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    Clinical Trial Results:
    A Phase III Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Neoadjuvant Anthracycline/Nab-Paclitaxel-Based Chemotherapy Compared With Placebo and Chemotherapy in Patients With Primary Invasive Triple-Negative Breast Cancer

    Summary
    EudraCT number
    		 2016-004734-22
    Trial protocol
    		 DE   GB   BE   PL   ES   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    14 Apr 2021
    First version publication date
    14 Apr 2021
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    WO39392
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03197935
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Other Sponsor ID: IMpassion031
    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
    03 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Apr 2020
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this study were to evaluate the efficacy, safety, and pharmacokinetics of neoadjuvant nab-paclitaxel and atezolizumab followed by doxorubicin and cyclophosphamide with atezolizumab or neoadjuvant nab-paclitaxel and placebo followed by doxorubicin and cyclophosphamide with placebo in participants with T2-4d triple-negative breast cancer (TNBC).
    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
    24 Jul 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 50 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Brazil: 113
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Germany: 48
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 36
    Country: Number of subjects enrolled
    Korea, Republic of: 27
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Taiwan: 21
    Country: Number of subjects enrolled
    United States: 41
    Worldwide total number of subjects
    333
    EEA total number of subjects
    74
    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)
    287
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants with clinically assessed T2-4d early or primary invasive triple-negative breast cancer (TNBC) who were eligible for surgery were included in the study.

    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
    		 Placebo and Chemotherapy
    Arm description
    		 Participants received placebo matched to atezolizumab via IV infusion every 2 weeks in combination with nab-paclitaxel (125 mg/m^2) via IV infusion every week for 12 weeks, followed by placebo matched to atezolizumab every 2 weeks in combination with doxorubicin (60 mg/m^2) and cyclophosphamide (600 mg/m^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants will continue to be followed.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    MPDL3280A, Tecentriq
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo matched to atezolizumab was administered intravenously every 2 weeks for 12 weeks, followed by placebo matched to atezolizumab administered intravenously every 2 weeks for 4 doses.

    Investigational medicinal product name
    Nab-paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nab-paclitaxel was administered at a dose of 125 milligrams per square meter [mg/m^2] intravenously every week for 12 weeks.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin was administered at a dose of 60 mg/m^2 every 2 weeks intravenously for 4 doses.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide was administered at a dose of 600 mg/m^2 every 2 weeks intravenously for 4 doses.

    Arm title
    		 Atezolizumab and Chemotherapy
    Arm description
    		 Participants received atezolizumab (840 milligrams [mg]) via intravenous (IV) infusion every 2 weeks in combination with nab-paclitaxel (125 milligrams per square meter [mg/m^2]) via IV infusion every week for 12 weeks, followed by atezolizumab (840 mg) every 2 weeks in combination with doxorubicin (60 mg/m^2) and cyclophosphamide (600 mg/m^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants continued to receive unblinded atezolizumab post-surgery at a fixed dose of 1200 mg by IV infusion every 3 weeks for 11 doses, for a total of approximately 12 months of atezolizumab therapy.
    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 was administered intravenously at a dose of 840 milligrams every 2 weeks for 12 weeks, followed by a dose of 840 mg of atezolizumab administered intravenously every 2 weeks for 4 doses. Participants continued to receive unblinded atezolizumab post-surgery at a fixed dose of 1200 mg intravenously every 3 weeks for 11 doses, for a total of approximately 12 months of atezolizumab therapy.

    Investigational medicinal product name
    Nab-paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Nab-paclitaxel was administered at a dose of 125 milligrams per square meter [mg/m^2] intravenously every week for 12 weeks.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin was administered at a dose of 60 mg/m^2 every 2 weeks intravenously for 4 doses.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide was administered at a dose of 600 mg/m^2 every 2 weeks intravenously for 4 doses.

    Number of subjects in period 1
    		Placebo and Chemotherapy Atezolizumab and Chemotherapy
    Started
    168
    165
    Completed
    0
    0
    Not completed
    168
    165
         On-Going in Study
    147
    146
         Consent withdrawn by subject
    11
    7
         Physician decision
    -
    1
         Death due to any cause
    9
    7
         Lost to follow-up
    -
    3
         Did not receive any study treatment
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo and Chemotherapy
    Reporting group description
    		 Participants received placebo matched to atezolizumab via IV infusion every 2 weeks in combination with nab-paclitaxel (125 mg/m^2) via IV infusion every week for 12 weeks, followed by placebo matched to atezolizumab every 2 weeks in combination with doxorubicin (60 mg/m^2) and cyclophosphamide (600 mg/m^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants will continue to be followed.

    Reporting group title
    Atezolizumab and Chemotherapy
    Reporting group description
    		 Participants received atezolizumab (840 milligrams [mg]) via intravenous (IV) infusion every 2 weeks in combination with nab-paclitaxel (125 milligrams per square meter [mg/m^2]) via IV infusion every week for 12 weeks, followed by atezolizumab (840 mg) every 2 weeks in combination with doxorubicin (60 mg/m^2) and cyclophosphamide (600 mg/m^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants continued to receive unblinded atezolizumab post-surgery at a fixed dose of 1200 mg by IV infusion every 3 weeks for 11 doses, for a total of approximately 12 months of atezolizumab therapy.

    Reporting group values
    		 Placebo and Chemotherapy Atezolizumab and Chemotherapy Total
    Number of subjects
    		 168 165 333
    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)
    		 139 148 287
        From 65-84 years
    		 29 17 46
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 50.3 ± 13.2 50.1 ± 11.6 -
    Sex: Female, Male
    Units: Participants
        Female
    		 168 165 333
        Male
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 41 47 88
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 15 9 24
        White
    		 108 102 210
        More than one race
    		 0 4 4
        Unknown or Not Reported
    		 4 3 7
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 47 45 92
        Not Hispanic or Latino
    		 114 114 228
        Unknown or Not Reported
    		 7 6 13

    End points

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    End points reporting groups
    Reporting group title
    Placebo and Chemotherapy
    Reporting group description
    		 Participants received placebo matched to atezolizumab via IV infusion every 2 weeks in combination with nab-paclitaxel (125 mg/m^2) via IV infusion every week for 12 weeks, followed by placebo matched to atezolizumab every 2 weeks in combination with doxorubicin (60 mg/m^2) and cyclophosphamide (600 mg/m^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants will continue to be followed.

    Reporting group title
    Atezolizumab and Chemotherapy
    Reporting group description
    		 Participants received atezolizumab (840 milligrams [mg]) via intravenous (IV) infusion every 2 weeks in combination with nab-paclitaxel (125 milligrams per square meter [mg/m^2]) via IV infusion every week for 12 weeks, followed by atezolizumab (840 mg) every 2 weeks in combination with doxorubicin (60 mg/m^2) and cyclophosphamide (600 mg/m^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants continued to receive unblinded atezolizumab post-surgery at a fixed dose of 1200 mg by IV infusion every 3 weeks for 11 doses, for a total of approximately 12 months of atezolizumab therapy.

    Primary: Number of Participants with Pathologic Complete Response (pCR) Using American Joint Committee on Cancer (AJCC) Staging System in ITT Population

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    End point title
    		 Number of Participants with Pathologic Complete Response (pCR) Using American Joint Committee on Cancer (AJCC) Staging System in ITT Population
    End point description
    Number of participants with Pathologic Complete Response (pCR) Using American Joint Committee on Cancer (AJCC) Staging System in ITT Population. pCR is defined as eradication of invasive tumor from both breast and lymph nodes (ypT0/is ypN0). Participants whose pCR assessment was missing will be counted as not achieving a pCR.
    End point type
    Primary
    End point timeframe
    Up to data cut-off on 3 April 2020
    End point values
    		 Placebo and Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    168
    165
    Units: Number of participants
        number (not applicable)
    69
    95
    Statistical analysis title
    		 pCR in ITT Population
    Comparison groups
    Placebo and Chemotherapy v Atezolizumab and Chemotherapy
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0044 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in pCR
    Point estimate
    16.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.91
         upper limit
    		 27.1
    Notes
    [1] - (one-sided)

    Primary: Number of Participants with pCR in Subpopulation with PD-L1-Positive Tumor Status (tumor-infiltrating immune cell [IC] 1/2/3) Using AJCC Staging System

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    End point title
    		 Number of Participants with pCR in Subpopulation with PD-L1-Positive Tumor Status (tumor-infiltrating immune cell [IC] 1/2/3) Using AJCC Staging System
    End point description
    Number of participants with Pathologic Complete Response (pCR) Using American Joint Committee on Cancer (AJCC) Staging System in the subpopulation with programmed death-ligand1 (PD-L1)-positive tumor status(tumor-infiltrating immune cell [IC] IC1/2/3) . pCR is defined as eradication of invasive tumor from both breast and lymph nodes (ypT0/is ypN0). Participants whose pCR assessment was missing will be counted as not achieving a pCR.
    End point type
    Primary
    End point timeframe
    Up to data cut-off on 3 April 2020
    End point values
    		 Placebo and Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    75
    77
    Units: Number of participants
        number (not applicable)
    37
    53
    Statistical analysis title
    		 pCR in PD-L1-Positive Tumor Status
    Comparison groups
    Placebo and Chemotherapy v Atezolizumab and Chemotherapy
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0206
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in pCR
    Point estimate
    19.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.17
         upper limit
    		 34.83

    Secondary: Event-Free Survival (EFS) in All Participants

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    End point title
    		 Event-Free Survival (EFS) in All Participants
    End point description
    Event-free survival (EFS) defined as the time from randomization until documented disease recurrence, progression, or death from any cause in all participants. EFS events covered under “disease recurrence” will include local, regional, or distant recurrence and contralateral breast cancer. Ipsilateral or contralateral in situ disease and second primary non-breast cancers will not be counted as EFS events.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 63 months
    End point values
    		 Placebo and Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [2] - Data will be submitted at the time of final results posting.
    [3] - Data will be submitted at the time of final results posting.
    No statistical analyses for this end point

    Secondary: Event-Free Survival (EFS) in Subpopulation with PD-L1-Postive Tumor Status

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    End point title
    		 Event-Free Survival (EFS) in Subpopulation with PD-L1-Postive Tumor Status
    End point description
    Event-free survival (EFS) defined as the time from randomization until documented disease recurrence, progression, or death from any cause in the subpopulation with PD-L1-positive tumor status. EFS events covered under “disease recurrence” will include local, regional, or distant recurrence and contralateral breast cancer. Ipsilateral or contralateral in situ disease and second primary non-breast cancers will not be counted as EFS events.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 63 months
    End point values
    		 Placebo and Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Months
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [4] - Data will be submitted at the time of final results posting.
    [5] - Data will be submitted at the time of final results posting.
    No statistical analyses for this end point

    Secondary: Disease-Free Survival (DFS) in All Participants Who Undergo Surgery

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    End point title
    		 Disease-Free Survival (DFS) in All Participants Who Undergo Surgery
    End point description
    Disease-free survival (DFS) defined as the time from surgery until documented disease recurrence or death from any cause in all patients (ITT population) who undergo surgery.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 63 months
    End point values
    		 Placebo and Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [6] - Data will be submitted at the time of final results posting.
    [7] - Data will be submitted at the time of final results posting.
    No statistical analyses for this end point

    Secondary: Disease-Free Survival (DFS) in Subpopulation of Participants with PD-L1-Positive Tumor Status Who Undergo Surgery

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    End point title
    		 Disease-Free Survival (DFS) in Subpopulation of Participants with PD-L1-Positive Tumor Status Who Undergo Surgery
    End point description
    Disease-free survival (DFS) defined as the time from surgery until documented disease recurrence or death from any cause in the subpopulation of participants with PD-L1-positive tumor status who undergo surgery.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 63 months
    End point values
    		 Placebo and Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [8] - Data will be submitted at the time of final results posting.
    [9] - Data will be submitted at the time of final results posting.
    No statistical analyses for this end point

    Secondary: Overall survival (OS) in All Participants

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    End point title
    		 Overall survival (OS) in All Participants
    End point description
    Overall survival (OS) defined as the time from randomization to the date of death from any cause in all participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 63 months
    End point values
    		 Placebo and Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [10] - Data will be submitted at the time of final results posting.
    [11] - Data will be submitted at the time of final results posting.
    No statistical analyses for this end point

    Secondary: Overall survival (OS) in Subpopulation with PD-L1-Positive Tumor Status

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    End point title
    		 Overall survival (OS) in Subpopulation with PD-L1-Positive Tumor Status
    End point description
    Overall survival (OS) defined as the time from randomization to the date of death from any cause in the subpopulation with PD-L1-positive tumor status.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 63 months
    End point values
    		 Placebo and Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: Months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [12] - Data will be submitted at the time of final results posting.
    [13] - Data will be submitted at the time of final results posting.
    No statistical analyses for this end point

    Secondary: Mean Scores for Function (Role/Physical) and GHS/HRQoL by Cycle and Between Treatment Arms as Assessed by the EORTC QLQ-C30

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    End point title
    		 Mean Scores for Function (Role/Physical) and GHS/HRQoL by Cycle and Between Treatment Arms as Assessed by the EORTC QLQ-C30
    End point description
    Mean score in function (role, physical) and global health status(GHS)/ health-related quality of life (HRQoL) by cycle and between treatment arms as assessed by the functional and HRQoL scales of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core30(QLQ C30). The EORTC QLQ-C30 includes five functional scales; a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms).
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1), on Day 1 of every cycle (C) thereafter (C=28 days from C1 to 5, and 21 days from C6 to 16), at Study Drug Completion/Early Discontinuation, Survival Follow-Up Months 3, 6, 9, 12, 18 and 24 (up to approximately 63 months)
    End point values
    		 Placebo and Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: Score on a 0-100 scale
        arithmetic mean (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [14] - Data will be submitted at the time of final results posting.
    [15] - Data will be submitted at the time of final results posting.
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline Scores for Function (Role, Physical) and GHS/HRQoL by Cycle and Between Treatment Arms as Assessed by the EORTC QLQ-C30

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    End point title
    		 Mean Change From Baseline Scores for Function (Role, Physical) and GHS/HRQoL by Cycle and Between Treatment Arms as Assessed by the EORTC QLQ-C30
    End point description
    Mean change from baseline score in function (role, physical) andglobal health status(GHS)/ health-related quality of life (HRQoL) by cycle and between treatment arms as assessed by the functional and HRQoL scales of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core30(QLQ C30).
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1), and on Day 1 of every cycle (C) thereafter (C length=28 days from C1 to 5, and 21 days from C6 to 16), at Study Drug Completion/Early Termination, Survival Follow-Up Months 12, 18, and 24 (up to approximately 63 months)
    End point values
    		 Placebo and Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: Score on a 0-100 scale
        arithmetic mean (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [16] - Data will be submitted at the time of final results posting.
    [17] - Data will be submitted at the time of final results posting.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Adverse Events (AEs)

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    End point title
    		 Percentage of Participants with Adverse Events (AEs)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 63 months
    End point values
    		 Placebo and Chemotherapy Atezolizumab and Chemotherapy
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: Percentage of participants
        number (not applicable)
    Notes
    [18] - Data will be submitted at the time of final results posting.
    [19] - Data will be submitted at the time of final results posting.
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Atezolizumab Concentration (Cmin)

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    End point title
    		 Minimum Observed Serum Atezolizumab Concentration (Cmin) [20]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 of Cycles 2, 3, 4, 6, 8, 12, and 16 (cycle length = 28 days from Cycles 1 to 5, and 21 days from Cycles 6 to 16)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this end point.
    End point values
    		 Atezolizumab and Chemotherapy
    Number of subjects analysed
    164
    Units: µg/mL
    arithmetic mean (standard deviation)
        Cycle 2 Day 1
    142 ± 54.3
        Cycle 3 Day 1
    189 ± 64.2
        Cycle 4 Day 1
    207 ± 77.3
        Cycle 6 Day 1
    78.7 ± 50.3
        Cycle 8 Day 1
    204 ± 62.7
        Cycle 12 Day 1
    267 ± 81.1
        Cycle 16 Day 1
    303 ± 89.1
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Atezolizumab Concentration (Cmax)

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    End point title
    		 Maximum Observed Serum Atezolizumab Concentration (Cmax) [21]
    End point description
    Maximum observed atezolizumab concentration (Cmax).
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1 post dose (cycle length = 28 days)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this end point.
    End point values
    		 Atezolizumab and Chemotherapy
    Number of subjects analysed
    164
    Units: µg/mL
        arithmetic mean (standard deviation)
    334 ± 63.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab

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    End point title
    		 Percentage of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab [22]
    End point description
    Percentage of participants with ADAs to atezolizumab.
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately 20 months
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this end point.
    End point values
    		 Atezolizumab and Chemotherapy
    Number of subjects analysed
    162
    Units: Percentage of participants
    number (not applicable)
        Baseline evaluable participants
    2.5
        Post-baseline evaluable participants
    13.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first study drug to the data cutoff date 3 April 2020 (up to approximately 32 months)
    Adverse event reporting additional description
    Safety evaluable population is defined as all participants who received at least one dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo + Nab-paclitaxel + AC
    Reporting group description
    		 Participants received placebo matched to atezolizumab via IV infusion every 2 weeks in combination with nab-paclitaxel (125 mg/m^2) via IV infusion every week for 12 weeks, followed by placebo matched to atezolizumab every 2 weeks in combination with doxorubicin (60 mg/m^2) and cyclophosphamide (600 mg/m^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants will be unblinded post-surgery and will continue to be followed.

    Reporting group title
    Atezolizumab + Nab-paclitaxel + AC
    Reporting group description
    		 Participants received atezolizumab (840 milligrams [mg]) via intravenous (IV) infusion every 2 weeks in combination with nab-paclitaxel (125 milligrams per square meter [mg/m^2]) via IV infusion every week for 12 weeks, followed by atezolizumab (840 mg) every 2 weeks in combination with doxorubicin (60 mg/m^2) and cyclophosphamide (600 mg/m^2) every 2 weeks via IV infusions with filgrastim/pegfilgrastim support for 4 doses. Participants continued to receive unblinded atezolizumab post-surgery at a fixed dose of 1200 mg by IV infusion every 3 weeks for 11 doses, for a total of approximately 12 months of atezolizumab therapy.

    Serious adverse events
    		 Placebo + Nab-paclitaxel + AC Atezolizumab + Nab-paclitaxel + AC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 167 (21.56%)
    57 / 164 (34.76%)
         number of deaths (all causes)
    9
    7
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    TUMOUR HAEMORRHAGE
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    EMBOLISM
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOSIS
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IMPAIRED HEALING
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALAISE
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    0 / 167 (0.00%)
    4 / 164 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         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
    DYSPNOEA
         subjects affected / exposed
    2 / 167 (1.20%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOPTYSIS
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    1 / 167 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    2 / 167 (1.20%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         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
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         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
    2 / 167 (1.20%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FRACTURE
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         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
    1 / 167 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS CHEMICAL
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    POST PROCEDURAL HAEMATOMA
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ROAD TRAFFIC ACCIDENT
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    WOUND DEHISCENCE
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIAC FAILURE
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    GUILLAIN-BARRE SYNDROME
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL MOTOR NEUROPATHY
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    2 / 167 (1.20%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POLYNEUROPATHY
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    0 / 167 (0.00%)
    3 / 164 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    3 / 167 (1.80%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    13 / 167 (7.78%)
    16 / 164 (9.76%)
         occurrences causally related to treatment / all
    14 / 14
    16 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    2 / 167 (1.20%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 167 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    0 / 167 (0.00%)
    2 / 164 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    2 / 167 (1.20%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OBSTRUCTIVE PANCREATITIS
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         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 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    0 / 167 (0.00%)
    3 / 164 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATITIS
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DERMATOMYOSITIS
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    RENAL INFARCT
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    HYPOPITUITARISM
         subjects affected / exposed
    1 / 167 (0.60%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    BACILLUS BACTERAEMIA
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CANDIDA INFECTION
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         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 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENCEPHALITIS
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MASTITIS
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIC SEPSIS
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIORBITAL CELLULITIS
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 167 (0.60%)
    6 / 164 (3.66%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PYELONEPHRITIS ACUTE
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL BACTERAEMIA
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    2 / 167 (1.20%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 167 (0.00%)
    1 / 164 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VITAMIN D DEFICIENCY
         subjects affected / exposed
    1 / 167 (0.60%)
    0 / 164 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Nab-paclitaxel + AC Atezolizumab + Nab-paclitaxel + AC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    167 / 167 (100.00%)
    161 / 164 (98.17%)
    Vascular disorders
    HOT FLUSH
         subjects affected / exposed
    17 / 167 (10.18%)
    28 / 164 (17.07%)
         occurrences all number
    20
    31
    HYPERTENSION
         subjects affected / exposed
    17 / 167 (10.18%)
    14 / 164 (8.54%)
         occurrences all number
    29
    26
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    36 / 167 (21.56%)
    42 / 164 (25.61%)
         occurrences all number
    40
    66
    FATIGUE
         subjects affected / exposed
    64 / 167 (38.32%)
    62 / 164 (37.80%)
         occurrences all number
    84
    91
    MALAISE
         subjects affected / exposed
    17 / 167 (10.18%)
    15 / 164 (9.15%)
         occurrences all number
    18
    34
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    15 / 167 (8.98%)
    18 / 164 (10.98%)
         occurrences all number
    19
    24
    OEDEMA PERIPHERAL
         subjects affected / exposed
    23 / 167 (13.77%)
    24 / 164 (14.63%)
         occurrences all number
    26
    30
    PAIN
         subjects affected / exposed
    11 / 167 (6.59%)
    19 / 164 (11.59%)
         occurrences all number
    11
    21
    PYREXIA
         subjects affected / exposed
    21 / 167 (12.57%)
    36 / 164 (21.95%)
         occurrences all number
    25
    55
    Reproductive system and breast disorders
    BREAST PAIN
         subjects affected / exposed
    14 / 167 (8.38%)
    14 / 164 (8.54%)
         occurrences all number
    14
    16
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    32 / 167 (19.16%)
    40 / 164 (24.39%)
         occurrences all number
    39
    51
    DYSPNOEA
         subjects affected / exposed
    20 / 167 (11.98%)
    22 / 164 (13.41%)
         occurrences all number
    22
    25
    EPISTAXIS
         subjects affected / exposed
    24 / 167 (14.37%)
    25 / 164 (15.24%)
         occurrences all number
    26
    26
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    18 / 167 (10.78%)
    19 / 164 (11.59%)
         occurrences all number
    19
    20
    RHINORRHOEA
         subjects affected / exposed
    0 / 167 (0.00%)
    12 / 164 (7.32%)
         occurrences all number
    0
    14
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    11 / 167 (6.59%)
    11 / 164 (6.71%)
         occurrences all number
    11
    11
    DEPRESSION
         subjects affected / exposed
    6 / 167 (3.59%)
    10 / 164 (6.10%)
         occurrences all number
    6
    10
    INSOMNIA
         subjects affected / exposed
    30 / 167 (17.96%)
    46 / 164 (28.05%)
         occurrences all number
    32
    58
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    35 / 167 (20.96%)
    38 / 164 (23.17%)
         occurrences all number
    54
    61
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    27 / 167 (16.17%)
    36 / 164 (21.95%)
         occurrences all number
    43
    59
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    4 / 167 (2.40%)
    14 / 164 (8.54%)
         occurrences all number
    4
    19
    BLOOD LACTATE DEHYDROGENASE INCREASED
         subjects affected / exposed
    7 / 167 (4.19%)
    10 / 164 (6.10%)
         occurrences all number
    7
    11
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    30 / 167 (17.96%)
    29 / 164 (17.68%)
         occurrences all number
    67
    61
    WEIGHT DECREASED
         subjects affected / exposed
    8 / 167 (4.79%)
    15 / 164 (9.15%)
         occurrences all number
    8
    17
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    15 / 167 (8.98%)
    14 / 164 (8.54%)
         occurrences all number
    35
    33
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    10 / 167 (5.99%)
    16 / 164 (9.76%)
         occurrences all number
    16
    28
    PROCEDURAL PAIN
         subjects affected / exposed
    2 / 167 (1.20%)
    13 / 164 (7.93%)
         occurrences all number
    2
    16
    RADIATION SKIN INJURY
         subjects affected / exposed
    0 / 167 (0.00%)
    28 / 164 (17.07%)
         occurrences all number
    0
    28
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    15 / 167 (8.98%)
    18 / 164 (10.98%)
         occurrences all number
    16
    31
    DYSGEUSIA
         subjects affected / exposed
    25 / 167 (14.97%)
    16 / 164 (9.76%)
         occurrences all number
    27
    20
    HEADACHE
         subjects affected / exposed
    35 / 167 (20.96%)
    50 / 164 (30.49%)
         occurrences all number
    45
    76
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    34 / 167 (20.36%)
    39 / 164 (23.78%)
         occurrences all number
    42
    47
    PARAESTHESIA
         subjects affected / exposed
    19 / 167 (11.38%)
    12 / 164 (7.32%)
         occurrences all number
    22
    13
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    43 / 167 (25.75%)
    57 / 164 (34.76%)
         occurrences all number
    46
    64
    POLYNEUROPATHY
         subjects affected / exposed
    14 / 167 (8.38%)
    9 / 164 (5.49%)
         occurrences all number
    15
    9
    TASTE DISORDER
         subjects affected / exposed
    13 / 167 (7.78%)
    10 / 164 (6.10%)
         occurrences all number
    13
    11
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    63 / 167 (37.72%)
    64 / 164 (39.02%)
         occurrences all number
    78
    87
    LEUKOPENIA
         subjects affected / exposed
    17 / 167 (10.18%)
    22 / 164 (13.41%)
         occurrences all number
    28
    42
    NEUTROPENIA
         subjects affected / exposed
    59 / 167 (35.33%)
    64 / 164 (39.02%)
         occurrences all number
    122
    137
    THROMBOCYTOPENIA
         subjects affected / exposed
    5 / 167 (2.99%)
    12 / 164 (7.32%)
         occurrences all number
    6
    14
    Eye disorders
    DRY EYE
         subjects affected / exposed
    5 / 167 (2.99%)
    13 / 164 (7.93%)
         occurrences all number
    5
    13
    LACRIMATION INCREASED
         subjects affected / exposed
    18 / 167 (10.78%)
    18 / 164 (10.98%)
         occurrences all number
    18
    21
    VISION BLURRED
         subjects affected / exposed
    11 / 167 (6.59%)
    16 / 164 (9.76%)
         occurrences all number
    12
    16
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    16 / 167 (9.58%)
    22 / 164 (13.41%)
         occurrences all number
    21
    28
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    13 / 167 (7.78%)
    20 / 164 (12.20%)
         occurrences all number
    16
    22
    CONSTIPATION
         subjects affected / exposed
    54 / 167 (32.34%)
    51 / 164 (31.10%)
         occurrences all number
    63
    73
    DIARRHOEA
         subjects affected / exposed
    74 / 167 (44.31%)
    73 / 164 (44.51%)
         occurrences all number
    117
    106
    DRY MOUTH
         subjects affected / exposed
    5 / 167 (2.99%)
    10 / 164 (6.10%)
         occurrences all number
    6
    10
    DYSPEPSIA
         subjects affected / exposed
    21 / 167 (12.57%)
    17 / 164 (10.37%)
         occurrences all number
    23
    20
    NAUSEA
         subjects affected / exposed
    110 / 167 (65.87%)
    107 / 164 (65.24%)
         occurrences all number
    189
    214
    STOMATITIS
         subjects affected / exposed
    29 / 167 (17.37%)
    40 / 164 (24.39%)
         occurrences all number
    32
    48
    VOMITING
         subjects affected / exposed
    51 / 167 (30.54%)
    62 / 164 (37.80%)
         occurrences all number
    70
    100
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    129 / 167 (77.25%)
    124 / 164 (75.61%)
         occurrences all number
    132
    126
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    10 / 167 (5.99%)
    6 / 164 (3.66%)
         occurrences all number
    10
    8
    DRY SKIN
         subjects affected / exposed
    13 / 167 (7.78%)
    18 / 164 (10.98%)
         occurrences all number
    13
    20
    ERYTHEMA
         subjects affected / exposed
    5 / 167 (2.99%)
    14 / 164 (8.54%)
         occurrences all number
    5
    16
    NAIL DISCOLOURATION
         subjects affected / exposed
    29 / 167 (17.37%)
    24 / 164 (14.63%)
         occurrences all number
    29
    24
    NAIL DISORDER
         subjects affected / exposed
    10 / 167 (5.99%)
    21 / 164 (12.80%)
         occurrences all number
    10
    22
    PRURITUS
         subjects affected / exposed
    24 / 167 (14.37%)
    33 / 164 (20.12%)
         occurrences all number
    30
    45
    RASH
         subjects affected / exposed
    42 / 167 (25.15%)
    51 / 164 (31.10%)
         occurrences all number
    53
    65
    RASH MACULO-PAPULAR
         subjects affected / exposed
    12 / 167 (7.19%)
    12 / 164 (7.32%)
         occurrences all number
    14
    12
    Endocrine disorders
    HYPOTHYROIDISM
         subjects affected / exposed
    0 / 167 (0.00%)
    16 / 164 (9.76%)
         occurrences all number
    0
    16
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    39 / 167 (23.35%)
    38 / 164 (23.17%)
         occurrences all number
    59
    61
    BACK PAIN
         subjects affected / exposed
    20 / 167 (11.98%)
    22 / 164 (13.41%)
         occurrences all number
    24
    24
    BONE PAIN
         subjects affected / exposed
    12 / 167 (7.19%)
    11 / 164 (6.71%)
         occurrences all number
    13
    12
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    3 / 167 (1.80%)
    15 / 164 (9.15%)
         occurrences all number
    4
    16
    MYALGIA
         subjects affected / exposed
    40 / 167 (23.95%)
    51 / 164 (31.10%)
         occurrences all number
    49
    84
    PAIN IN EXTREMITY
         subjects affected / exposed
    19 / 167 (11.38%)
    27 / 164 (16.46%)
         occurrences all number
    25
    33
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    13 / 167 (7.78%)
    23 / 164 (14.02%)
         occurrences all number
    16
    28
    PARONYCHIA
         subjects affected / exposed
    21 / 167 (12.57%)
    18 / 164 (10.98%)
         occurrences all number
    21
    19
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    16 / 167 (9.58%)
    23 / 164 (14.02%)
         occurrences all number
    16
    30
    URINARY TRACT INFECTION
         subjects affected / exposed
    11 / 167 (6.59%)
    18 / 164 (10.98%)
         occurrences all number
    11
    25
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    33 / 167 (19.76%)
    28 / 164 (17.07%)
         occurrences all number
    36
    37
    HYPOKALAEMIA
         subjects affected / exposed
    7 / 167 (4.19%)
    12 / 164 (7.32%)
         occurrences all number
    8
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2017
    Protocol was amended to add a cardiac safety cohort. A mandatory baseline pulmonary function evaluation conducted via spirometry has been added to the Schedule of Activities. It has been clarified that patients who do not initially meet all eligibility criteria, other than TNBC status, may be rescreened only once. Pregnancy reporting timeline requirement for nab-paclitaxel has been amended to be 1 month after last dose. Event-free survival (EFS) has been clarified, EFS is defined as "the time from randomization to the first documented occurrence of disease recurrence, disease progression, or death from any cause." Language has been updated to indicate that if nab-paclitaxel is discontinued due to any reason, patients can proceed to AC chemotherapy plus atezolizumab/placebo at the discretion of the investigator. If AC chemotherapy is discontinued, the date of surgery can be brought forward and patients can proceed to surgery at the discretion of the investigator.
    11 May 2018
    Protocol was amended to include addition of history of cerebrovascular accident within 12 months prior to randomization as an exclusion criteria. Ductal carcinoma in situ (DCIS) is no longer an exception to the exclusion criterion of history of other malignancy within 5 years prior to screening as there was already a dedicated section to DCIS. History of a cerebrovascular accident within 12 months prior to randomization has been added as an exclusion criterion. It has been clarified that anticipation of need for a major surgical procedure as an exclusion criterion does not pertain to anticipated breast surgery. The risks associated with atezolizumab have been updated to include hypophysitis and myocarditis as adverse events. The safety profile of and risk management guidelines for nab-paclitaxel has been updated or clarified to include febrile neutropenia, infections, and depression.
    10 Oct 2018
    Protocol was amended to add an adaptive two stage design using accumulating data to inform the study. Study duration and recruitment period were updated to reflect potential change in study duration. The primary efficacy objective was modified to include the endpoint of pCR in the subpopulation with the PD-L1-positive tumor status (moved from the secondary efficacy objective). The secondary efficacy endpoints were modified to include disease-free survival. Lists of risks for atezolizumab and guidelines for managing participants who experience atezolizumab-associated adverse events have been revised to include nephritis.
    07 Jun 2019
    Protocol was amended to clarify the baseline staging and surgical management of clinically enlarged and/or suspicious internal mammary and infraclavicular and/or supraclavicular lymph nodes. Language has been modified to reflect the fact that systemic immune activation is a potential risk with atezolizumab, regardless of whether atezolizumab is given alone or in combination with other immunomodulating agents. The lists of risks associated with doxorubicin and cyclophosphamide have been updated to align with the latest safety information available on their corresponding SmPCs.
    11 Feb 2020
    Protocol was amended to include changing "immune-related" to "immune-mediated" when describing events associated with atezolizumab. Systemic immune activation has been replaced by hemophagocytic lymphohistiocytosis and macrophage activation syndrome in the list of potential risks for atezolizumab and the management guidelines for systemic immune activation have been replaced with management guidelines for hemophagocytic lymphohistiocytosis and macrophage activation syndrome. In addition, systemic immune activation has been removed from the list of adverse events of special interest. To align with the nab-paclitaxel (Abraxane®) prescribing information, the risk of tumor lysis syndrome has been included. The atezolizumab adverse event management guidelines have been revised to add laboratory and cardiac imaging abnormalities as signs or symptoms that are suggestive of myocarditis. The management guidelines for infusion-related reactions associated with atezolizumab have been updated to include guidelines for cytokine-release syndrome (CRS).

    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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