total of 59 participants were enrolled in the study, out of which only 54 participants received treatment. Out of 59 enrolled, four participants were incorrectly enrolled and one participant was excluded due to the investigator’s decision.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Continuous Dosing
    Arm description
    		 Participants received oral olaparib capsule 50 mg once on Study Day 1 and thereafter received combination therapy of oral olaparib capsule 50 mg twice daily (BID) and intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle. Participants continued receiving oral olaparib 50 mg BID until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle as combination therapy. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity.

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    AZD2281
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral olaparib capsule 50 mg once on Study Day 1 and thereafter twice daily (BID) as combination therapy on Day 1 (Study Day 8) of 21-day cycle until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post discontinuation of combination therapy after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Arm title
    		 Cohort 2: Continuous Dosing
    Arm description
    		 Participants received oral olaparib capsule 100 mg once on Study Day 1 and thereafter received combination therapy of oral olaparib capsule 100 mg twice daily (BID) and intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle. Participants continued receiving oral olaparib 100 mg BID until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The IV cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle as combination therapy. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity.

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    AZD2281
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral olaparib capsule 100 mg once on Study Day 1 and thereafter BID as combination therapy on Day 1 (Study Day 8) of 21-day cycle until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post discontinuation of combination therapy after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Arm title
    		 Cohort 3: Continuous Dosing
    Arm description
    		 Participants received oral olaparib capsule 200 mg once on Study Day 1 and thereafter received combination therapy of oral olaparib capsule 200 mg twice daily (BID) and intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle. Participants continued receiving oral olaparib 200 mg BID until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The IV cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle as combination therapy. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity.

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    AZD2281
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral olaparib capsule 200 mg once on Study Day 1 and thereafter BID as combination therapy on Day 1 (Study Day 8) of 21-day cycle until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post discontinuation of combination therapy after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Arm title
    		 Cohort 4: Intermittent Dosing
    Arm description
    		 Participants received oral olaparib capsule 100 mg BID on Days 1 to 10 and IV cisplatin infusion 75 mg/m^2 on Day 1 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The IV cisplatin infusion 75 mg/m^2 on Day 1 of 21-day cycle as combination therapy. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity.

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    AZD2281
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral olaparib capsule 100 mg BID on Days 1 to 10 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post discontinuation of combination therapy after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Arm title
    		 Cohort 5: Intermittent Dosing
    Arm description
    		 Participants received oral olaparib capsule 50 mg BID on Days 1 to 10 and IV cisplatin infusion 75 mg/m^2 on Day 1 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The IV cisplatin infusion 75 mg/m^2 on Day 1 of 21-day cycle as combination therapy. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity.

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    AZD2281
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral olaparib capsule 50 mg BID on Days 1 to 10 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post discontinuation of combination therapy after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Arm title
    		 Cohort 6: Intermittent Dosing
    Arm description
    		 Participants received oral olaparib capsule 50 mg BID on Days 1 to 10 and IV cisplatin infusion 60 mg/m^2 on Day 1 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The IV cisplatin infusion 60 mg/m^2 on Day 1 of 21-day cycle as combination therapy. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity.

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    AZD2281
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral olaparib capsule 50 mg BID on Days 1 to 10 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post discontinuation of combination therapy after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Number of subjects in period 1
    		Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 6: Intermittent Dosing
    Started
    3
    13
    6
    14
    6
    12
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    3
    13
    6
    14
    6
    12
         Ongoing study at data cutoff
    2
    -
    -
    1
    1
    6
         Adverse event, non-fatal
    -
    2
    2
    -
    -
    -
         Condition under investigation worsened
    1
    11
    4
    12
    5
    6
         Not specified
    -
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Continuous Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 50 mg once on Study Day 1 and thereafter received combination therapy of oral olaparib capsule 50 mg twice daily (BID) and intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle. Participants continued receiving oral olaparib 50 mg BID until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 2: Continuous Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 100 mg once on Study Day 1 and thereafter received combination therapy of oral olaparib capsule 100 mg twice daily (BID) and intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle. Participants continued receiving oral olaparib 100 mg BID until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 3: Continuous Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 200 mg once on Study Day 1 and thereafter received combination therapy of oral olaparib capsule 200 mg twice daily (BID) and intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle. Participants continued receiving oral olaparib 200 mg BID until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 4: Intermittent Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 100 mg BID on Days 1 to 10 and IV cisplatin infusion 75 mg/m^2 on Day 1 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 5: Intermittent Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 50 mg BID on Days 1 to 10 and IV cisplatin infusion 75 mg/m^2 on Day 1 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 6: Intermittent Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 50 mg BID on Days 1 to 10 and IV cisplatin infusion 60 mg/m^2 on Day 1 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 6: Intermittent Dosing Total
    Number of subjects
    		 3 13 6 14 6 12 54
    Age categorical
    Units: Participants
        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)
    		 3 12 4 13 6 10 48
        From 65-84 years
    		 0 1 2 1 0 2 6
        85 years and over
    		 0 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 50.7 ( 12.0 ) 49.2 ( 10.8 ) 53.2 ( 14.9 ) 47.7 ( 9.3 ) 49.7 ( 9.6 ) 48.3 ( 11.0 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 3 13 6 14 6 10 52
        Male
    		 0 0 0 0 0 2 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0
        Asian
    		 0 1 0 0 0 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0 0 0
        White
    		 3 12 6 14 6 12 53
        More than one race
    		 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0 0 0
        Not Hispanic or Latino
    		 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 3 13 6 14 6 12 54

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Continuous Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 50 mg once on Study Day 1 and thereafter received combination therapy of oral olaparib capsule 50 mg twice daily (BID) and intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle. Participants continued receiving oral olaparib 50 mg BID until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 2: Continuous Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 100 mg once on Study Day 1 and thereafter received combination therapy of oral olaparib capsule 100 mg twice daily (BID) and intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle. Participants continued receiving oral olaparib 100 mg BID until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 3: Continuous Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 200 mg once on Study Day 1 and thereafter received combination therapy of oral olaparib capsule 200 mg twice daily (BID) and intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle. Participants continued receiving oral olaparib 200 mg BID until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 4: Intermittent Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 100 mg BID on Days 1 to 10 and IV cisplatin infusion 75 mg/m^2 on Day 1 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 5: Intermittent Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 50 mg BID on Days 1 to 10 and IV cisplatin infusion 75 mg/m^2 on Day 1 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 6: Intermittent Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 50 mg BID on Days 1 to 10 and IV cisplatin infusion 60 mg/m^2 on Day 1 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) [1]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. Safety analysis set included all participants who received at least one dose of olaparib.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 1181 (maximum observed duration)
    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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 6: Intermittent Dosing
    Number of subjects analysed
    3
    13
    6
    14
    6
    12
    Units: Participants
        TEAEs
    3
    13
    6
    14
    6
    12
        TESAEs
    0
    3
    2
    2
    4
    5
    No statistical analyses for this end point

    Primary: Number of Participants With Clinically Significant Abnormalities in Vital Signs

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    End point title
    		 Number of Participants With Clinically Significant Abnormalities in Vital Signs [2]
    End point description
    Number of participants with clinically significant abnormalities in vital signs are reported. Clinically significant abnormal vital signs are defined as any significant abnormal finding in the vital sign parameters (blood pressure, pulse rate, and body temperature). Safety analysis set included all participants who received at least one dose of olaparib.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 1181 (maximum observed duration)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 6: Intermittent Dosing
    Number of subjects analysed
    3
    13
    6
    14
    6
    12
    Units: Participants
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs

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    End point title
    		 Number of Participants With Abnormal Electrocardiogram (ECG) Reported as TEAEs [3]
    End point description
    Number of participants with abnormal ECG reported as TEAEs are reported. Safety analysis set included all participants who received at least one dose of olaparib.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 1181 (maximum observed duration)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 6: Intermittent Dosing
    Number of subjects analysed
    3
    13
    6
    14
    6
    12
    Units: Participants
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs

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    End point title
    		 Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs [4]
    End point description
    Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported. Abnormal clinical laboratory parameters defined as any abnormal finding during analysis of haematology, clinical chemistry, and urinalysis. Safety analysis set included all participants who received at least one dose of olaparib.
    End point type
    Primary
    End point timeframe
    Day 1 through Day 1181 (maximum observed duration)
    Notes
    [4] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 6: Intermittent Dosing
    Number of subjects analysed
    3
    13
    6
    14
    6
    12
    Units: Participants
        Anaemia
    1
    6
    4
    3
    3
    3
        Hypoglobulinaemia
    0
    0
    0
    0
    0
    1
        Leukocytosis
    0
    0
    0
    1
    0
    0
        Leukopenia
    1
    6
    0
    5
    0
    0
        Lymphopenia
    1
    1
    0
    3
    0
    1
        Macrocytosis
    0
    0
    1
    0
    0
    0
        Neutropenia
    3
    5
    4
    6
    1
    3
        Thrombocytopenia
    2
    4
    3
    2
    0
    0
        Thrombocytosis
    0
    1
    0
    0
    0
    0
        Ketonuria
    1
    0
    0
    0
    0
    0
        Proteinuria
    1
    1
    0
    1
    0
    0
        Activated partial thromboplastin time prolonged
    0
    1
    0
    0
    0
    0
        Activated partial thromboplastin time shortened
    0
    1
    0
    1
    0
    0
        Alanine aminotransferase increased
    1
    3
    0
    1
    1
    3
        Aspartate aminotransferase increased
    0
    1
    0
    0
    0
    1
        Blood alkaline phosphatase increased
    2
    2
    1
    1
    0
    1
        Blood amylase increased
    1
    0
    0
    1
    0
    0
        Blood chloride decreased
    0
    0
    0
    1
    0
    0
        Blood creatinine increased
    0
    1
    0
    0
    1
    0
        Blood glucose increased
    0
    0
    0
    2
    0
    0
        Blood lactate dehydrogenase increased
    0
    3
    0
    1
    0
    0
        Blood phosphorus decreased
    0
    0
    0
    0
    0
    1
        Blood potassium decreased
    0
    0
    0
    0
    0
    1
        Blood urea increased
    0
    1
    0
    1
    0
    1
        Blood urine present
    0
    0
    0
    1
    0
    0
        Gamma-glutamyltransferase increased
    0
    3
    0
    0
    0
    1
        Globulin
    0
    1
    0
    0
    0
    0
        Globulins decreased
    0
    0
    0
    1
    0
    0
        Glucose urine
    0
    0
    0
    1
    0
    0
        Glucose urine present
    0
    0
    0
    0
    0
    1
        International normalised ratio increased
    0
    1
    0
    0
    0
    0
        Lipase
    0
    0
    0
    0
    0
    1
        Lipase increased
    0
    0
    1
    2
    0
    0
        Low density lipoprotein increased
    0
    0
    0
    1
    0
    0
        Neutrophil count decreased
    0
    1
    0
    0
    0
    1
        Neutrophil count increased
    0
    0
    0
    1
    0
    0
        Protein total decreased
    0
    0
    0
    1
    0
    0
        Protein urine present
    0
    0
    0
    2
    0
    0
        Prothrombin time prolonged
    0
    1
    0
    0
    0
    0
        Red blood cells urine
    0
    0
    0
    1
    0
    0
        Red blood cells urine positive
    0
    0
    0
    1
    0
    0
        Urinary sediment present
    0
    0
    0
    1
    0
    0
        White blood cell count decreased
    0
    0
    0
    0
    0
    1
        White blood cell count increased
    0
    2
    0
    1
    0
    1
        White blood cells urine positive
    0
    1
    0
    2
    0
    0
        Hypercholesterolaemia
    0
    1
    0
    1
    0
    0
        Hyperglycaemia
    0
    3
    1
    1
    0
    1
        Hyperkalaemia
    1
    0
    0
    0
    0
    0
        Hyperphosphataemia
    0
    1
    0
    0
    0
    0
        Hypertriglyceridaemia
    0
    1
    0
    0
    0
    0
        Hypoalbuminaemia
    0
    0
    0
    1
    0
    0
        Hypocalcaemia
    0
    0
    0
    1
    0
    0
        Hypochloraemia
    1
    0
    0
    0
    0
    1
        Hypokalaemia
    1
    0
    1
    1
    0
    0
        Hypomagnesaemia
    1
    3
    2
    1
    0
    0
        Hyponatraemia
    1
    0
    0
    1
    0
    1
        Hypophosphataemia
    0
    0
    1
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of Participants With Abnormality or Aggravation in Physical Examination

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    End point title
    		 Number of Participants With Abnormality or Aggravation in Physical Examination [5]
    End point description
    Number of participants with abnormality or aggravation in physical examination are reported. Safety analysis set included all participants who received at least one dose of olaparib.
    End point type
    Primary
    End point timeframe
    Baseline (screening), at Weeks 2, 5, and 8, every week following Week 8, and at withdrawal, and 30-day follow-up; for olaparib monotherapy on Days, 1, 43, then every 6 weeks, at olaparib discontinuation
    Notes
    [5] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 6: Intermittent Dosing
    Number of subjects analysed
    3
    13
    6
    14
    6
    12
    Units: Participants
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Objective Response by Response Evaluation Criteria in Solid Tumors (RECIST)

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    End point title
    		 Percentage of Participants With Objective Response by Response Evaluation Criteria in Solid Tumors (RECIST)
    End point description
    Objective response was defined as participants with a best response of complete response (CR) or partial response (PR) based on RECIST assessment response. The CR is defined as disappearance of all target and non-target lesions and no new lesions. The PR is defined as >=30% decrease in the sum of the diameters of target lesions compared to baseline and no new non-target lesion. Percentage of participants with objective response was reported. Full analysis set included all participants who received at least one dose of study drug. Here, number of participants analyzed denotes those participants who had target tumour at baseline and were evaluable for RECIST response. The arbitrary numbers 9.9999 and 99999 signified low and high value of confidence interval (CI) was not calculated as cohort size was less than 10.
    End point type
    Secondary
    End point timeframe
    Baseline (within 28 days pre-dose), end of every 2 cycles of treatment, at study withdrawal; for olaparib monotherapy at Weeks 9, 18, then every 12 weeks relative to Cycle 1 Day 1 of combination therapy until disease progression (approx. 15.1 years)
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 6: Intermittent Dosing
    Number of subjects analysed
    3
    12
    4
    10
    6
    11
    Units: Percentage of Participants
        number (confidence interval 95%)
    100 (9.9999 to 99999)
    0 (0.0 to 24.2)
    75.0 (9.9999 to 99999)
    50.0 (23.7 to 76.3)
    50.0 (9.9999 to 99999)
    45.5 (21.3 to 72.0)
    No statistical analyses for this end point

    Secondary: Duration of Objective Response

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    End point title
    		 Duration of Objective Response
    End point description
    Duration of objective response was defined as the time from the initial assessment prior of PR or CR (the assessment prior to being a confirmed response), until the earliest date of objective disease progression or death. The median duration of response was derived from Kaplan Meier analysis. Full analysis set included all participants who received at least one dose of study drug. The arbitrary number 999.99 signified the median was not calculated due to insufficient number to calculate. Here, number of participants analyzed denotes those participants who had objective response. Responses were still ongoing in Cohorts 1, 4, 5, and 6 at data cut-off.
    End point type
    Secondary
    End point timeframe
    Baseline (within 28 days pre-dose), end of every 2 cycles of treatment, at study withdrawal; for olaparib monotherapy at Weeks 9, 18, then every 12 weeks relative to Cycle 1 Day 1 of combination therapy until disease progression (approx. 15.1 years)
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 6: Intermittent Dosing
    Number of subjects analysed
    3
    0 [6]
    3
    5
    3
    5
    Units: Days
        median (full range (min-max))
    999.99 (88 to 1092)
    ( to )
    316 (41 to 887)
    133 (91 to 694)
    307 (179 to 388)
    162 (83 to 245)
    Notes
    [6] - Number of subjects analyzed is zero as for this cohort, zero participant had objective response.
    No statistical analyses for this end point

    Secondary: Time to Onset of Objective Response

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    End point title
    		 Time to Onset of Objective Response
    End point description
    Onset of response was defined as the time interval from first taking study drug to the assessment when CR or PR was first observed, providing it was subsequently confirmed. The median time to onset response was derived from Kaplan Meier analysis. Full analysis set included all participants who received at least one dose of study drug. Here, number of participants analyzed those participants who had objective response.
    End point type
    Secondary
    End point timeframe
    Baseline (within 28 days pre-dose), end of every 2 cycles of treatment, at study withdrawal; for olaparib monotherapy at Weeks 9, 18, then every 12 weeks relative to Cycle 1 Day 1 of combination therapy until disease progression (approx. 15.1 years)
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 6: Intermittent Dosing
    Number of subjects analysed
    3
    0 [7]
    3
    5
    3
    5
    Units: Days
        median (full range (min-max))
    128 (41 to 172)
    ( to )
    46 (35 to 48)
    49 (44 to 101)
    40 (38 to 84)
    56 (35 to 96)
    Notes
    [7] - Number of subjects analyzed is zero as for this cohort, zero participant had objective response.
    No statistical analyses for this end point

    Secondary: Best Percentage Change From Baseline in Target Lesion Size

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    End point title
    		 Best Percentage Change From Baseline in Target Lesion Size
    End point description
    The total tumor size was defined as the sum of the longest diameter of the target lesions. Best change in target lesion size is the maximum reduction from baseline or minimum increase in the absence of a reduction. The percentage change in total tumor (target lesion) size at each scheduled visit was calculated as the [(visit sum target lesions – baseline sum of target lesions)/baseline sum target lesions]*100. A negative change denotes a reduction in target lesion size. Full analysis set included all participants who received at least one dose of study drug. Here, number of participants analyzed denotes the number of participants evaluated for this outcome measure.
    End point type
    Secondary
    End point timeframe
    For combination therapy at baseline (up to 28 days prior to Study Day 1), Day 50, and at time of withdrawal; for olaparib monotherapy at Weeks 9, 18, thereafter every 12 weeks relative to Cycle 1 Day 1 of combination therapy until disease progression
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 6: Intermittent Dosing
    Number of subjects analysed
    3
    12
    4
    10
    6
    11
    Units: Percent Change in Lesion Size
        arithmetic mean (standard deviation)
    -56.9 ( 16.34 )
    -6.1 ( 21.95 )
    -52.2 ( 31.21 )
    -32.5 ( 27.32 )
    -39.3 ( 29.48 )
    -21.0 ( 36.94 )
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Olaparib

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    End point title
    		 Plasma Concentration of Olaparib [8]
    End point description
    Plasma concentration of olaparib at Visit (V) 2 (Study Day 1) and 3 (Study Day 8) is reported. Pharmacokinetic (PK) analysis set included subset of safety analysis set including participants who had reportable PK data for olaparib both alone at Visit 2 and in combination with cisplatin at Visit 3. Number analyzed (n) denotes those participants who were evaluable at the specified time point. The arbitrary numbers 9.9999 and 99999 signified geometric mean and geometric CV%, respectively, not reported as the geometric mean and geometric CV% were not calculated due to insufficient number to calculate.
    End point type
    Secondary
    End point timeframe
    Predose, 1, 2, 3, 4, 6, 8, and 12 hours post dose on V2 (Study Day 1) and V3 (Study Day 8)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing
    Number of subjects analysed
    3
    12
    6
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        V2: 1 hour (n=3,12,6)
    0.591 ( 176.200 )
    1.404 ( 198.200 )
    1.640 ( 86.440 )
        V2: 2 hours (n=3,12,6)
    1.168 ( 150.200 )
    2.439 ( 91.100 )
    3.080 ( 29.990 )
        V2: 3 hours (n=3,12,6)
    0.669 ( 169.400 )
    2.213 ( 104.400 )
    2.769 ( 36.610 )
        V2: 4 hours (n=3,12,6)
    0.430 ( 161.500 )
    1.864 ( 128.200 )
    2.113 ( 47.280 )
        V2: 6 hours (n=3,12,6)
    0.222 ( 110.300 )
    1.208 ( 176.200 )
    1.277 ( 54.360 )
        V2: 8 hours (n=3,12,6)
    0.117 ( 111.100 )
    0.754 ( 200.400 )
    0.771 ( 45.770 )
        V2: 12 hours (n=3,11,6)
    0.057 ( 123.900 )
    0.451 ( 197.500 )
    0.455 ( 41.040 )
        V3: 1 hour (n=3,11,6)
    2.895 ( 26.430 )
    1.607 ( 133.800 )
    1.481 ( 136.600 )
        V3: 2 hours (n=3,12,6)
    1.059 ( 71.460 )
    2.349 ( 81.450 )
    2.546 ( 36.230 )
        V3: 3 hours (n=3,12,6)
    0.738 ( 123.900 )
    2.376 ( 102.800 )
    2.321 ( 40.360 )
        V3: 4 hours (n=3,12,6)
    0.502 ( 158.300 )
    1.921 ( 125.900 )
    1.836 ( 44.910 )
        V3: 6 hours (n=3,12,6)
    0.250 ( 210.700 )
    1.400 ( 162.300 )
    1.130 ( 59.780 )
        V3: 8 hours (n=3,11,6)
    0.163 ( 287.500 )
    0.889 ( 218.100 )
    0.670 ( 70.100 )
        V3: 12 hours (n=2,12,5)
    9.9999 ( 99999 )
    0.629 ( 254.300 )
    0.356 ( 99.260 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax) of Olaparib

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    End point title
    		 Maximum Observed Concentration (Cmax) of Olaparib [9]
    End point description
    The Cmax of olaparib at V2 (Study Day 1) and V3 (Study Day 8) is reported. The PK analysis set included subset of safety analysis set including participants who had reportable PK data for olaparib both alone at V2 and in combination with cisplatin at V3.
    End point type
    Secondary
    End point timeframe
    Predose, 1, 2, 3, 4, 6, 8, and 12 hours post dose on V2 (Study Day 1) and V3 (Study Day 8)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing
    Number of subjects analysed
    3
    12
    6
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        V2
    1.581 ( 117.900 )
    3.272 ( 56.600 )
    3.557 ( 13.620 )
        V3
    2.895 ( 26.430 )
    3.185 ( 68.180 )
    3.020 ( 37.560 )
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Serum Concentration (Tmax) of Olaparib

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    End point title
    		 Time to Reach Maximum Observed Serum Concentration (Tmax) of Olaparib [10]
    End point description
    The Tmax of olaparib at V2 (Study Day 1) and V3 (Study Day 8) is reported. The PK analysis set included subset of safety analysis set including participants who had reportable PK data for olaparib both alone at V2 and in combination with cisplatin at V3.
    End point type
    Secondary
    End point timeframe
    Predose, 1, 2, 3, 4, 6, 8, and 12 hours post dose on V2 (Study Day 1) and V3 (Study Day 8)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing
    Number of subjects analysed
    3
    12
    6
    Units: Hour
    median (full range (min-max))
        V2
    1.000 (1.000 to 2.000)
    2.000 (1.000 to 4.000)
    2.000 (1.000 to 3.000)
        V3
    1.000 (1.000 to 1.000)
    2.000 (1.000 to 6.000)
    1.500 (1.000 to 3.000)
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Olaparib

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    End point title
    		 Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Olaparib [11]
    End point description
    The AUC0-t of olaparib at V2 (Study Day 1) and V3 (Study Day 8) is reported. The PK analysis set included subset of safety analysis set including participants who had reportable PK data for olaparib both alone at V2 and in combination with cisplatin at V3.
    End point type
    Secondary
    End point timeframe
    Predose, 1, 2, 3, 4, 6, 8, and 12 hours post dose on V2 (Study Day 1) and V3 (Study Day 8)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only those baseline period arms for which analysis was planned were reported in the end point.
    End point values
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 3: Continuous Dosing
    Number of subjects analysed
    3
    12
    6
    Units: μg.h/mL
    geometric mean (geometric coefficient of variation)
        V2
    4.433 ( 109.800 )
    15.310 ( 103.500 )
    16.520 ( 25.470 )
        V3
    7.401 ( 40.560 )
    16.210 ( 113.600 )
    14.380 ( 35.230 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 through Day 1181 (maximum observed duration)
    Adverse event reporting additional description
    Safety analysis set included all participants who received at least one dose of olaparib.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Cohort 1: Continuous Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 50 mg once on Study Day 1 and thereafter received combination therapy of oral olaparib capsule 50 mg twice daily (BID) and intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle. Participants continued receiving oral olaparib 50 mg BID until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 2: Continuous Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 100 mg once on Study Day 1 and thereafter received combination therapy of oral olaparib capsule 100 mg twice daily (BID) and intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle. Participants continued receiving oral olaparib 100 mg BID until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 6: Intermittent Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 50 mg BID on Days 1 to 10 and IV cisplatin infusion 60 mg/m^2 on Day 1 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 4: Intermittent Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 100 mg BID on Days 1 to 10 and IV cisplatin infusion 75 mg/m^2 on Day 1 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 5: Intermittent Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 50 mg BID on Days 1 to 10 and IV cisplatin infusion 75 mg/m^2 on Day 1 of 21-day cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Reporting group title
    Cohort 3: Continuous Dosing
    Reporting group description
    		 Participants received oral olaparib capsule 200 mg once on Study Day 1 and thereafter received combination therapy of oral olaparib capsule 200 mg twice daily (BID) and intravenous (IV) cisplatin infusion 75 mg/m^2 on Day 1 (Study Day 8) of 21-day cycle. Participants continued receiving oral olaparib 200 mg BID until Day 21 of the cycle. Participants continued receiving combination therapy until Cycle 6 or until they received benefit and were free from significant toxicity. Post cisplatin discontinuation after Cycle 6, participants continued receiving oral olaparib capsule 400 mg BID (monotherapy phase) at the investigator’s discretion until participants received benefit or not met disease progression or any other discontinuation criteria.

    Serious adverse events
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 6: Intermittent Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 3: Continuous Dosing
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    5 / 12 (41.67%)
    2 / 14 (14.29%)
    4 / 6 (66.67%)
    2 / 6 (33.33%)
         number of deaths (all causes)
    0
    1
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    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
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (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
    Neuralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (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
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (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
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 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 / 13 (0.00%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (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
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (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
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    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
    Renal vein thrombosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (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
    Bronchitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    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
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    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
    Device related infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (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
    Metabolism and nutrition disorders
    Electrolyte imbalance
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    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
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    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
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1: Continuous Dosing Cohort 2: Continuous Dosing Cohort 6: Intermittent Dosing Cohort 4: Intermittent Dosing Cohort 5: Intermittent Dosing Cohort 3: Continuous Dosing
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    13 / 13 (100.00%)
    12 / 12 (100.00%)
    14 / 14 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant muscle neoplasm
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Tumour associated fever
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hot flush
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    2
    1
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Lymphoedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    1
    1
    3
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Asthenia
         subjects affected / exposed
    1 / 3 (33.33%)
    6 / 13 (46.15%)
    2 / 12 (16.67%)
    6 / 14 (42.86%)
    4 / 6 (66.67%)
    3 / 6 (50.00%)
         occurrences all number
    1
    10
    7
    17
    14
    17
    Atrophy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Axillary pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 3 (66.67%)
    6 / 13 (46.15%)
    7 / 12 (58.33%)
    5 / 14 (35.71%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
         occurrences all number
    2
    6
    7
    6
    1
    4
    Feeling jittery
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    1
    2
    0
    2
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    0
    Thrombosis in device
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    0
    Breast discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    4 / 12 (33.33%)
    4 / 14 (28.57%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    4
    5
    2
    0
    Bronchial secretion retention
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 13 (15.38%)
    1 / 12 (8.33%)
    2 / 14 (14.29%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    1
    2
    2
    1
    Hypoxia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    2
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    4 / 12 (33.33%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    4
    2
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pneumothorax
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pleuritic pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pharyngeal inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Orthopnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    1
    1
    0
    1
    Wheezing
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nightmare
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nervousness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    2 / 12 (16.67%)
    5 / 14 (35.71%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    2
    5
    2
    4
    Depression
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    3
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    2
    1
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 13 (23.08%)
    3 / 12 (25.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    3
    2
    1
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Activated partial thromboplastin time shortened
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Bacterial test
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Bacterial test positive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 13 (15.38%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    2
    1
    1
    0
    1
    Blood amylase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Blood chloride decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood urine present
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    6
    0
    1
    0
    0
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood urea increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    1
    0
    0
    0
    Globulin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Globulins decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Glucose urine
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Glucose urine present
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Lipase
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Low density lipoprotein increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Protein total decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Red blood cells urine
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    1
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    Urinary sediment present
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Red blood cells urine positive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Protein urine present
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Foot fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Humerus fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Thermal burn
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Tooth injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Urinary anastomotic leak
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Sunburn
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Hyperaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 13 (7.69%)
    4 / 12 (33.33%)
    4 / 14 (28.57%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
         occurrences all number
    1
    1
    6
    6
    4
    4
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    3 / 12 (25.00%)
    5 / 14 (35.71%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    6
    8
    3
    2
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 13 (30.77%)
    2 / 12 (16.67%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    0
    5
    2
    0
    1
    3
    Disturbance in attention
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Coordination abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Burning sensation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Amnesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Aphasia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Neurotoxicity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    3
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    2
    3
    0
    1
    Post-traumatic headache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hypokinesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 13 (7.69%)
    3 / 12 (25.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    3
    1
    1
    0
    Sinus headache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Tension headache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 13 (30.77%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    0
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    6 / 13 (46.15%)
    3 / 12 (25.00%)
    3 / 14 (21.43%)
    3 / 6 (50.00%)
    4 / 6 (66.67%)
         occurrences all number
    1
    7
    3
    3
    3
    4
    Leukopenia
         subjects affected / exposed
    1 / 3 (33.33%)
    6 / 13 (46.15%)
    0 / 12 (0.00%)
    5 / 14 (35.71%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    7
    0
    5
    0
    0
    Leukocytosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hypoglobulinaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Lymphopenia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    1
    3
    0
    0
    Macrocytosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Neutropenia
         subjects affected / exposed
    3 / 3 (100.00%)
    5 / 13 (38.46%)
    3 / 12 (25.00%)
    6 / 14 (42.86%)
    1 / 6 (16.67%)
    4 / 6 (66.67%)
         occurrences all number
    3
    5
    4
    6
    1
    4
    Thrombocytopenia
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 13 (23.08%)
    0 / 12 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    2
    3
    0
    2
    0
    3
    Thrombocytosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Ear and labyrinth disorders
    Ototoxicity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    Deafness
         subjects affected / exposed
    3 / 3 (100.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    3
    1
    1
    2
    0
    2
    Deafness unilateral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Ear pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Hearing impaired
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 13 (30.77%)
    4 / 12 (33.33%)
    7 / 14 (50.00%)
    3 / 6 (50.00%)
    4 / 6 (66.67%)
         occurrences all number
    1
    4
    9
    10
    5
    4
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Eye pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Miosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Scotoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Macular degeneration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    Abdominal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    2 / 12 (16.67%)
    2 / 14 (14.29%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    4
    2
    3
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 13 (15.38%)
    1 / 12 (8.33%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    2
    3
    2
    0
    2
    Aerophagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Anal pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ascites
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Constipation
         subjects affected / exposed
    1 / 3 (33.33%)
    7 / 13 (53.85%)
    7 / 12 (58.33%)
    5 / 14 (35.71%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
         occurrences all number
    1
    9
    12
    6
    2
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    3 / 14 (21.43%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    4
    2
    1
    Dysphagia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    0
    1
    1
    2
    Gastric ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 13 (30.77%)
    6 / 12 (50.00%)
    4 / 14 (28.57%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    4
    11
    5
    4
    1
    Gingival pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Glossodynia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    2 / 3 (66.67%)
    9 / 13 (69.23%)
    9 / 12 (75.00%)
    12 / 14 (85.71%)
    4 / 6 (66.67%)
    4 / 6 (66.67%)
         occurrences all number
    2
    16
    16
    23
    18
    13
    Oral pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Pancreatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 3 (66.67%)
    8 / 13 (61.54%)
    4 / 12 (33.33%)
    7 / 14 (50.00%)
    4 / 6 (66.67%)
    2 / 6 (33.33%)
         occurrences all number
    2
    14
    9
    12
    10
    2
    Stomatitis
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    2 / 12 (16.67%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    2
    1
    0
    0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    3 / 12 (25.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    3
    2
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    2 / 12 (16.67%)
    2 / 14 (14.29%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    2
    2
    3
    0
    Onychoclasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Erythema nodosum
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cold sweat
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    Ecchymosis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    3
    1
    0
    Swelling face
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    3
    1
    0
    Rash papular
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Nephropathy toxic
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    Ketonuria
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    0
    Bladder pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nocturia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    1 / 12 (8.33%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    3
    1
    1
    Arthralgia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    3 / 12 (25.00%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    4
    3
    0
    2
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 13 (15.38%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    0
    1
    3
    1
    Pain in extremity
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    3
    0
    0
    Neck pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    2
    1
    0
    Myalgia
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
         occurrences all number
    3
    0
    0
    0
    2
    2
    Musculoskeletal pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    2 / 14 (14.29%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    1
    3
    2
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 13 (30.77%)
    0 / 12 (0.00%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
         occurrences all number
    0
    4
    0
    4
    1
    2
    Muscular weakness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Muscle contracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Groin pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pain in jaw
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Tendon pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Cystitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Infected bites
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    2
    2
    3
    2
    Onychomycosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    2
    0
    Herpes zoster
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 3 (33.33%)
    5 / 13 (38.46%)
    2 / 12 (16.67%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    4
    5
    3
    3
    2
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    3 / 12 (25.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    3
    2
    0
    2
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 13 (53.85%)
    3 / 12 (25.00%)
    2 / 14 (14.29%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
         occurrences all number
    0
    9
    5
    3
    2
    2
    Acidosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 13 (23.08%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    5
    0
    1
    0
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    Hypochloraemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 13 (0.00%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 13 (23.08%)
    1 / 12 (8.33%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    5
    1
    1
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Gout
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 13 (7.69%)
    0 / 12 (0.00%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 13 (0.00%)
    1 / 12 (8.33%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2008
    Added inclusion criteria # 2 and 7; creatinine clearance and histological confirmation of metastatic cancer, Management of toxicity due to cisplatin: additional paragraph entitled ototoxicity and clarifications to other paragraphs.
    27 May 2009
    Synopsis/Section 4.1.1.1 of clinical study protocol (CSP): study design/stopping criteria for dose escalation (Part A/Phase I): additional details on the last cohort; once the desired doses or maximum tolerated dose (MTD) of the combination therapy had been determined (or the highest dose level had been explored) the cohort was expanded to a minimum of 6 participants and a maximum of 12 participants in order to ensure that there were 6 evaluable participants who had completed 4 cycles of treatment. Synopsis/Sections 4.1.1 and 4.4.6.2 of CSP and Section 5.1.5.3 of clinical study report (CSR): duration of treatment; olaparib monotherapy dose (Synopsis of CSP). Sections 4.4.3 and 4.4.5 of CSP and Section 5.3.1 of CSR: Exclusion criteria, # 7, # 16; pregnancy exclusion and prior use of any polyadenosine 5’-diphosphoribose polymerase (PARP) inhibitor and section on contraception. Sections 4.5.2.2 and 4.4.5 of CSP and Section 5.4.2.2 of CSR; cisplatin preparation. Sections 4.5.4 of CSP and Section 5.4.2.2 of CSR; management of toxicity due to cisplatin. Section 7.5.2 of CSP and Section 5.1.1 of CSR; description of variables in relation to hypotheses.
    29 Oct 2009
    Synopsis of CSP: Study Design, Table 2, Figure 2, Part A/Phase I; addition of a new intermittent dosing schedule in Part A/Phase I. Section 4.5.3 of the CSP: management of toxicity; the management of toxicity and additional management for intermittent dose schedule. Synopsis of CSP and page 88 of CSP: Study centre(s), type and number of participants planned; an increase in maximum number of participants in Part A/Phase I. Synopsis of CSP and page 88, Section 4.1.4 of CSP: Study centre(s), type and number of participants planned; reduction of participant number in Part B/ Phase II.
    01 Jul 2010
    Synopsis of CSP: study centre(s), type and number of participants planned; removal of the Phase II/Part B part of the study - Triple Negative Breast Cancer part of the study. Section 6.5 of CSP: duration of treatment; increase in timelines of the study. Synopsis of CSP/Figure 3: addition of further participant cohorts to explore intermittent dosing schedules. Synopsis of CSP/Section 4.1 overall study design: increase in the number of participants in the Phase I/Part A part of the study; increased to 60 participants. Synopsis of CSP/Study Design: reduction in the overall number of sites. Removal of the Central nervous system function from baseline assessments. Section 4.1.3 of the CSP: maximum tolerated dose; allowed for exploration of different combination dosing regimens to provide a tolerated dose of Olaparib combined with cisplatin which can be investigated in further studies, however the highest dose explored was set as 400 mg BID (the MTD established in a monotherapy Phase I study). Sections 4.5.3.2, 4.5.3.4, 4.5.3.4.1, 4.5.3.7, and 4.5.3.5 of CSP: management of neutropenic events and non-haematological toxicity attributable to olaparib; clarification on the management of toxicity and additional management for intermittent dose schedule.
    11 Mar 2011
    Clarifications to Amendment 4 affecting several sections of CSP: Amendment 4 was written to allow an initial dose level option of olaparib with a reduced dose of cisplatin at 60 mg/m^2 (Further reductions of cisplatin due to toxicity needed to be clarified for participants that started on the low dose cisplatin dosing schedule.)
    06 Jan 2012
    Removal of Appendices related to study design that are not required after Amendment 4, renumbering of appendices, and addition of Appendix C i.e. an AstraZeneca standard to be included in protocols (List of Appendices). Inclusion of breast cancer antigen (BRCA) mutation status as part of screening assessment. Added a separate table to detail assessments and visit schedule when a participant moves to olaparib monotherapy. Added details of olaparib monotherapy in case cisplatin was discontinued due to cisplatin related toxicity. Expansion and clarification of list of allowed concomitant medications to include anticoagulant therapy and anti-emetics, and clarification on use of granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin. Clarified that live virus and bacterial vaccines should not be administered while receiving study medication and during 30-day follow-up period and further expanded list of prohibited medications with clarifications. Updated information on laboratory safety measurements to specify which measurements will be performed. Section on adverse events modified and updated. Clarification to range of absolute neutrophil count (ANC) in management of neutropenic events. Updates to section on ethics review in accordance with the current guidelines followed by AstraZeneca on ethical conduct of study and following regulatory guidelines. Updated guidelines in obtaining informed consent to clarify that any incentives to participants as well as provisions for participants harmed as consequence of study participation are described in the informed consent form (ICF). Added sections on procedures in case pregnancy, related to maternal and paternal exposure and updated section on procedures in case of overdose. Change in information on identity of investigational product to clarify that olaparib was manufactured by Patheon Inc on behalf of AstraZeneca.

    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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