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    Clinical Trial Results:
    A Randomized, Phase II, Multicenter, Placebo-Controlled Study of Ipatasertib (GDC-0068), an Inhibitor of Akt, in Combination with Paclitaxel as Front-Line Treatment for Patients with Metastatic Triple-Negative Breast Cancer

    Summary
    EudraCT number
    		 2014-000469-35
    Trial protocol
    		 IT   BE   ES   FR  
    Global end of trial date
    31 Aug 2019

    Results information
    Results version number
    		 v3(current)
    This version publication date
    10 Mar 2021
    First version publication date
    24 Jun 2017
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    GO29227
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02162719
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 LOTUS: Alias ID
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    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
    31 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate the efficacy of ipatasertib combined with paclitaxel compared with placebo combined with paclitaxel in subjects with inoperable locally advanced metastatic triple-negative breast cancer (mTNBC), as measured by PFS in all subjects and in subjects with PTEN-low tumors.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Aug 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 56 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 31
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 41
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    Singapore: 7
    Country: Number of subjects enrolled
    Italy: 6
    Worldwide total number of subjects
    124
    EEA total number of subjects
    34
    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)
    101
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 166 subjects were screened, out of which 42 subjects failed screening. A total of 124 subjects were enrolled at 44 sites. Results are reported here up to clinical cut-off date of 31st August 2019.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ipatasertib and Paclitaxel
    Arm description
    		 Subjects randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 80 mg/m^2 as intravenous (IV) infusion on Days 1, 8, and 15 of each cycle of 28 days.

    Investigational medicinal product name
    Ipatasertib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ipatasertib 400 mg once daily (QD), beginning on Cycle 1, Day 1 through Day 21 of each 28-day cycle until disease progression or intolerable toxicity.

    Arm title
    		 Placebo and Paclitaxel
    Arm description
    		 Subjects randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel 80 mg/m^2 as intravenous (IV) infusion on Days 1, 8, and 15 of each cycle of 28 days.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching Ipatasertib orally, once daily on Cycle 1, Day 1 through Day 21 of each 28-day cycle until disease progression or intolerable toxicity.

    Number of subjects in period 1
    		Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Started
    62
    62
    Completed
    0
    0
    Not completed
    62
    62
         Death
    41
    46
         Withdrawal by Subject
    8
    2
         Lost to follow-up
    1
    3
         Disease Progression
    2
    1
         Discontinuation of Overall Survival Follow-up
    10
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ipatasertib and Paclitaxel
    Reporting group description
    		 Subjects randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Reporting group title
    Placebo and Paclitaxel
    Reporting group description
    		 Subjects randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Reporting group values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel Total
    Number of subjects
    		 62 62 124
    Age categorical
    Units: Subjects
        Adults (18-40 years)
    		 10 5 15
        From 41-64 years
    		 40 46 86
        65 years and over
    		 12 11 23
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.6 ± 13.4 54.4 ± 10.9 -
    Gender categorical
    Units: Subjects
        Female
    		 62 62 124

    End points

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    End points reporting groups
    Reporting group title
    Ipatasertib and Paclitaxel
    Reporting group description
    		 Subjects randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Reporting group title
    Placebo and Paclitaxel
    Reporting group description
    		 Subjects randomised to receive paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Subject analysis set title
    Ipatasertib and Paclitaxel (Safety Population)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Subject analysis set title
    Placebo and Paclitaxel (Safety Population)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first. Intent to treat population included all randomized subjects allocated to the treatment arm to which they were randomized.
    End point type
    Primary
    End point timeframe
    Baseline up to Primary Completion Date (07 June 2016)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    62
    62
    Units: Months
        median (confidence interval 90%)
    6.18 (4.57 to 7.33)
    4.93 (3.58 to 5.36)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ipatasertib and Paclitaxel v Placebo and Paclitaxel
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0372 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard Ratio (Stratified Analysis)
    Point estimate
    0.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.91
    Notes
    [1] - Stratification variables were adjuvant/neoadjuvant treatment including treatment with or without radiation, disease-free interval from last dose (<=12 vs >12 months vs. no prior chemotherapy), PTEN status of tumor (H-score 0, vs. 1 to 150, vs. >150).

    Primary: PFS in Subjects with Phosphatase and Tensin Homolog (PTEN)-Low Tumors

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    End point title
    		 PFS in Subjects with Phosphatase and Tensin Homolog (PTEN)-Low Tumors
    End point description
    PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized. Subjects with PTEN-low tumors were evaluated for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to Primary Completion Date (07 June 2016)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    25
    23
    Units: Months
        median (confidence interval 90%)
    6.18 (3.65 to 9.10)
    3.65 (2.53 to 5.75)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ipatasertib and Paclitaxel v Placebo and Paclitaxel
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1753 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard Ratio (Stratified Analysis)
    Point estimate
    0.59
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 1.16
    Notes
    [2] - Stratification variables were adjuvant/neoadjuvant treatment including treatment with or without radiation, disease-free interval from last dose (<=12 vs >12 months vs. no prior chemotherapy), PTEN status of tumor (H-score 0, vs. 1 to 150, vs. >150).

    Secondary: PFS in Subjects with Phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit Alpha (PIK3CA)/ Protein Kinase B (AKT1)/ PTEN-altered Tumors

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    End point title
    		 PFS in Subjects with Phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit Alpha (PIK3CA)/ Protein Kinase B (AKT1)/ PTEN-altered Tumors
    End point description
    PFS was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1 or death on study (<=30 days after the last dose of study treatment regimen) from any cause, whichever occurred first. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized. Subjects with PIK3CA/AKT1/PTEN-altered tumors were evaluated for this endpoint. Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Primary Completion Date (07 June 2016)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    26
    16
    Units: Months
        median (confidence interval 90%)
    9.03 (4.57 to 12.88)
    4.93 (3.58 to 5.39)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ipatasertib and Paclitaxel v Placebo and Paclitaxel
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.3636
    Method
    		 Logrank
    Parameter type
    		 Hazard Ratio (Unstratified Analysis)
    Point estimate
    0.76
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.27

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the date of randomization to the date of death from any cause. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline up to Clinical Cut Off Date (31 August 2019)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    62
    62
    Units: months
    median (confidence interval 95%)
        Overall Survival
    25.8 (18.6 to 28.6)
    16.9 (14.6 to 24.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ipatasertib and Paclitaxel v Placebo and Paclitaxel
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3607 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard Ratio (Stratified Analysis)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.28
    Notes
    [3] - Stratification variables were adjuvant/neoadjuvant treatment including treatment with/without radiation, disease-free interval from last dose (<=12 vs >12 months vs. no prior chemotherapy), PTEN status of tumor (H-score 0, vs. 1 to 150, vs. >150).

    Secondary: OS in Subjects with PTEN-Low Tumors

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    End point title
    		 OS in Subjects with PTEN-Low Tumors
    End point description
    OS was defined as the time from the date of randomization to the date of death from any cause. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized. Subjects with PTEN-low tumors were evaluated for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Clinical Cut Off Date (31 August 2019)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    25
    23
    Units: months
    median (confidence interval 95%)
        Overall Survival
    23.1 (18.3 to 28.6)
    15.8 (9.0 to 29.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ipatasertib and Paclitaxel v Placebo and Paclitaxel
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4422 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard Ratio (Stratified Analysis)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 1.65
    Notes
    [4] - Stratification variables were adjuvant/neoadjuvant treatment including treatment with/without radiation, disease-free interval from last dose (<=12 vs >12 months vs. no prior chemotherapy), PTEN status of tumor (H-score 0, vs. 1 to 150, vs. >150).

    Secondary: OS in Subjects with PIK3CA/AKT1/PTEN-altered Tumors

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    End point title
    		 OS in Subjects with PIK3CA/AKT1/PTEN-altered Tumors
    End point description
    OS was defined as the time from the date of randomization to the date of death from any cause. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized. Subjects with PIK3CA/AKT1/PTEN-altered tumors were evaluated for this endpoint. 999 = Not Estimable.
    End point type
    Secondary
    End point timeframe
    Baseline up to Clinical Cut Off Date (31 August 2019)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    26
    16
    Units: months
    median (confidence interval 95%)
        Overall Survival
    25.8 (18.6 to 35.2)
    22.1 (8.7 to 999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ipatasertib and Paclitaxel v Placebo and Paclitaxel
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7599
    Method
    		 Logrank
    Parameter type
    		 Hazard Ratio (Unstratified Analysis)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 2.47

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    Confirmed tumor ORR in subjects with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of subjects who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Subjects for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline up to Primary Completion Date (07 June 2016)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    62 [5]
    62 [6]
    Units: percentage of subjects
        number (confidence interval 90%)
    40.3 (30.64 to 50.90)
    32.3 (23.35 to 42.36)
    Notes
    [5] - Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    [6] - Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    No statistical analyses for this end point

    Secondary: ORR in Subjects with PTEN-Low Tumors

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    End point title
    		 ORR in Subjects with PTEN-Low Tumors
    End point description
    Confirmed tumor ORR in subjects with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of subjects who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Subjects for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized. Subjects with PTEN-Low Tumors were evaluated for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Primary Completion Date (07 June 2016)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    25 [7]
    23 [8]
    Units: percentage of subjects
        number (confidence interval 90%)
    48.0 (30.73 to 64.00)
    26.1 (12.02 to 43.12)
    Notes
    [7] - Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    [8] - Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    No statistical analyses for this end point

    Secondary: ORR in Subjects with PIK3CA/AKT1/PTEN-altered Tumors

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    End point title
    		 ORR in Subjects with PIK3CA/AKT1/PTEN-altered Tumors
    End point description
    Confirmed tumor ORR in subjects with measurable disease at baseline was assessed by the investigator per RECIST, v1.1. Confirmed ORR was defined as the percentage of subjects who achieved either a complete response or partial response based on the investigator assessment that was confirmed by a repeat assessment no less than 4 weeks after the criteria for response was first met. Subjects for whom no records of post-baseline tumor assessments were reported were counted as non-responders. Complete response (CR): disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized. Subjects with PIK3CA/AKT1/PTEN-altered tumors were evaluated for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Primary Completion Date (07 June 2016)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    26 [9]
    16 [10]
    Units: percentage of subjects
        number (confidence interval 90%)
    50.0 (34.24 to 65.76)
    43.8 (23.53 to 66.66)
    Notes
    [9] - Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    [10] - Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of objective response in subjects with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1. Only subjects who achieved a confirmed objective response were included in the analysis. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized. Here, 99999 indicates that upper limit of duration of response was not reached due to low number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Baseline up to Primary Completion Date (07 June 2016)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    25 [11]
    20 [12]
    Units: months
        median (confidence interval 90%)
    7.85 (5.65 to 99999)
    7.43 (3.88 to 9.20)
    Notes
    [11] - Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    [12] - Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    No statistical analyses for this end point

    Secondary: Duration of Response in Subjects with PTEN-Low Tumors

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    End point title
    		 Duration of Response in Subjects with PTEN-Low Tumors
    End point description
    Duration of objective response in subjects with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1. Only subjects who achieved a confirmed objective response were included in the analysis. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized. Subjects with PTEN-low tumors were evaluated for this endpoint. Here, 99999 indicates that upper limit of duration of response was not reached due to low number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Baseline up to Primary Completion Date (07 June 2016)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    12 [13]
    6 [14]
    Units: Months
        median (confidence interval 90%)
    6.54 (4.44 to 99999)
    7.49 (7.29 to 99999)
    Notes
    [13] - Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    [14] - Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    No statistical analyses for this end point

    Secondary: Duration of Response in Subjects with PIK3CA/AKT1/PTEN-altered Tumors

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    End point title
    		 Duration of Response in Subjects with PIK3CA/AKT1/PTEN-altered Tumors
    End point description
    Duration of objective response in subjects with measurable disease at baseline was defined as the time from first observation of an objective tumor response until first observation of disease progression, as assessed by the investigator per modified RECIST, v1.1. Only subjects who achieved a confirmed objective response were included in the analysis. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized. Subjects with PIK3CA/AKT1/PTEN-altered tumors were evaluated for this endpoint. Here, 99999 indicates that upper limit of duration of response was not reached due to low number of subjects with events.
    End point type
    Secondary
    End point timeframe
    Baseline up to Primary Completion Date (07 June 2016)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    13 [15]
    7 [16]
    Units: Months
        median (confidence interval 90%)
    11.24 (5.59 to 99999)
    6.06 (3.78 to 7.56)
    Notes
    [15] - Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    [16] - Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    No statistical analyses for this end point

    Secondary: Time to Disease Progression

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    End point title
    		 Time to Disease Progression
    End point description
    Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized. Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Primary Completion Date (07 June 2016)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    62
    62
    Units: Months
        median (confidence interval 90%)
    6.18 (4.57 to 7.33)
    4.96 (3.61 to 5.39)
    No statistical analyses for this end point

    Secondary: Time to Disease Progression in Subjects with PTEN-Low Tumors

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    End point title
    		 Time to Disease Progression in Subjects with PTEN-Low Tumors
    End point description
    Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized. Subjects with PTEN low tumors were evaluated for this endpoint. Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Primary Completion Date (07 June 2016)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    25
    23
    Units: Months
        median (confidence interval 90%)
    6.18 (3.65 to 9.10)
    3.94 (2.53 to 7.33)
    No statistical analyses for this end point

    Secondary: Time to Disease Progression in Subjects with PIK3CA/AKT1/PTEN-altered Tumors

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    End point title
    		 Time to Disease Progression in Subjects with PIK3CA/AKT1/PTEN-altered Tumors
    End point description
    Time to disease progression was defined as the time from randomization to the first occurrence of disease progression, as determined by investigator review of tumor assessments by RECIST, v1.1. ITT population included all randomized subjects allocated to the treatment arm to which they were randomized. Subjects with PIK3CA/AKT1/PTEN-altered tumors were evaluated for this endpoint. Please note that there were no data updates since Primary Completion Date for this Outcome Measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Primary Completion Date (07 June 2016)
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    26
    16
    Units: Months
        median (confidence interval 90%)
    9.03 (4.57 to 12.88)
    4.93 (3.58 to 5.39)
    No statistical analyses for this end point

    Secondary: Safety: Percentage of Subjects with Adverse Events

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    End point title
    		 Safety: Percentage of Subjects with Adverse Events
    End point description
    An adverse event was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. The Safety population included all treated subjects with subjects allocated to the treatment arm associated with the regimen that they actually received.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after the last dose of study drug or until initiation of another anti-cancer therapy, whichever occurs first (up to 3 years, 3 months)
    End point values
    		 Ipatasertib and Paclitaxel (Safety Population) Placebo and Paclitaxel (Safety Population)
    Number of subjects analysed
    61
    62
    Units: percentage of subjects
        number (not applicable)
    100.0
    96.8
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Endpoint: Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) of Ipatasertib

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    End point title
    		 Pharmacokinetic Endpoint: Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero to 24 Hours (AUC0-24h) of Ipatasertib
    End point description
    The pharmacokinetic (PK) analysis population consisted of all subjects who had evaluable PK data. PK parameters were not calculated due to sparse PK sampling.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1, Cycle 1 Day 8
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: h*ng/mL/mg
    Notes
    [17] - PK parameters were not calculated due to sparse PK sampling.
    [18] - PK parameters were not calculated due to sparse PK sampling.
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Endpoint: Apparent Clearance Following Oral Dosing (CL/F) of Ipatasertib

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    End point title
    		 Pharmacokinetic Endpoint: Apparent Clearance Following Oral Dosing (CL/F) of Ipatasertib
    End point description
    The pharmacokinetic (PK) analysis population consisted of all subjects who had evaluable PK data. PK parameters were not calculated due to sparse PK sampling.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1, Cycle 1 Day 8
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    0 [19]
    0 [20]
    Units: ml/hr
    Notes
    [19] - PK parameters were not calculated due to sparse PK sampling.
    [20] - PK parameters were not calculated due to sparse PK sampling.
    No statistical analyses for this end point

    Secondary: Patient Reported Outcome (PRO) Measure: Mean Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) Score

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    End point title
    		 Patient Reported Outcome (PRO) Measure: Mean Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) Score
    End point description
    EORTC QLQ-C30 included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting), single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea, financial difficulties). Most questions used 4-point scale (1=Not at all to 4=Very much; 2 questions used 7-point scale [1=very poor to 7=Excellent]). Scores averaged, transformed to 0-100 scale; a higher score=better level of functioning. For symptom scale scores, higher level=severe level of symptoms. "A change of at least 10 points from baseline is considered clinically meaningful (Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality of life score. J Clin Oncol 1998;16:139−44). PRO measures were analyzed from baseline up to cycle 5. Scores from later timepoints were not analyzed due to attrition (in both arms, fewer than 50% of subjects remained on treatment beyond cycle 5). ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1) up to Cycle 5 Day 1
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    62
    62
    Units: unit on a scale
    arithmetic mean (standard deviation)
        Appetite loss:Cycle 2 Day 1 (n=57, 53)
    7.60 ± 28.18
    -0.63 ± 24.88
        Appetite loss:Cycle 3 Day 1 (n=46, 43)
    9.42 ± 21.84
    -3.88 ± 24.35
        Appetite loss:Cycle 4 Day 1 (n=49,40)
    5.44 ± 23.91
    -4.17 ± 25.25
        Appetite loss:Cycle 5 Day 1 (n=35,30)
    0.00 ± 18.08
    -1.11 ± 25.50
        Cognitive Functioning: Cycle 2 Day 1 (n=57, 53)
    1.17 ± 14.04
    0.63 ± 17.28
        Cognitive Functioning: Cycle 3 Day 1 (n=46, 43)
    -1.81 ± 19.64
    -1.81 ± 19.64
        Cognitive Functioning: Cycle 4 Day 1 (n=49, 40)
    -3.40 ± 15.95
    0.00 ± 20.32
        Cognitive Functioning: Cycle 5 Day 1 (n=36, 30)
    0.00 ± 13.80
    -4.44 ± 19.54
        Constipation: Cycle 2 Day 1 (n=57, 53)
    5.85 ± 24.50
    0.63 ± 25.73
        Constipation: Cycle 3 Day 1 (n=46, 42)
    2.90 ± 19.66
    1.59 ± 22.03
        Constipation: Cycle 4 Day 1 (n=48, 40)
    1.39 ± 16.78
    0.83 ± 30.65
        Constipation: Cycle 5 Day 1 (n=36, 30)
    2.78 ± 14.64
    1.11 ± 20.50
        Diarrhoea: Cycle 2 Day 1 (n=57, 53)
    17.54 ± 30.28
    1.89 ± 15.21
        Diarrhoea: Cycle 3 Day 1 (n=46, 43)
    23.91 ± 34.90
    3.88 ± 18.13
        Diarrhoea: Cycle 4 Day 1 (n=49, 40)
    19.73 ± 34.64
    0.83 ± 15.99
        Diarrhoea: Cycle 5 Day 1 (n=35, 30)
    21.90 ± 37.87
    1.11 ± 16.34
        Dyspnea: Cycle 2 Day 1 (n=57, 52)
    2.92 ± 19.19
    0.00 ± 18.67
        Dyspnea: Cycle 3 Day 1 (n=46, 41)
    5.07 ± 23.27
    2.44 ± 22.84
        Dyspnea: Cycle 4 Day 1 (n=49, 39)
    3.40 ± 25.68
    5.13 ± 22.35
        Dyspnea: Cycle 5 Day 1 (n=36, 28)
    5.56 ± 25.82
    4.76 ± 23.51
        Emotional Functioning: Cycle 2 Day 1 (n=57, 53)
    12.09 ± 15.90
    4.72 ± 16.87
        Emotional Functioning: Cycle 3 Day 1 (n=46, 43)
    7.37 ± 17.18
    3.88 ± 20.36
        Emotional Functioning: Cycle 4 Day 1 (n=49, 40)
    8.22 ± 16.53
    2.71 ± 21.47
        Emotional Functioning: Cycle 5 Day 1 (n=35, 30)
    8.73 ± 16.30
    1.39 ± 17.79
        Fatigue: Cycle 2 Day 1 (n=57, 53)
    7.99 ± 22.69
    -1.36 ± 16.98
        Fatigue: Cycle 3 Day 1 (n=46, 43)
    9.18 ± 22.63
    1.42 ± 19.44
        Fatigue: Cycle 4 Day 1 (n=49, 39)
    7.94 ± 20.91
    1.85 ± 21.64
        Fatigue: Cycle 5 Day 1 (n=35, 30)
    10.32 ± 20.35
    1.67 ± 20.59
        Financial difficulties Cycle 2 Day 1 (n=56, 52)
    3.57 ± 21.72
    0.00 ± 20.87
        Financial difficulties Cycle 3 Day 1 (n=46, 43)
    0.72 ± 22.76
    -3.88 ± 24.35
        Financial difficulties Cycle 4 Day 1 (n=49, 40)
    3.40 ± 23.81
    -0.83 ± 29.71
        Financial difficulties Cycle 5 Day 1 (n=36, 30)
    2.78 ± 25.67
    1.11 ± 26.96
        Nausea/Vomiting Cycle 2 Day 1 (n=57, 53)
    9.06 ± 19.43
    2.83 ± 15.24
        Nausea/Vomiting Cycle 3 Day 1 (n=46, 43)
    6.52 ± 14.26
    3.10 ± 14.21
        Nausea/Vomiting Cycle 4 Day 1 (n=49, 40)
    6.80 ± 17.32
    3.75 ± 17.50
        Nausea/Vomiting Cycle 5 Day 1 (n=36, 30)
    3.70 ± 7.03
    0.00 ± 23.16
        Pain Cycle 2 Day 1 (n=57, 53)
    -3.80 ± 22.93
    -7.86 ± 23.02
        Pain Cycle 3 Day 1 (n=46, 43)
    -4.71 ± 26.45
    -7.36 ± 26.80
        Pain Cycle 4 Day 1 (n=49, 40)
    1.36 ± 28.63
    -3.33 ± 31.62
        Pain Cycle 5 Day 1 (n=36, 30)
    0.00 ± 26.13
    -5.56 ± 25.27
        Physical Functioning Cycle 2 Day 1 (n=57, 53)
    -4.53 ± 14.23
    -0.16 ± 12.96
        Physical Functioning Cycle 3 Day 1 (n=46, 43)
    -5.94 ± 15.54
    -1.71 ± 13.88
        Physical Functioning Cycle 4 Day 1 (n=49, 40)
    -9.12 ± 13.92
    -3.17 ± 16.54
        Physical Functioning Cycle 5 Day 1 (n=36, 30)
    -8.56 ± 13.47
    -4.44 ± 14.26
        Global health status Cycle 2 Day 1 (n=57, 53)
    -4.68 ± 22.33
    4.72 ± 18.38
        Global health status Cycle 3 Day 1 (n=46, 43)
    -8.15 ± 21.55
    3.29 ± 21.37
        Global health status Cycle 4 Day 1 (n=49, 40)
    -8.50 ± 21.62
    -1.46 ± 26.61
        Global health status Cycle 5 Day 1 (n=36, 30)
    -6.48 ± 22.55
    -5.00 ± 21.62
        Role Functioning Cycle 2 Day 1 (n=57, 53)
    -5.85 ± 20.04
    0.63 ± 22.40
        Role Functioning Cycle 3 Day 1 (n=46, 43)
    -10.51 ± 24.43
    -2.71 ± 22.69
        Role Functioning Cycle 4 Day 1 (n=49, 40)
    -13.95 ± 25.76
    -6.25 ± 26.34
        Role Functioning Cycle 5 Day 1 (n=36, 30)
    -11.57 ± 21.76
    -7.22 ± 21.30
        Social Functioning Cycle 2 Day 1 (n=57, 53)
    -2.05 ± 26.92
    0.00 ± 23.34
        Social Functioning Cycle 3 Day 1 (n=46, 43)
    -2.17 ± 23.99
    -3.49 ± 26.11
        Social Functioning Cycle 4 Day 1 (n=49, 40)
    -7.14 ± 27.00
    -5.83 ± 23.74
        Social Functioning Cycle 5 Day 1 (n=35, 30)
    -4.76 ± 31.72
    -9.44 ± 24.24
        Insomnia Cycle 2 Day 1 (n=57, 53)
    2.92 ± 31.67
    -5.03 ± 24.80
        Insomnia Cycle 3 Day 1 (n=46, 43)
    2.90 ± 25.17
    -3.10 ± 25.00
        Insomnia Cycle 4 Day 1 (n=46, 43)
    7.48 ± 28.27
    5.83 ± 31.02
        Insomnia Cycle 5 Day 1 (n=36, 30)
    1.85 ± 34.68
    -5.56 ± 29.14
    No statistical analyses for this end point

    Secondary: PRO Measure: Percentage of Subject With Improved, Worsened, or Remained Stable for Bothersome Side Effects of Treatment Measured by the Scales of the EORTC QLQ-C30

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    End point title
    		 PRO Measure: Percentage of Subject With Improved, Worsened, or Remained Stable for Bothersome Side Effects of Treatment Measured by the Scales of the EORTC QLQ-C30
    End point description
    Subjects reporting >/= 10-point increase compared to baseline (Cycle 1 Day 1) were considered “improved”, those reporting <10-point difference were considered “remained stable”, and those reporting >/=10-point decrease were considered “worsened”. A change of at least 10 points from baseline is considered clinically meaningful (Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-related quality of life score. J Clin Oncol 1998;16:139−44). Patient reported outcome measures were analyzed from baseline up to and including cycle 5. Scores from later timepoints were not analyzed due to attrition (in both arms, fewer than 50% of subjects remained on treatment beyond cycle 5). ITT population included all randomized subjects allocated to treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline (Cycle 1 Day 1) up to Cycle 5 Day 1
    End point values
    		 Ipatasertib and Paclitaxel Placebo and Paclitaxel
    Number of subjects analysed
    57
    53
    Units: Percentage of subjects
    number (not applicable)
        Improved Appetite Loss: Cycle 2 (n=57, 53)
    10.5
    18.9
        Maintained Appetite Loss: Cycle 2 (n=57, 53)
    64.9
    66.0
        Worsened Appetite Loss: Cycle 2 (n=57, 53)
    24.6
    15.1
        Improved Appetite Loss: Cycle 3 (n=46, 43)
    8.7
    27.9
        Maintained Appetite Loss: Cycle 3 (n=46, 43)
    56.5
    53.5
        Worsened Appetite Loss: Cycle 3 (n=46, 43)
    34.8
    18.6
        Improved Appetite Loss: Cycle 4 (n=49, 40)
    10.2
    30.0
        Maintained Appetite Loss: Cycle 4 (n=49, 40)
    65.3
    57.5
        Worsened Appetite Loss: Cycle 4 (n=49, 40)
    24.5
    12.5
        Improved Appetite Loss: Cycle 5 (n=35, 30)
    8.6
    26.7
        Maintained Appetite Loss: Cycle 5 (n=35, 30)
    80.0
    53.3
        Wirsened Appetite Loss: Cycle 5 (n=35, 30)
    11.4
    20.0
        Improved Diarrhea: Cycle 2 (n=57, 53)
    3.5
    7.5
        Maintained Diarrhea: Cycle 2 (n=57, 53)
    50.9
    79.2
        Worsened Diarrhea: Cycle 2 (n=57, 53)
    45.6
    13.2
        Improved Diarrhea: Cycle 3 (n=46, 43)
    8.7
    9.3
        Maintained Diarrhea: Cycle 3 (n=46, 43)
    39.1
    69.8
        Worsened Diarrhea: Cycle 3 (n=46, 43)
    52.2
    20.9
        Improved Diarrhea: Cycle 4 (n=49, 40)
    10.2
    10.0
        Maintained Diarrhea: Cycle 4 (n=49, 40)
    38.8
    77.5
        Worsened Diarrhea: Cycle 4 (n=49, 40)
    51.0
    12.5
        Improved Diarrhea: Cycle 5 (n=35, 30)
    14.3
    10.0
        Maintained Diarrhea: Cycle 5 (n=35, 30)
    34.3
    76.7
        Worsened Diarrhea: Cycle 5 (n=35, 30)
    51.4
    13.3
        Improved Fatigue: Cycle 2 (n=57, 53)
    21.1
    34.0
        Maintained Fatigue: Cycle 2 (n=57, 53)
    29.85
    30.2
        Worsened Fatigue: Cycle 2 (n=57, 53)
    49.1
    35.8
        Improved Fatigue: Cycle 3 (n=46, 43)
    23.9
    34.9
        Maintained Fatigue: Cycle 3 (n=57, 53)
    15.2
    30.2
        Worsened Fatigue: Cycle 3 (n=57, 53)
    60.9
    34.9
        Improved Fatigue: Cycle 4 (n=46, 43)
    24.5
    28.2
        Maintained Fatigue: Cycle 4 (n=46, 43)
    28.6
    28.2
        Worsened Fatigue: Cycle 4 (n=46, 43)
    46.9
    43.6
        Improved Fatigue: Cycle 5 (n=46, 43)
    20.0
    30.0
        Maintained Fatigue: Cycle 5 (n=46, 43)
    20.0
    43.3
        Worsened Fatigue: Cycle 5 (n=46, 43)
    60.0
    26.7
        Improved Nausea/Vomiting Cycle 2 (n=57,53)
    3.5
    11.3
        Maintained Nausea/Vomiting Cycle 2 (n=57,53)
    61.4
    64.2
        Worsened Nausea/Vomiting Cycle 2 (n=57,53)
    35.1
    24.5
        Improved Nausea/Vomiting Cycle 3 (n=46,43)
    4.3
    9.3
        Maintained Nausea/Vomiting Cycle 3 (n=46,43)
    65.2
    62.8
        Worsened Nausea/Vomiting Cycle 3 (n=46,43)
    30.4
    27.9
        Improved Nausea/Vomiting Cycle 4 (n=49,39)
    2.0
    7.5
        Maintained Nausea/Vomiting Cycle 4 (n=49,39)
    73.5
    67.5
        Worsened Nausea/Vomiting Cycle 4 (n=49,39)
    24.5
    25.0
        Improved Nausea/Vomiting Cycle 5 (n=36,30)
    0
    16.7
        Maintained Nausea/Vomiting Cycle 5 (n=36,30)
    77.8
    60.0
        Worsened Nausea/Vomiting Cycle 5 (n=36,30)
    22.2
    23.3
        Improved Cognitive Functioning Cycle 2 (n=57,53)
    22.8
    17.0
        Maintained Cognitive Function Cycle 2 (n=57,53)
    61.4
    60.4
        Worsened Cognitive Function Cycle 2 (n=57,53)
    15.8
    22.6
        Improved Cognitive Functioning Cycle 3 (n=46,43)
    26.1
    16.3
        Maintained Cognitive Functioning Cycle 3 (n=46,43)
    47.8
    53.5
        Worsened Cognitive Functioning Cycle 3 (n=46,43)
    26.1
    30.2
        Improved Cognitive Functioning Cycle 4 (n=49,40)
    20.4
    22.5
        Maintained Cognitive Functioning Cycle 4 (n=49,40)
    51.0
    52.5
        Worsened Cognitive Functioning Cycle 4 (n=49,40)
    28.6
    25.0
        Improved Cognitive Functioning Cycle 5 (n=36,30)
    19.4
    20.0
        Maintained Cognitive Functioning Cycle 5 (n=36,30)
    58.3
    46.7
        Worsened Cognitive Functioning Cycle 5 (n=36,30)
    22.2
    33.3
        Improved Constipation Cycle 2 (n=57,53)
    8.8
    17.0
        Maintained Constipation Cycle 2 (n=57,53)
    73.7
    64.2
        Worsened Constipation Cycle 2 (n=57,53)
    17.5
    18.9
        Improved Constipation Cycle 3 (n=46,42)
    10.9
    9.5
        Maintained Constipation Cycle 3 (n=46,42)
    71.7
    71.4
        Worsened Constipation Cycle 3 (n=46,42)
    17.4
    19.0
        Improved Constipation Cycle 4 (n=48,40)
    10.4
    15.0
        Maintained Constipation Cycle 4 (n=48,40)
    75.0
    60.0
        Worsened Constipation Cycle 4 (n=48,40)
    14.6
    25.0
        Improved Constipation Cycle 5 (n=36,30)
    5.6
    13.3
        Maintained Constipation Cycle 5 (n=36,30)
    80.6
    73.3
        Worsened Constipation Cycle 5 (n=36,30)
    13.9
    13.3
        Improved Dyspnea Cycle 2 (n=57,52)
    5.3
    15.4
        Maintained Dyspnea Cycle 2 (n=57,52)
    77.2
    69.2
        Worsened Dyspnea Cycle 2 (n=57,52)
    17.5
    15.4
        Improved Dyspnea Cycle 3 (n=46,41)
    6.5
    14.6
        Maintained Dyspnea Cycle 3 (n=46,41)
    67.4
    68.3
        Worsened Dyspnea Cycle 3 (n=46,41)
    26.1
    17.1
        Improved Dyspnea Cycle 4 (n=49,39)
    10.2
    12.8
        Maintained Dyspnea Cycle 4 (n=49,39)
    69.4
    61.5
        Worsened Dyspnea Cycle 4 (n=49,39)
    20.4
    25.6
        Improved Dyspnea Cycle 5 (n=36,28)
    8.3
    14.3
        Maintained Dyspnea Cycle 5 (n=36,28)
    69.4
    60.7
        Worsened Dyspnea Cycle 5 (n=36,28)
    22.2
    25.0
        Improved Emotional Functioning Cycle 2 (n=57,53)
    50.9
    35.8
        Maintained Emotional Functioning Cycle 2 (n=57,53)
    43.9
    50.9
        Worsened Emotional Functioning Cycle 2 (n=57,53)
    5.3
    13.2
        Improved Emotional Functioning Cycle 3 (n=46,43)
    45.7
    37.2
        Maintained Emotional Functioning Cycle 3 (n=46,43)
    45.7
    41.9
        Worsened Emotional Functioning Cycle 3 (n=46,43)
    8.7
    20.9
        Improved Emotional Functioning Cycle 4 (n=49,40)
    42.9
    30.0
        Maintained Emotional Functioning Cycle 4 (n=49,40)
    49.0
    45.0
        Worsened Emotional Functioning Cycle 4 (n=49,40)
    8.2
    25.0
        Improved Emotional Functioning Cycle 5 (n=35,30)
    42.9
    36.7
        Maintained Emotional Functioning Cycle 5 (n=35,30)
    48.6
    36.7
        Worsened Emotional Functioning Cycle 5 (n=35,30)
    8.6
    26.7
        Improved Financial Difficulties Cycle 2 (n=56,52)
    10.7
    13.5
        Maintained Financial Difficulties Cycle 2(n=56,52)
    73.2
    73.1
        Worsened Financial Difficulties Cycle 2 (n=56,52)
    16.1
    13.5
        Improved Financial Difficulties Cycle 3 (n=46,43)
    13.0
    18.6
        Maintained Financial Difficulties Cycle 3(n=46,43)
    73.9
    72.1
        Worsened Financial Difficulties Cycle 3 (n=46,43)
    13.0
    9.3
        Improved Financial Difficulties Cycle 4 (n=49,40)
    10.2
    17.5
        Maintained Financial Difficulties Cycle 4(n=49,40)
    73.5
    70.0
        Worsened Financial Difficulties Cycle 4 (n=49,40)
    16.3
    12.5
        Improved Financial Difficulties Cycle 5 (n=36,30)
    13.9
    20.0
        Maintained Financial Difficulties Cycle 5(n=36,30)
    66.7
    63.3
        Worsened Financial Difficulties Cycle 5 (n=36,30)
    19.4
    16.7
        Improved Pain Cycle 2 (n=57,53)
    35.1
    35.8
        Maintained Pain Cycle 2 (n=57,53)
    40.4
    45.3
        Worsened Pain Cycle 2 (n=57,53)
    24.6
    18.9
        Improved Pain Cycle 3 (n=46,43)
    37.0
    39.5
        Maintained Pain Cycle 3 (n=46,43)
    39.1
    39.5
        Worsened Pain Cycle (n=46,43)
    23.9
    20.9
        Improved Pain Cycle 4 (n=49,40)
    32.7
    37.5
        Maintained Pain Cycle 4 (n=49,40)
    32.7
    35.0
        Worsened Pain Cycle 4 (n=49,40)
    34.7
    27.5
        Improved Pain Cycle 5 (n=36,30)
    33.3
    33.3
        Maintained Pain Cycle 5 (n=36,30)
    30.6
    40.0
        Worsened Pain Cycle 5 (n=36,30)
    36.1
    26.7
        Improved Physical Functioning Cycle 2 (n= 57,53)
    7.0
    13.2
        Maintained Physical Functioning Cycle 2 (n= 57,53)
    68.4
    75.5
        Worsened Physical Functioning Cycle 2 (n= 57,53)
    24.6
    11.3
        Improved Physical Functioning Cycle 3 (n= 46,43)
    8.7
    16.3
        Maintained Physical Functioning Cycle 3 (n= 46,43)
    67.4
    60.5
        Worsened Physical Functioning Cycle 3 (n= 46,43)
    23.9
    23.3
        Improved Physical Functioning Cycle 4 (n= 49,40)
    4.1
    17.5
        Maintained Physical Functioning Cycle 4 (n= 49,40)
    55.1
    57.5
        Worsened Physical Functioning Cycle 4 (n= 49,40)
    40.8
    25.0
        Improved Physical Functioning Cycle 5 (n= 36,30)
    8.3
    16.7
        Maintained Physical Functioning Cycle 5 (n= 36,30)
    44.4
    46.7
        Worsened Physical Functioning Cycle 5 (n= 36,30)
    47.2
    36.7
        Improved Global Health Status/QoL Cycle 2(n=57,53)
    19.3
    26.4
        Maintained Global Health Status/QoL Cycle2(n=57,53
    45.6
    58.5
        Worsened Global Health Status/QoL Cycle 2(n=57,53)
    35.1
    15.1
        Improved Global Health Status/QoL Cycle 3(n=46,43)
    17.4
    25.6
        Maintained Global Health Status/QoL Cycle3(n=46,43
    37.0
    60.5
        Worsened Global Health Status/QoL Cycle 3(n=46,43)
    45.7
    14.0
        Improved Global Health Status/QoL Cycle 4(n=49,40)
    14.3
    25.0
        Maintained Global Health Status/QoL Cycle4(n=49,40
    51.0
    42.5
        Worsened Global Health Status/QoL Cycle 4(n=49,40)
    34.7
    32.5
        Improved Global Health Status/QoL Cycle 5(n=36,30)
    11.1
    20.0
        Maintained Global Health Status/QoL Cycle5(n=36,30
    58.3
    46.7
        Worsened Global Health Status/QoL Cycle 5(n=36,30)
    30.6
    33.3
        Improved Role Functioning Cycle 2 (n=57,53)
    17.5
    24.5
        Maintained Role Functioning Cycle 2 (n=57,53)
    52.6
    45.3
        Worsened Role Functioning Cycle 2 (n=57,53)
    29.8
    30.2
        Improved Role Functioning Cycle 3 (n=46,43)
    13.0
    27.9
        Maintained Role Functioning Cycle 3 (n=46,43)
    47.8
    46.5
        Worsened Role Functioning Cycle 3 (n=46,43)
    39.1
    25.6
        Improved Role Functioning Cycle 4 (n=49,40)
    12.2
    25.0
        Maintained Role Functioning Cycle 4 (n=49,40)
    38.8
    37.5
        Worsened Role Functioning Cycle 4 (n=49,40)
    49.0
    37.5
        Improved Role Functioning Cycle 5 (n=36,30)
    11.1
    16.7
        Maintained Role Functioning Cycle 5 (n=36,30)
    47.2
    40.0
        Worsened Role Functioning Cycle 5 (n=36,30)
    41.7
    43.3
        Improved Social Functioning Cycle 2 (n=57, 53)
    21.1
    22.6
        Maintained Social Functioning Cycle 2 (n=57, 53)
    49.1
    49.1
        Worsened Social Functioning Cycle 2 (n=57, 53)
    29.8
    28.3
        Improved Social Functioning Cycle 3 (n=46, 43)
    17.4
    16.3
        Maintained Social Functioning Cycle 3 (n=46, 43)
    52.2
    53.5
        Worsened Social Functioning Cycle 3 (n=46, 43)
    30.4
    30.2
        Improved Social Functioning Cycle 4 (n=49, 40)
    16.3
    10.0
        Maintained Social Functioning Cycle 4 (n=49, 40)
    49.0
    47.5
        Worsened Social Functioning Cycle 4 (n=49, 40)
    34.7
    42.5
        Improved Social Functioning Cycle 5 (n=35, 30)
    17.1
    13.3
        Maintained Social Functioning Cycle 5 (n=35, 30)
    48.6
    36.7
        Worsened Social Functioning Cycle 5 (n=35, 30)
    34.3
    50.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 30 days after the last dose of study drug or until initiation of another anti-cancer therapy, whichever occurs first (up to 3 years, 3 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Placebo and Paclitaxel
    Reporting group description
    		 Subjects received paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with placebo matching ipatasertib, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Reporting group title
    Ipatasertib and Paclitaxel
    Reporting group description
    		 Subjects received paclitaxel 80 mg/m^2, intravenously on Days 1, 8, and 15 along with ipatasertib 400 mg, orally, once daily from Days 1-21 in each cycle of 28 days until disease progression, intolerable toxicity, elective withdrawal from the study, or study completion or termination.

    Serious adverse events
    		 Placebo and Paclitaxel Ipatasertib and Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 62 (19.35%)
    18 / 61 (29.51%)
         number of deaths (all causes)
    46
    41
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Triple negative breast cancer
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 62 (1.61%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Spinal Cord Compression
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 61 (3.28%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 61 (4.92%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone Pain
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Atypical Pneumonia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 61 (4.92%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Retroperitoneal Infection
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cell Death
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Decreased Appetite
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo and Paclitaxel Ipatasertib and Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 62 (95.16%)
    61 / 61 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    3 / 62 (4.84%)
    4 / 61 (6.56%)
         occurrences all number
    3
    4
    Hot Flush
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 61 (8.20%)
         occurrences all number
    3
    5
    Hypertension
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 61 (4.92%)
         occurrences all number
    4
    3
    General disorders and administration site conditions
    Chest Discomfort
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 61 (6.56%)
         occurrences all number
    1
    4
    Asthenia
         subjects affected / exposed
    7 / 62 (11.29%)
    17 / 61 (27.87%)
         occurrences all number
    7
    41
    Chest Pain
         subjects affected / exposed
    6 / 62 (9.68%)
    4 / 61 (6.56%)
         occurrences all number
    6
    5
    Fatigue
         subjects affected / exposed
    20 / 62 (32.26%)
    18 / 61 (29.51%)
         occurrences all number
    32
    26
    Oedema Peripheral
         subjects affected / exposed
    5 / 62 (8.06%)
    7 / 61 (11.48%)
         occurrences all number
    6
    9
    Mucosal Inflammation
         subjects affected / exposed
    4 / 62 (6.45%)
    4 / 61 (6.56%)
         occurrences all number
    5
    7
    Pyrexia
         subjects affected / exposed
    7 / 62 (11.29%)
    11 / 61 (18.03%)
         occurrences all number
    9
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 62 (12.90%)
    9 / 61 (14.75%)
         occurrences all number
    12
    11
    Dyspnoea
         subjects affected / exposed
    5 / 62 (8.06%)
    9 / 61 (14.75%)
         occurrences all number
    6
    13
    Epistaxis
         subjects affected / exposed
    2 / 62 (3.23%)
    7 / 61 (11.48%)
         occurrences all number
    2
    8
    Productive cough
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 61 (6.56%)
         occurrences all number
    2
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 62 (6.45%)
    2 / 61 (3.28%)
         occurrences all number
    6
    3
    Insomnia
         subjects affected / exposed
    8 / 62 (12.90%)
    13 / 61 (21.31%)
         occurrences all number
    9
    19
    Depression
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 61 (6.56%)
         occurrences all number
    2
    4
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 61 (4.92%)
         occurrences all number
    4
    5
    Neutrophil Count Decreased
         subjects affected / exposed
    9 / 62 (14.52%)
    8 / 61 (13.11%)
         occurrences all number
    20
    19
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 61 (8.20%)
         occurrences all number
    6
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 62 (14.52%)
    11 / 61 (18.03%)
         occurrences all number
    10
    19
    Dysgeusia
         subjects affected / exposed
    5 / 62 (8.06%)
    4 / 61 (6.56%)
         occurrences all number
    5
    4
    Headache
         subjects affected / exposed
    13 / 62 (20.97%)
    11 / 61 (18.03%)
         occurrences all number
    14
    15
    Hypoaesthesia
         subjects affected / exposed
    0 / 62 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    0
    6
    Paraesthesia
         subjects affected / exposed
    7 / 62 (11.29%)
    6 / 61 (9.84%)
         occurrences all number
    10
    10
    Neuropathy Peripheral
         subjects affected / exposed
    14 / 62 (22.58%)
    12 / 61 (19.67%)
         occurrences all number
    18
    17
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    10 / 62 (16.13%)
    16 / 61 (26.23%)
         occurrences all number
    16
    33
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 62 (12.90%)
    9 / 61 (14.75%)
         occurrences all number
    11
    17
    Leukopenia
         subjects affected / exposed
    4 / 62 (6.45%)
    2 / 61 (3.28%)
         occurrences all number
    6
    3
    Neutropenia
         subjects affected / exposed
    15 / 62 (24.19%)
    13 / 61 (21.31%)
         occurrences all number
    36
    38
    Eye disorders
    Dry Eye
         subjects affected / exposed
    3 / 62 (4.84%)
    4 / 61 (6.56%)
         occurrences all number
    3
    5
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    7 / 62 (11.29%)
    9 / 61 (14.75%)
         occurrences all number
    9
    13
    Abdominal Pain Upper
         subjects affected / exposed
    4 / 62 (6.45%)
    4 / 61 (6.56%)
         occurrences all number
    5
    4
    Constipation
         subjects affected / exposed
    9 / 62 (14.52%)
    12 / 61 (19.67%)
         occurrences all number
    11
    17
    Diarrhoea
         subjects affected / exposed
    13 / 62 (20.97%)
    56 / 61 (91.80%)
         occurrences all number
    19
    205
    Dry Mouth
         subjects affected / exposed
    5 / 62 (8.06%)
    2 / 61 (3.28%)
         occurrences all number
    5
    3
    Dyspepsia
         subjects affected / exposed
    6 / 62 (9.68%)
    8 / 61 (13.11%)
         occurrences all number
    6
    11
    Flatulence
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 61 (6.56%)
         occurrences all number
    2
    4
    Nausea
         subjects affected / exposed
    21 / 62 (33.87%)
    32 / 61 (52.46%)
         occurrences all number
    28
    67
    Gastritis
         subjects affected / exposed
    0 / 62 (0.00%)
    4 / 61 (6.56%)
         occurrences all number
    0
    5
    Stomatitis
         subjects affected / exposed
    5 / 62 (8.06%)
    11 / 61 (18.03%)
         occurrences all number
    6
    14
    Vomiting
         subjects affected / exposed
    14 / 62 (22.58%)
    17 / 61 (27.87%)
         occurrences all number
    15
    39
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    29 / 62 (46.77%)
    33 / 61 (54.10%)
         occurrences all number
    34
    37
    Dermatitis Acneiform
         subjects affected / exposed
    5 / 62 (8.06%)
    10 / 61 (16.39%)
         occurrences all number
    5
    17
    Nail Disorder
         subjects affected / exposed
    4 / 62 (6.45%)
    4 / 61 (6.56%)
         occurrences all number
    4
    7
    Onycholysis
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 61 (6.56%)
         occurrences all number
    1
    4
    Pruritus
         subjects affected / exposed
    5 / 62 (8.06%)
    9 / 61 (14.75%)
         occurrences all number
    5
    14
    Rash
         subjects affected / exposed
    13 / 62 (20.97%)
    17 / 61 (27.87%)
         occurrences all number
    17
    28
    Rash Maculo-Papular
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 61 (1.64%)
         occurrences all number
    7
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 62 (8.06%)
    12 / 61 (19.67%)
         occurrences all number
    5
    16
    Back Pain
         subjects affected / exposed
    6 / 62 (9.68%)
    7 / 61 (11.48%)
         occurrences all number
    7
    10
    Musculoskeletal Chest Pain
         subjects affected / exposed
    4 / 62 (6.45%)
    4 / 61 (6.56%)
         occurrences all number
    4
    9
    Musculoskeletal Pain
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 61 (4.92%)
         occurrences all number
    4
    4
    Myalgia
         subjects affected / exposed
    15 / 62 (24.19%)
    17 / 61 (27.87%)
         occurrences all number
    25
    42
    Pain in Extremity
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 61 (8.20%)
         occurrences all number
    2
    8
    Bone pain
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 61 (6.56%)
         occurrences all number
    1
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 62 (8.06%)
    8 / 61 (13.11%)
         occurrences all number
    6
    12
    Upper Respiratory Tract Infection
         subjects affected / exposed
    4 / 62 (6.45%)
    10 / 61 (16.39%)
         occurrences all number
    10
    15
    Urinary Tract Infection
         subjects affected / exposed
    4 / 62 (6.45%)
    5 / 61 (8.20%)
         occurrences all number
    4
    6
    Influenza
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 61 (6.56%)
         occurrences all number
    1
    6
    Rhinitis
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 61 (6.56%)
         occurrences all number
    1
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 62 (17.74%)
    12 / 61 (19.67%)
         occurrences all number
    15
    15
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 62 (1.61%)
    6 / 61 (9.84%)
         occurrences all number
    2
    6
    Hypokalaemia
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 61 (6.56%)
         occurrences all number
    2
    7
    Hyperglycaemia
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 61 (8.20%)
         occurrences all number
    3
    10

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2014
    This amendment was made prior to the enrollment of any subject on study: It was clarified that all subjects had to be pre-medicated prior to the infusion of paclitaxel. Criteria for the infusion of paclitaxel, including information regarding neutropenia and platelet count, were clarified. Additional pregnancy tests were added to the protocol.
    05 Jul 2016
    - Reporting criteria for events that occur after the AE reporting period (defined as 30 days after the last dose of study drug) were updated to clarify that SAEs related to study drug treatment were to be reported in Adverse Event eCRFs, and all deaths were to be reported in the Survival Follow-up and Study Discontinuation eCRFs. - Additional guidance on treatment, dose modification, supportive care, and AESI reporting was added to the diarrhea management guideline. - The criteria of non-serious AESIs were updated to include Grade ≥ 3 diarrhea as a non-serious AESI to facilitate real-time monitoring of this AE. In addition, the AESI category of Grade ≥ 3 colitis has been expanded to include enterocolitis, and the AESI category of Grade ≥ 4 hepatotoxicity has been modified to Grade 3 hepatotoxicity and Grade ≥ 3 ALT/AST elevations to align with program-level AESIs. - The assay methods were updated to include mutation detection and copy number analysis by NGS, and accordingly, the precise definition of “PTEN-low” and “PI3K/Akt pathway activated” status were to be determined prior to primary analysis. - For the EU version of Protocol Amendment 2 only, the safety analysis section was updated to explicitly state that MedDRA was the thesaurus used for mapping verbatim terms, and that MedDRA preferred terms were to be used to describe and summarize AEs.
    21 Dec 2017
    Following updates were made: [1] Summary of Primary Analysis Results provided; [2] Description of process for informing subjects of the primary analysis results and unblinded treatment assignment information; [3] Current formulation/s of Ipatasertib; [4] Updated Diarrhea management guidelines; [5] Reduction in the number and scope of assessments; [6] Modification to prohibit use of the term 'sudden death' on the Adverse Event eCRF; [7] Clarification to reporting of adverse events leading to hospitalization; [8] Updating of Study Medical Monitor contact information; [9] Clarification of timing of final analysis for overall survival and [10] Clarification that the Sponsor will review all protocol deviations as per the Sponsor’s Standard Operating Procedures and prospective requests to deviate from the protocol are not allowed.

    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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