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    Clinical Trial Results:
    A Phase II, Randomized, Double-Blind Placebo-Controlled Study of Atezolizumab With or Without Bevacizumab in Combination With Cisplatin Plus Gemcitabine in Patients With Untreated, Advanced Biliary Tract Cancer

    Summary
    EudraCT number
    		 2020-003759-14
    Trial protocol
    		 PL   IT  
    Global end of trial date
    25 Aug 2023

    Results information
    Results version number
    		 v3(current)
    This version publication date
    27 Jun 2024
    First version publication date
    27 May 2023
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GO42661
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04677504
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4058
    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
    25 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study evaluated the efficacy and safety of atezolizumab with bevacizumab in combination with cisplatin and gemcitabine (CisGem), compared with atezolizumab in combination with CisGem, in participants with advanced biliary tract cancer (BTC) (i.e., intrahepatic cholangiocarcinoma [iCCA], extrahepatic CCA [eCCA], or gallbladder cancer [GBC]) who did not received prior systemic therapy.
    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
    23 Feb 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 6
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 44
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Russian Federation: 16
    Country: Number of subjects enrolled
    Thailand: 8
    Country: Number of subjects enrolled
    Türkiye: 8
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Ukraine: 7
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    162
    EEA total number of subjects
    39
    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)
    89
    From 65 to 84 years
    73
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This is a global multicenter study.

    Pre-assignment
    Screening details
    		 This study included participants with advanced biliary tract cancer (i.e., intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer) who did not receive prior systemic therapy.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO
    Arm description
    		 Participants received atezolizumab intravenously on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, and clinical status. Participants received placebo matching bevacizumab intravenously on Day 1 of each 21-day cycle. Participants received cisplatin intravenously followed by gemcitabine on Days 1 and 8 of each 21-day cycle for Cycles 1-8.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine was administered intravenously at a dose of 1000 mg/m^2 on Days 1 and 8 of each 21-day cycle for Cycles 1-8.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered intravenously at a dose of 25 mg/m^2 on Days 1 and 8 of each 21-day cycle for Cycles 1-8.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo matching bevacizumab was administered intravenously on Day 1 of each 21-day cycle after atezolizumab.

    Arm title
    		 Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Arm description
    		 Participants received atezolizumab intravenously on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, and clinical status. Participants received bevacizumab intravenously on Day 1 of each 21-day cycle. Participants received cisplatin intravenously followed by gemcitabine on Days 1 and 8 of each 21-day cycle for Cycles 1-8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Gemcitabine was administered intravenously at a dose of 1000 mg/m^2 on Days 1 and 8 of each 21-day cycle for Cycles 1-8.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin was administered intravenously at a dose of 25 mg/m^2 on Days 1 and 8 of each 21-day cycle for Cycles 1-8.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered at a dose of 15 mg/kg intravenously on Day 1 of each 21-day cycle after atezolizumab.

    Number of subjects in period 1
    		Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Started
    83
    79
    Completed
    0
    0
    Not completed
    83
    79
         Consent withdrawn by subject
    2
    5
         Adverse Event
    -
    1
         Study Terminated By Sponsor
    28
    24
         Death
    51
    49
         Progressive Disease
    1
    -
         Symptomatic Deterioration
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO
    Reporting group description
    		 Participants received atezolizumab intravenously on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, and clinical status. Participants received placebo matching bevacizumab intravenously on Day 1 of each 21-day cycle. Participants received cisplatin intravenously followed by gemcitabine on Days 1 and 8 of each 21-day cycle for Cycles 1-8.

    Reporting group title
    Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Reporting group description
    		 Participants received atezolizumab intravenously on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, and clinical status. Participants received bevacizumab intravenously on Day 1 of each 21-day cycle. Participants received cisplatin intravenously followed by gemcitabine on Days 1 and 8 of each 21-day cycle for Cycles 1-8.

    Reporting group values
    		 Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev Total
    Number of subjects
    		 83 79 162
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 38 51 89
        From 65-84 years
    		 45 28 73
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 63.0 ( 9.8 ) 59.6 ( 9.9 ) -
    Sex: Female, Male
    Units:
        Female
    		 45 30 75
        Male
    		 38 49 87
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 35 37 72
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 1 2
        White
    		 46 41 87
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 1 2
        Not Hispanic or Latino
    		 82 78 160
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO
    Reporting group description
    		 Participants received atezolizumab intravenously on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, and clinical status. Participants received placebo matching bevacizumab intravenously on Day 1 of each 21-day cycle. Participants received cisplatin intravenously followed by gemcitabine on Days 1 and 8 of each 21-day cycle for Cycles 1-8.

    Reporting group title
    Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Reporting group description
    		 Participants received atezolizumab intravenously on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, and clinical status. Participants received bevacizumab intravenously on Day 1 of each 21-day cycle. Participants received cisplatin intravenously followed by gemcitabine on Days 1 and 8 of each 21-day cycle for Cycles 1-8.

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS is defined as the time from randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first)
    End point type
    Primary
    End point timeframe
    Randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first)(up to approximately 14 months)
    End point values
    		 Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects analysed
    83
    79
    Units: Months
        median (confidence interval 95%)
    7.92 (6.18 to 8.41)
    8.35 (6.83 to 9.96)
    Statistical analysis title
    		 PFS Statistical Analysis
    Statistical analysis description
    Stratified analysis. Stratification factors are: Location of primary tumor (iCCA vs. eCCA vs. GBC), Geographic region (Asia vs. Rest of the World).
    Comparison groups
    Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO v Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.14

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from randomization to death from any cause. 999999=not estimable.
    End point type
    Secondary
    End point timeframe
    Randomization to death from any cause (up to approximately 23 months)
    End point values
    		 Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects analysed
    83
    79
    Units: Months
        median (confidence interval 95%)
    14.59 (11.17 to 999999)
    14.85 (11.63 to 17.97)
    Statistical analysis title
    		 OS Statistical Analysis
    Statistical analysis description
    Stratified analysis. Stratification factors are: Location of primary tumor (iCCA vs. eCCA vs. GBC), Geographic region (Asia vs. Rest of the World).
    Comparison groups
    Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO v Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8857
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.47

    Secondary: Confirmed Objective Response Rate (ORR)

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    End point title
    		 Confirmed Objective Response Rate (ORR)
    End point description
    Confirmed ORR is defined as the proportion of participants with Complete Response (CR) or Partial Response (PR) on two consecutive occasions >=4 weeks apart, as determined by the investigator according to RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Randomization up to approximately 14 months
    End point values
    		 Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects analysed
    83
    79
    Units: Percentage of participants
        number (not applicable)
    25.3
    24.1
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR is defined as the time from the first occurrence of a confirmed objective response to disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first). 999999=not estimable.
    End point type
    Secondary
    End point timeframe
    First occurrence of a confirmed objective response to disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first)(up to approximately 14 months)
    End point values
    		 Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects analysed
    21
    19
    Units: Months
        median (confidence interval 95%)
    5.78 (4.27 to 6.70)
    999999 (6.44 to 999999)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR is defined as the proportion of participants with a CR or a PR on two consecutive occasions >= 4 weeks apart or SD with a minimum duration of 9weeks, as determined by the investigator according to RECIST v1.1
    End point type
    Secondary
    End point timeframe
    Randomization up to approximately 14 months
    End point values
    		 Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects analysed
    83
    79
    Units: Percentage of participants
        number (not applicable)
    75.9
    78.5
    No statistical analyses for this end point

    Secondary: Time to Confirmed Deterioration (TTCD)

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    End point title
    		 Time to Confirmed Deterioration (TTCD)
    End point description
    TTCD in patient-reported physical functioning, role functioning, and quality of life, as measured by the respective scales of the EORTC QLQ-C30 and/or EORTC IL77, and defined as the time from randomization to the first clinically meaningful deterioration that is either maintained for two consecutive assessments or followed by death from any cause within 3 weeks. 999999=not estimable.
    End point type
    Secondary
    End point timeframe
    Randomization to the first clinically meaningful deterioration (up to approximately 14 months)
    End point values
    		 Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects analysed
    83
    79
    Units: Months
    median (confidence interval 95%)
        Quality of Life
    6.28 (3.06 to 999999)
    2.79 (1.58 to 5.32)
        Physical Function Scale
    3.29 (1.87 to 10.58)
    6.21 (4.63 to 999999)
        Role Function Scale
    3.52 (2.20 to 8.51)
    4.24 (2.10 to 6.28)
    Statistical analysis title
    		 Quality of Life Statistical Analysis
    Statistical analysis description
    Stratified analysis. Stratification factors are: Location of primary tumor (iCCA vs. eCCA vs. GBC), Geographic region (Asia vs. Rest of the World).
    Comparison groups
    Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO v Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 2.63
    Statistical analysis title
    		 Role Function Scale Statistical Analysis
    Statistical analysis description
    Stratified analysis. Stratification factors are: Location of primary tumor (iCCA vs. eCCA vs. GBC), Geographic region (Asia vs. Rest of the World).
    Comparison groups
    Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO v Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.85
    Statistical analysis title
    		 Physical Function Scale Statistical Analysis
    Statistical analysis description
    Stratified analysis. Stratification factors are: Location of primary tumor (iCCA vs. eCCA vs. GBC), Geographic region (Asia vs. Rest of the World).
    Comparison groups
    Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO v Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.36

    Secondary: Percentage of Participants With Adverse Events

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    End point title
    		 Percentage of Participants With Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment start up to approximately 30 months.
    End point values
    		 Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects analysed
    81
    78
    Units: Percentage of participants
    100
    100
    No statistical analyses for this end point

    Secondary: Serum Concentration of Atezolizumab

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    End point title
    		 Serum Concentration of Atezolizumab
    End point description
    Serum concentration of atezolizumab at specified timepoints. Note: 999999= below the level of detection.
    End point type
    Secondary
    End point timeframe
    Pre-Dose on Day 1 of Cycles 1, 2, 3, 4, 8, 12, and 16, and Post Dose Day 1 of Cycle 1 (cycle length=21 days)
    End point values
    		 Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects analysed
    81
    78
    Units: μg/ mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 Pre-Dose (n=74, 78)
    999999 ( 999999 )
    999999 ( 999999 )
        Cycle 1 Day 1 Post Dose (n=75, 80)
    416 ( 173 )
    411 ( 73.8 )
        Cycle 2 Day 1 Pre-Dose (n=75, 78)
    85.0 ( 71.7 )
    79.4 ( 46.1 )
        Cycle 3 Day 1 Pre-Dose (n=72, 74)
    129 ( 83.5 )
    118 ( 41.4 )
        Cycle 4 Day 1 Pre-Dose (n=69, 64)
    153 ( 74.8 )
    155 ( 50.6 )
        Cycle 8 Day 1 Pre-Dose (n=54, 51)
    224 ( 126 )
    200 ( 100 )
        Cycle 12 Day 1 Pre-Dose (n=31, 28)
    223 ( 103 )
    210 ( 76.4 )
        Cycle 16 Day 1 Pre-Dose (n=8, 6)
    230 ( 71.6 )
    174 ( 64.9 )
    No statistical analyses for this end point

    Secondary: Prevalence of ADAs to Atezolizumab

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    End point title
    		 Prevalence of ADAs to Atezolizumab
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: Percentage of participants
    Notes
    [1] - No data were collected because the study was discontinued before any measurements were completed.
    [2] - No data were collected because the study was discontinued before any measurements were completed.
    No statistical analyses for this end point

    Secondary: Incidence of ADAs to Atezolizumab

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    End point title
    		 Incidence of ADAs to Atezolizumab
    End point description
    End point type
    Secondary
    End point timeframe
    At pre-defined intervals from administration of study drug up to approximately 3-5 years
    End point values
    		 Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Percentage of participants
    Notes
    [3] - No data were collected because the study was discontinued before any measurements were completed.
    [4] - No data were collected because the study was discontinued before any measurements were completed.
    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 until the data cut-off on 25 August 2023 (up to approximately 30 months)
    Adverse event reporting additional description
    Safety-evaluable population included all randomized participants who receive any amount of any component of protocol treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev
    Reporting group description
    		 Participants received atezolizumab intravenously on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, and clinical status. Participants received bevacizumab intravenously on Day 1 of each 21-day cycle. Participants received cisplatin intravenously followed by gemcitabine on Days 1 and 8 of each 21-day cycle for Cycles 1-8.

    Reporting group title
    Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO
    Reporting group description
    		 Participants received atezolizumab intravenously on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, and clinical status. Participants received placebo matching bevacizumab intravenously on Day 1 of each 21-day cycle. Participants received cisplatin intravenously followed by gemcitabine on Days 1 and 8 of each 21-day cycle for Cycles 1-8.

    Serious adverse events
    		 Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 78 (46.15%)
    43 / 81 (53.09%)
         number of deaths (all causes)
    50
    51
         number of deaths resulting from adverse events
    1
    3
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         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
    Asthenia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Fatigue
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 78 (3.85%)
    5 / 81 (6.17%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer haemorrhage
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Prostatic obstruction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         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 / 78 (2.56%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood culture positive
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         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
    Spinal compression fracture
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain stem infarction
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neutropenia
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    6 / 81 (7.41%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Ocular myasthenia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal stenosis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal obstruction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary dilatation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 81 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    2 / 78 (2.56%)
    5 / 81 (6.17%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disease
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 81 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gallbladder obstruction
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (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
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Enterocolitis infectious
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (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
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Recurrent pyogenic cholangitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematological infection
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 81 (1.23%)
         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
    1 / 78 (1.28%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: Atezo+Bev+CisGem, followed by Atezo+Bev Arm B: Atezo+PBO+CisGem, followed by Atezo+PBO
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 78 (98.72%)
    81 / 81 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    29 / 78 (37.18%)
    15 / 81 (18.52%)
         occurrences all number
    36
    17
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 78 (17.95%)
    16 / 81 (19.75%)
         occurrences all number
    28
    33
    Pyrexia
         subjects affected / exposed
    14 / 78 (17.95%)
    20 / 81 (24.69%)
         occurrences all number
    26
    44
    Oedema peripheral
         subjects affected / exposed
    6 / 78 (7.69%)
    7 / 81 (8.64%)
         occurrences all number
    6
    8
    Fatigue
         subjects affected / exposed
    21 / 78 (26.92%)
    18 / 81 (22.22%)
         occurrences all number
    29
    22
    Mucosal inflammation
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 81 (2.47%)
         occurrences all number
    9
    3
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    11 / 78 (14.10%)
    2 / 81 (2.47%)
         occurrences all number
    13
    3
    Cough
         subjects affected / exposed
    3 / 78 (3.85%)
    9 / 81 (11.11%)
         occurrences all number
    3
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 78 (3.85%)
    7 / 81 (8.64%)
         occurrences all number
    3
    7
    Anxiety
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 81 (0.00%)
         occurrences all number
    4
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    22 / 78 (28.21%)
    22 / 81 (27.16%)
         occurrences all number
    48
    49
    Neutrophil count decreased
         subjects affected / exposed
    38 / 78 (48.72%)
    32 / 81 (39.51%)
         occurrences all number
    93
    80
    Lymphocyte count decreased
         subjects affected / exposed
    7 / 78 (8.97%)
    7 / 81 (8.64%)
         occurrences all number
    17
    19
    Blood creatinine increased
         subjects affected / exposed
    7 / 78 (8.97%)
    11 / 81 (13.58%)
         occurrences all number
    7
    13
    Blood bilirubin increased
         subjects affected / exposed
    8 / 78 (10.26%)
    7 / 81 (8.64%)
         occurrences all number
    8
    11
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 78 (6.41%)
    5 / 81 (6.17%)
         occurrences all number
    9
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 78 (12.82%)
    17 / 81 (20.99%)
         occurrences all number
    15
    20
    Alanine aminotransferase increased
         subjects affected / exposed
    11 / 78 (14.10%)
    15 / 81 (18.52%)
         occurrences all number
    15
    22
    Weight decreased
         subjects affected / exposed
    10 / 78 (12.82%)
    7 / 81 (8.64%)
         occurrences all number
    10
    7
    Weight increased
         subjects affected / exposed
    5 / 78 (6.41%)
    5 / 81 (6.17%)
         occurrences all number
    5
    5
    White blood cell count decreased
         subjects affected / exposed
    15 / 78 (19.23%)
    13 / 81 (16.05%)
         occurrences all number
    32
    34
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 78 (8.97%)
    5 / 81 (6.17%)
         occurrences all number
    7
    8
    Dizziness
         subjects affected / exposed
    6 / 78 (7.69%)
    3 / 81 (3.70%)
         occurrences all number
    6
    3
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    7 / 78 (8.97%)
    6 / 81 (7.41%)
         occurrences all number
    18
    13
    Neutropenia
         subjects affected / exposed
    17 / 78 (21.79%)
    17 / 81 (20.99%)
         occurrences all number
    37
    31
    Anaemia
         subjects affected / exposed
    37 / 78 (47.44%)
    51 / 81 (62.96%)
         occurrences all number
    59
    88
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    16 / 78 (20.51%)
    12 / 81 (14.81%)
         occurrences all number
    23
    12
    Stomatitis
         subjects affected / exposed
    10 / 78 (12.82%)
    5 / 81 (6.17%)
         occurrences all number
    10
    5
    Nausea
         subjects affected / exposed
    32 / 78 (41.03%)
    32 / 81 (39.51%)
         occurrences all number
    51
    44
    Haemorrhoids
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 81 (1.23%)
         occurrences all number
    4
    1
    Dyspepsia
         subjects affected / exposed
    3 / 78 (3.85%)
    7 / 81 (8.64%)
         occurrences all number
    3
    7
    Diarrhoea
         subjects affected / exposed
    14 / 78 (17.95%)
    13 / 81 (16.05%)
         occurrences all number
    22
    16
    Ascites
         subjects affected / exposed
    5 / 78 (6.41%)
    5 / 81 (6.17%)
         occurrences all number
    6
    5
    Abdominal pain
         subjects affected / exposed
    15 / 78 (19.23%)
    13 / 81 (16.05%)
         occurrences all number
    16
    16
    Constipation
         subjects affected / exposed
    30 / 78 (38.46%)
    23 / 81 (28.40%)
         occurrences all number
    39
    25
    Abdominal pain upper
         subjects affected / exposed
    4 / 78 (5.13%)
    5 / 81 (6.17%)
         occurrences all number
    4
    7
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 81 (2.47%)
         occurrences all number
    4
    2
    Urticaria
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 81 (1.23%)
         occurrences all number
    5
    1
    Rash
         subjects affected / exposed
    11 / 78 (14.10%)
    9 / 81 (11.11%)
         occurrences all number
    15
    9
    Alopecia
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 81 (2.47%)
         occurrences all number
    4
    2
    Pruritus
         subjects affected / exposed
    7 / 78 (8.97%)
    7 / 81 (8.64%)
         occurrences all number
    9
    11
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    16 / 78 (20.51%)
    9 / 81 (11.11%)
         occurrences all number
    21
    9
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    6 / 78 (7.69%)
    6 / 81 (7.41%)
         occurrences all number
    6
    6
    Hyperthyroidism
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 81 (1.23%)
         occurrences all number
    4
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 78 (10.26%)
    5 / 81 (6.17%)
         occurrences all number
    13
    5
    Arthralgia
         subjects affected / exposed
    9 / 78 (11.54%)
    5 / 81 (6.17%)
         occurrences all number
    13
    6
    Myalgia
         subjects affected / exposed
    1 / 78 (1.28%)
    5 / 81 (6.17%)
         occurrences all number
    1
    5
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 78 (5.13%)
    7 / 81 (8.64%)
         occurrences all number
    4
    7
    COVID-19
         subjects affected / exposed
    11 / 78 (14.10%)
    13 / 81 (16.05%)
         occurrences all number
    12
    13
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    7 / 78 (8.97%)
    11 / 81 (13.58%)
         occurrences all number
    10
    12
    Hypomagnesaemia
         subjects affected / exposed
    10 / 78 (12.82%)
    8 / 81 (9.88%)
         occurrences all number
    15
    12
    Hypokalaemia
         subjects affected / exposed
    6 / 78 (7.69%)
    11 / 81 (13.58%)
         occurrences all number
    7
    14
    Hypoalbuminaemia
         subjects affected / exposed
    9 / 78 (11.54%)
    6 / 81 (7.41%)
         occurrences all number
    9
    6
    Hyperglycaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    5 / 81 (6.17%)
         occurrences all number
    1
    6
    Decreased appetite
         subjects affected / exposed
    15 / 78 (19.23%)
    14 / 81 (17.28%)
         occurrences all number
    16
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2020
    Protocol has been amended to include sensitivity analysis to assess the robustness of the primary progression-free survival analysis. A sensitivity analysis will be performed by incorporating an additional censoring rule for participants who take new anti-cancer therapy prior to occurrence of radiographic progression. These participants will be censored at the last tumor assessment before the start of the new treatment, regardless of progression or death afterwards.
    03 Mar 2021
    Protocol has been amended to include updates to the exclusion criteria around symptomatic and asymptomatic brain metastasis. Also, participants with large centrally located pulmonary metastases; clear tumor infiltration into the thoracic great vessels seen on imaging; and clear cavitation of pulmonary lesions seen on imaging will be excluded from this study. The order of administration of cisplatin and gemcitabine has been clarified. The list of identified risks for atezolizumab have been revised to include severe cutaneous adverse reactions. Language has been added to clarify that hemophagocytic lymphohistiocytosis and macrophage activation syndrome are considered potential risks for atezolizumab.
    27 Sep 2022
    Protocol has been amended to add a final overall survival analysis. The timing of the patient-reported outcome assessments has been clarified.
    03 Feb 2023
    Protocol has been amended to include pericardial disorders, myelitis, and facial paresis in the list of identified risks for atezolizumab. Hemophagocytic lymphohistiocytosis has been updated from a potential risk to an identified risk associated with atezolizumab.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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