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    Clinical Trial Results:
    A Phase III Randomized Clinical Trial of Pembrolizumab (MK-3475) versus Paclitaxel, Docetaxel or Vinflunine in Subjects with Recurrent or Progressive Metastatic Urothelial Cancer

    Summary
    EudraCT number
    2014-002009-40
    Trial protocol
    BE   IE   IT   DE   ES   HU   AT   NL   SE   DK   GB   PT   FR   PL  
    Global end of trial date
    01 Oct 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Oct 2021
    First version publication date
    07 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3475-045
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02256436
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Merck Protocol Number: MK-3475-045
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Participants with metastatic or locally advanced/unresectable urothelial cancer that has recurred or progressed following platinum-based chemotherapy will be randomly assigned to receive Investigator's choice of paclitaxel, docetaxel, or vinflunine (Control), or pembrolizumab. The primary study hypotheses are that pembrolizumab will prolong Overall Survival (OS) and Progression-free Survival (PFS) compared to paclitaxel, docetaxel, or vinflunine.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    Denmark: 19
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Israel: 40
    Country: Number of subjects enrolled
    Italy: 36
    Country: Number of subjects enrolled
    Japan: 52
    Country: Number of subjects enrolled
    Korea, Republic of: 31
    Country: Number of subjects enrolled
    Netherlands: 29
    Country: Number of subjects enrolled
    New Zealand: 4
    Country: Number of subjects enrolled
    Norway: 6
    Country: Number of subjects enrolled
    Peru: 2
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Singapore: 7
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Taiwan: 23
    Country: Number of subjects enrolled
    Turkey: 13
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 106
    Worldwide total number of subjects
    542
    EEA total number of subjects
    219
    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)
    230
    From 65 to 84 years
    306
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    13 participants randomized to receive Control switched over to receive Pembrolizumab. Per protocol, response/progression or adverse events that occurred during a non-randomized switch-over or second course of pembrolizumab were not counted towards efficacy or safety outcome measures, respectively. These results are for randomized treatment only.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Control
    Arm description
    Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).
    Arm type
    Active comparator

    Investigational medicinal product name
    paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    175 mg/m^2 IV on Day 1 Q3W

    Investigational medicinal product name
    docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m^2 IV on Day 1 Q3W

    Investigational medicinal product name
    vinflunine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    320 mg/m^2 IV on Day 1 Q3W

    Arm title
    Pembrolizumab
    Arm description
    Participants received pembrolizumab 200 mg IV on Day 1 Q3W. Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).
    Arm type
    Experimental

    Investigational medicinal product name
    pembrolizumab
    Investigational medicinal product code
    Other name
    KEYTRUDA®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    200 mg IV on Day 1 Q3W.

    Number of subjects in period 1
    Control Pembrolizumab
    Started
    272
    270
    Treated
    255
    266
    Switched Over to Pembrolizumab
    13
    0
    Completed
    0
    0
    Not completed
    272
    270
         Protocol deviation
    -
    1
         Physician decision
    1
    -
         Did Not Continue on Extension Study
    8
    12
         Adverse event, serious fatal
    216
    208
         Transferred to Extension Study
    11
    23
         Adverse event, non-fatal
    9
    14
         Consent withdrawn by subject
    26
    10
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control
    Reporting group description
    Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).

    Reporting group title
    Pembrolizumab
    Reporting group description
    Participants received pembrolizumab 200 mg IV on Day 1 Q3W. Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).

    Reporting group values
    Control Pembrolizumab Total
    Number of subjects
    272 270 542
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    125 105 230
        Elderly (From 65-84 years)
    147 159 306
        Elderly 85 years and over
    0 6 6
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    65.1 ± 9.2 66.0 ± 10.2 -
    Sex: Female, Male
    Units:
        Female
    70 70 140
        Male
    202 200 402

    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    Participants received paclitaxel 175 mg/m^2 intravenously (IV) or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).

    Reporting group title
    Pembrolizumab
    Reporting group description
    Participants received pembrolizumab 200 mg IV on Day 1 Q3W. Eligible participants who stopped pembrolizumab with Stable Disease (SD) or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).

    Primary: Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - All Participants

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    End point title
    Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) - All Participants
    End point description
    PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. The PFS per RECIST 1.1 was assessed by blinded independent central review (BICR) in all participants up through the primary analysis database cut-off date of 07-Sep-2016. The analysis population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    272
    270
    Units: Months
        median (confidence interval 95%)
    3.3 (2.3 to 3.5)
    2.1 (2.0 to 2.2)
    Statistical analysis title
    PFS - All Participants
    Comparison groups
    Pembrolizumab v Control
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    [1]
    P-value
    = 0.41648 [2]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.19
    Notes
    [1] - Treatment as a covariate stratified by Eastern Cooperative Oncology Group Performance Status (ECOG PS), presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [2] - One-sided p-value based on stratified log-rank test

    Primary: Overall Survival (OS) - All Participants

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    End point title
    Overall Survival (OS) - All Participants
    End point description
    OS was defined as the time from randomization to death due to any cause. The OS was assessed in all participants up through the primary analysis database cut-off date of 07-Sep-2016. The analysis population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    272
    270
    Units: Months
        median (confidence interval 95%)
    7.4 (6.1 to 8.3)
    10.3 (8.0 to 11.8)
    Statistical analysis title
    OS - All Participants
    Comparison groups
    Pembrolizumab v Control
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    [3]
    P-value
    = 0.00224 [4]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    0.91
    Notes
    [3] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [4] - One-sided p-value based on stratified log-rank test

    Primary: PFS per RECIST 1.1 - Participants with Programmed Cell Death-Ligand (PD-L1) Positive Tumors

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    End point title
    PFS per RECIST 1.1 - Participants with Programmed Cell Death-Ligand (PD-L1) Positive Tumors
    End point description
    PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. PFS per RECIST 1.1 was assessed by BICR in all participants who had PD-L1 positive tumors (combined positive score [CPS] ≥1%) up through the primary analysis database cut-off date of 07-Sep-2016. The analysis population consisted of all randomized PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    120
    110
    Units: Months
        median (confidence interval 95%)
    3.2 (2.2 to 3.4)
    2.1 (2.0 to 2.4)
    Statistical analysis title
    PFS - PD-L1 positive participants
    Comparison groups
    Pembrolizumab v Control
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    [5]
    P-value
    = 0.26443 [6]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    1.24
    Notes
    [5] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [6] - One-sided p-value based on stratified log-rank test

    Primary: OS - Participants with PD-L1 Positive Tumors

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    End point title
    OS - Participants with PD-L1 Positive Tumors
    End point description
    OS was defined as the time from randomization to death due to any cause. For the purposes of this study, participants with PD-L1 CPS ≥1% were considered to have a PD-L1 positive tumor status. OS was assessed in all participants who had PD-L1 positive tumors (CPS ≥1%) up through the primary analysis database cut-off date of 07-Sep-2016. The analysis population consisted of all randomized PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    120
    110
    Units: Months
        median (confidence interval 95%)
    6.9 (4.7 to 8.8)
    11.3 (7.7 to 16.0)
    Statistical analysis title
    OS - PD-L1 positive participants
    Comparison groups
    Pembrolizumab v Control
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    [7]
    P-value
    = 0.00239 [8]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    0.86
    Notes
    [7] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [8] - One-sided p-value based on stratified log-rank test

    Primary: PFS per RECIST 1.1 - Participants with Strongly PD-L1 Positive Tumors

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    End point title
    PFS per RECIST 1.1 - Participants with Strongly PD-L1 Positive Tumors
    End point description
    PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. PFS per RECIST 1.1 was assessed by BICR in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) up through the primary analysis database cut-off date of 07-Sep-2016. The analysis population consisted of all randomized strongly PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    90
    74
    Units: Months
        median (confidence interval 95%)
    3.1 (2.2 to 3.4)
    2.1 (1.9 to 2.1)
    Statistical analysis title
    PFS - Strongly PD-L1 positive participants
    Comparison groups
    Pembrolizumab v Control
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    [9]
    P-value
    = 0.23958 [10]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.28
    Notes
    [9] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [10] - One-sided p-value based on stratified log-rank test

    Primary: OS - Participants with Strongly PD-L1 Positive Tumors

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    End point title
    OS - Participants with Strongly PD-L1 Positive Tumors
    End point description
    OS was defined as the time from randomization to death due to any cause. For the purposes of this study, participants with a PD-L1 CPS ≥10% were considered to have a strongly PD-L1 positive tumor status. The OS was assessed in all participants who had strongly PD-L1 positive tumors (CPS ≥10%) up through the primary analysis database cut-off date of 07-Sep-2016. The analysis population consisted of all randomized strongly PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.
    End point type
    Primary
    End point timeframe
    Through primary analysis database cut-off date of 07-Sep-2016 (Up to approximately 20 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    90
    74
    Units: Months
        median (confidence interval 95%)
    5.2 (4.0 to 7.4)
    8.0 (5.0 to 12.3)
    Statistical analysis title
    OS - Strongly PD-L1 positive participants
    Comparison groups
    Pembrolizumab v Control
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    [11]
    P-value
    = 0.00483 [12]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.37
         upper limit
    0.88
    Notes
    [11] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [12] - One-sided p-value based on stratified log-rank test

    Secondary: Number of Participants Who Experienced an Adverse Event (AE)

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    End point title
    Number of Participants Who Experienced an Adverse Event (AE)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. Participants were monitored for the occurrence of nonserious AEs for up to 30 days after last dose of study treatment and for serious AEs for up to 90 days after last dose of study treatment. The number of participants who experienced an AE was reported for each arm. The analysis population consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    255
    266
    Units: Participants
    250
    250
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Study Treatment Due to an AE

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    End point title
    Number of Participants Who Discontinued Study Treatment Due to an AE
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. Participants were monitored for the occurrence of nonserious AEs for up to 30 days after last dose of study treatment and for serious AEs for up to 90 days after last dose of study treatment. The number of participants who discontinued study treatment due to an AE was reported for each arm. The analysis population consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    255
    266
    Units: Participants
    36
    28
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) per RECIST 1.1 - Participants with Strongly PD-L1 Positive Tumors

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    End point title
    Objective Response Rate (ORR) per RECIST 1.1 - Participants with Strongly PD-L1 Positive Tumors
    End point description
    ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by BICR in participants with strongly PD-L1 positive tumors (CPS ≥10%) up through the final analysis database cut-off date of 26-Oct-2017. The analysis population consisted of all randomized strongly PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    90
    74
    Units: Percentage of Participants
        number (confidence interval 95%)
    6.7 (2.5 to 13.9)
    20.3 (11.8 to 31.2)
    Statistical analysis title
    ORR per RECIST 1.1 - Strongly PD-L1 Positive Pts
    Comparison groups
    Control v Pembrolizumab
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    [13]
    P-value
    = 0.00061 [14]
    Method
    Miettinen & Nurminen method
    Parameter type
    Difference in Percentages
    Point estimate
    17.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.8
         upper limit
    29.4
    Notes
    [13] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [14] - One-sided p-value for testing H0: difference in %=0; H1: difference in %>0

    Secondary: ORR per RECIST 1.1 - Participants with PD-L1 Positive Tumors

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    End point title
    ORR per RECIST 1.1 - Participants with PD-L1 Positive Tumors
    End point description
    ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by BICR in participants with PD-L1 positive tumors (CPS ≥1%) up through the final analysis database cut-off date of 26-Oct-2017. The analysis population consisted of all randomized PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    120
    110
    Units: Percentage of Participants
        number (confidence interval 95%)
    8.3 (4.1 to 14.8)
    22.7 (15.3 to 31.7)
    Statistical analysis title
    ORR per RECIST 1.1 - PD-L1 Positive Participants
    Comparison groups
    Control v Pembrolizumab
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    [15]
    P-value
    = 0.00049 [16]
    Method
    Miettinen & Nurminen method
    Parameter type
    Difference in Percentages
    Point estimate
    15.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.5
         upper limit
    25.7
    Notes
    [15] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [16] - One-sided p-value for testing H0: difference in %=0; H1: difference in %>0

    Secondary: ORR Per RECIST 1.1 - All Participants

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    End point title
    ORR Per RECIST 1.1 - All Participants
    End point description
    ORR was defined as the percentage of participants in the analysis population who had a CR (disappearance of all target lesions) or a PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. ORR was assessed by BICR in all participants up through the final analysis database cut-off date of 26-Oct-2017. The analysis population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    272
    270
    Units: Percentage of Participants
        number (confidence interval 95%)
    11.0 (7.6 to 15.4)
    21.1 (16.4 to 26.5)
    Statistical analysis title
    ORR per RECIST 1.1 - All Participants
    Comparison groups
    Control v Pembrolizumab
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    [17]
    P-value
    = 0.00068 [18]
    Method
    Miettinen & Nurminen method
    Parameter type
    Difference in Percentages
    Point estimate
    10
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.9
         upper limit
    16.2
    Notes
    [17] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [18] - One-sided p-value for testing H0: difference in %=0; H1: difference in %>0

    Secondary: PFS per Modified RECIST (mRECIST) - Participants with Strongly PD-L1 Positive Tumors

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    End point title
    PFS per Modified RECIST (mRECIST) - Participants with Strongly PD-L1 Positive Tumors
    End point description
    PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per mRECIST, PD was defined as at least 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Per mRECIST, confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required for participants remaining on treatment following PD per RECIST 1.1. PFS per mRECIST was assessed by BICR in participants with strongly PD-L1 positive tumors (CPS ≥10%) up through the final analysis database cut-off date of 26-Oct-2017. All randomized strongly PD-L1 positive participants [Pts] were analysed, according to the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    90
    74
    Units: Months
        median (confidence interval 95%)
    3.3 (2.4 to 3.7)
    2.1 (2.0 to 3.7)
    Statistical analysis title
    PFS per mRECIST - Strongly PD-L1 Positive Pts
    Comparison groups
    Control v Pembrolizumab
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    [19]
    P-value
    = 0.07066 [20]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    1.11
    Notes
    [19] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [20] - One-sided p-value based on stratified log-rank test

    Secondary: PFS per mRECIST - Participants with PD-L1 Positive Tumors

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    End point title
    PFS per mRECIST - Participants with PD-L1 Positive Tumors
    End point description
    PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per mRECIST, PD was defined as at least 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Per mRECIST, confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required for participants remaining on treatment following PD per RECIST 1.1. PFS per mRECIST was assessed by BICR in participants with PD-L1 positive tumors (CPS ≥1%) up through the final analysis database cut-off date of 26-Oct-2017. All randomized PD-L1 positive participants were analysed, according to the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    120
    110
    Units: Months
        median (confidence interval 95%)
    3.3 (2.6 to 3.6)
    2.1 (2.0 to 3.7)
    Statistical analysis title
    PFS per mRECIST - PD-L1 Positive Participants
    Comparison groups
    Control v Pembrolizumab
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    [21]
    P-value
    = 0.08745 [22]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.1
    Notes
    [21] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [22] - One-sided p-value based on stratified log-rank test

    Secondary: PFS per mRECIST - All Participants

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    End point title
    PFS per mRECIST - All Participants
    End point description
    PFS was defined as the time from randomization to the first documented disease progression, or death due to any cause, whichever occurred first. Per mRECIST, PD was defined as at least 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered PD. Per mRECIST, confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented was required for participants remaining on treatment following PD per RECIST 1.1. PFS per mRECIST was assessed by BICR in all randomized participants up through the final analysis database cut-off date of 26-Oct-2017. All randomized participants were analysed, according to the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    272
    270
    Units: Months
        median (confidence interval 95%)
    3.4 (3.1 to 3.8)
    2.2 (2.1 to 3.3)
    Statistical analysis title
    PFS per mRECIST - All Participants
    Comparison groups
    Control v Pembrolizumab
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    [23]
    P-value
    = 0.05328 [24]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.04
    Notes
    [23] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [24] - One-sided p-value based on stratified log-rank test

    Secondary: ORR per mRECIST - Participants with Strongly PD-L1 Positive Tumors

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    End point title
    ORR per mRECIST - Participants with Strongly PD-L1 Positive Tumors
    End point description
    ORR per mRECIST was defined as the percentage of participants in the analysis population who had a CR (complete disappearance of all lesions (and no new lesions), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented) or a PR (decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation). ORR per mRECIST was assessed by BICR in participants with strongly PD-L1 positive tumors (CPS ≥10%) up through the final analysis database cut-off date of 26-Oct-2017. The analysis population consisted of all randomized strongly PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    90
    74
    Units: Percentage of Participants
        number (confidence interval 95%)
    7.8 (3.2 to 15.4)
    24.3 (15.1 to 35.7)
    Statistical analysis title
    ORR per mRECIST - Strongly PD-L1 Positive Pts
    Comparison groups
    Control v Pembrolizumab
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    [25]
    P-value
    = 0.00009 [26]
    Method
    Miettinen & Nurminen method
    Parameter type
    Difference in Percentages
    Point estimate
    21.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.1
         upper limit
    34.2
    Notes
    [25] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [26] - One-sided p-value for testing H0: difference in %=0; H1: difference in %>0

    Secondary: ORR per mRECIST - Participants with PD-L1 Positive Tumors

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    End point title
    ORR per mRECIST - Participants with PD-L1 Positive Tumors
    End point description
    ORR per mRECIST was defined as the percentage of participants in the analysis population who had a CR (complete disappearance of all lesions (and no new lesions), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented) or a PR (decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation). ORR per mRECIST was assessed by BICR in participants with PD-L1 positive tumors (CPS ≥1%) up through the final analysis database cut-off date of 26-Oct-2017. The analysis population consisted of all randomized PD-L1 positive participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    120
    110
    Units: Percentage of Participants
        number (confidence interval 95%)
    9.2 (4.7 to 15.8)
    28.2 (20.0 to 37.6)
    Statistical analysis title
    ORR per mRECIST - PD-L1 Positive Participants
    Comparison groups
    Control v Pembrolizumab
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    [27]
    P-value
    = 0.00002 [28]
    Method
    Miettinen & Nurminen method
    Parameter type
    Difference in Percentages
    Point estimate
    21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.1
         upper limit
    31.5
    Notes
    [27] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [28] - One-sided p-value for testing H0: difference in %=0; H1: difference in %>0

    Secondary: ORR per mRECIST - All Participants

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    End point title
    ORR per mRECIST - All Participants
    End point description
    ORR per mRECIST was defined as the percentage of participants in the analysis population who had a CR (complete disappearance of all lesions (and no new lesions), with confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented) or a PR (decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive assessment at least 4 weeks after first documentation). ORR per mRECIST was assessed by BICR in all participants up through the final analysis database cut-off date of 26-Oct-2017. The analysis population consisted of all randomized participants, regardless of whether or not they received study treatment. Participants were included in the treatment group to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    272
    270
    Units: Percentage of Participants
        number (confidence interval 95%)
    11.4 (7.9 to 15.8)
    25.2 (20.1 to 30.8)
    Statistical analysis title
    ORR per mRECIST - All Participants
    Comparison groups
    Control v Pembrolizumab
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    [29]
    P-value
    = 0.00001 [30]
    Method
    Miettinen & Nurminen method
    Parameter type
    Difference in Percentages
    Point estimate
    13.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.4
         upper limit
    20.3
    Notes
    [29] - Treatment as a covariate stratified by ECOG PS, presence/absence of liver metastases, hemoglobin and time from completion of most recent chemotherapy
    [30] - One-sided p-value for testing H0: difference in %=0; H1: difference in %>0

    Secondary: Duration of Response (DOR) per RECIST 1.1 - Participants with Strongly PD-L1 Positive Tumors

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    End point title
    Duration of Response (DOR) per RECIST 1.1 - Participants with Strongly PD-L1 Positive Tumors
    End point description
    DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. Per protocol, the DOR for participants who had progressed or died at the time of analysis, who had started a new anti-cancer treatment, who were lost to follow-up, or who had an ongoing response was to be censored at the date of their last tumor assessment. DOR was analysed in all randomized participants who had strongly PD-L1 positive tumors (CPS ≥10%) and who demonstrated a confirmed CR or PR per RECIST 1.1 based on BICR using the Kaplan-Meier method. Values of 8888 indicate the DOR upper 95% confidence limit was undefined because the DOR rate was not low enough at the time of the cut-off date. Values of 9999 indicate the median DOR was not reached because there were not enough events and the DOR upper 95% confidence limit was undefined because the DOR rate was not low enough at the time of the cut-off date.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    6
    15
    Units: Months
        median (confidence interval 95%)
    4.4 (2.8 to 8888)
    9999 (8.2 to 9999)
    No statistical analyses for this end point

    Secondary: DOR per RECIST 1.1 - Participants with PD-L1 Positive Tumors

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    End point title
    DOR per RECIST 1.1 - Participants with PD-L1 Positive Tumors
    End point description
    DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. Per protocol, the DOR for participants who had progressed or died at the time of analysis, who had started a new anti-cancer treatment, who were lost to follow-up, or who had an ongoing response was to be censored at the date of their last tumor assessment. DOR was analysed in all randomized participants who had PD-L1 positive tumors (CPS ≥1%) and who demonstrated a confirmed CR or PR per RECIST 1.1 based on BICR using the Kaplan-Meier method. Values of 9999 indicate the median DOR was not reached because there were not enough events and the DOR upper 95% confidence limit was undefined because the DOR rate was not low enough at the time of the cut-off date.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    10
    25
    Units: Months
        median (confidence interval 95%)
    9999 (2.8 to 9999)
    9999 (21.8 to 9999)
    No statistical analyses for this end point

    Secondary: DOR per RECIST 1.1 - All Participants

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    End point title
    DOR per RECIST 1.1 - All Participants
    End point description
    DOR was defined as the time from first documented evidence of CR or PR until disease progression or death. Per protocol, the DOR for participants who had progressed or died at the time of analysis, who had started a new anti-cancer treatment, who were lost to follow-up, or who had an ongoing response was to be censored at the date of their last tumor assessment. DOR was analysed in all randomized participants who demonstrated a confirmed CR or PR per RECIST 1.1 based on BICR using the Kaplan-Meier method. Values of 9999 indicate the median DOR was not reached because there were not enough events and the DOR upper 95% confidence limit was undefined because the DOR rate was not low enough at the time of the cut-off date.
    End point type
    Secondary
    End point timeframe
    Through final analysis database cut-off date of 26-Oct-2017 (Up to approximately 34 months)
    End point values
    Control Pembrolizumab
    Number of subjects analysed
    30
    57
    Units: Months
        median (confidence interval 95%)
    4.4 (4.0 to 20.3)
    9999 (15.9 to 9999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Through end of trial analysis database cut-off date of 01-Oct-2020 (Up to approximately 71 months)
    Adverse event reporting additional description
    AEs include all treated participants according to treatment received. MedDRA preferred terms "Neoplasm progression", "Malignant neoplasm progression" and "Disease progression" unrelated to drug excluded as AEs. 13 participants randomized to receive Control were switched over to pembrolizumab per protocol and monitored for AEs separately.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Control
    Reporting group description
    Participants received paclitaxel 175 mg/m^2 IV or docetaxel 75 mg/m^2 IV or vinflunine 320 mg/m^2 IV, on Day 1 of each 3-week cycle (Q3W). Eligible participants who experienced disease progression may have been able to switch over to receive pembrolizumab 200 mg IV Q3W for up to 35 treatment administrations (up to approximately 2 years).

    Reporting group title
    Control Switched Over to Pembrolizumab
    Reporting group description
    Per protocol, participants originally randomized to the Control arm that experienced disease progression were switched over to receive pembrolizumab 200 mg IV on Day 1 Q3W.

    Reporting group title
    Pembrolizumab
    Reporting group description
    Participants receive pembrolizumab 200 mg IV on Day 1 Q3W. Eligible participants who stopped pembrolizumab with SD or better but progressed after discontinuation may have been able to initiate a second course of pembrolizumab 200 mg IV Q3W for up to 17 cycles (up to approximately 1 additional year).

    Serious adverse events
    Control Control Switched Over to Pembrolizumab Pembrolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    104 / 255 (40.78%)
    8 / 13 (61.54%)
    107 / 266 (40.23%)
         number of deaths (all causes)
    230
    9
    224
         number of deaths resulting from adverse events
    4
    0
    4
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iliac artery occlusion
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasoconstriction
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 13 (7.69%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    3 / 255 (1.18%)
    0 / 13 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral cancer
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    5 / 255 (1.96%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 5
    0 / 0
    1 / 1
    Fatigue
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hyperthermia malignant
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 255 (1.96%)
    2 / 13 (15.38%)
    5 / 266 (1.88%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fluid collection
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 13 (7.69%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 13 (7.69%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial test positive
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood calcium increased
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 13 (7.69%)
    6 / 266 (2.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 255 (2.75%)
    0 / 13 (0.00%)
    6 / 266 (2.26%)
         occurrences causally related to treatment / all
    6 / 8
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    16 / 255 (6.27%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    16 / 16
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrogenic anaemia
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    5 / 255 (1.96%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Normocytic anaemia
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 255 (1.57%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal incontinence
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 13 (7.69%)
    5 / 266 (1.88%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    7 / 255 (2.75%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Ileus
         subjects affected / exposed
    3 / 255 (1.18%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    8 / 255 (3.14%)
    2 / 13 (15.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    5 / 8
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal pseudo-obstruction
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 13 (7.69%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 13 (7.69%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 255 (2.35%)
    0 / 13 (0.00%)
    5 / 266 (1.88%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune nephritis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder neck obstruction
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    4 / 255 (1.57%)
    0 / 13 (0.00%)
    6 / 266 (2.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 13 (7.69%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periostitis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophysitis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Decreased appetite
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 255 (0.78%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitamin B1 deficiency
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bacteraemia
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 13 (7.69%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fournier's gangrene
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic infection
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    8 / 255 (3.14%)
    1 / 13 (7.69%)
    11 / 266 (4.14%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 1
    2 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    Post procedural infection
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psoas abscess
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 255 (1.96%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    12 / 255 (4.71%)
    0 / 13 (0.00%)
    12 / 266 (4.51%)
         occurrences causally related to treatment / all
    4 / 13
    0 / 0
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 255 (0.39%)
    0 / 13 (0.00%)
    5 / 266 (1.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Vascular device infection
         subjects affected / exposed
    0 / 255 (0.00%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Control Control Switched Over to Pembrolizumab Pembrolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    237 / 255 (92.94%)
    11 / 13 (84.62%)
    236 / 266 (88.72%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 255 (3.14%)
    1 / 13 (7.69%)
    14 / 266 (5.26%)
         occurrences all number
    8
    1
    19
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    52 / 255 (20.39%)
    0 / 13 (0.00%)
    33 / 266 (12.41%)
         occurrences all number
    67
    0
    36
    Fatigue
         subjects affected / exposed
    85 / 255 (33.33%)
    3 / 13 (23.08%)
    66 / 266 (24.81%)
         occurrences all number
    107
    3
    83
    Influenza like illness
         subjects affected / exposed
    7 / 255 (2.75%)
    1 / 13 (7.69%)
    10 / 266 (3.76%)
         occurrences all number
    8
    2
    14
    Mucosal inflammation
         subjects affected / exposed
    18 / 255 (7.06%)
    0 / 13 (0.00%)
    6 / 266 (2.26%)
         occurrences all number
    24
    0
    8
    Pyrexia
         subjects affected / exposed
    30 / 255 (11.76%)
    1 / 13 (7.69%)
    36 / 266 (13.53%)
         occurrences all number
    38
    1
    44
    Oedema peripheral
         subjects affected / exposed
    39 / 255 (15.29%)
    0 / 13 (0.00%)
    31 / 266 (11.65%)
         occurrences all number
    48
    0
    36
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 255 (0.78%)
    1 / 13 (7.69%)
    5 / 266 (1.88%)
         occurrences all number
    2
    1
    6
    Delirium
         subjects affected / exposed
    4 / 255 (1.57%)
    1 / 13 (7.69%)
    3 / 266 (1.13%)
         occurrences all number
    5
    1
    3
    Insomnia
         subjects affected / exposed
    20 / 255 (7.84%)
    2 / 13 (15.38%)
    19 / 266 (7.14%)
         occurrences all number
    20
    2
    22
    Injury, poisoning and procedural complications
    Procedural pneumothorax
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 13 (7.69%)
    0 / 266 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 255 (1.18%)
    0 / 13 (0.00%)
    14 / 266 (5.26%)
         occurrences all number
    4
    0
    15
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 255 (1.57%)
    0 / 13 (0.00%)
    14 / 266 (5.26%)
         occurrences all number
    5
    0
    15
    Blood alkaline phosphatase increased
         subjects affected / exposed
    8 / 255 (3.14%)
    1 / 13 (7.69%)
    9 / 266 (3.38%)
         occurrences all number
    8
    1
    9
    Blood creatinine increased
         subjects affected / exposed
    13 / 255 (5.10%)
    2 / 13 (15.38%)
    13 / 266 (4.89%)
         occurrences all number
    16
    2
    22
    Blood bilirubin increased
         subjects affected / exposed
    2 / 255 (0.78%)
    1 / 13 (7.69%)
    4 / 266 (1.50%)
         occurrences all number
    2
    1
    4
    Neutrophil count decreased
         subjects affected / exposed
    40 / 255 (15.69%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences all number
    73
    0
    1
    Platelet count decreased
         subjects affected / exposed
    8 / 255 (3.14%)
    1 / 13 (7.69%)
    4 / 266 (1.50%)
         occurrences all number
    11
    1
    4
    Weight decreased
         subjects affected / exposed
    22 / 255 (8.63%)
    1 / 13 (7.69%)
    25 / 266 (9.40%)
         occurrences all number
    23
    1
    30
    White blood cell count decreased
         subjects affected / exposed
    22 / 255 (8.63%)
    0 / 13 (0.00%)
    1 / 266 (0.38%)
         occurrences all number
    41
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    18 / 255 (7.06%)
    3 / 13 (23.08%)
    39 / 266 (14.66%)
         occurrences all number
    20
    3
    51
    Dyspnoea exertional
         subjects affected / exposed
    9 / 255 (3.53%)
    1 / 13 (7.69%)
    5 / 266 (1.88%)
         occurrences all number
    11
    1
    5
    Dyspnoea
         subjects affected / exposed
    23 / 255 (9.02%)
    0 / 13 (0.00%)
    31 / 266 (11.65%)
         occurrences all number
    23
    0
    38
    Productive cough
         subjects affected / exposed
    5 / 255 (1.96%)
    1 / 13 (7.69%)
    8 / 266 (3.01%)
         occurrences all number
    5
    1
    12
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    86 / 255 (33.73%)
    1 / 13 (7.69%)
    45 / 266 (16.92%)
         occurrences all number
    139
    1
    61
    Neutropenia
         subjects affected / exposed
    41 / 255 (16.08%)
    0 / 13 (0.00%)
    0 / 266 (0.00%)
         occurrences all number
    74
    0
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    14 / 255 (5.49%)
    0 / 13 (0.00%)
    7 / 266 (2.63%)
         occurrences all number
    16
    0
    7
    Dizziness
         subjects affected / exposed
    19 / 255 (7.45%)
    0 / 13 (0.00%)
    19 / 266 (7.14%)
         occurrences all number
    26
    0
    22
    Headache
         subjects affected / exposed
    14 / 255 (5.49%)
    2 / 13 (15.38%)
    14 / 266 (5.26%)
         occurrences all number
    18
    2
    19
    Neuropathy peripheral
         subjects affected / exposed
    31 / 255 (12.16%)
    0 / 13 (0.00%)
    3 / 266 (1.13%)
         occurrences all number
    43
    0
    3
    Paraesthesia
         subjects affected / exposed
    4 / 255 (1.57%)
    1 / 13 (7.69%)
    6 / 266 (2.26%)
         occurrences all number
    4
    1
    9
    Peripheral sensory neuropathy
         subjects affected / exposed
    28 / 255 (10.98%)
    0 / 13 (0.00%)
    2 / 266 (0.75%)
         occurrences all number
    34
    0
    3
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 13 (7.69%)
    5 / 266 (1.88%)
         occurrences all number
    0
    1
    5
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    14 / 255 (5.49%)
    0 / 13 (0.00%)
    9 / 266 (3.38%)
         occurrences all number
    16
    0
    11
    Abdominal pain
         subjects affected / exposed
    33 / 255 (12.94%)
    1 / 13 (7.69%)
    32 / 266 (12.03%)
         occurrences all number
    40
    1
    37
    Nausea
         subjects affected / exposed
    73 / 255 (28.63%)
    2 / 13 (15.38%)
    56 / 266 (21.05%)
         occurrences all number
    100
    2
    62
    Constipation
         subjects affected / exposed
    79 / 255 (30.98%)
    2 / 13 (15.38%)
    54 / 266 (20.30%)
         occurrences all number
    105
    2
    63
    Diarrhoea
         subjects affected / exposed
    47 / 255 (18.43%)
    1 / 13 (7.69%)
    43 / 266 (16.17%)
         occurrences all number
    69
    2
    72
    Stomatitis
         subjects affected / exposed
    23 / 255 (9.02%)
    0 / 13 (0.00%)
    7 / 266 (2.63%)
         occurrences all number
    35
    0
    8
    Vomiting
         subjects affected / exposed
    34 / 255 (13.33%)
    0 / 13 (0.00%)
    38 / 266 (14.29%)
         occurrences all number
    47
    0
    47
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    17 / 255 (6.67%)
    1 / 13 (7.69%)
    30 / 266 (11.28%)
         occurrences all number
    21
    1
    43
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    100 / 255 (39.22%)
    0 / 13 (0.00%)
    2 / 266 (0.75%)
         occurrences all number
    106
    0
    2
    Dermatitis acneiform
         subjects affected / exposed
    3 / 255 (1.18%)
    1 / 13 (7.69%)
    4 / 266 (1.50%)
         occurrences all number
    3
    1
    4
    Dermatitis allergic
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 13 (7.69%)
    0 / 266 (0.00%)
         occurrences all number
    0
    1
    0
    Dry skin
         subjects affected / exposed
    9 / 255 (3.53%)
    1 / 13 (7.69%)
    17 / 266 (6.39%)
         occurrences all number
    9
    1
    19
    Rash
         subjects affected / exposed
    18 / 255 (7.06%)
    1 / 13 (7.69%)
    32 / 266 (12.03%)
         occurrences all number
    19
    1
    40
    Pruritus
         subjects affected / exposed
    15 / 255 (5.88%)
    0 / 13 (0.00%)
    66 / 266 (24.81%)
         occurrences all number
    17
    0
    88
    Rash maculo-papular
         subjects affected / exposed
    3 / 255 (1.18%)
    1 / 13 (7.69%)
    7 / 266 (2.63%)
         occurrences all number
    5
    1
    8
    Urticaria
         subjects affected / exposed
    5 / 255 (1.96%)
    1 / 13 (7.69%)
    6 / 266 (2.26%)
         occurrences all number
    5
    1
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    31 / 255 (12.16%)
    1 / 13 (7.69%)
    30 / 266 (11.28%)
         occurrences all number
    57
    1
    35
    Musculoskeletal pain
         subjects affected / exposed
    9 / 255 (3.53%)
    1 / 13 (7.69%)
    15 / 266 (5.64%)
         occurrences all number
    10
    1
    16
    Myalgia
         subjects affected / exposed
    17 / 255 (6.67%)
    1 / 13 (7.69%)
    17 / 266 (6.39%)
         occurrences all number
    24
    1
    20
    Back pain
         subjects affected / exposed
    21 / 255 (8.24%)
    2 / 13 (15.38%)
    40 / 266 (15.04%)
         occurrences all number
    22
    2
    47
    Pain in extremity
         subjects affected / exposed
    27 / 255 (10.59%)
    0 / 13 (0.00%)
    24 / 266 (9.02%)
         occurrences all number
    31
    0
    28
    Synovitis
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 13 (7.69%)
    0 / 266 (0.00%)
         occurrences all number
    0
    2
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 255 (0.00%)
    1 / 13 (7.69%)
    11 / 266 (4.14%)
         occurrences all number
    0
    1
    11
    Hypothyroidism
         subjects affected / exposed
    3 / 255 (1.18%)
    1 / 13 (7.69%)
    21 / 266 (7.89%)
         occurrences all number
    3
    1
    24
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    9 / 255 (3.53%)
    1 / 13 (7.69%)
    9 / 266 (3.38%)
         occurrences all number
    9
    1
    10
    Decreased appetite
         subjects affected / exposed
    53 / 255 (20.78%)
    4 / 13 (30.77%)
    57 / 266 (21.43%)
         occurrences all number
    65
    4
    64
    Hyponatraemia
         subjects affected / exposed
    18 / 255 (7.06%)
    0 / 13 (0.00%)
    16 / 266 (6.02%)
         occurrences all number
    21
    0
    20
    Hypomagnesaemia
         subjects affected / exposed
    4 / 255 (1.57%)
    1 / 13 (7.69%)
    5 / 266 (1.88%)
         occurrences all number
    5
    2
    6
    Hypophosphataemia
         subjects affected / exposed
    8 / 255 (3.14%)
    1 / 13 (7.69%)
    5 / 266 (1.88%)
         occurrences all number
    16
    2
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 255 (1.57%)
    1 / 13 (7.69%)
    15 / 266 (5.64%)
         occurrences all number
    4
    1
    23
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 255 (0.78%)
    1 / 13 (7.69%)
    10 / 266 (3.76%)
         occurrences all number
    2
    1
    12
    Pharyngitis
         subjects affected / exposed
    1 / 255 (0.39%)
    1 / 13 (7.69%)
    1 / 266 (0.38%)
         occurrences all number
    1
    2
    1
    Urinary tract infection
         subjects affected / exposed
    27 / 255 (10.59%)
    2 / 13 (15.38%)
    33 / 266 (12.41%)
         occurrences all number
    30
    2
    45

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Oct 2014
    The primary changes of amendment 2 (AM2) included the addition of docetaxel as a comparator to the Control arm and changes to study eligibility.
    19 Nov 2015
    The primary changes of AM4 included elevating PFS and OS in participants with PD-L1 positive and PD-L1 strongly positive tumors to co-primary objectives.
    15 Mar 2016
    The primary changes of AM9 included elevating PFS and OS in participants with PD-L1 positive and PD-L1 strongly positive tumors to co-primary objectives.
    19 Jun 2016
    The primary changes of AM11 included allowing the second interim analysis and/or the final analysis to be postponed to accrue additional OS events in PD-L1 positive participants after the planned number of OS events in all participants was achieved.
    27 Sep 2016
    The primary changes of AM13 included clarifying the basis for PD-L1 positive and strongly positive categories using CPS cut-points determined from other pembrolizumab studies.
    21 Dec 2016
    The primary changes of AM15 included adding a Crossover phase to the study to allow eligible participants in the Control arm who experienced PD to crossover to pembrolizumab 200 mg Q3W.
    22 Nov 2017
    The primary changes of AM17 included changes to dose modification language, addition of study extension language, and clarifying the approved dose of pembrolizumab.

    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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