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    Clinical Trial Results:
    A Phase I/III, Randomized, Double-Blind, Placebo-Controlled Study of Carboplatin Plus Etoposide With or Without Atezolizumab (Anti-PD-L1 Antibody) in Patients With Untreated Extensive-Stage Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2015-004861-97
    Trial protocol
    		 DE   PL   HU   CZ   GB   AT   GR   ES   FR   IT  
    Global end of trial date

    Results information
    Results version number
    		 v2
    This version publication date
    06 Jun 2019
    First version publication date
    05 May 2019
    Other versions
    		 v1 , v3
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    GO30081
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02763579
    WHO universal trial number (UTN)
    		 -
    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
    Interim
    Date of interim/final analysis
    24 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Apr 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This randomized, Phase I/III, multicenter, double-blinded, placebo-controlled study was designed to evaluate the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1] antibody) in combination with carboplatin plus (+) etoposide compared with treatment with placebo + carboplatin + etoposide in subjects with chemotherapy-naive extensive-stage small cell lung cancer.
    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
    07 Jun 2016
    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: 11
    Country: Number of subjects enrolled
    China: 1
    Country: Number of subjects enrolled
    Japan: 42
    Country: Number of subjects enrolled
    Korea, Republic of: 17
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Austria: 20
    Country: Number of subjects enrolled
    Czech Republic: 17
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    United States: 86
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Poland: 45
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Serbia: 15
    Worldwide total number of subjects
    403
    EEA total number of subjects
    178
    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)
    217
    From 65 to 84 years
    184
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects in this study included: extensive-stage small cell lung cancer (ES-SCLC) with no prior systemic treatment for ES-SCLC.

    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
    		 Atezolizumab + Carboplatin + Etoposide
    Arm description
    		 Subjects received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, subjects received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    MPDL3280A, Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab intravenous infusion was administered at a dose of 1200 mg on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward).

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin intravenous infusion to achieve an initial target AUC of 5 mg/mL/min was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4).

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide intravenous infusion was administered at a dose of 100 mg/m^2 on Days 1, 2, and 3 of each 21-day cycle during the induction phase (Cycles 1-4).

    Arm title
    		 Placebo + Carboplatin + Etoposide
    Arm description
    		 Subjects received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, subjects received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo intravenous infusion was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4) and maintenance phase (Cycle 5 onward).

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin intravenous infusion to achieve an initial target AUC of 5 mg/mL/min was administered on Day 1 of each 21-day cycle during the induction phase (Cycles 1-4).

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide intravenous infusion was administered at a dose of 100 mg/m^2 on Days 1, 2, and 3 of each 21-day cycle during the induction phase (Cycles 1-4).

    Number of subjects in period 1
    		Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Started
    201
    202
    Completed
    0
    0
    Not completed
    201
    202
         Adverse event, serious fatal
    101
    132
         Consent withdrawn by subject
    18
    9
         Physician decision
    2
    -
         On-going in study
    77
    60
         Lost to follow-up
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Atezolizumab + Carboplatin + Etoposide
    Reporting group description
    		 Subjects received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, subjects received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Reporting group title
    Placebo + Carboplatin + Etoposide
    Reporting group description
    		 Subjects received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, subjects received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Reporting group values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide Total
    Number of subjects
    		 201 202 403
    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)
    		 111 106 217
        From 65-84 years
    		 89 95 184
        85 years and over
    		 1 1 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.8 ± 8.8 63.6 ± 9.0 -
    Gender categorical
    As reported from Electronic Case Report Form (eCRF).
    Units: Subjects
        Female
    		 72 70 142
        Male
    		 129 132 261

    End points

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    End points reporting groups
    Reporting group title
    Atezolizumab + Carboplatin + Etoposide
    Reporting group description
    		 Subjects received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, subjects received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Reporting group title
    Placebo + Carboplatin + Etoposide
    Reporting group description
    		 Subjects received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, subjects received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Primary: Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1

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    End point title
    		 Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1
    End point description
    Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as at least 20% increase in the sum of the longest diameter of target lesions compared to baseline, or unequivocal progression in non-target lesion(s), or the appearance of new lesion(s).
    End point type
    Primary
    End point timeframe
    Baseline until PD or death, whichever occurs first (up to approximately 23 months)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    201
    202
    Units: Months
        median (confidence interval 95%)
    5.2 (4.4 to 5.6)
    4.3 (4.2 to 4.5)
    Statistical analysis title
    		 Statistical Analysis for PFS
    Comparison groups
    Atezolizumab + Carboplatin + Etoposide v Placebo + Carboplatin + Etoposide
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 Logrank
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.96

    Primary: Duration of Overall Survival (OS)

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    End point title
    		 Duration of Overall Survival (OS)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline until death from any cause (up to approximately 23 months)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    201
    202
    Units: Months
        median (confidence interval 95%)
    12.3 (10.8 to 15.9)
    10.3 (9.3 to 11.3)
    Statistical analysis title
    		 Statistical Analysis for OS
    Comparison groups
    Atezolizumab + Carboplatin + Etoposide v Placebo + Carboplatin + Etoposide
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0069
    Method
    		 Logrank
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.91

    Secondary: Percentage of Participants With Objective Response (OR) as Assessed by the Investigator Using RECIST v1.1

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    End point title
    		 Percentage of Participants With Objective Response (OR) as Assessed by the Investigator Using RECIST v1.1
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline until partial response (PR) or complete response (CR), whichever occurs first (up to approximately 46 months)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: Percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [1] - Data will be analyzed at the time of study completion.
    [2] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1

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    End point title
    		 Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1
    End point description
    End point type
    Secondary
    End point timeframe
    First occurrence of PR or CR until PD or death, whichever occurs first (up to approximately 46 months)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: Months
        median (standard deviation)
    ±
    ±
    Notes
    [3] - Data will be analyzed at the time of study completion.
    [4] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Alive and Without PD, as Assessed by the Investigator Using RECIST v1.1, at 6 Months and 1 Year

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    End point title
    		 Percentage of Participants Alive and Without PD, as Assessed by the Investigator Using RECIST v1.1, at 6 Months and 1 Year
    End point description
    End point type
    Secondary
    End point timeframe
    6 months, 1 year (up to approximately 46 months)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Percentage
        number (not applicable)
    Notes
    [5] - Data will be analyzed at the time of study completion.
    [6] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Alive at 1 Year and 2 Years

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    End point title
    		 Percentage of Participants Alive at 1 Year and 2 Years
    End point description
    End point type
    Secondary
    End point timeframe
    1 year, 2 years (up to approximately 46 months)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: Percentage
        number (not applicable)
    Notes
    [7] - Data will be analyzed at the time of study completion.
    [8] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Time to Deterioration (TTD) per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) Score

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    End point title
    		 Time to Deterioration (TTD) per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) Score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline until deterioration per symptom subscale (up to approximately 46 months)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: Month
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [9] - Data will be analyzed at the time of study completion.
    [10] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: TTD per EORTC QLQ Lung Cancer Module (LC13) Score

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    End point title
    		 TTD per EORTC QLQ Lung Cancer Module (LC13) Score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline until deterioration per symptom subscale (up to approximately 46 months)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: Month
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [11] - Data will be analyzed at the time of study completion.
    [12] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    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
    Baseline until up to 90 days after end of treatment (up to approximately 46 months)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: Percentage
        number (not applicable)
    Notes
    [13] - Data will be analyzed at the time of study completion.
    [14] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Therapeutic Antibodies (ATAs)

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    End point title
    		 Percentage of Participants With Anti-Therapeutic Antibodies (ATAs)
    End point description
    End point type
    Secondary
    End point timeframe
    Predose (0 hours [H]) on Day (D) 1 of Cycles (C) 1, 2, 3, 4, 8, 16, and every 8 cycles (Q8C) thereafter (cycle = 21 days) until treatment discontinuation (up to 46 months) and 120 days after last dose (up to approximately 46 months overall)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: Percentage
        number (not applicable)
    Notes
    [15] - Data will be analyzed at the time of study completion.
    [16] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of Atezolizumab

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of Atezolizumab
    End point description
    Atezolizumab infusion duration is 60 minutes for the first infusion and 30 minutes for subsequent infusions.
    End point type
    Secondary
    End point timeframe
    Predose (0 H) and postdose (0.5 H) on D1 of C1; predose (0 H) on D1 of C2, 3, 4, 8, 16, and Q8C thereafter (cycle = 21 days) until treatment discontinuation (up to 46 months) and 120 days after last dose (up to approximately 46 months overall)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: mcg/mL
        geometric mean (standard deviation)
    ±
    ±
    Notes
    [17] - Data will be analyzed at the time of study completion.
    [18] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) of Atezolizumab

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    End point title
    		 Minimum Observed Serum Concentration (Cmin) of Atezolizumab
    End point description
    Atezolizumab infusion duration is 60 minutes for the first infusion and 30 minutes for subsequent infusions.
    End point type
    Secondary
    End point timeframe
    Predose (0 H) on D1 of C1, 2, 3, 4, 8, 16, and Q8C thereafter (cycle = 21 days) until treatment discontinuation (up to 46 months) and 120 days after last dose (up to approximately 46 months overall)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    0 [19]
    0 [20]
    Units: mcg/mL
        geometric mean (standard deviation)
    ±
    ±
    Notes
    [19] - Data will be analyzed at the time of study completion.
    [20] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Carboplatin

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    End point title
    		 Plasma Concentration of Carboplatin
    End point description
    End point type
    Secondary
    End point timeframe
    Predose (0 H) and 5-10 minutes before end/1 H after end of carboplatin infusion (infusion duration = 1 H) on D1 of C1 and C3 (cycle = 21 days)(up to approximately 46 months)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    0 [21]
    0 [22]
    Units: mcg/mL
        geometric mean (standard deviation)
    ±
    ±
    Notes
    [21] - Data will be analyzed at the time of study completion.
    [22] - Data will be analyzed at the time of study completion.
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Etoposide

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    End point title
    		 Plasma Concentration of Etoposide
    End point description
    End point type
    Secondary
    End point timeframe
    Predose (0 H) and 5-10 minutes before end/1 H and 4H after end of etoposide infusion (infusion duration = 1 H) on D1 of C1 and C3 (cycle = 21 days)(up to approximately 46 months)
    End point values
    		 Atezolizumab + Carboplatin + Etoposide Placebo + Carboplatin + Etoposide
    Number of subjects analysed
    0 [23]
    0 [24]
    Units: mcg/mL
        geometric mean (standard deviation)
    ±
    ±
    Notes
    [23] - Data will be analyzed at the time of study completion.
    [24] - Data will be analyzed at the time of study completion.
    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 administration to the data cutoff date: 24 April 2018 (up to 23 months).
    Adverse event reporting additional description
    Adverse Events reporting is for the Safety Evaluable Participants. Safety Evaluable Participants is defined as patients who received any amount of any component of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo + Carboplatin + Etoposide
    Reporting group description
    		 Subjects received intravenous infusions of placebo in combination with carboplatin to achieve an initial target AUC of 5 mg/mL/min followed by etoposide 100 mg/m^2 on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, subjects received maintenance (Cycle 5 onward) placebo on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Reporting group title
    Atezolizumab + Carboplatin + Etoposide
    Reporting group description
    		 Subjects received intravenous infusions of atezolizumab 1200 milligrams (mg) in combination with carboplatin to achieve an initial target area under the concentration-time curve (AUC) of 5 milligrams per milliliter per minute (mg/mL/min) followed by etoposide 100 milligrams per square meter (mg/m^2) on Day 1 of every 21-day cycle during the induction phase (Cycles 1-4). On Days 2 and 3 of every 21-day cycle during the induction phase (Cycles 1-4), etoposide 100 mg/m^2 was administered alone. Thereafter, subjects received maintenance (Cycle 5 onward) atezolizumab 1200 mg on Day 1 of every 21-day cycle until persistent radiographic PD, symptomatic deterioration, intolerable toxicity, withdrawal of consent, death, or study termination by the Sponsor.

    Serious adverse events
    		 Placebo + Carboplatin + Etoposide Atezolizumab + Carboplatin + Etoposide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 196 (34.69%)
    74 / 198 (37.37%)
         number of deaths (all causes)
    130
    103
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    METASTATIC NEOPLASM
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR PAIN
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL ARTERY OCCLUSION
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUPERIOR VENA CAVA SYNDROME
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOPHLEBITIS
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         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 / 196 (0.51%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (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
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    FATIGUE
         subjects affected / exposed
    0 / 196 (0.00%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 196 (0.51%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    NON−CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (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
    0 / 196 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    BRONCHIAL OBSTRUCTION
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    2 / 196 (1.02%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    2 / 196 (1.02%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    1 / 196 (0.51%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    HYPERCAPNIA
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    1 / 196 (0.51%)
    2 / 198 (1.01%)
         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 / 196 (1.02%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY OEDEMA
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         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 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    ALCOHOL ABUSE
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSION
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         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
    1 / 196 (0.51%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         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 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIVER FUNCTION TEST INCREASED
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSAMINASES INCREASED
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         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 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FEMUR FRACTURE
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEAD INJURY
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFUSION RELATED REACTION
         subjects affected / exposed
    2 / 196 (1.02%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RADIATION OESOPHAGITIS
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THORACIC VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    2 / 196 (1.02%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIOVENTRICULAR BLOCK COMPLETE
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC TAMPONADE
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIOPULMONARY FAILURE
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (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
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GUILLAIN−BARRE SYNDROME
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SOMNOLENCE
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         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 / 196 (0.00%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL CORD OEDEMA
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRIGEMINAL NEURALGIA
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         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
    ANAEMIA
         subjects affected / exposed
    2 / 196 (1.02%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DISSEMINATED INTRAVASCULAR COAGULATION
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    9 / 196 (4.59%)
    5 / 198 (2.53%)
         occurrences causally related to treatment / all
    9 / 9
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEUKOCYTOSIS
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    1 / 196 (0.51%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    8 / 196 (4.08%)
    7 / 198 (3.54%)
         occurrences causally related to treatment / all
    8 / 8
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    PANCYTOPENIA
         subjects affected / exposed
    4 / 196 (2.04%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    4 / 196 (2.04%)
    5 / 198 (2.53%)
         occurrences causally related to treatment / all
    4 / 4
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL ADHESIONS
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         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
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         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
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIP OEDEMA
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ILEUS
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FAECES DISCOLOURED
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC ULCER PERFORATION
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULAR PERFORATION
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 196 (0.51%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS ACUTE
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROCTITIS
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AUTOIMMUNE COLITIS
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    3 / 196 (1.53%)
    3 / 198 (1.52%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLANGITIS
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JAUNDICE
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN TOXICITY
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         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
    0 / 196 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUBULOINTERSTITIAL NEPHRITIS
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    AUTOIMMUNE THYROIDITIS
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTHRALGIA
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS INFECTION
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG ABSCESS
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG INFECTION
         subjects affected / exposed
    3 / 196 (1.53%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    7 / 196 (3.57%)
    9 / 198 (4.55%)
         occurrences causally related to treatment / all
    1 / 8
    4 / 12
         deaths causally related to treatment / all
    1 / 3
    1 / 1
    PULMONARY SEPSIS
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PYOPNEUMOTHORAX
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 196 (0.51%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (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
    2 / 196 (1.02%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 196 (0.00%)
    2 / 198 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOMAGNESAEMIA
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    4 / 196 (2.04%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Carboplatin + Etoposide Atezolizumab + Carboplatin + Etoposide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    186 / 196 (94.90%)
    190 / 198 (95.96%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    6 / 196 (3.06%)
    15 / 198 (7.58%)
         occurrences all number
    8
    20
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    19 / 196 (9.69%)
    23 / 198 (11.62%)
         occurrences all number
    25
    27
    CHEST PAIN
         subjects affected / exposed
    12 / 196 (6.12%)
    16 / 198 (8.08%)
         occurrences all number
    12
    19
    FATIGUE
         subjects affected / exposed
    49 / 196 (25.00%)
    51 / 198 (25.76%)
         occurrences all number
    61
    65
    OEDEMA PERIPHERAL
         subjects affected / exposed
    7 / 196 (3.57%)
    13 / 198 (6.57%)
         occurrences all number
    8
    14
    PYREXIA
         subjects affected / exposed
    16 / 196 (8.16%)
    18 / 198 (9.09%)
         occurrences all number
    18
    29
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    25 / 196 (12.76%)
    18 / 198 (9.09%)
         occurrences all number
    29
    22
    DYSPNOEA
         subjects affected / exposed
    16 / 196 (8.16%)
    19 / 198 (9.60%)
         occurrences all number
    17
    22
    HAEMOPTYSIS
         subjects affected / exposed
    10 / 196 (5.10%)
    14 / 198 (7.07%)
         occurrences all number
    10
    20
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    5 / 196 (2.55%)
    12 / 198 (6.06%)
         occurrences all number
    6
    15
    PRODUCTIVE COUGH
         subjects affected / exposed
    9 / 196 (4.59%)
    10 / 198 (5.05%)
         occurrences all number
    14
    10
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    13 / 196 (6.63%)
    15 / 198 (7.58%)
         occurrences all number
    13
    18
    Investigations
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    45 / 196 (22.96%)
    37 / 198 (18.69%)
         occurrences all number
    80
    74
    PLATELET COUNT DECREASED
         subjects affected / exposed
    28 / 196 (14.29%)
    25 / 198 (12.63%)
         occurrences all number
    39
    36
    WEIGHT DECREASED
         subjects affected / exposed
    10 / 196 (5.10%)
    20 / 198 (10.10%)
         occurrences all number
    11
    20
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    24 / 196 (12.24%)
    18 / 198 (9.09%)
         occurrences all number
    43
    35
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    8 / 196 (4.08%)
    10 / 198 (5.05%)
         occurrences all number
    9
    13
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    11 / 196 (5.61%)
    19 / 198 (9.60%)
         occurrences all number
    14
    22
    HEADACHE
         subjects affected / exposed
    23 / 196 (11.73%)
    24 / 198 (12.12%)
         occurrences all number
    25
    28
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    67 / 196 (34.18%)
    84 / 198 (42.42%)
         occurrences all number
    83
    95
    LEUKOPENIA
         subjects affected / exposed
    19 / 196 (9.69%)
    24 / 198 (12.12%)
         occurrences all number
    32
    42
    NEUTROPENIA
         subjects affected / exposed
    66 / 196 (33.67%)
    71 / 198 (35.86%)
         occurrences all number
    105
    122
    THROMBOCYTOPENIA
         subjects affected / exposed
    29 / 196 (14.80%)
    31 / 198 (15.66%)
         occurrences all number
    44
    45
    Gastrointestinal disorders
    CONSTIPATION
         subjects affected / exposed
    58 / 196 (29.59%)
    51 / 198 (25.76%)
         occurrences all number
    69
    61
    DIARRHOEA
         subjects affected / exposed
    30 / 196 (15.31%)
    32 / 198 (16.16%)
         occurrences all number
    46
    42
    NAUSEA
         subjects affected / exposed
    64 / 196 (32.65%)
    74 / 198 (37.37%)
         occurrences all number
    89
    99
    STOMATITIS
         subjects affected / exposed
    9 / 196 (4.59%)
    11 / 198 (5.56%)
         occurrences all number
    9
    11
    VOMITING
         subjects affected / exposed
    31 / 196 (15.82%)
    38 / 198 (19.19%)
         occurrences all number
    45
    47
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    68 / 196 (34.69%)
    73 / 198 (36.87%)
         occurrences all number
    71
    75
    PRURITUS
         subjects affected / exposed
    9 / 196 (4.59%)
    12 / 198 (6.06%)
         occurrences all number
    10
    12
    RASH
         subjects affected / exposed
    11 / 196 (5.61%)
    14 / 198 (7.07%)
         occurrences all number
    13
    21
    RASH MACULO−PAPULAR
         subjects affected / exposed
    2 / 196 (1.02%)
    10 / 198 (5.05%)
         occurrences all number
    3
    10
    Endocrine disorders
    HYPERTHYROIDISM
         subjects affected / exposed
    5 / 196 (2.55%)
    11 / 198 (5.56%)
         occurrences all number
    5
    11
    HYPOTHYROIDISM
         subjects affected / exposed
    1 / 196 (0.51%)
    20 / 198 (10.10%)
         occurrences all number
    1
    20
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    13 / 196 (6.63%)
    18 / 198 (9.09%)
         occurrences all number
    16
    20
    BACK PAIN
         subjects affected / exposed
    19 / 196 (9.69%)
    17 / 198 (8.59%)
         occurrences all number
    21
    17
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    11 / 196 (5.61%)
    12 / 198 (6.06%)
         occurrences all number
    13
    14
    PAIN IN EXTREMITY
         subjects affected / exposed
    6 / 196 (3.06%)
    13 / 198 (6.57%)
         occurrences all number
    7
    13
    Infections and infestations
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    16 / 196 (8.16%)
    14 / 198 (7.07%)
         occurrences all number
    19
    16
    URINARY TRACT INFECTION
         subjects affected / exposed
    5 / 196 (2.55%)
    12 / 198 (6.06%)
         occurrences all number
    5
    16
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    36 / 196 (18.37%)
    54 / 198 (27.27%)
         occurrences all number
    39
    62
    HYPOKALAEMIA
         subjects affected / exposed
    17 / 196 (8.67%)
    8 / 198 (4.04%)
         occurrences all number
    18
    8
    HYPOMAGNESAEMIA
         subjects affected / exposed
    9 / 196 (4.59%)
    12 / 198 (6.06%)
         occurrences all number
    9
    17
    HYPONATRAEMIA
         subjects affected / exposed
    12 / 196 (6.12%)
    10 / 198 (5.05%)
         occurrences all number
    14
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Aug 2016
    Protocol was amended to include change of phase from Phase III to Phase I/III. A secondary objective and corresponding outcome measure has been added to evaluate the efficacy of atezolizumab + carboplatin + etoposide compared with placebo + carboplatin + etoposide as measured by investigator-assessed time to response (TTR). TTR will be assessed in the intent-to-treat (ITT) population for patients who had an objective response as determined by the investigator according to RECIST v1.1. Clarifications were made around eligibility criteria and study conduct.
    29 Aug 2017
    Protocol was amended to include modifications to the statistical analysis plan and the timing for the efficacy analyses for progression-free survival (PFS) and overall survival (OS).
    06 Mar 2019
    Protocol was amended to include additional language to the end of study definition to clarify that if the Sponsor decides to terminate the study, subjects who are still receiving study treatment or are in survival follow-up may be enrolled into an extension study or non-interventional study. The timing of the interim and final analysis were modified to be aligned with the statistical analysis plan.

    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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