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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled, Randomized Phase III Study of Ipatasertib in Combination With Paclitaxel as a Treatment for Patients With PIK3CA/AKT1/PTEN-Altered, Locally Advanced or Metastatic, Triple-Negative Breast Cancer or Hormone Receptor–Positive, HER2-Negative Breast Cancer

    Summary
    EudraCT number
    		 2017-001548-36
    Trial protocol
    		 DE   ES   GB   CZ   HU   PL   BE   FR   GR   SI   IT  
    Global end of trial date
    04 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jan 2024
    First version publication date
    18 Jan 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CO40016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03337724
    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
    Final
    Date of interim/final analysis
    04 Jan 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study is to evaluate the efficacy of ipatasertib + paclitaxel versus placebo + paclitaxel in participants with histologically confirmed, locally advanced or metastatic triple-negative breast cancer (TNBC) and in participants with locally advanced or metastatic hormone receptor positive (HR+)/ human epidermal growth factor receptor 2 negative (HER2−) breast adenocarcinoma who are not suitable for endocrine therapy.The study will also assess the efficacy of ipatasertib+atezolizumab+paclitaxel in participants with TNBC, screened for Cohort A but without phosphatidylinositol-4,5-bisphosphate3-kinase,catalytic subunit,alpha(PIK3CA)/serine-threonine kinase(AKT1)/phosphatase and tensin homolog(PTEN)-altered tumor.
    Protection of trial subjects
    All study participants were required to read and sign an informed consent form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jan 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 45 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Greece: 9
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    North Macedonia: 12
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Russian Federation: 27
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Ukraine: 48
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    United States: 33
    Country: Number of subjects enrolled
    Brazil: 72
    Country: Number of subjects enrolled
    Chile: 5
    Country: Number of subjects enrolled
    Costa Rica: 6
    Country: Number of subjects enrolled
    Mexico: 17
    Country: Number of subjects enrolled
    Peru: 60
    Country: Number of subjects enrolled
    India: 1
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Argentina: 4
    Country: Number of subjects enrolled
    Türkiye: 11
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Japan: 52
    Country: Number of subjects enrolled
    Korea, Republic of: 40
    Country: Number of subjects enrolled
    Taiwan: 23
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Czechia: 13
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    United Kingdom: 14
    Worldwide total number of subjects
    579
    EEA total number of subjects
    141
    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)
    442
    From 65 to 84 years
    137
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants with TNBC or HR+/HER- breast cancer took part in the study in Argentina, Australia, Belgium, Brazil, Canada,Chile, Costa Rica,Czech Republic,France, Greece,Germany, Hungary, Italy, India, Japan,Macedonia,Mexico,Poland,Peru,Korea,Russia,Slovenia,Spain,Singapore,South Africa, Taiwan, Turkey, Ukraine,UK,&USA from 06-01-2018 to 04-01-2023.

    Pre-assignment
    Screening details
    		 Participants with TNBC or HR+/HER2- breast adenocarcinoma with PIK3CA/AKT1/PTEN-altered tumor were randomized to ipatasertib 400 mg + paclitaxel or placebo + paclitaxel (Cohorts A,B) & those with TNBC without PIK3CA/ AKT1/PTEN-altered tumor received ipatasertib + atezolizumab +paclitaxel (Cohort C).

    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, Assessor
    Blinding implementation details
    Cohorts A and B were randomised controlled double-blind and Cohort C was open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A: Placebo + Paclitaxel
    Arm description
    		 Participants with histologically confirmed locally advanced unresectable or metastatic TNBC with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 milligram per square meter (mg/m^2), intravenously (IV), on Days 1, 8, and 15 of each 28-day cycle and placebo, orally once a day (QD), on Days 1 to 21 of each 28-day cycle up to 58.9 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered orally QD on Days 1 to 21 of each 28-day cycle.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel chemotherapy 80 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle

    Arm title
    		 Cohort A: Ipatasertib + Paclitaxel
    Arm description
    		 Participants with histologically confirmed locally advanced unresectable or metastatic TNBC with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 mg/m^2, IV, on Days 1, 8, and 15 of each 28-day cycle and ipatasertib, at a dose of 400 mg, administered orally QD, on Days 1 to 21 of each 28-day cycle up to 58.9 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipatasertib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg administered orally QD on Days 1 to 21 of each 28-day cycle

    Arm title
    		 Cohort B: Placebo + Paclitaxel
    Arm description
    		 Participants with histologically confirmed HR+ /HER2- adenocarcinoma of the breast with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy 80 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle and placebo orally QD on Days 1 to 21 of each 28-day cycle up to 59.9 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered orally QD on Days 1 to 21 of each 28-day cycle.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel chemotherapy 80 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle

    Arm title
    		 Cohort B: Ipatasertib + Paclitaxel
    Arm description
    		 Participants with histologically confirmed HR+/HER2- adenocarcinoma of the breast with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy 80 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle and ipatasertib at a dose of 400 mg administered orally QD on Days 1 to 21 of each 28-day cycle up to 59.9 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipatasertib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg administered orally QD on Days 1 to 21 of each 28-day cycle

    Arm title
    		 Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Arm description
    		 Participants with histologically confirmed locally advanced unresectable or metastatic TNBC without PIK3CA/AKT1/PTEN-altered tumors and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy 80 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle, ipatasertib at a dose of 400 mg administered orally QD on Days 1 to 21 of each 28-day cycle, and atezolizumab 840 mg IV on Days 1 and 15 of each 28-day cycle up to 45.5 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    840 mg IV on Days 1 and 15 of each 28-day cycle

    Investigational medicinal product name
    Ipatasertib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg administered orally QD on Days 1 to 21 of each 28-day cycle

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel chemotherapy 80 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle

    Number of subjects in period 1
    		Cohort A: Placebo + Paclitaxel Cohort A: Ipatasertib + Paclitaxel Cohort B: Placebo + Paclitaxel Cohort B: Ipatasertib + Paclitaxel Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Started
    87
    168
    76
    146
    102
    Safety Evaluable Population
    87
    166
    75
    145
    102
    Completed
    0
    0
    0
    0
    0
    Not completed
    87
    168
    76
    146
    102
         Physician decision
    16
    34
    14
    34
    13
         Adverse Event
    1
    1
    -
    1
    -
         Protocol Deviation
    -
    1
    1
    1
    -
         Death
    40
    89
    43
    76
    50
         Progressive Disease
    -
    2
    1
    2
    -
         Withdrawal by Subject
    13
    15
    4
    15
    6
         Symptomatic Deterioration
    -
    -
    -
    1
    -
         Reason not specified
    12
    21
    9
    9
    29
         Lost to follow-up
    5
    5
    4
    7
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A: Placebo + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed locally advanced unresectable or metastatic TNBC with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 milligram per square meter (mg/m^2), intravenously (IV), on Days 1, 8, and 15 of each 28-day cycle and placebo, orally once a day (QD), on Days 1 to 21 of each 28-day cycle up to 58.9 months.

    Reporting group title
    Cohort A: Ipatasertib + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed locally advanced unresectable or metastatic TNBC with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 mg/m^2, IV, on Days 1, 8, and 15 of each 28-day cycle and ipatasertib, at a dose of 400 mg, administered orally QD, on Days 1 to 21 of each 28-day cycle up to 58.9 months.

    Reporting group title
    Cohort B: Placebo + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed HR+ /HER2- adenocarcinoma of the breast with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy 80 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle and placebo orally QD on Days 1 to 21 of each 28-day cycle up to 59.9 months.

    Reporting group title
    Cohort B: Ipatasertib + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed HR+/HER2- adenocarcinoma of the breast with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy 80 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle and ipatasertib at a dose of 400 mg administered orally QD on Days 1 to 21 of each 28-day cycle up to 59.9 months.

    Reporting group title
    Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed locally advanced unresectable or metastatic TNBC without PIK3CA/AKT1/PTEN-altered tumors and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy 80 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle, ipatasertib at a dose of 400 mg administered orally QD on Days 1 to 21 of each 28-day cycle, and atezolizumab 840 mg IV on Days 1 and 15 of each 28-day cycle up to 45.5 months.

    Reporting group values
    		 Cohort A: Placebo + Paclitaxel Cohort A: Ipatasertib + Paclitaxel Cohort B: Placebo + Paclitaxel Cohort B: Ipatasertib + Paclitaxel Cohort C: Ipatasertib + Atezolizumab + Paclitaxel Total
    Number of subjects
    		 87 168 76 146 102 579
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.2 ± 12.6 54.6 ± 12.8 54.5 ± 11.3 57.2 ± 11.1 54.6 ± 11.7 -
    Gender Categorical
    Units: participants
        Female
    		 87 167 76 144 102 576
        Male
    		 0 1 0 2 0 3
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 13 15 3 4 5 40
        Asian
    		 17 37 22 38 12 126
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 1 1
        Black or African American
    		 1 5 3 2 9 20
        White
    		 51 99 45 93 55 343
        More than one race
    		 0 4 2 0 5 11
        Unknown or Not Reported
    		 5 8 1 9 15 38
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 29 59 13 29 36 166
        Not Hispanic or Latino
    		 57 101 62 115 58 393
        Unknown or Not Reported
    		 1 8 1 2 8 20

    End points

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    End points reporting groups
    Reporting group title
    Cohort A: Placebo + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed locally advanced unresectable or metastatic TNBC with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 milligram per square meter (mg/m^2), intravenously (IV), on Days 1, 8, and 15 of each 28-day cycle and placebo, orally once a day (QD), on Days 1 to 21 of each 28-day cycle up to 58.9 months.

    Reporting group title
    Cohort A: Ipatasertib + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed locally advanced unresectable or metastatic TNBC with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 mg/m^2, IV, on Days 1, 8, and 15 of each 28-day cycle and ipatasertib, at a dose of 400 mg, administered orally QD, on Days 1 to 21 of each 28-day cycle up to 58.9 months.

    Reporting group title
    Cohort B: Placebo + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed HR+ /HER2- adenocarcinoma of the breast with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy 80 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle and placebo orally QD on Days 1 to 21 of each 28-day cycle up to 59.9 months.

    Reporting group title
    Cohort B: Ipatasertib + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed HR+/HER2- adenocarcinoma of the breast with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy 80 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle and ipatasertib at a dose of 400 mg administered orally QD on Days 1 to 21 of each 28-day cycle up to 59.9 months.

    Reporting group title
    Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed locally advanced unresectable or metastatic TNBC without PIK3CA/AKT1/PTEN-altered tumors and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy 80 mg/m^2 IV on Days 1, 8, and 15 of each 28-day cycle, ipatasertib at a dose of 400 mg administered orally QD on Days 1 to 21 of each 28-day cycle, and atezolizumab 840 mg IV on Days 1 and 15 of each 28-day cycle up to 45.5 months.

    Primary: Cohort A: Progression-Free Survival (PFS)

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    End point title
    		 Cohort A: Progression-Free Survival (PFS) [1]
    End point description
    PFS was defined as the time from randomization to the first occurrence of disease progression, as determined locally by the investigator through the use of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1), or death from any cause, whichever occurred first, assessed up to 28 months for this endpoint. Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). ITT Population included all randomized participants in Cohort A regardless of whether the participants received the assigned treatment.
    End point type
    Primary
    End point timeframe
    From randomization up to 27 months
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting data for only Cohort A. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort A: Placebo + Paclitaxel Cohort A: Ipatasertib + Paclitaxel
    Number of subjects analysed
    87
    168
    Units: months
        median (confidence interval 95%)
    6.1 (5.5 to 9.0)
    7.4 (5.6 to 8.5)
    Statistical analysis title
    		 Progression-Free Survival (PFS)
    Comparison groups
    Cohort A: Placebo + Paclitaxel v Cohort A: Ipatasertib + Paclitaxel
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.9237
    Method
    		 Logrank
    Parameter type
    		 Stratified Hazard Ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.45
    Notes
    [2] - Stratification variables were: prior adjuvant/neoadjuvant chemotherapy (yes vs. no), region, tumor PIK3CA/AKT1/PTEN alteration status (PIK3CA/AKT1-activating mutations vs. PTEN alterations with no PIK3CA/AKT1-activating mutations).

    Primary: Cohort B: PFS

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    End point title
    		 Cohort B: PFS [3]
    End point description
    PFS was defined as the time from randomization to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurred first, assessed up to 24.4 months for this outcome measure. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Abbreviation used in statistical analysis: PI3K=phosphoinositide 3-kinase and mTOR=mammalian target of rapamycin inhibitor. ITT Population included all randomized participants in Cohort B regardless of whether the participants received the assigned treatment.
    End point type
    Primary
    End point timeframe
    From randomization up to 24.4 months
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is reporting data for only Cohort B. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort B: Placebo + Paclitaxel Cohort B: Ipatasertib + Paclitaxel
    Number of subjects analysed
    76
    127
    Units: months
        median (confidence interval 95%)
    9.3 (7.2 to 12.2)
    9.3 (8.0 to 11.0)
    Statistical analysis title
    		 Superiority
    Comparison groups
    Cohort B: Placebo + Paclitaxel v Cohort B: Ipatasertib + Paclitaxel
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.9965
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.4
    Notes
    [4] - Stratification variables were: prior adjuvant/neoadjuvant chemotherapy (yes vs. no), region, prior therapy with a PI3K or mTOR inhibitor (yes vs. no).

    Primary: Cohort C: PFS

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    End point title
    		 Cohort C: PFS [5] [6]
    End point description
    PFS for cohort C was defined as the time from enrollment to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. ITT population included of all enrolled participants in Cohort C.
    End point type
    Primary
    End point timeframe
    From enrollment up to 31 months
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No descriptive statistics were planned for this endpoint.
    [6] - 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: This endpoint is reporting data for only Cohort B. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    102
    Units: months
        median (confidence interval 95%)
    7.1 (5.5 to 9.1)
    No statistical analyses for this end point

    Secondary: Cohort C: ORR

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    End point title
    		 Cohort C: ORR [7]
    End point description
    ORR was defined as percentage of participants with PR or CR on 2 consecutive occasions ≥4 weeks apart as determined by the investigator using RECIST v.1.1. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Percentages are rounded off to the nearest decimal point. ITT population consisted of all enrolled participants in Cohort C.
    End point type
    Secondary
    End point timeframe
    From enrollment up to 31 months
    Notes
    [7] - 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: This endpoint is reporting data for only Cohort C. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    102
    Units: percentage of participants
        number (confidence interval 95%)
    52.9 (42.80 to 62.90)
    No statistical analyses for this end point

    Secondary: Cohort A and B: Objective Response Rate (ORR)

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    End point title
    		 Cohort A and B: Objective Response Rate (ORR) [8]
    End point description
    ORR was defined as percentage of participants with partial response (PR) or complete response (CR) on 2 consecutive occasions ≥4 weeks apart as determined by the investigator using RECIST v.1.1 assessed up to 28 months for this endpoint. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (LN; whether target or non-target) having a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters(SoD) of target lesions, taking as reference the baseline sum of diameters. Percentages are rounded off to the nearest decimal point. ITT Population included all randomized participants in Cohorts A and B regardless of whether the participants received the assigned treatment. Number analyzed is the number of participants with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B
    Notes
    [8] - 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: This endpoint is reporting data for only Cohorts A and B. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort A: Placebo + Paclitaxel Cohort A: Ipatasertib + Paclitaxel Cohort B: Placebo + Paclitaxel Cohort B: Ipatasertib + Paclitaxel
    Number of subjects analysed
    86
    167
    75
    144
    Units: percentage of participants
        number (confidence interval 95%)
    34.9 (24.92 to 45.92)
    38.9 (31.49 to 46.76)
    46.7 (35.05 to 58.55)
    46.5 (38.18 to 55.02)
    No statistical analyses for this end point

    Secondary: Cohort A and B: Duration of Response (DOR)

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    End point title
    		 Cohort A and B: Duration of Response (DOR) [9]
    End point description
    DOR= time from the first occurrence of a documented OR (CR or PR) to PD, per investigator per RECIST v1.1,/death from any cause, whichever occurred first assessed up to 28 months for this endpoint. CR=disappearance of all target lesions or any pathological LN (whether target or non-target) having a reduction in short axis to <10 mm. PR=at least a 30% decrease in the SoD of target lesions, taking as reference baseline SoD. PD=at least a 20% increase in SoD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one/more new lesions was also considered PD. ITT Population (Cohorts A & B) participants. Number analyzed=number of participants with OR i.e.responders.9999= upper limit of 95% confidence interval (CI) was not estimable due to insufficient number of participants with event.
    End point type
    Secondary
    End point timeframe
    From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B
    Notes
    [9] - 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: This endpoint is reporting data for only Cohorts A and B. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort A: Placebo + Paclitaxel Cohort A: Ipatasertib + Paclitaxel Cohort B: Placebo + Paclitaxel Cohort B: Ipatasertib + Paclitaxel
    Number of subjects analysed
    30
    65
    35
    67
    Units: months
        median (confidence interval 95%)
    16.6 (4.9 to 9999)
    9.4 (7.3 to 11.1)
    9.2 (6.8 to 12.5)
    9.2 (7.2 to 11.3)
    No statistical analyses for this end point

    Secondary: Cohort C: DOR

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    End point title
    		 Cohort C: DOR [10]
    End point description
    DOR= time from the first occurrence of a documented OR (CR or PR) to PD, per investigator per RECIST v1.1,/death from any cause, whichever occurred first assessed up to 28 months for this endpoint. CR=disappearance of all target lesions or any pathological LN (whether target or non-target) having a reduction in short axis to <10 mm. PR=at least a 30% decrease in the SoD of target lesions, taking as reference baseline SoD. PD=at least a 20% increase in SoD of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one/more new lesions was also considered PD. ITT Population (Cohorts C) participants. Number analyzed=number of participants with OR i.e.responders.9999= upper limit of 95% confidence interval (CI) was not estimable due to insufficient number of participants with event.
    End point type
    Secondary
    End point timeframe
    From enrollment up to 31 months
    Notes
    [10] - 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: This endpoint is reporting data for only Cohort C. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    54
    Units: months
        median (confidence interval 95%)
    8.77 (5.7 to 12.7)
    No statistical analyses for this end point

    Secondary: Cohort A and B: Clinical Benefit Rate (CBR)

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    End point title
    		 Cohort A and B: Clinical Benefit Rate (CBR)
    End point description
    CBR was defined as percentage of participants with an objective response (CR or PR), or stable disease (SD) for at least 24 weeks, as determined by the investigator through the use of RECIST v.1.1 assessed up to 28 months for this endpoint.CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Percentages are rounded off to the nearest decimal point. ITT Population included all randomized participants in Cohorts A and B regardless of whether the participants received the assigned treatment. Number analyzed is the number of participants with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    From randomization up to 27 months for Cohort A and up to 24.4 months for Cohort B
    End point values
    		 Cohort A: Placebo + Paclitaxel Cohort A: Ipatasertib + Paclitaxel Cohort B: Placebo + Paclitaxel Cohort B: Ipatasertib + Paclitaxel Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    86
    167
    75
    144
    102
    Units: percentage of participants
        number (confidence interval 95%)
    45.3 (34.58 to 56.45)
    46.7 (38.96 to 54.57)
    65.3 (53.46 to 75.96)
    68.8 (60.50 to 76.21)
    54.9 (44.74 to 64.78)
    No statistical analyses for this end point

    Secondary: Cohort C: CBR

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    End point title
    		 Cohort C: CBR [11]
    End point description
    CBR was defined as percentage of participants with an objective response (CR or PR), or SD for at least 24 weeks, as determined by the investigator through the use of RECIST v.1.1. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Percentages are rounded off to the nearest decimal point. ITT population consisted of all enrolled participants in Cohort C.
    End point type
    Secondary
    End point timeframe
    From enrollment up to 31 months
    Notes
    [11] - 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: This endpoint is reporting data for only Cohort C. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    102
    Units: percentage of participants
        number (confidence interval 95%)
    54.9 (44.74 to 64.78)
    No statistical analyses for this end point

    Secondary: Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30

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    End point title
    		 Cohort A and B: Change From Baseline in Global Health Status (GHS)/Health-Related Quality of Life (HRQoL) Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 [12]
    End point description
    European Organisation for Research&Treatment of Cancer Quality of Life Questionnaire Core 30(EORTC QLQ-C30)=cancer-specific instrument with 30 questions to assess overall QoL. First 28 questions used 4-point scale(1=not at all,2=a little,3=quite a bit,4=very much)to evaluate 5 functional scales(physical,role,social,cognitive,emotional),8 symptom scales(diarrhea,fatigue,dyspnea,appetite loss,insomnia,nausea & vomiting,constipation,& pain)&1 item(financial difficulties).Last 2 questions=participant's opinion of overall HQoL,used 7-point scale(1=very poor-7=excellent).Scores were linearly transformed on a scale of 0-100,high score=better GHS/QoL.Negative change from Baseline=deterioration in QoL/functioning & positive values=improvement.PRO-evaluable Population.Number analyzed= number of participants with data available for analyses.‘n’=number of participants with data available for analysis at given time point.99999=SD not estimable for a single participant.999=0 participants analysed.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 (cycle length=28 days)
    Notes
    [12] - 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: This endpoint is reporting data for only Cohorts A and B. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort A: Placebo + Paclitaxel Cohort A: Ipatasertib + Paclitaxel Cohort B: Placebo + Paclitaxel Cohort B: Ipatasertib + Paclitaxel
    Number of subjects analysed
    79
    160
    73
    127
    Units: score on scale
    arithmetic mean (standard deviation)
        Day 1 Cycle 2 (n= 79, 60, 73, 127)
    0.95 ± 20.59
    -0.26 ± 24.58
    4.79 ± 15.83
    -3.61 ± 21.45
        Day 1 Cycle 3 (n= 72, 143, 70, 121)
    -0.93 ± 20.53
    0.35 ± 21.73
    1.19 ± 19.62
    -2.13 ± 17.99
        Day 1 Cycle 4 (n= 62, 124, 63, 113)
    -4.44 ± 19.42
    -2.42 ± 21.95
    -0.79 ± 21.10
    -1.99 ± 20.75
        Day 1 Cycle 5 (n= 56, 93, 56, 108)
    -2.08 ± 16.46
    -2.87 ± 18.61
    -1.19 ± 20.00
    -3.01 ± 18.70
        Day 1 Cycle 6 (n= 48, 77, 53, 101)
    -6.94 ± 15.97
    -2.06 ± 21.04
    1.42 ± 19.18
    -3.88 ± 20.67
        Day 1 Cycle 7 (n= 35, 61, 49, 94)
    -5.48 ± 12.45
    -3.28 ± 20.93
    0.34 ± 20.34
    -4.17 ± 19.47
        Day 1 Cycle 8 (n= 29, 51, 48, 89)
    -6.90 ± 13.56
    0.33 ± 22.11
    0.35 ± 16.84
    -5.99 ± 18.55
        Day 1 Cycle 9 (n= 22, 43, 38, 78)
    0.00 ± 10.29
    -3.49 ± 25.28
    1.10 ± 18.80
    -7.37 ± 20.05
        Day 1 Cycle 10 (n= 21, 35, 39, 70)
    -2.38 ± 9.91
    -4.52 ± 21.61
    1.28 ± 19.64
    -6.43 ± 18.83
        Day 1 Cycle 11 (n= 17, 28, 35, 65)
    -3.43 ± 15.88
    -4.46 ± 21.09
    2.38 ± 22.83
    -5.13 ± 19.30
        Day 1 Cycle 12 (n= 11, 23, 31, 58)
    0.76 ± 11.46
    -8.33 ± 19.94
    0.00 ± 22.46
    -4.02 ± 16.32
        Day 1 Cycle 13 (n= 8, 19, 24, 43)
    -5.21 ± 10.85
    -8.33 ± 23.57
    -2.43 ± 21.63
    -4.65 ± 18.57
        Day 1 Cycle 14 (n= 7, 14, 22, 38)
    -2.38 ± 10.45
    -3.57 ± 19.26
    -0.76 ± 21.81
    -3.29 ± 15.68
        Day 1 Cycle 15 (n= 6, 13, 15, 27)
    -9.72 ± 11.08
    -5.77 ± 12.90
    -2.22 ± 18.49
    -0.62 ± 20.14
        Day 1 Cycle 16 (n= 5, 11, 14, 25)
    -6.67 ± 13.69
    -8.33 ± 14.91
    -4.7 ± 19.27
    -2.33 ± 16.05
        Day 1 Cycle 17 (n= 4, 11, 12, 21)
    -8.33 ± 9.62
    -6.82 ± 13.34
    -7.64 ± 15.27
    -5.95 ± 13.73
        Day 1 Cycle 18 (n= 4, 7, 9, 14)
    -8.33 ± 9.62
    -15.48 ± 16.96
    -9.26 ± 19.74
    -6.55 ± 16.07
        Day 1 Cycle 19 (n= 4, 5, 5, 12)
    -4.17 ± 8.33
    -20.00 ± 7.45
    -11.67 ± 16.24
    -7.64 ± 23.96
        Day 1 Cycle 20 (n= 2, 3, 4, 10)
    -8.33 ± 11.79
    -5.56 ± 9.62
    -16.67 ± 11.79
    -10.00 ± 12.30
        Day 1 Cycle 21 (n= 1, 2, 3, 7)
    -16.67 ± 99999
    -16.67 ± 0.00
    -13.89 ± 20.97
    -10.71 ± 13.36
        Day 1 Cycle 22 (n= 0, 0, 3, 7)
    -16.67 ± 99999
    -16.67 ± 99999
    -11.11 ± 9.62
    -14.29 ± 15.00
        Day 1 Cycle 23 (n= 1, 1, 3, 7)
    -16.67 ± 99999
    -25.00 ± 99999
    -16.67 ± 16.67
    -15.00 ± 18.07
        Day 1 Cycle 24 (n= 0, 0, 3, 7)
    -16.67 ± 99999
    -41.67 ± 99999
    -16.67 ± 0.00
    -16.67 ± 11.79
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to death from any cause. ITT Population included all randomized participants in Cohorts A and B regardless of whether the participants received the assigned treatment. For Cohort C, the ITT population consisted of all enrolled participants in Cohort C. 9999 indicates that upper limit of 95% CI was not estimable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    From randomization up to death from any cause, up to 45 months for Cohort A, up to 46 months for Cohort B and up to 31 months for Cohort C
    End point values
    		 Cohort A: Placebo + Paclitaxel Cohort A: Ipatasertib + Paclitaxel Cohort B: Placebo + Paclitaxel Cohort B: Ipatasertib + Paclitaxel Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    87
    168
    76
    146
    102
    Units: months
        median (confidence interval 95%)
    24.9 (16.9 to 40.4)
    24.2 (19.2 to 29.4)
    28.4 (20.6 to 37.3)
    29.0 (22.4 to 34.8)
    22.8 (17.8 to 9999)
    Statistical analysis title
    		 Placebo vs Ipatasertib
    Comparison groups
    Cohort B: Placebo + Paclitaxel v Cohort B: Ipatasertib + Paclitaxel
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    Method
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.37
    Notes
    [13] - Stratification variables were: prior adjuvant/neoadjuvant chemotherapy (yes vs. no), region, prior therapy with a PI3K or mTOR inhibitor (yes vs. no).
    Statistical analysis title
    		 OS
    Comparison groups
    Cohort A: Placebo + Paclitaxel v Cohort A: Ipatasertib + Paclitaxel
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    Method
    Parameter type
    		 Stratified Hazard Ratio
    Point estimate
    1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.58
    Notes
    [14] - Stratification was done prior adjuvant/neoadjuvant chemotherapy (yes vs. no), region, tumor PIK3CA/AKT1/PTEN alteration status (PIK3CA/AKT1-activating mutations vs. PTEN alterations with no PIK3CA/AKT1-activating mutations).

    Secondary: Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30

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    End point title
    		 Cohort C: Change From Baseline in GHS/HRQoL Score Measured by GHS/HRQoL Scale (Questions 29 and 30) of the EORTC QLQ-C30 [15]
    End point description
    (EORTC QLQ-C30)=cancer-specific instrument with 30 questions to assess overall QoL. First 28 questions used 4-point scale(1=not at all,2=a little,3=quite a bit,4=very much)to evaluate 5 functional scales(physical,role,social,cognitive,emotional),8 symptom scales(diarrhea,fatigue,dyspnea,appetite loss,insomnia,nausea & vomiting,constipation,& pain)&1 item(financial difficulties).Last 2 questions=participant's opinion of overall HQoL,used 7-point scale(1=very poor-7=excellent).Scores were linearly transformed on a scale of 0-100,high score=better GHS/QoL.Negative change from Baseline=deterioration in QoL/functioning & positive values=improvement.PRO-evaluable Population.Number analyzed= number of participants with data available for analyses.‘n’=number of participants with data available for analysis at given time point.99999=SD not estimable for a single participant.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44 (cycle length=28 days)
    Notes
    [15] - 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: This endpoint is reporting data for only Cohort C. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    100
    Units: score on scale
    arithmetic mean (standard deviation)
        Day 1 Cycle 2 (n= 100)
    -0.42 ± 18.02
        Day 1 Cycle 3 (n=92)
    0.18 ± 18.32
        Day 1 Cycle 4 (n=84)
    -4.37 ± 22.83
        Day 1 Cycle 5 (n=65)
    -6.41 ± 20.19
        Day 1 Cycle 6 (n=61)
    -7.10 ± 21.24
        Day 1 Cycle 7 (n=54)
    -5.09 ± 18.02
        Day 1 Cycle 8 (n=50)
    -4.83 ± 21.24
        Day 1 Cycle 9 (n=37)
    -7.66 ± 23.68
        Day 1 Cycle 10 (n=33)
    -7.07 ± 18.76
        Day 1 Cycle 11 (n=25)
    -6.00 ± 19.02
        Day 1 Cycle 12 (n=23)
    -2.90 ± 18.57
        Day 1 Cycle 13 (n=23)
    -1.45 ± 19.08
        Day 1 Cycle 14 (n=19)
    -7.89 ± 21.24
        Day 1 Cycle 15 (n=18)
    -5.09 ± 26.37
        Day 1 Cycle 16 (n=16)
    -11.98 ± 27.55
        Day 1 Cycle 17 (n=13)
    -10.90 ± 32.96
        Day 1 Cycle 18 (n=13)
    -3.85 ± 20.30
        Day 1 Cycle 19 (n=13)
    -3.21 ± 25.35
        Day 1 Cycle 20 (n=13)
    -3.21 ± 24.89
        Day 1 Cycle 21 (n=13)
    -2.56 ± 24.86
        Day 1 Cycle 22 (n=13)
    -12.18 ± 32.92
        Day 1 Cycle 23 (n=11)
    3.03 ± 24.23
        Day 1 Cycle 24 (n=11)
    3.79 ± 24.54
        Day 1 Cycle 25 (n=9)
    -4.63 ± 21.29
        Day 1 Cycle 26 (n=10)
    -0.83 ± 19.82
        Day 1 Cycle 27 (n=8)
    2.08 ± 26.63
        Day 1 Cycle 28 (n= 6)
    1.39 ± 23.81
        Day 1 Cycle 29 (n= 7)
    -1.19 ± 28.64
        Day 1 Cycle 30 (n= 5)
    3.33 ± 24.01
        Day 1 Cycle 31 (n=3)
    22.22 ± 12.73
        Day 1 Cycle 32 (n=4)
    10.42 ± 23.94
        Day 1 Cycle 33 (n=3)
    16.67 ± 22.05
        Day 1 Cycle 34 (n=3)
    16.67 ± 30.05
        Day 1 Cycle 35 (n=3)
    13.89 ± 17.35
        Day 1 Cycle 36 (n=2)
    20.83 ± 29.46
        Day 1 Cycle 37 (n=2)
    16.67 ± 23.57
        Day 1 Cycle 38 (n=2)
    16.67 ± 23.57
        Day 1 Cycle 39 (n=2)
    25.00 ± 35.36
        Day 1 Cycle 40 (n=1)
    33.33 ± 99999
        Day 1 Cycle 41 (n=1)
    50.00 ± 99999
        Day 1 Cycle 42 (n=1)
    41.67 ± 99999
        Day 1 Cycle 43 (n=1)
    41.67 ± 99999
        Day 1 Cycle 44 (n=1)
    50.00 ± 99999
    No statistical analyses for this end point

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs were reported based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0. Safety Evaluable Population included all participants who received any amount of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 58.9 months for Cohort A, up to 59.9 months for Cohort B and up to 45.5 months for Cohort C
    End point values
    		 Cohort A: Placebo + Paclitaxel Cohort A: Ipatasertib + Paclitaxel Cohort B: Placebo + Paclitaxel Cohort B: Ipatasertib + Paclitaxel Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    87
    166
    75
    145
    102
    Units: participants
    84
    162
    74
    144
    102
    No statistical analyses for this end point

    Secondary: Cohort B: Time to Deterioration in Pain

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    End point title
    		 Cohort B: Time to Deterioration in Pain [16]
    End point description
    Time to deterioration in GHS/HRQoL was defined as the time from randomization to first observed ≥ 11-point increase from Baseline in pain scale score (Question 9 and 19) in EORTC QLQ-C30 linearly transformed GHS/HRQoL scale score and was planned to be assessed only in cohort with HR+/HER2 - breast cancer participants (Cohort B). Questions 9 and 19 , that assessed pain, used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). The scores were linearly transformed on a scale of 0 to 100, with higher scores indicating increased severity in symptoms. ITT Population for Cohort B included as all randomized participants regardless of whether the participants received the assigned treatment. 9999 indicates that data were not estimable not estimable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    Baseline up to 24.4 months
    Notes
    [16] - 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: This endpoint is reporting data for only Cohort B. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort B: Placebo + Paclitaxel Cohort B: Ipatasertib + Paclitaxel
    Number of subjects analysed
    76
    146
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (11.1 to 9999)
    Statistical analysis title
    		 Stratified Analysis
    Comparison groups
    Cohort B: Placebo + Paclitaxel v Cohort B: Ipatasertib + Paclitaxel
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2162 [17]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 2.22
    Notes
    [17] - Stratification variables were: prior adjuvant/neoadjuvant chemotherapy (yes vs. no), region, prior therapy with a PI3K or mTOR inhibitor (yes vs. no).

    Secondary: Number of Participants with at Least one Adverse Events of Special Interest (AESI)

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    End point title
    		 Number of Participants with at Least one Adverse Events of Special Interest (AESI)
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs were reported based on the NCI CTCAE, Version 4.0. AESI include cases of potential drug-induced liver injury that include an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law. Suspected transmission of an infectious agent by the study drug, Grade >= 3 fasting hyperglycemia, hepatotoxicity, diarrhea, rash, ALT/AST elevations. Grade >= 2 colitis/enterocolitis.
    End point type
    Secondary
    End point timeframe
    Up to 58.9 months for Cohort A, up to 59.9 months for Cohort B and up to 45.5 months for Cohort C
    End point values
    		 Cohort A: Placebo + Paclitaxel Cohort A: Ipatasertib + Paclitaxel Cohort B: Placebo + Paclitaxel Cohort B: Ipatasertib + Paclitaxel Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    87
    166
    75
    141
    102
    Units: participants
    79
    157
    73
    141
    101
    No statistical analyses for this end point

    Secondary: Cohorts A and B: Plasma Concentration of Ipatasertib

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    End point title
    		 Cohorts A and B: Plasma Concentration of Ipatasertib [18]
    End point description
    PK Evaluable Population included all participants who had at least one evaluable plasma sample. Number analyzed is the number of participants with data available for analyses. 'n' is the number of participants with data available for analysis for the specified time point.
    End point type
    Secondary
    End point timeframe
    Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days)
    Notes
    [18] - 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: This endpoint is reporting data for only Cohorts A and B. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort A: Ipatasertib + Paclitaxel Cohort B: Ipatasertib + Paclitaxel
    Number of subjects analysed
    146
    132
    Units: nanograms per millilitre (ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 (n=146, 132, 94)
    176 ± 232
    165 ± 326
        Cycle 1 Day 15 (n=132, 119, 82)
    191 ± 184
    211 ± 216
        Cycle 3 Day 15 (n=110, 102, 62)
    165 ± 169
    234 ± 149
    No statistical analyses for this end point

    Secondary: Cohorts C: Plasma Concentration of Ipatasertib

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    End point title
    		 Cohorts C: Plasma Concentration of Ipatasertib [19]
    End point description
    PK Evaluable Population included all participants who had at least one evaluable plasma sample. Number analyzed is the number of participants with data available for analyses. 'n' is the number of participants with data available for analysis for the specified time point.
    End point type
    Secondary
    End point timeframe
    Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days)
    Notes
    [19] - 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: This endpoint is reporting data for only Cohort C. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    94
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 (n=94)
    175 ± 183
        Cycle 1 Day 15 (n=82)
    233 ± 161.6
        Cycle 3 Day 15 (n=62)
    207 ± 197.6
    No statistical analyses for this end point

    Secondary: Cohorts A and B: Plasma Concentration of G-037720

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    End point title
    		 Cohorts A and B: Plasma Concentration of G-037720 [20]
    End point description
    G-037720 was a metabolite of ipatasertib. PK Evaluable Population included all participants who had at least one evaluable plasma sample. Number analyzed is the number of participants with data available for analyses. 'n' is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours post dose (cycle length= 28 days)
    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: This endpoint is reporting data for only Cohorts A and B. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort A: Ipatasertib + Paclitaxel Cohort B: Ipatasertib + Paclitaxel
    Number of subjects analysed
    146
    123
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 (n=146, 123, 91)
    45.6 ± 777
    68.2 ± 405
        Cycle 1 Day 15 (n=132, 119, 82)
    83.9 ± 183
    95.1 ± 211
        Cycle 3 Day 15 (n=110, 102, 62)
    90.8 ± 180
    109 ± 169
    No statistical analyses for this end point

    Secondary: Cohort C: Plasma Concentration of G-037720

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    End point title
    		 Cohort C: Plasma Concentration of G-037720 [21]
    End point description
    G-037720 was a metabolite of ipatasertib. PK Evaluable Population included all participants who had at least one evaluable plasma sample. Overall number analyzed is the number of participants with data available for analyses. Number analyzed is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Days 1 and 15 of Cycle 1: 1 to 3 hours post dose, and on Day 15 of Cycle 3: 2 to 4 hours 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: This endpoint is reporting data for only Cohort C. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    91
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 (n=91)
    67.3 ± 222.3
        Cycle 1 Day 15 (n=82)
    96.8 ± 140.7
        Cycle 3 Day 15 (n=62)
    96.5 ± 167.9
    No statistical analyses for this end point

    Secondary: Cohort C: Serum Concentration of Atezolizumab

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    End point title
    		 Cohort C: Serum Concentration of Atezolizumab [22]
    End point description
    As prespecified in the protocol, this endpoint was applicable only to Cohort C. For Cohort C, PK Evaluable Population included all participants who had at least one evaluable plasma sample in Cohort C. Number analyzed is the number of participants with data available for analysis. 'n' is the number of participants with data available for analysis at the specified time point.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1: 30 minutes post dose, predose on Day 15 of Cycle 1 and predose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (cycle length=28 days)
    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: This endpoint is reporting data for only Cohort C. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    101
    Units: micrograms per milliliter (ug/mL)
    geometric mean (geometric coefficient of variation)
        Day 1 Cycle 1 (n=84)
    309 ± 31.7
        Day 15 Cycle 1 (n=78)
    91.5 ± 23.9
        Day 1 Cycle 2 (n=92)
    130 ± 54.1
        Day 1 Cycle 3 (n=84)
    200 ± 41.1
        Day 1 Cycle 4 (n=80)
    231 ± 52.3
        Day 1 Cycle 8 (n=46)
    327 ± 27.6
        Day 1 Cycle 12 (n=21)
    371 ± 30.5
        Day 1 Cycle 16 (n=12)
    402 ± 42.4
    No statistical analyses for this end point

    Secondary: Cohort C: 1-year Event-free OS Rate

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    End point title
    		 Cohort C: 1-year Event-free OS Rate [23]
    End point description
    OS was defined as the time from enrollment to death from any cause. Event-free OS rate was defined as percentage of participants who did not experience any event and survived at 1 year after enrollment. As prespecified in the protocol, this outcome measure was applicable only to Cohort C. ITT Population for Cohort C included all enrolled participants in Cohort C.
    End point type
    Secondary
    End point timeframe
    From randomization up to death from any cause, up to 1 year
    Notes
    [23] - 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: This endpoint is reporting data for only Cohort C. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    102
    Units: percentage of participants
        number (confidence interval 95%)
    79.38 (71.31 to 87.44)
    No statistical analyses for this end point

    Secondary: Cohort C: 1-year Event-free PFS Rate

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    End point title
    		 Cohort C: 1-year Event-free PFS Rate [24]
    End point description
    PFS was defined as the time from enrollment to the first occurrence of disease progression, as determined locally by the investigator through the use of RECIST v.1.1, or death from any cause, whichever occurred first. Event-free PFS rate was defined as percentage of participants who did not experience any event and survived at 1 year after enrollment. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Percentages are rounded off to the nearest decimal point. As prespecified in the protocol, this outcome measure was applicable only to Cohort C. ITT Population for Cohort C included all enrolled participants in Cohort C.
    End point type
    Secondary
    End point timeframe
    From enrollment until the occurrence of disease progression or death from any cause, whichever occurred earlier, up to 1 year
    Notes
    [24] - 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: This endpoint is reporting data for only Cohort C. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    102
    Units: percentage of participants
        number (confidence interval 95%)
    31.17 (21.59 to 40.76)
    No statistical analyses for this end point

    Secondary: Cohort C: Number of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab

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    End point title
    		 Cohort C: Number of Participants with Anti-Drug Antibodies (ADAs) to Atezolizumab [25]
    End point description
    The numbers of ADA-positive participants after drug administration were summarized for participants exposed to atezolizumab. As prespecified in the protocol, this endpoint was applicable only to Cohort C. For Cohort C, Safety Evaluable Population included all participants who received any amount of study treatment in Cohort C. Number analyzed is the number of participants with an ADA assay result from at least one post-baseline sample.
    End point type
    Secondary
    End point timeframe
    Up to 45.5 months
    Notes
    [25] - 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: This endpoint is reporting data for only Cohort C. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Cohort C: Ipatasertib + Atezolizumab + Paclitaxel
    Number of subjects analysed
    101
    Units: participants
    18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 58.9 months for Cohort A, up to 59.9 months for Cohort B and up to 45.5 months for Cohort C
    Adverse event reporting additional description
    All-cause Mortality: ITT Population=all randomized participants(Cohorts A & B) & enrolled participants (Cohort C) regardless of whether the participants received the assigned treatment.Serious and Other Adverse Events: Safety Evaluable Population=all participants who received any amount of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    COHORT A Placebo + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed locally advanced unresectable or metastatic TNBC with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 mg/m^2, IV, on Days 1, 8, and 15 of each 28-day cycle and placebo, QD, on Days 1 to 21 of each 28-day cycle up to 58.9 months.

    Reporting group title
    COHORT A Ipatasertib + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed locally advanced unresectable or metastatic TNBC with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 mg/m^2, IV, on Days 1, 8, and 15 of each 28-day cycle and ipatasertib, at a dose of 400 mg, administered orally QD, on Days 1 to 21 of each 28-day cycle up to 58.9 months.

    Reporting group title
    COHORT C Ipatasertib + Atezolizumab + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed locally advanced unresectable or metastatic TNBC without PIK3CA/AKT1/PTEN-altered tumors and no prior systemic chemotherapy in the advanced disease setting received paclitaxel chemotherapy 80 mg/m^2, IV, on Days 1, 8, and 15 of each 28-day cycle, ipatasertib at a dose of 400 mg, administered orally QD, on Days 1 to 21 of each 28-day cycle, and atezolizumab 840 mg, IV, on Days 1 and 15 of each 28-day cycle up to 45.5 months.

    Reporting group title
    COHORT B Ipatasertib + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed HR+/HER2- adenocarcinoma of the breast with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 mg/m^2, IV, on Days 1, 8, and 15 of each 28-day cycle and ipatasertib, at a dose of 400 mg, administered orally QD, on Days 1 to 21 of each 28-day cycle up to 59.9 months.

    Reporting group title
    COHORT B Placebo + Paclitaxel
    Reporting group description
    		 Participants with histologically confirmed HR+ /HER2- adenocarcinoma of the breast with PIK3CA/AKT1/PTEN alteration and no prior systemic chemotherapy in the advanced disease setting and who were candidates for taxane monotherapy received paclitaxel chemotherapy, 80 mg/m^2, IV, on Days 1, 8, and 15 of each 28-day cycle and placebo, orally QD, on Days 1 to 21 of each 28-day cycle up to 59.9 months.

    Serious adverse events
    		 COHORT A Placebo + Paclitaxel COHORT A Ipatasertib + Paclitaxel COHORT C Ipatasertib + Atezolizumab + Paclitaxel COHORT B Ipatasertib + Paclitaxel COHORT B Placebo + Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 87 (22.99%)
    34 / 166 (20.48%)
    29 / 102 (28.43%)
    30 / 145 (20.69%)
    11 / 75 (14.67%)
         number of deaths (all causes)
    41
    91
    50
    78
    44
         number of deaths resulting from adverse events
    1
    0
    1
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour fistulisation
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    2 / 102 (1.96%)
    0 / 145 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schwannoma
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    2 / 102 (1.96%)
    0 / 145 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    4 / 102 (3.92%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    1 / 102 (0.98%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Immune-mediated lung disease
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 87 (0.00%)
    3 / 166 (1.81%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 87 (2.30%)
    1 / 166 (0.60%)
    1 / 102 (0.98%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    2 / 102 (1.96%)
    2 / 145 (1.38%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Dystonia
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    2 / 145 (1.38%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 87 (0.00%)
    3 / 166 (1.81%)
    2 / 102 (1.96%)
    2 / 145 (1.38%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Macular oedema
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epiretinal membrane
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eyelid oedema
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 87 (0.00%)
    2 / 166 (1.20%)
    2 / 102 (1.96%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 87 (0.00%)
    2 / 166 (1.20%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 87 (0.00%)
    6 / 166 (3.61%)
    4 / 102 (3.92%)
    4 / 145 (2.76%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 8
    4 / 4
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    2 / 102 (1.96%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    2 / 102 (1.96%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc compression
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 87 (4.60%)
    2 / 166 (1.20%)
    3 / 102 (2.94%)
    2 / 145 (1.38%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
    0 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess jaw
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suspected COVID-19
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    1 / 102 (0.98%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Emphysematous cystitis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Influenza
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal abscess
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    3 / 102 (2.94%)
    0 / 145 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 166 (0.60%)
    0 / 102 (0.00%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 166 (0.00%)
    0 / 102 (0.00%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    2 / 102 (1.96%)
    1 / 145 (0.69%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 COHORT A Placebo + Paclitaxel COHORT A Ipatasertib + Paclitaxel COHORT C Ipatasertib + Atezolizumab + Paclitaxel COHORT B Ipatasertib + Paclitaxel COHORT B Placebo + Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 87 (94.25%)
    161 / 166 (96.99%)
    101 / 102 (99.02%)
    141 / 145 (97.24%)
    72 / 75 (96.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 87 (3.45%)
    6 / 166 (3.61%)
    8 / 102 (7.84%)
    8 / 145 (5.52%)
    4 / 75 (5.33%)
         occurrences all number
    3
    12
    9
    8
    7
    Flushing
         subjects affected / exposed
    1 / 87 (1.15%)
    3 / 166 (1.81%)
    8 / 102 (7.84%)
    4 / 145 (2.76%)
    2 / 75 (2.67%)
         occurrences all number
    2
    6
    8
    5
    2
    Lymphoedema
         subjects affected / exposed
    0 / 87 (0.00%)
    7 / 166 (4.22%)
    2 / 102 (1.96%)
    6 / 145 (4.14%)
    5 / 75 (6.67%)
         occurrences all number
    0
    7
    2
    6
    6
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    10 / 87 (11.49%)
    35 / 166 (21.08%)
    19 / 102 (18.63%)
    27 / 145 (18.62%)
    13 / 75 (17.33%)
         occurrences all number
    12
    40
    22
    36
    17
    Mucosal inflammation
         subjects affected / exposed
    2 / 87 (2.30%)
    11 / 166 (6.63%)
    12 / 102 (11.76%)
    8 / 145 (5.52%)
    3 / 75 (4.00%)
         occurrences all number
    4
    13
    12
    11
    4
    Oedema
         subjects affected / exposed
    2 / 87 (2.30%)
    5 / 166 (3.01%)
    3 / 102 (2.94%)
    9 / 145 (6.21%)
    4 / 75 (5.33%)
         occurrences all number
    2
    5
    3
    10
    4
    Pyrexia
         subjects affected / exposed
    6 / 87 (6.90%)
    16 / 166 (9.64%)
    9 / 102 (8.82%)
    23 / 145 (15.86%)
    4 / 75 (5.33%)
         occurrences all number
    6
    17
    13
    30
    5
    Fatigue
         subjects affected / exposed
    15 / 87 (17.24%)
    30 / 166 (18.07%)
    23 / 102 (22.55%)
    29 / 145 (20.00%)
    19 / 75 (25.33%)
         occurrences all number
    16
    33
    35
    36
    30
    Oedema peripheral
         subjects affected / exposed
    7 / 87 (8.05%)
    18 / 166 (10.84%)
    7 / 102 (6.86%)
    21 / 145 (14.48%)
    14 / 75 (18.67%)
         occurrences all number
    7
    23
    9
    28
    19
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    5 / 87 (5.75%)
    4 / 166 (2.41%)
    1 / 102 (0.98%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    5
    8
    1
    0
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    3 / 87 (3.45%)
    9 / 166 (5.42%)
    4 / 102 (3.92%)
    3 / 145 (2.07%)
    0 / 75 (0.00%)
         occurrences all number
    3
    11
    5
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    3 / 87 (3.45%)
    12 / 166 (7.23%)
    8 / 102 (7.84%)
    15 / 145 (10.34%)
    4 / 75 (5.33%)
         occurrences all number
    5
    14
    10
    17
    4
    Dyspnoea
         subjects affected / exposed
    7 / 87 (8.05%)
    7 / 166 (4.22%)
    9 / 102 (8.82%)
    10 / 145 (6.90%)
    2 / 75 (2.67%)
         occurrences all number
    9
    10
    11
    13
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 87 (0.00%)
    13 / 166 (7.83%)
    6 / 102 (5.88%)
    11 / 145 (7.59%)
    2 / 75 (2.67%)
         occurrences all number
    0
    18
    8
    15
    3
    Cough
         subjects affected / exposed
    10 / 87 (11.49%)
    14 / 166 (8.43%)
    16 / 102 (15.69%)
    23 / 145 (15.86%)
    6 / 75 (8.00%)
         occurrences all number
    11
    15
    18
    32
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 87 (5.75%)
    10 / 166 (6.02%)
    10 / 102 (9.80%)
    6 / 145 (4.14%)
    6 / 75 (8.00%)
         occurrences all number
    6
    11
    10
    7
    6
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 87 (6.90%)
    18 / 166 (10.84%)
    21 / 102 (20.59%)
    13 / 145 (8.97%)
    10 / 75 (13.33%)
         occurrences all number
    7
    23
    39
    18
    16
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    4 / 87 (4.60%)
    7 / 166 (4.22%)
    7 / 102 (6.86%)
    5 / 145 (3.45%)
    8 / 75 (10.67%)
         occurrences all number
    4
    9
    10
    7
    11
    Neutrophil count decreased
         subjects affected / exposed
    10 / 87 (11.49%)
    22 / 166 (13.25%)
    8 / 102 (7.84%)
    23 / 145 (15.86%)
    18 / 75 (24.00%)
         occurrences all number
    23
    49
    33
    94
    65
    Weight decreased
         subjects affected / exposed
    3 / 87 (3.45%)
    12 / 166 (7.23%)
    7 / 102 (6.86%)
    7 / 145 (4.83%)
    2 / 75 (2.67%)
         occurrences all number
    3
    13
    7
    8
    2
    Weight increased
         subjects affected / exposed
    1 / 87 (1.15%)
    3 / 166 (1.81%)
    6 / 102 (5.88%)
    0 / 145 (0.00%)
    3 / 75 (4.00%)
         occurrences all number
    4
    4
    6
    0
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 87 (1.15%)
    9 / 166 (5.42%)
    12 / 102 (11.76%)
    3 / 145 (2.07%)
    7 / 75 (9.33%)
         occurrences all number
    1
    12
    20
    4
    9
    White blood cell count decreased
         subjects affected / exposed
    7 / 87 (8.05%)
    11 / 166 (6.63%)
    5 / 102 (4.90%)
    10 / 145 (6.90%)
    5 / 75 (6.67%)
         occurrences all number
    15
    28
    10
    44
    27
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 87 (8.05%)
    23 / 166 (13.86%)
    25 / 102 (24.51%)
    19 / 145 (13.10%)
    15 / 75 (20.00%)
         occurrences all number
    16
    29
    59
    27
    30
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    3 / 87 (3.45%)
    6 / 166 (3.61%)
    6 / 102 (5.88%)
    6 / 145 (4.14%)
    1 / 75 (1.33%)
         occurrences all number
    8
    6
    12
    6
    1
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    20 / 87 (22.99%)
    39 / 166 (23.49%)
    30 / 102 (29.41%)
    46 / 145 (31.72%)
    12 / 75 (16.00%)
         occurrences all number
    23
    49
    41
    63
    15
    Paraesthesia
         subjects affected / exposed
    2 / 87 (2.30%)
    8 / 166 (4.82%)
    5 / 102 (4.90%)
    13 / 145 (8.97%)
    6 / 75 (8.00%)
         occurrences all number
    3
    11
    7
    14
    8
    Dysgeusia
         subjects affected / exposed
    8 / 87 (9.20%)
    10 / 166 (6.02%)
    6 / 102 (5.88%)
    11 / 145 (7.59%)
    4 / 75 (5.33%)
         occurrences all number
    8
    11
    6
    12
    4
    Headache
         subjects affected / exposed
    10 / 87 (11.49%)
    28 / 166 (16.87%)
    21 / 102 (20.59%)
    24 / 145 (16.55%)
    8 / 75 (10.67%)
         occurrences all number
    19
    56
    33
    37
    19
    Dizziness
         subjects affected / exposed
    8 / 87 (9.20%)
    6 / 166 (3.61%)
    10 / 102 (9.80%)
    10 / 145 (6.90%)
    3 / 75 (4.00%)
         occurrences all number
    8
    8
    14
    12
    4
    Polyneuropathy
         subjects affected / exposed
    7 / 87 (8.05%)
    5 / 166 (3.01%)
    8 / 102 (7.84%)
    12 / 145 (8.28%)
    6 / 75 (8.00%)
         occurrences all number
    7
    5
    8
    13
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    19 / 87 (21.84%)
    32 / 166 (19.28%)
    8 / 102 (7.84%)
    23 / 145 (15.86%)
    23 / 75 (30.67%)
         occurrences all number
    19
    38
    8
    30
    24
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 87 (26.44%)
    43 / 166 (25.90%)
    34 / 102 (33.33%)
    45 / 145 (31.03%)
    15 / 75 (20.00%)
         occurrences all number
    34
    58
    50
    57
    28
    Leukopenia
         subjects affected / exposed
    4 / 87 (4.60%)
    7 / 166 (4.22%)
    11 / 102 (10.78%)
    8 / 145 (5.52%)
    7 / 75 (9.33%)
         occurrences all number
    11
    23
    49
    18
    16
    Neutropenia
         subjects affected / exposed
    20 / 87 (22.99%)
    28 / 166 (16.87%)
    25 / 102 (24.51%)
    36 / 145 (24.83%)
    18 / 75 (24.00%)
         occurrences all number
    39
    92
    114
    95
    58
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 87 (1.15%)
    9 / 166 (5.42%)
    2 / 102 (1.96%)
    4 / 145 (2.76%)
    2 / 75 (2.67%)
         occurrences all number
    1
    11
    2
    4
    2
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    6 / 87 (6.90%)
    18 / 166 (10.84%)
    7 / 102 (6.86%)
    16 / 145 (11.03%)
    6 / 75 (8.00%)
         occurrences all number
    12
    31
    8
    27
    8
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 87 (0.00%)
    4 / 166 (2.41%)
    5 / 102 (4.90%)
    4 / 145 (2.76%)
    4 / 75 (5.33%)
         occurrences all number
    0
    5
    5
    5
    4
    Constipation
         subjects affected / exposed
    31 / 87 (35.63%)
    49 / 166 (29.52%)
    13 / 102 (12.75%)
    42 / 145 (28.97%)
    26 / 75 (34.67%)
         occurrences all number
    40
    56
    20
    54
    33
    Nausea
         subjects affected / exposed
    22 / 87 (25.29%)
    66 / 166 (39.76%)
    42 / 102 (41.18%)
    60 / 145 (41.38%)
    17 / 75 (22.67%)
         occurrences all number
    29
    106
    65
    94
    28
    Dyspepsia
         subjects affected / exposed
    4 / 87 (4.60%)
    14 / 166 (8.43%)
    6 / 102 (5.88%)
    9 / 145 (6.21%)
    4 / 75 (5.33%)
         occurrences all number
    4
    18
    7
    11
    6
    Vomiting
         subjects affected / exposed
    8 / 87 (9.20%)
    53 / 166 (31.93%)
    28 / 102 (27.45%)
    45 / 145 (31.03%)
    6 / 75 (8.00%)
         occurrences all number
    10
    112
    43
    67
    10
    Abdominal pain upper
         subjects affected / exposed
    8 / 87 (9.20%)
    16 / 166 (9.64%)
    6 / 102 (5.88%)
    15 / 145 (10.34%)
    5 / 75 (6.67%)
         occurrences all number
    10
    16
    6
    21
    7
    Abdominal pain
         subjects affected / exposed
    5 / 87 (5.75%)
    15 / 166 (9.04%)
    12 / 102 (11.76%)
    11 / 145 (7.59%)
    7 / 75 (9.33%)
         occurrences all number
    6
    16
    13
    17
    9
    Diarrhoea
         subjects affected / exposed
    28 / 87 (32.18%)
    138 / 166 (83.13%)
    86 / 102 (84.31%)
    125 / 145 (86.21%)
    29 / 75 (38.67%)
         occurrences all number
    56
    477
    324
    461
    64
    Flatulence
         subjects affected / exposed
    1 / 87 (1.15%)
    5 / 166 (3.01%)
    3 / 102 (2.94%)
    7 / 145 (4.83%)
    4 / 75 (5.33%)
         occurrences all number
    1
    6
    3
    7
    6
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 87 (3.45%)
    0 / 166 (0.00%)
    6 / 102 (5.88%)
    6 / 145 (4.14%)
    4 / 75 (5.33%)
         occurrences all number
    12
    0
    13
    12
    38
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    4 / 87 (4.60%)
    0 / 166 (0.00%)
    1 / 102 (0.98%)
    5 / 145 (3.45%)
    5 / 75 (6.67%)
         occurrences all number
    5
    0
    1
    5
    6
    Alopecia
         subjects affected / exposed
    38 / 87 (43.68%)
    78 / 166 (46.99%)
    42 / 102 (41.18%)
    75 / 145 (51.72%)
    44 / 75 (58.67%)
         occurrences all number
    39
    80
    42
    79
    46
    Rash
         subjects affected / exposed
    11 / 87 (12.64%)
    26 / 166 (15.66%)
    29 / 102 (28.43%)
    31 / 145 (21.38%)
    9 / 75 (12.00%)
         occurrences all number
    13
    37
    40
    55
    13
    Nail discolouration
         subjects affected / exposed
    4 / 87 (4.60%)
    6 / 166 (3.61%)
    1 / 102 (0.98%)
    9 / 145 (6.21%)
    8 / 75 (10.67%)
         occurrences all number
    4
    7
    1
    9
    8
    Rash maculo-papular
         subjects affected / exposed
    0 / 87 (0.00%)
    5 / 166 (3.01%)
    5 / 102 (4.90%)
    7 / 145 (4.83%)
    4 / 75 (5.33%)
         occurrences all number
    0
    6
    5
    7
    7
    Erythema
         subjects affected / exposed
    5 / 87 (5.75%)
    3 / 166 (1.81%)
    3 / 102 (2.94%)
    5 / 145 (3.45%)
    3 / 75 (4.00%)
         occurrences all number
    6
    3
    3
    5
    4
    Pruritus
         subjects affected / exposed
    7 / 87 (8.05%)
    15 / 166 (9.04%)
    17 / 102 (16.67%)
    15 / 145 (10.34%)
    3 / 75 (4.00%)
         occurrences all number
    8
    21
    24
    25
    5
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 166 (0.00%)
    6 / 102 (5.88%)
    0 / 145 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    0
    0
    6
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    5 / 87 (5.75%)
    16 / 166 (9.64%)
    10 / 102 (9.80%)
    15 / 145 (10.34%)
    9 / 75 (12.00%)
         occurrences all number
    5
    24
    14
    17
    12
    Muscle spasms
         subjects affected / exposed
    1 / 87 (1.15%)
    4 / 166 (2.41%)
    5 / 102 (4.90%)
    3 / 145 (2.07%)
    5 / 75 (6.67%)
         occurrences all number
    1
    4
    5
    5
    6
    Arthralgia
         subjects affected / exposed
    12 / 87 (13.79%)
    16 / 166 (9.64%)
    13 / 102 (12.75%)
    26 / 145 (17.93%)
    10 / 75 (13.33%)
         occurrences all number
    18
    24
    19
    40
    16
    Pain in extremity
         subjects affected / exposed
    4 / 87 (4.60%)
    14 / 166 (8.43%)
    4 / 102 (3.92%)
    13 / 145 (8.97%)
    6 / 75 (8.00%)
         occurrences all number
    5
    18
    5
    24
    6
    Back pain
         subjects affected / exposed
    9 / 87 (10.34%)
    16 / 166 (9.64%)
    10 / 102 (9.80%)
    21 / 145 (14.48%)
    7 / 75 (9.33%)
         occurrences all number
    14
    21
    11
    25
    8
    Bone pain
         subjects affected / exposed
    0 / 87 (0.00%)
    7 / 166 (4.22%)
    2 / 102 (1.96%)
    9 / 145 (6.21%)
    4 / 75 (5.33%)
         occurrences all number
    0
    9
    2
    17
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 87 (2.30%)
    12 / 166 (7.23%)
    7 / 102 (6.86%)
    16 / 145 (11.03%)
    4 / 75 (5.33%)
         occurrences all number
    3
    16
    9
    18
    7
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 87 (3.45%)
    12 / 166 (7.23%)
    8 / 102 (7.84%)
    14 / 145 (9.66%)
    6 / 75 (8.00%)
         occurrences all number
    3
    13
    10
    19
    7
    Nasopharyngitis
         subjects affected / exposed
    3 / 87 (3.45%)
    11 / 166 (6.63%)
    5 / 102 (4.90%)
    19 / 145 (13.10%)
    7 / 75 (9.33%)
         occurrences all number
    4
    16
    5
    24
    11
    Cystitis
         subjects affected / exposed
    3 / 87 (3.45%)
    8 / 166 (4.82%)
    2 / 102 (1.96%)
    7 / 145 (4.83%)
    6 / 75 (8.00%)
         occurrences all number
    5
    9
    2
    12
    9
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    9 / 87 (10.34%)
    31 / 166 (18.67%)
    22 / 102 (21.57%)
    19 / 145 (13.10%)
    10 / 75 (13.33%)
         occurrences all number
    16
    49
    42
    27
    39
    Hypokalaemia
         subjects affected / exposed
    3 / 87 (3.45%)
    5 / 166 (3.01%)
    8 / 102 (7.84%)
    6 / 145 (4.14%)
    2 / 75 (2.67%)
         occurrences all number
    3
    6
    10
    8
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 87 (2.30%)
    9 / 166 (5.42%)
    4 / 102 (3.92%)
    7 / 145 (4.83%)
    5 / 75 (6.67%)
         occurrences all number
    2
    11
    5
    8
    8
    Decreased appetite
         subjects affected / exposed
    10 / 87 (11.49%)
    29 / 166 (17.47%)
    14 / 102 (13.73%)
    21 / 145 (14.48%)
    7 / 75 (9.33%)
         occurrences all number
    10
    35
    15
    29
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jun 2017
    The following changes were made as per amendment 1: Inclusion criteria was updated to clarify that the pathological diagnosis of receptor status at the time of study entry should be based on the most recent (local or central) testing of Estrogen receptor (ER), progesterone receptor (PR), and HER2 status performed on a biopsy of recurrent or metastatic tissue.
    16 Feb 2018
    The following changes were made as per amendment 2: Cohort B participants were required to meet at least one of these criteria •Have primary endocrine resistance, defined as a relapse during the first 2 years of adjuvant endocrine treatment. •Have progressed following at least one line of endocrine-based treatment in the advanced BC setting. •Experience visceral crisis.
    15 Jun 2018
    Protocol was updated primarily to expand the testing methods that could be used for biomarker eligibility (to allow local/commercial and blood-based testing), with other minor updates to provide clarity and consistency throughout the protocol. To be eligible for this study, all patients were required to have a valid PIK3CA/AKT1/PTEN alteration by either local/commercial or central testing. In previous versions of the protocol, testing was required to be performed centrally at Foundation Medicine, Inc (FMI) prior to randomization; however, because of the availability of local testing, and the potentially extended time required to obtain central testing results, the protocol was updated to expand the testing methods that could be used for biomarker eligibility. In summary, the inclusion criterion was expanded to also allow tissue or blood-based results from local/commercial tests (using a Clinical Laboratory Improvement Amendments (CLIA) or equivalently accredited diagnostic laboratory) or centrally tested blood-based FMI assay demonstrating a valid PIK3CA/AKT1/PTEN alteration to qualify patients for enrollment in the study. The newly allowed methods enabled patients with existing test results that show qualifying biomarkers to enroll and be randomized without having to wait for the centralized testing result to be completed. It was anticipated that this would shorten the time to treatment for patients and encourage screening for the study.
    16 Aug 2018
    The following changes were made as per amendment 5: Updated Cohort B (participants with HR+/HER2- BC) inclusion and exclusion criteria to ensure that participants enrolled were considered to be those patients most likely to benefit from ipatasertib in combination with paclitaxel. Disease-specific inclusion criteria were modified to specify that all participants with HR+/HER2-BC who were not considered appropriate for endocrine-based treatment must also have met one of the following criteria: • Participants had recurrent disease (locoregional or metastatic) during adjuvant endocrine therapy (i.e., ≤5 years of being on therapy). •If participant had de novo metastatic disease, participant has progressive disease within 6 months of being on first-line endocrine treatment of metastatic disease.
    04 Oct 2018
    The following changes were made as per amendment 6: Introduced an additional cohort (Cohort C) with an open-label treatment assignment of ipatasertib + atezolizumab + paclitaxel for approximately 100 participants who initially screen for Cohort A (TNBC) but do not qualify for the study (i.e., lack of PIK3CA/AKT1/PTEN alteration validated by central tumor tissue testing using the FMI clinical trial assay (CTA)). Cohort C was introduced as a high biomarker-negative rate, as well as the changing landscape of clinical trial options for patients with first-line advanced TNBC, made recruitment into Cohort A (biomarker-restricted) study. With the addition of Cohort C, up to approximately 100 participants consenting to the lengthy screening process and associated waiting period for biomarker results would have a study treatment assignment even if they do not meet biomarker eligibility for Cohort A, provided other eligibility requirements were met.
    27 Mar 2019
    The following changes were made as per amendment 7: Added 5 more countries and updated AE management guidelines in Cohort C for atezolizumab and for the combination of ipatasertib, atezolizumab, and paclitaxel.

    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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