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    Clinical Trial Results:
    A Phase III, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) Compared With Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer After Failure With Platinum-Containing Chemotherapy

    Summary
    EudraCT number
    2014-003231-19
    Trial protocol
    CZ   IT   PL   SI   SE   DE   GB   HU   PT   NL   FI   NO   DK   BE   AT   ES   FR   GR   RO  
    Global end of trial date
    08 Nov 2018

    Results information
    Results version number
    v3(current)
    This version publication date
    26 Jun 2019
    First version publication date
    29 Mar 2018
    Other versions
    v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    GO29294
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02302807
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Other Sponsor ID: IMvigor211
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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
    08 Nov 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this Phase III, open-label, multicenter, randomized study was to investigate the efficacy of atezolizumab (Anti-PD-L1 Antibody) compared with chemotherapy in subjects with locally advanced or metastatic urothelial bladder cancer after failure with platinum-containing chemotherapy.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Jan 2015
    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: 19
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Canada: 47
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    France: 176
    Country: Number of subjects enrolled
    Spain: 110
    Country: Number of subjects enrolled
    United Kingdom: 84
    Country: Number of subjects enrolled
    Italy: 73
    Country: Number of subjects enrolled
    Japan: 56
    Country: Number of subjects enrolled
    Germany: 54
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Slovenia: 7
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Serbia: 5
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    United States: 24
    Country: Number of subjects enrolled
    Korea, Republic of: 31
    Country: Number of subjects enrolled
    Turkey: 16
    Country: Number of subjects enrolled
    Taiwan: 26
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Portugal: 15
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Netherlands: 52
    Country: Number of subjects enrolled
    Greece: 22
    Country: Number of subjects enrolled
    Switzerland: 25
    Worldwide total number of subjects
    931
    EEA total number of subjects
    676
    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)
    371
    From 65 to 84 years
    558
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    Recruitment included in 198 centers in 29 countries: France, Spain, Great Britain, Italy, Japan, Germany, Netherlands, Canada, Korea, Taiwan, Switzerland, United States, Greece, Belgium, Australia, Turkey, Poland, Portugal, Romania, Denmark, Czechoslovakia, Slovenia, Russia, Hungary, Norway, Serbia, Sweden, Finland, and Austria.

    Pre-assignment
    Screening details
    Subjects in the study included: histologically or cytologically documented locally advanced or metastatic UBC; and disease progression during or following treatment with at least one platinum containing regimen for inoperable, locally advanced or metastatic UBC or disease recurrence.

    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
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel)
    Arm description
    Subjects randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigator's choice. Vinflunine 320 milligrams per square meter (mg/m^2), paclitaxel 175 mg/m^2, or docetaxel 75 mg/m^2 was administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.
    Arm type
    Active comparator

    Investigational medicinal product name
    Vinflunine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects randomized to the chemotherapy arm received vinflunine, per the investigator's choice. Vinflunine 320 milligrams per square meter (mg/m^2) was administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects randomized to the chemotherapy received paclitaxel, per the investigator's choice. Paclitaxel 175 mg/m^2 was administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects randomized to the chemotherapy arm received docetaxel per the investigator's choice. Docetaxel 75 mg/m^2 was administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.

    Arm title
    Atezolizumab
    Arm description
    Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Subjects received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator
    Arm type
    Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Subjects received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator

    Number of subjects in period 1
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Atezolizumab
    Started
    464
    467
    Received Treatment
    443
    459
    Completed
    0
    0
    Not completed
    464
    467
         Physician decision
    -
    1
         Adverse event, serious fatal
    397
    385
         Consent withdrawn by subject
    28
    11
         Study Terminated By Sponsor
    35
    64
         Lost to follow-up
    4
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel)
    Reporting group description
    Subjects randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigator's choice. Vinflunine 320 milligrams per square meter (mg/m^2), paclitaxel 175 mg/m^2, or docetaxel 75 mg/m^2 was administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.

    Reporting group title
    Atezolizumab
    Reporting group description
    Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Subjects received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator

    Reporting group values
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Atezolizumab Total
    Number of subjects
    464 467 931
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    66.1 ± 9.3 65.9 ± 9.6 -
    Sex: Female, Male
    Units: Subjects
        Female
    103 110 213
        Male
    361 357 718
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    55 63 118
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    2 1 3
        White
    336 335 671
        More than one race
    1 0 1
        Unknown or Not Reported
    70 68 138
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    16 13 29
        Not Hispanic or Latino
    368 363 731
        Unknown or Not Reported
    80 91 171

    End points

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    End points reporting groups
    Reporting group title
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel)
    Reporting group description
    Subjects randomized to the chemotherapy arm received vinflunine, paclitaxel, or docetaxel per the investigator's choice. Vinflunine 320 milligrams per square meter (mg/m^2), paclitaxel 175 mg/m^2, or docetaxel 75 mg/m^2 was administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.

    Reporting group title
    Atezolizumab
    Reporting group description
    Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Subjects received atezolizumab as long as they continued to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator

    Subject analysis set title
    IC2/3 Chemotherapy Subset 1
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT population, defined as all randomized subjects, irrespective of whether the assigned treatment was actually received, with PD-L1 immunohistochemistry (IHC) score of IC2/3 analyzed for Overall Survival and Progression-Free Survival

    Subject analysis set title
    IC2/3 Atezolizumab Subset 1
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT population, defined as all randomized subjects, irrespective of whether the assigned treatment was actually received, with PD-L1 immunohistochemistry (IHC) score of IC2/3 analyzed for Overall Survival and Progression-Free Survival

    Subject analysis set title
    IC1/2/3 Chemotherapy Subset 1
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT population, defined as all randomized subjects, irrespective of whether the assigned treatment was actually received, with PD-L1 immunohistochemistry (IHC) score of IC1/2/3 analyzed for Overall Survival and Progression-Free Survival

    Subject analysis set title
    IC1/2/3 Atezolizumab Subset 1
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT population, defined as all randomized subjects, irrespective of whether the assigned treatment was actually received, with PD-L1 immunohistochemistry (IHC) score of IC1/2/3 analyzed for Overall Survival and Progression-Free Survival

    Subject analysis set title
    IC2/3 Chemotherapy Subset 2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD-L1 immunohistochemistry (IHC) score of IC2/3 analyzed for Objective Response Rate. ORR analyses was performed on all randomized subjects who had measureable disease at baseline.

    Subject analysis set title
    IC2/3 Atezolizumab Subset 2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD-L1 immunohistochemistry (IHC) score of IC2/3 analyzed for Objective Response Rate. ORR analyses was performed on all randomized subjects who had measureable disease at baseline.

    Subject analysis set title
    IC1/2/3 Chemotherapy Subset 2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD-L1 immunohistochemistry (IHC) score of IC1/2/3 analyzed for Objective Response Rate. ORR analyses was performed on all randomized subjects who had measureable disease at baseline.

    Subject analysis set title
    IC1/2/3 Atezolizumab Subset 2
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD-L1 immunohistochemistry (IHC) score of IC1/2/3 analyzed for Objective Response Rate. ORR analyses was performed on all randomized subjects who had measureable disease at baseline. PD-L1 immunohistochemistry (IHC) score of IC1/2/3 analyzed for Adverse Events. Safety analyses was performed on all randomized subjects who received any amount of study treatment, with patients grouped according to whether any amount of atezolizumab was received including the case when atezolizumab was received in error.

    Subject analysis set title
    IC2/3 Chemotherapy Subset 3
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD-L1 immunohistochemistry (IHC) score of IC2/3 analyzed for Duration of Response. DOR analyses was performed on the subset of subjects who achieved an objective response.

    Subject analysis set title
    IC2/3 Atezolizumab Subset 3
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD-L1 immunohistochemistry (IHC) score of IC2/3 analyzed for Duration of Response. DOR analyses was performed on the subset of subjects who achieved an objective response.

    Subject analysis set title
    IC1/2/3 Chemotherapy Subset 3
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD-L1 immunohistochemistry (IHC) score of IC1/2/3 analyzed for Duration of Response. DOR analyses was performed on the subset of subjects who achieved an objective response.

    Subject analysis set title
    IC1/2/3 Atezolizumab Subset 3
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD-L1 immunohistochemistry (IHC) score of IC1/2/3 analyzed for Duration of Response. DOR analyses was performed on the subset of subjects who achieved an objective response.

    Subject analysis set title
    IC2/3 Chemotherapy Subset 4
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD-L1 immunohistochemistry (IHC) score of IC2/3 analyzed for Adverse Events. Safety analyses was performed on all randomized subjects who received any amount of study treatment, with subjects grouped according to whether any amount of atezolizumab was received including the case when atezolizumab was received in error.

    Subject analysis set title
    IC2/3 Atezolizumab Subset 4
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD-L1 immunohistochemistry (IHC) score of IC2/3 analyzed for Adverse Events. Safety analyses was performed on all randomized subjects who received any amount of study treatment, with subjects grouped according to whether any amount of atezolizumab was received including the case when atezolizumab was received in error.

    Subject analysis set title
    IC1/2/3 Chemotherapy Subset 4
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD-L1 immunohistochemistry (IHC) score of IC1/2/3 analyzed for Adverse Events. Safety analyses was performed on all randomized subjects who received any amount of study treatment, with subjects grouped according to whether any amount of atezolizumab was received including the case when atezolizumab was received in error.

    Subject analysis set title
    IC1/2/3 Atezolizumab Subset 4
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PD-L1 immunohistochemistry (IHC) score of IC1/2/3 analyzed for Adverse Events. Safety analyses was performed on all randomized subjects who received any amount of study treatment, with subjects grouped according to whether any amount of atezolizumab was received including the case when atezolizumab was received in error.

    Subject analysis set title
    IC1/2/3 Atezolizumab Subset 5
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ATA evaluable population, defined as patients who received atezolizumab treatment and had at least one post-treatment ATA result, with PD-L1 immunohistochemistry (IHC) score of IC1/2/3

    Subject analysis set title
    IC2/3 Atezolizumab Subset 5
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ATA evaluable population, defined as subjects who received atezolizumab treatment and had at least one post-treatment ATA result, with PD-L1 immunohistochemistry (IHC) score of IC2/3.

    Primary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as time from randomization to death from any cause.
    End point type
    Primary
    End point timeframe
    Between randomization and death due to any cause, up to approximately 25 months after first participant enrolled
    End point values
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Atezolizumab IC2/3 Chemotherapy Subset 1 IC2/3 Atezolizumab Subset 1 IC1/2/3 Chemotherapy Subset 1 IC1/2/3 Atezolizumab Subset 1
    Number of subjects analysed
    464
    467
    118
    116
    309
    316
    Units: Months
        median (confidence interval 95%)
    8.0 (7.2 to 8.6)
    8.6 (7.8 to 9.6)
    10.6 (8.4 to 12.2)
    11.1 (8.6 to 15.5)
    8.2 (7.4 to 9.5)
    8.9 (8.2 to 10.9)
    Statistical analysis title
    Overall Survival
    Comparison groups
    Atezolizumab v Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel)
    Number of subjects included in analysis
    931
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    0.99
    Statistical analysis title
    Overall Survival
    Comparison groups
    IC2/3 Chemotherapy Subset 1 v IC2/3 Atezolizumab Subset 1
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4134
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.63
         upper limit
    1.21
    Statistical analysis title
    Overall Survival
    Comparison groups
    IC1/2/3 Chemotherapy Subset 1 v IC1/2/3 Atezolizumab Subset 1
    Number of subjects included in analysis
    625
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.05

    Secondary: Percentage of Participants With Unconfirmed Objective Response Rate (ORR) as Determined by the Investigator With Use of Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)

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    End point title
    Percentage of Participants With Unconfirmed Objective Response Rate (ORR) as Determined by the Investigator With Use of Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)
    End point description
    ORR was defined as the percentage of participants who had an objective response. Objective response was defined as either a complete response (CR) or partial response (PR) as determined by the investigator with use of Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). Objective response in this study did not need to be a confirmed response. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. ORR=CR+PR
    End point type
    Secondary
    End point timeframe
    Up to approximately 25 months after first participant enrolled
    End point values
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Atezolizumab IC2/3 Chemotherapy Subset 2 IC2/3 Atezolizumab Subset 2 IC1/2/3 Chemotherapy Subset 2 IC1/2/3 Atezolizumab Subset 2
    Number of subjects analysed
    461
    462
    116
    113
    306
    312
    Units: Percentage of participants
        number (confidence interval 95%)
    20.8 (17.21 to 24.82)
    15.4 (12.20 to 18.99)
    29.3 (21.23 to 38.48)
    26.5 (18.68 to 35.68)
    22.2 (17.69 to 27.30)
    16.3 (12.42 to 20.93)
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) as Determined by the Investigator With Use of RECIST v1.1

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    End point title
    Progression-free Survival (PFS) as Determined by the Investigator With Use of RECIST v1.1
    End point description
    PFS was defined as the time between the date of randomization and the date of first documented progression of disease (PD) or death, whichever occurred first. PD was determined on the basis of investigator assessment with use of RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters had to demonstrate an absolute increase of >/= 5 millimeters (mm).
    End point type
    Secondary
    End point timeframe
    Up to approximately 25 months after first participant enrolled
    End point values
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Atezolizumab IC2/3 Chemotherapy Subset 1 IC2/3 Atezolizumab Subset 1 IC1/2/3 Chemotherapy Subset 1 IC1/2/3 Atezolizumab Subset 1
    Number of subjects analysed
    464
    467
    118
    116
    309
    316
    Units: months
        median (confidence interval 95%)
    4.0 (3.4 to 4.2)
    2.1 (2.1 to 2.2)
    4.2 (3.7 to 5.0)
    2.4 (2.1 to 4.2)
    4.1 (3.6 to 4.2)
    2.1 (2.1 to 2.2)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) as Determined by the Investigator With Use of RECIST v1.1

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    End point title
    Duration of Response (DOR) as Determined by the Investigator With Use of RECIST v1.1
    End point description
    DOR was defined as the time from first occurrence of a CR or PR, whichever came first, to first documented PD or death, whichever occurred first. PD was determined on the basis of investigator assessment with use of RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm. Note: 999999 = The DOR data was not mature at the time of clinical cutoff (i.e., majority of the responders are still ongoing), so the upper confidence interval was not estimable.
    End point type
    Secondary
    End point timeframe
    Up to approximately 25 months after first participant enrolled
    End point values
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Atezolizumab IC2/3 Chemotherapy Subset 3 IC2/3 Atezolizumab Subset 3 IC1/2/3 Chemotherapy Subset 3 IC1/2/3 Atezolizumab Subset 3
    Number of subjects analysed
    96
    71
    34
    30
    68
    51
    Units: months
        median (confidence interval 95%)
    5.3 (4.2 to 6.3)
    21.7 (9.9 to 21.7)
    6.4 (4.2 to 8.3)
    13.0 (6.6 to 999999)
    5.5 (4.2 to 7.4)
    13.0 (6.9 to 999999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events (AEs)

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    End point title
    Percentage of Participants With Adverse Events (AEs)
    End point description
    An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 46 months after first participant enrolled
    End point values
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Atezolizumab IC1/2/3 Atezolizumab Subset 2 IC2/3 Chemotherapy Subset 4 IC2/3 Atezolizumab Subset 4 IC1/2/3 Chemotherapy Subset 4
    Number of subjects analysed
    443
    459
    312
    112
    114
    297
    Units: percentage
        number (not applicable)
    98.2
    95.0
    96.2
    98.2
    96.5
    98.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Post-Baeline Anti-therapeutic Antibodies (ATA) to Atezolizumab

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    End point title
    Percentage of Participants With Post-Baeline Anti-therapeutic Antibodies (ATA) to Atezolizumab [1]
    End point description
    Subjects were considered post-baseline ATA positive if they had post-baseline ATAs to Atezolizumab that were treatment-induced or treatment-enhanced. Subjects had treatment-induced ATAs if they had a baseline-negative ATA result and developed ATAs at any time after initial drug administration. Subjects had treatment-enhanced ATAs if they had a baseline-positive ATA result that showed an enhanced signal that was >/= 0.60 titer units at any time after initial drug initiation.
    End point type
    Secondary
    End point timeframe
    Predose (0 hours) on Day 1 of Cycles 1, 2, 3, 4 and every 8 cycles thereafter; at treatment discontinuation (up to 25 months); at 120 days after last dose of atezolizumab (up to 25 months; each cycle is 21 days)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point.
    End point values
    Atezolizumab IC1/2/3 Atezolizumab Subset 5 IC2/3 Atezolizumab Subset 5
    Number of subjects analysed
    427
    289
    106
    Units: percentage of participants
        number (not applicable)
    33.3
    35.0
    33.0
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Atezolizumab Concentration (Cmax)

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    End point title
    Maximum Observed Serum Atezolizumab Concentration (Cmax) [2]
    End point description
    Cmax was measured for all subjects that received at least one dose of Atezolizumab.
    End point type
    Secondary
    End point timeframe
    30 minutes post dose on Day 1 of Cycles 1
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point.
    End point values
    Atezolizumab
    Number of subjects analysed
    467
    Units: mcg/mL
        geometric mean (standard deviation)
    334 ± 125
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Atezolizumab Concentration (Cmin)

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    End point title
    Minimum Observed Serum Atezolizumab Concentration (Cmin) [3]
    End point description
    Cmin was measured for all subjects that received at least one dose of Atezolizumab.
    End point type
    Secondary
    End point timeframe
    Predose (0 hours) on Day 1 of Cycles 1, 2, 3, 4 and every 8 cycles thereafter; at treatment discontinuation (up to 25 months); at 120 days after last dose of atezolizumab (up to 25 months; each cycle is 21 days)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point.
    End point values
    Atezolizumab
    Number of subjects analysed
    467
    Units: mcg/mL
    geometric mean (standard deviation)
        Cycle 2, day 1|
    67.5 ± 29.1
        Cycle 3, day 1|
    95.1 ± 46.5
        Cycle 4, day 1|
    122 ± 56.9
        Cycle 8, day 1|
    159 ± 72.4
        Cycle 16, day 1|
    190 ± 94.7
        Cycle 24, day 1|
    190 ± 98.7
        Cycle 32, day 1|
    223 ± 87.4
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Global Health Status Scale

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    End point title
    Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Global Health Status Scale
    End point description
    The EORTC QLQ-C30 includes five functional scales (physical, role, cognitive, emotional, social); a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms). Key scales included physical functioning, and fatigue, and GHS.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (prior to any health care interaction), on Day 1 of each subsequent cycle, and at 30 days after the last treatment dose (Up to approximately 25 months; each cycle is 21 days)
    End point values
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Atezolizumab
    Number of subjects analysed
    381
    408
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (Cycle 1, Day 1)
    61.49 ± 22.30
    64.19 ± 21.72
        Change from baseline: Cycle 2, Day 1
    -5.47 ± 20.02
    -6.18 ± 20.07
        Change from baseline: Cycle 3, Day 1
    -3.76 ± 22.34
    -4.67 ± 20.89
        Change from baseline: Cycle 4, Day 1
    -1.48 ± 19.71
    -0.53 ± 20.23
        Change from baseline: Cycle 12, Day 1
    -3.95 ± 24.33
    -0.56 ± 22.31
        Change from baseline: Cycle 20, Day 1
    -2.27 ± 16.28
    1.10 ± 21.88
        Change from baseline: Cycle 28, Day 1
    -11.67 ± 7.45
    -5.26 ± 33.82
        Change from baseline:Treatment Discont. Visit
    -10.77 ± 24.15
    -16.71 ± 24.39
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Physical Functioning Scale

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    End point title
    Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Physical Functioning Scale
    End point description
    The EORTC QLQ-C30 includes five functional scales (physical, role, cognitive, emotional, social); a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms). Key scales included physical functioning, and fatigue, and GHS.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (prior to any health care interaction), on Day 1 of each subsequent cycle, and at 30 days after the last treatment dose (Up to approximately 25 months; each cycle is 21 days)
    End point values
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Atezolizumab
    Number of subjects analysed
    381
    408
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (Cycle 1, Day 1)|
    74.23 ± 22.55
    76.37 ± 19.66
        Change from baseline: Cycle 2, Day 1|
    -4.80 ± 15.70
    -7.56 ± 18.24
        Change from baseline: Cycle 3, Day 1|
    -5.64 ± 17.37
    -7.06 ± 19.62
        Change from baseline: Cycle 4, Day 1|
    -4.41 ± 16.25
    -3.81 ± 17.49
        Change from baseline: Cycle 12, Day 1|
    -6.97 ± 20.20
    0.89 ± 16.23
        Change from baseline: Cycle 20, Day 1|
    -3.03 ± 11.30
    3.48 ± 13.56
        Change from baseline: Cycle 28, Day 1|
    -18.67 ± 24.68
    3.51 ± 20.53
        Change from baseline: Treatment Discont. Visit|
    -15.58 ± 25.67
    -20.19 ± 25.52
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Fatigue Symptom Scale

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    End point title
    Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Fatigue Symptom Scale
    End point description
    The EORTC QLQ-C30 includes five functional scales (physical, role, cognitive, emotional, social); a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms). Key scales included physical functioning, and fatigue, and GHS.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (prior to any health care interaction), on Day 1 of each subsequent cycle, and at 30 days after the last treatment dose (Up to approximately 25 months; each cycle is 21 days)
    End point values
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Atezolizumab
    Number of subjects analysed
    381
    408
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Fatigue Symptom: Baseline (Cycle 1, Day 1)|
    34.67 ± 26.66
    32.87 ± 23.88
        Change from baseline: Cycle 2, Day 1|
    10.71 ± 23.13
    10.56 ± 21.82
        Change from baseline: Cycle 3, Day 1|
    11.04 ± 25.48
    9.41 ± 24.80
        Change from baseline: Cycle 4, Day 1|
    7.48 ± 22.63
    3.67 ± 23.57
        Change from baseline: Cycle 12, Day 1|
    5.70 ± 27.44
    -0.95 ± 23.27
        Change from baseline: Cycle 20, Day 1|
    11.11 ± 28.97
    -8.05 ± 21.97
        Change from baseline: Cycle 28, Day 1|
    15.56 ± 16.85
    -12.28 ± 28.42
        Change from baseline: Treatment Discont. Visit|
    17.27 ± 28.15
    19.60 ± 25.95
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first study drug to the data cutoff date: 8 November 2018 (up to 46 months)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel)
    Reporting group description
    Participants randomized to the chemotherapy arm will receive vinflunine, paclitaxel, or docetaxel per the investigator's choice. Vinflunine 320 milligrams per square meter (mg/m^2), paclitaxel 175 mg/m^2, or docetaxel 75 mg/m^2 will be administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.

    Reporting group title
    Atezolizumab
    Reporting group description
    Atezolizumab was administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants received atezolizumab as long as they continue to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator

    Serious adverse events
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Atezolizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    189 / 443 (42.66%)
    192 / 459 (41.83%)
         number of deaths (all causes)
    393
    379
         number of deaths resulting from adverse events
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    2 / 443 (0.45%)
    4 / 459 (0.87%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypertension
         subjects affected / exposed
    2 / 443 (0.45%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    3 / 443 (0.68%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Internal Haemorrhage
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon Cancer
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mantle Cell Lymphoma
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm Malignant
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumor Associated Fever
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer Pain
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Cancer
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    2 / 443 (0.45%)
    3 / 459 (0.65%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    1 / 2
    0 / 3
    Fatigue
         subjects affected / exposed
    5 / 443 (1.13%)
    4 / 459 (0.87%)
         occurrences causally related to treatment / all
    5 / 6
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    4 / 443 (0.90%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Influenza Like Illness
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection Site Reaction
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 443 (0.45%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    2 / 443 (0.45%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    4 / 443 (0.90%)
    3 / 459 (0.65%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Swelling
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 443 (1.13%)
    17 / 459 (3.70%)
         occurrences causally related to treatment / all
    3 / 5
    6 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strangulated Hernia
         subjects affected / exposed
    1 / 443 (0.23%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unevaluable Event
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed Suicide
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Confusional State
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal Haemorrhage
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital Haemorrhage
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Compression Fracture
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion Related Reaction
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Limb Fracture
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma Site Haemorrhage
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to Various Agents
         subjects affected / exposed
    1 / 443 (0.23%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urostomy Complication
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Injury
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Bilirubin Increased
         subjects affected / exposed
    1 / 443 (0.23%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Creatinine Increased
         subjects affected / exposed
    1 / 443 (0.23%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Function Test Abnormal
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil Count Decreased
         subjects affected / exposed
    4 / 443 (0.90%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White Blood Cell Count Decreased
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    2 / 443 (0.45%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-Respiratory Arrest
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial Effusion
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 443 (0.00%)
    7 / 459 (1.53%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 443 (0.23%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 443 (0.45%)
    4 / 459 (0.87%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 443 (0.23%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive Cough
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    2 / 443 (0.45%)
    4 / 459 (0.87%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Distress
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Haemoptysis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    5 / 443 (1.13%)
    9 / 459 (1.96%)
         occurrences causally related to treatment / all
    3 / 5
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Marrow Failure
         subjects affected / exposed
    2 / 443 (0.45%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    22 / 443 (4.97%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    23 / 25
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    14 / 443 (3.16%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    15 / 15
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 443 (0.23%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain Oedema
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Leukoencephalopathy
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's Disease
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 443 (0.23%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular Fibrosis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloedema
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual Impairment
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    9 / 443 (2.03%)
    5 / 459 (1.09%)
         occurrences causally related to treatment / all
    7 / 9
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 443 (0.00%)
    3 / 459 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal Haemorrhage
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 443 (0.00%)
    3 / 459 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune Colitis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis Ulcerative
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    20 / 443 (4.51%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    21 / 23
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Obstruction
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 443 (0.68%)
    6 / 459 (1.31%)
         occurrences causally related to treatment / all
    2 / 3
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eterovesical Fistula
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal Disorder
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Haemorrhage
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal Perforation
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    6 / 443 (1.35%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    5 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    2 / 443 (0.45%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Perforation
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Large Intestinal Obstruction
         subjects affected / exposed
    2 / 443 (0.45%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Jejunal Perforation
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 443 (0.90%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 443 (0.00%)
    3 / 459 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    4 / 443 (0.90%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    4 / 443 (0.90%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 443 (0.45%)
    4 / 459 (0.87%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis Haemorrhagic
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    6 / 443 (1.35%)
    11 / 459 (2.40%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder Perforation
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder Tamponade
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    7 / 443 (1.58%)
    10 / 459 (2.18%)
         occurrences causally related to treatment / all
    0 / 9
    1 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 443 (0.00%)
    3 / 459 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postrenal Failure
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    5 / 443 (1.13%)
    4 / 459 (0.87%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Haematoma
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral Haemorrhage
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Bladder Haemorrhage
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    1 / 443 (0.23%)
    6 / 459 (1.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary Tract Obstruction
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Pain
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinoma
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune Hepatitis
         subjects affected / exposed
    0 / 443 (0.00%)
    4 / 459 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary Dilation
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular Injury
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal Vein Thrombosis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Psoriasis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic Epidermal Necrolysis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device Dislocation
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Occlusion
         subjects affected / exposed
    3 / 443 (0.68%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 443 (0.23%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    4 / 443 (0.90%)
    6 / 459 (1.31%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    3 / 443 (0.68%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin Pain
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    1 / 443 (0.23%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gouty Arthritis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal Insufficiency
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 443 (0.68%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Ketoacidosis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to Thrive
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypercalcaemia
         subjects affected / exposed
    1 / 443 (0.23%)
    3 / 459 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 443 (0.23%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 443 (0.68%)
    4 / 459 (0.87%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis Infective
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial Infection
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal Sepsis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal Infection
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Infection
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 443 (0.23%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Pyelonephritis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Sepsis
         subjects affected / exposed
    1 / 443 (0.23%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 443 (0.68%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney Infection
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella Infection
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningoencephalitis Viral
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    0 / 443 (0.00%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Infection
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    2 / 443 (0.45%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic Herpes Zoster
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 443 (1.58%)
    4 / 459 (0.87%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 5
         deaths causally related to treatment / all
    2 / 3
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 443 (0.23%)
    3 / 459 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    15 / 443 (3.39%)
    8 / 459 (1.74%)
         occurrences causally related to treatment / all
    6 / 16
    1 / 8
         deaths causally related to treatment / all
    1 / 4
    0 / 1
    Septic Shock
         subjects affected / exposed
    2 / 443 (0.45%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Spinal Cord Infection
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Infection
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic Shock Syndrome
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    14 / 443 (3.16%)
    21 / 459 (4.58%)
         occurrences causally related to treatment / all
    1 / 17
    0 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection Bacterial
         subjects affected / exposed
    1 / 443 (0.23%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    12 / 443 (2.71%)
    2 / 459 (0.44%)
         occurrences causally related to treatment / all
    6 / 12
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Bacteraemia
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyonephrosis
         subjects affected / exposed
    0 / 443 (0.00%)
    1 / 459 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Device Infection
         subjects affected / exposed
    4 / 443 (0.90%)
    0 / 459 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel) Atezolizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    417 / 443 (94.13%)
    413 / 459 (89.98%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    20 / 443 (4.51%)
    23 / 459 (5.01%)
         occurrences all number
    22
    24
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    107 / 443 (24.15%)
    92 / 459 (20.04%)
         occurrences all number
    144
    108
    Fatigue
         subjects affected / exposed
    136 / 443 (30.70%)
    129 / 459 (28.10%)
         occurrences all number
    162
    153
    Mucosal Inflammation
         subjects affected / exposed
    47 / 443 (10.61%)
    27 / 459 (5.88%)
         occurrences all number
    64
    30
    Oedema Peripheral
         subjects affected / exposed
    36 / 443 (8.13%)
    52 / 459 (11.33%)
         occurrences all number
    43
    59
    Pyrexia
         subjects affected / exposed
    62 / 443 (14.00%)
    93 / 459 (20.26%)
         occurrences all number
    76
    128
    Pain
         subjects affected / exposed
    31 / 443 (7.00%)
    24 / 459 (5.23%)
         occurrences all number
    34
    24
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    42 / 443 (9.48%)
    45 / 459 (9.80%)
         occurrences all number
    42
    48
    Anxiety
         subjects affected / exposed
    24 / 443 (5.42%)
    27 / 459 (5.88%)
         occurrences all number
    24
    27
    Investigations
    Blood Creatinine Increased
         subjects affected / exposed
    11 / 443 (2.48%)
    36 / 459 (7.84%)
         occurrences all number
    12
    38
    Neutrophil Count Decreased
         subjects affected / exposed
    26 / 443 (5.87%)
    0 / 459 (0.00%)
         occurrences all number
    49
    0
    Weight Decreased
         subjects affected / exposed
    45 / 443 (10.16%)
    47 / 459 (10.24%)
         occurrences all number
    46
    47
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    124 / 443 (27.99%)
    90 / 459 (19.61%)
         occurrences all number
    142
    94
    Neutropenia
         subjects affected / exposed
    57 / 443 (12.87%)
    5 / 459 (1.09%)
         occurrences all number
    75
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    30 / 443 (6.77%)
    59 / 459 (12.85%)
         occurrences all number
    36
    69
    Dyspnoea
         subjects affected / exposed
    46 / 443 (10.38%)
    62 / 459 (13.51%)
         occurrences all number
    50
    70
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    30 / 443 (6.77%)
    29 / 459 (6.32%)
         occurrences all number
    32
    29
    Dysgeusia
         subjects affected / exposed
    25 / 443 (5.64%)
    12 / 459 (2.61%)
         occurrences all number
    27
    14
    Neuropathy Peripheral
         subjects affected / exposed
    55 / 443 (12.42%)
    8 / 459 (1.74%)
         occurrences all number
    67
    9
    Headache
         subjects affected / exposed
    26 / 443 (5.87%)
    38 / 459 (8.28%)
         occurrences all number
    35
    44
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    41 / 443 (9.26%)
    6 / 459 (1.31%)
         occurrences all number
    43
    7
    Paraesthesia
         subjects affected / exposed
    29 / 443 (6.55%)
    18 / 459 (3.92%)
         occurrences all number
    32
    18
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    27 / 443 (6.09%)
    23 / 459 (5.01%)
         occurrences all number
    32
    23
    Abdominal Pain
         subjects affected / exposed
    58 / 443 (13.09%)
    52 / 459 (11.33%)
         occurrences all number
    63
    60
    Diarrhoea
         subjects affected / exposed
    94 / 443 (21.22%)
    97 / 459 (21.13%)
         occurrences all number
    115
    145
    Constipation
         subjects affected / exposed
    163 / 443 (36.79%)
    131 / 459 (28.54%)
         occurrences all number
    221
    147
    Nausea
         subjects affected / exposed
    137 / 443 (30.93%)
    106 / 459 (23.09%)
         occurrences all number
    171
    124
    Dry Mouth
         subjects affected / exposed
    8 / 443 (1.81%)
    30 / 459 (6.54%)
         occurrences all number
    8
    36
    Stomatitis
         subjects affected / exposed
    35 / 443 (7.90%)
    13 / 459 (2.83%)
         occurrences all number
    41
    16
    Vomiting
         subjects affected / exposed
    81 / 443 (18.28%)
    55 / 459 (11.98%)
         occurrences all number
    108
    67
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    26 / 443 (5.87%)
    45 / 459 (9.80%)
         occurrences all number
    32
    60
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    125 / 443 (28.22%)
    1 / 459 (0.22%)
         occurrences all number
    127
    1
    Pruritus
         subjects affected / exposed
    19 / 443 (4.29%)
    64 / 459 (13.94%)
         occurrences all number
    27
    86
    Rash
         subjects affected / exposed
    28 / 443 (6.32%)
    54 / 459 (11.76%)
         occurrences all number
    37
    72
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    60 / 443 (13.54%)
    47 / 459 (10.24%)
         occurrences all number
    79
    66
    Back Pain
         subjects affected / exposed
    51 / 443 (11.51%)
    80 / 459 (17.43%)
         occurrences all number
    53
    95
    Bone Pain
         subjects affected / exposed
    24 / 443 (5.42%)
    24 / 459 (5.23%)
         occurrences all number
    28
    27
    Myalgia
         subjects affected / exposed
    55 / 443 (12.42%)
    25 / 459 (5.45%)
         occurrences all number
    68
    27
    Pain in Extremity
         subjects affected / exposed
    48 / 443 (10.84%)
    37 / 459 (8.06%)
         occurrences all number
    55
    46
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    113 / 443 (25.51%)
    135 / 459 (29.41%)
         occurrences all number
    136
    147
    Hypokalaemia
         subjects affected / exposed
    23 / 443 (5.19%)
    16 / 459 (3.49%)
         occurrences all number
    26
    17
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    58 / 443 (13.09%)
    84 / 459 (18.30%)
         occurrences all number
    76
    141
    Nasopharyngitis
         subjects affected / exposed
    11 / 443 (2.48%)
    27 / 459 (5.88%)
         occurrences all number
    15
    43

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2015
    Protocol was amended to include changing the ratio of patients treated with vinflunine versus taxane such that it will be possible to conduct a subgroup analysis of patients treated with vinflunine versus atezolizumab. Within the control arm of the study, to allow more patients intended to receive vinflunine treatment when randomized into this trial, the maximum percentage of the patients who are treated with a taxane (paclitaxel or docetaxel) will be decreased from 50% to 40% with implementation of a cap. Once enrollment has reached 40% within the taxane intent-to-treat population, subsequent patients randomized to the control arm will receive vinflunine treatment.
    08 Mar 2016
    Protocol was amended to include an update to the use of any live vaccine to be prohibited 28 days prior to randomization.
    21 Jun 2016
    Protocol was amended to include an increase in the total number of patients enrolled in the study from 767 to 931 to achieve the pre-specified minimum number of 230 IC2/3 patients and 537 IC1/2/3 patients. Subsequently, the numbers of events were revised to ensure the study retains sufficient power and follow-up to estimate overall survival (OS).
    28 Oct 2016
    Protocol was amended based on updated clinical data regarding the atezolizumab half-life of 27 days, the following changes have been implemented: The period during which female patients must remain abstinent or use contraception and the length of follow-up of pregnancy reporting has been revised from 90 days to 5 months after the last dose of atezolizumab;The period during which patients must agree not to receive live, attenuated vaccine has been revised from 90 days to 5 months after the last dose of atezolizumab.
    01 Mar 2018
    Protocol was amended to include guidelines on the management of atezolizumab specific adverse events.

    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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