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    Clinical Trial Results:
    A PHASE II RANDOMIZED, DOUBLE-BLIND, STUDY OF IPATASERTIB (GDC‑0068), AN INHIBITOR TO AKT, IN COMBINATION WITH PACLITAXEL AS NEOADJUVANT TREATMENT FOR PATIENTS WITH EARLY STAGE TRIPLE NEGATIVE BREAST CANCER

    Summary
    EudraCT number
    		 2014-003029-16
    Trial protocol
    		 ES   PT  
    Global end of trial date
    02 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Aug 2018
    First version publication date
    11 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GO29505
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02301988
    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
    02 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a randomized, double-blind, placebo-controlled, multicenter, pre-operative Phase II study designed to estimate the efficacy of ipatasertib combined with paclitaxel chemotherapy versus placebo combined with paclitaxel chemotherapy in women with Stage Ia - IIIa triple-negative breast adenocarcinoma. The anticipated time on study treatment is 12 weeks.
    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
    17 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 91
    Country: Number of subjects enrolled
    Portugal: 12
    Country: Number of subjects enrolled
    United States: 48
    Worldwide total number of subjects
    151
    EEA total number of subjects
    103
    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)
    123
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 151 subjects were randomized to either receive 400 mg ipatasertib + paclitaxel (76 subjects) or placebo + paclitaxel (75 subjects).

    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 + Paclitaxel
    Arm description
    		 Participants received ipatasertib orally daily on Days 1-21 of each 28-day cycle for 3 cycles and paclitaxel intravenous (IV) infusion every week (QW) for 3 cycles (12 total doses).
    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 will be administered at a dose of 80 milligrams per square meter (mg/m^2) as IV infusion QW for 3 cycles.

    Investigational medicinal product name
    Ipatasertib
    Investigational medicinal product code
    Other name
    GDC‑0068
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ipatasertib will be administered at a dose of 400 milligrams (mg) orally daily on Days 1-21 of each 28-day cycle for 3 cycles.

    Arm title
    		 Placebo + Paclitaxel
    Arm description
    		 Participants received placebo (matching to ipatasertib) orally daily on Days 1-21 of each 28-day cycle for 3 cycles and paclitaxel IV infusion QW for 3 cycles (12 total doses).
    Arm type
    		 Placebo

    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 will be administered at a dose of 80 milligrams per square meter (mg/m^2) as IV infusion QW for 3 cycles.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive placebo (matching to ipatasertib) orally daily on Days 1-21 of each 28-day cycle for 3 cycles.

    Number of subjects in period 1
    		Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Started
    76
    75
    Completed
    66
    66
    Not completed
    10
    9
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    2
    1
         Physician decision
    2
    2
         Unknown Reason
    1
    3
         Adverse event, non-fatal
    1
    1
         Lack of efficacy
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ipatasertib + Paclitaxel
    Reporting group description
    		 Participants received ipatasertib orally daily on Days 1-21 of each 28-day cycle for 3 cycles and paclitaxel intravenous (IV) infusion every week (QW) for 3 cycles (12 total doses).

    Reporting group title
    Placebo + Paclitaxel
    Reporting group description
    		 Participants received placebo (matching to ipatasertib) orally daily on Days 1-21 of each 28-day cycle for 3 cycles and paclitaxel IV infusion QW for 3 cycles (12 total doses).

    Reporting group values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel Total
    Number of subjects
    		 76 75 151
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 62 61 123
        From 65-84 years
    		 14 14 28
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.8 ( 10.9 ) 53.8 ( 12.0 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 76 75 151
        Male
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 2 3 5
        White
    		 71 70 141
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 2 1 3

    End points

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    End points reporting groups
    Reporting group title
    Ipatasertib + Paclitaxel
    Reporting group description
    		 Participants received ipatasertib orally daily on Days 1-21 of each 28-day cycle for 3 cycles and paclitaxel intravenous (IV) infusion every week (QW) for 3 cycles (12 total doses).

    Reporting group title
    Placebo + Paclitaxel
    Reporting group description
    		 Participants received placebo (matching to ipatasertib) orally daily on Days 1-21 of each 28-day cycle for 3 cycles and paclitaxel IV infusion QW for 3 cycles (12 total doses).

    Primary: Percentage of Participants With Pathological Complete Response (pCR) in Breast and Axilla as Defined by ypT0/Tis ypN0 in the American Joint Committee on Cancer Staging System (in All Participants)

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    End point title
    		 Percentage of Participants With Pathological Complete Response (pCR) in Breast and Axilla as Defined by ypT0/Tis ypN0 in the American Joint Committee on Cancer Staging System (in All Participants)
    End point description
    pCR was defined by ypT0/Tis ypN0 in the American Joint Committee on Cancer (AJCC) Staging System with the following determination for breast and axilla by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue and N0: no cancer found in the lymph nodes.
    End point type
    Primary
    End point timeframe
    Surgery visit (at approximately Weeks 14 to 19)
    End point values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    76
    75
    Units: percentage of participants
        number (confidence interval 95%)
    17.1 (9.82 to 27.25)
    13.3 (6.58 to 22.86)
    Statistical analysis title
    		 pCR in Breast and Axilla for All Participants
    Statistical analysis description
    Unstratified Analysis
    Comparison groups
    Ipatasertib + Paclitaxel v Placebo + Paclitaxel
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.519
    Method
    		 Chi-squared
    Parameter type
    		 Difference in Response Rates
    Point estimate
    3.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.99
         upper limit
    		 16.54

    Primary: Percentage of Participants With pCR in Breast and Axilla as Defined by ypT0/Tis ypN0 in the American Joint Committee on Cancer Staging System (in Participants Who Have Phosphatase and Tensin Homolog [PTEN]-low Tumors)

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    End point title
    		 Percentage of Participants With pCR in Breast and Axilla as Defined by ypT0/Tis ypN0 in the American Joint Committee on Cancer Staging System (in Participants Who Have Phosphatase and Tensin Homolog [PTEN]-low Tumors)
    End point description
    pCR was defined by ypT0/Tis ypN0 in the AJCC Staging System with the following determination for breast and axilla by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue and N0: no cancer found in the lymph nodes.
    End point type
    Primary
    End point timeframe
    Surgery visit (at approximately Weeks 14 to 19)
    End point values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    19
    16
    Units: percentage of participants
        number (confidence interval 95%)
    15.8 (4.45 to 38.36)
    12.5 (2.27 to 35.43)
    Statistical analysis title
    		 pCR in Breast and Axilla in PTEN-low Tumors
    Statistical analysis description
    Unstratified analysis
    Comparison groups
    Ipatasertib + Paclitaxel v Placebo + Paclitaxel
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7817
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    3.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.52
         upper limit
    		 32.1

    Secondary: Percentage of Participants With pCR in Breast as Defined by ypT0/Tis in the American Joint Committee on Cancer Staging System (in All Participants)

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    End point title
    		 Percentage of Participants With pCR in Breast as Defined by ypT0/Tis in the American Joint Committee on Cancer Staging System (in All Participants)
    End point description
    pCR was defined by ypT0/Tis in the AJCC Staging System with the following determination for breast by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue.
    End point type
    Secondary
    End point timeframe
    Surgery visit (at approximately Weeks 14 to 19)
    End point values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    76
    75
    Units: percentage of participants
        number (confidence interval 95%)
    22.4 (14.33 to 33.31)
    14.7 (7.98 to 24.04)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With pCR in Breast as Defined by ypT0/Tis in the American Joint Committee on Cancer Staging System (in Participants Who Have PTEN-low Tumors)

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    End point title
    		 Percentage of Participants With pCR in Breast as Defined by ypT0/Tis in the American Joint Committee on Cancer Staging System (in Participants Who Have PTEN-low Tumors)
    End point description
    pCR was defined by ypT0/Tis in the AJCC Staging System with the following determination for breast by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue.
    End point type
    Secondary
    End point timeframe
    Surgery visit (at approximately Weeks 14 to 19)
    End point values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    19
    16
    Units: percentage of participants
        number (confidence interval 95%)
    15.8 (4.45 to 38.36)
    18.8 (5.31 to 42.94)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Objective Tumor Response by Magnetic Resonance Imaging (MRI), As Assessed by Investigator per the Modified Response Evaluation Criteria in Solid Tumors (RECIST) (in All Participants)

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    End point title
    		 Percentage of Participants With Objective Tumor Response by Magnetic Resonance Imaging (MRI), As Assessed by Investigator per the Modified Response Evaluation Criteria in Solid Tumors (RECIST) (in All Participants)
    End point description
    ORR was based on criteria related to changes in size of target lesions according to modified RECIST. Target lesions were selected on the basis of their size (lesions with the longest diameter) as well as the feasibility of reproducible repeated measurements. ORR was the sum of complete response (CR) and partial response (PR). CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Screening up to disease progression or death (assessed at screening, pre-surgical visit [approximately Weeks 10-12], early termination visit [up to Week 16])
    End point values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    76
    75
    Units: percentage of participants
        number (confidence interval 95%)
    67.1 (55.86 to 77.46)
    56.0 (44.46 to 66.84)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Objective Tumor Response by MRI, As Assessed by Investigator per Modified RECIST (in Participants Who Have PTEN-low Tumors)

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    End point title
    		 Percentage of Participants With Objective Tumor Response by MRI, As Assessed by Investigator per Modified RECIST (in Participants Who Have PTEN-low Tumors)
    End point description
    ORR was based on criteria related to changes in size of target lesions according to modified RECIST. Target lesions were selected on the basis of their size (lesions with the longest diameter) as well as the feasibility of reproducible repeated measurements. ORR was the sum of complete response (CR) and partial response (PR). CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
    End point type
    Secondary
    End point timeframe
    Screening up to disease progression or death (assessed at screening, pre-surgical visit [approximately Weeks 10-12], early termination visit [up to Week 16])
    End point values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    19
    16
    Units: percentage of participants
        number (confidence interval 95%)
    73.7 (50.00 to 89.01)
    50.0 (27.20 to 72.80)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With pCR in Breast and Axilla as Defined by ypT0/Tis ypN0 in the American Joint Committee on Cancer Staging System (in Participants Who Are Akt diagnostic positive [Dx+])

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    End point title
    		 Percentage of Participants With pCR in Breast and Axilla as Defined by ypT0/Tis ypN0 in the American Joint Committee on Cancer Staging System (in Participants Who Are Akt diagnostic positive [Dx+])
    End point description
    pCR was defined by ypT0/Tis ypN0 in the AJCC Staging System with the following determination for breast and axilla by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue and N0: no cancer found in the lymph nodes.
    End point type
    Secondary
    End point timeframe
    Surgery visit (at approximately Weeks 14 to 19)
    End point values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    28
    34
    Units: percentage of participants
        number (confidence interval 95%)
    17.9 (7.31 to 35.71)
    11.8 (4.12 to 27.19)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With pCR in Breast as Defined by ypT0/Tis in the American Joint Committee on Cancer Staging System (in Participants Who Are Akt Dx+)

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    End point title
    		 Percentage of Participants With pCR in Breast as Defined by ypT0/Tis in the American Joint Committee on Cancer Staging System (in Participants Who Are Akt Dx+)
    End point description
    pCR was defined by ypT0/Tis in the AJCC Staging System with the following determination for breast by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue.
    End point type
    Secondary
    End point timeframe
    Surgery visit (at approximately Weeks 14 to 19)
    End point values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    28
    34
    Units: percentage of participants
        number (confidence interval 95%)
    21.4 (9.77 to 40.58)
    11.8 (4.12 to 27.19)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With pCR According to American Joint Committee on Cancer Staging System, by Breast Cancer Subtype

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    End point title
    		 Percentage of Participants With pCR According to American Joint Committee on Cancer Staging System, by Breast Cancer Subtype
    End point description
    pCR was defined by ypT0/Tis in the AJCC Staging System with the following determination for breast subtypes by local pathology laboratory evaluation: T0: no evidence of primary tumor; Tis: early cancer that has not spread to neighboring tissue. The intrinsic molecular subtypes of breast cancer included here are luminal A (LumA), Her-2, basal-like, normal and unknown.
    End point type
    Secondary
    End point timeframe
    Surgery visit (at approximately Weeks 14 to 19)
    End point values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    27
    32
    Units: percentage of participants
    number (not applicable)
        Unknown
    18.5
    21.9
        Basal
    22.0
    10.8
        Her2
    33.3
    0
        LumA
    0
    0
        Normal
    50.0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Response to Undergoing Breast Conserving Surgery (BCS) Among Participants With T2 or T3 Tumors

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    End point title
    		 Percentage of Participants With Response to Undergoing Breast Conserving Surgery (BCS) Among Participants With T2 or T3 Tumors
    End point description
    After neoadjuvant treatment, the number of patients who is appropriate for breast conserving surgery is reported as a measure of efficacy of the treatment to shrink the tumor enough for patients to benefit from less aggressive surgical management. Breast-conserving surgery was defined as removal of part of the breast tissue during surgery. T2 or T3 in the AJCC Staging System were defined as follows: T2: tumor was more than 2 centimeter (cm) but no more than 5 cm across; T3: tumor was larger than 5 cm across.
    End point type
    Secondary
    End point timeframe
    Surgery visit (at approximately Weeks 14 to 19)
    End point values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    62
    63
    Units: percentage of participants
        number (confidence interval 95%)
    64.5 (51.93 to 76.26)
    60.3 (47.20 to 71.74)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Response to Conversion to BCS Among Participants With T2 or T3 Tumors

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    End point title
    		 Percentage of Participants With Response to Conversion to BCS Among Participants With T2 or T3 Tumors
    End point description
    After neoadjuvant treatment, the number of patients who is appropriate for breast conserving surgery is reported as a measure of efficacy of the treatment to shrink the tumor enough for patients to benefit from less aggressive surgical management. Breast-conserving surgery was defined as removal of part of the breast tissue during surgery. T2 or T3 in the AJCC Staging System were defined as follows: T2: tumor was more than 2 centimeter (cm) but no more than 5 cm across; T3: tumor was larger than 5 cm across.
    End point type
    Secondary
    End point timeframe
    From screening to surgery visit (at approximately Weeks 14 to 19)
    End point values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    12
    16
    Units: percentage of participants
        number (confidence interval 95%)
    33.3 (12.29 to 65.11)
    25 (9.03 to 50.00)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events

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    End point title
    		 Percentage of Participants With Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event 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.
    End point type
    Secondary
    End point timeframe
    Screening up to Week 24
    End point values
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Number of subjects analysed
    76
    75
    Units: percentage of participants
        number (not applicable)
    100
    98.7
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Ipatasertib on Day 1 and Day 8

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    End point title
    		 Plasma Concentrations of Ipatasertib on Day 1 and Day 8 [1]
    End point description
    Plasma samples for pharmacokinetic characterization was collected at various timepoints in all participants.
    End point type
    Secondary
    End point timeframe
    0.5 and 4 hours post dose on Day 1 of Cycle 1, 166 and 170 hours post dose from Day 1 of Cycle 1 (Cycle length = 28 days)
    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: Only Plasma concentrations of ipatasertib were collected.
    End point values
    		 Ipatasertib + Paclitaxel
    Number of subjects analysed
    73
    Units: ng/mL
    arithmetic mean (standard deviation)
        0.5 hours (73 subjects analyzed)
    290 ( 312 )
        4 hours (72 subjects analyzed)
    196 ( 93.0 )
        166 hours (71 subjects analyzed)
    37.5 ( 28.3 )
        170 hours (71 subjects analyzed)
    355 ( 204 )
    No statistical analyses for this end point

    Secondary: Minimum Observed Plasma Concentration (Cmin) of Ipatasertib

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    End point title
    		 Minimum Observed Plasma Concentration (Cmin) of Ipatasertib [2]
    End point description
    Plasma samples for pharmacokinetic characterization was collected on Day 1 and Day 8 in all participants.
    End point type
    Secondary
    End point timeframe
    0.5 and 4 hours post dose on Day 1 of Cycle 1, 166 and 170 hours post dose from Day 1 of Cycle 1 (Cycle length = 28 days)
    Notes
    [2] - 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: Only Plasma concentrations of ipatasertib were collected.
    End point values
    		 Ipatasertib + Paclitaxel
    Number of subjects analysed
    71
    Units: ng/mL
        arithmetic mean (standard deviation)
    37.5 ( 28.3 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    2 years and 6 months
    Adverse event reporting additional description
    The safety population was identical to the ITT population. The ITT population comprised all 151 randomized patients.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Ipatasertib + Paclitaxel
    Reporting group description
    		 Participants received ipatasertib orally daily on Days 1-21 of each 28-day cycle for 3 cycles and paclitaxel intravenous (IV) infusion every week (QW) for 3 cycles (12 total doses).

    Reporting group title
    Placebo + Paclitaxel
    Reporting group description
    		 Participants received placebo (matching to ipatasertib) orally daily on Days 1-21 of each 28-day cycle for 3 cycles and paclitaxel IV infusion QW for 3 cycles (12 total doses).

    Serious adverse events
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 76 (13.16%)
    3 / 75 (4.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 75 (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
    Device related infection
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ipatasertib + Paclitaxel Placebo + Paclitaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    76 / 76 (100.00%)
    73 / 75 (97.33%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    7 / 76 (9.21%)
    4 / 75 (5.33%)
         occurrences all number
    8
    4
    Hot flush
         subjects affected / exposed
    6 / 76 (7.89%)
    5 / 75 (6.67%)
         occurrences all number
    6
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    32 / 76 (42.11%)
    29 / 75 (38.67%)
         occurrences all number
    52
    55
    Fatigue
         subjects affected / exposed
    23 / 76 (30.26%)
    24 / 75 (32.00%)
         occurrences all number
    31
    36
    Mucosal dryness
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 75 (0.00%)
         occurrences all number
    5
    0
    Mucosal inflammation
         subjects affected / exposed
    14 / 76 (18.42%)
    5 / 75 (6.67%)
         occurrences all number
    16
    7
    Oedema peripheral
         subjects affected / exposed
    3 / 76 (3.95%)
    5 / 75 (6.67%)
         occurrences all number
    3
    6
    Pyrexia
         subjects affected / exposed
    8 / 76 (10.53%)
    4 / 75 (5.33%)
         occurrences all number
    9
    4
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    1 / 76 (1.32%)
    5 / 75 (6.67%)
         occurrences all number
    1
    5
    Breast pain
         subjects affected / exposed
    4 / 76 (5.26%)
    2 / 75 (2.67%)
         occurrences all number
    4
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 76 (13.16%)
    8 / 75 (10.67%)
         occurrences all number
    13
    9
    Epistaxis
         subjects affected / exposed
    12 / 76 (15.79%)
    9 / 75 (12.00%)
         occurrences all number
    13
    14
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 76 (3.95%)
    6 / 75 (8.00%)
         occurrences all number
    3
    7
    Insomnia
         subjects affected / exposed
    15 / 76 (19.74%)
    15 / 75 (20.00%)
         occurrences all number
    19
    17
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 76 (6.58%)
    5 / 75 (6.67%)
         occurrences all number
    7
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 76 (3.95%)
    4 / 75 (5.33%)
         occurrences all number
    5
    4
    Neutrophil count decreased
         subjects affected / exposed
    4 / 76 (5.26%)
    4 / 75 (5.33%)
         occurrences all number
    9
    7
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    5 / 76 (6.58%)
    4 / 75 (5.33%)
         occurrences all number
    7
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 76 (9.21%)
    8 / 75 (10.67%)
         occurrences all number
    8
    9
    Dysgeusia
         subjects affected / exposed
    18 / 76 (23.68%)
    17 / 75 (22.67%)
         occurrences all number
    20
    19
    Hypoaesthesia
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 75 (5.33%)
         occurrences all number
    1
    6
    Neuropathy peripheral
         subjects affected / exposed
    14 / 76 (18.42%)
    14 / 75 (18.67%)
         occurrences all number
    17
    19
    Neurotoxicity
         subjects affected / exposed
    9 / 76 (11.84%)
    6 / 75 (8.00%)
         occurrences all number
    12
    10
    Paraesthesia
         subjects affected / exposed
    12 / 76 (15.79%)
    9 / 75 (12.00%)
         occurrences all number
    15
    13
    Peripheral sensory neuropathy
         subjects affected / exposed
    8 / 76 (10.53%)
    13 / 75 (17.33%)
         occurrences all number
    13
    16
    Headache
         subjects affected / exposed
    14 / 76 (18.42%)
    15 / 75 (20.00%)
         occurrences all number
    21
    20
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 76 (18.42%)
    11 / 75 (14.67%)
         occurrences all number
    20
    17
    Neutropenia
         subjects affected / exposed
    7 / 76 (9.21%)
    6 / 75 (8.00%)
         occurrences all number
    15
    12
    Eye disorders
    Dry eye
         subjects affected / exposed
    3 / 76 (3.95%)
    4 / 75 (5.33%)
         occurrences all number
    3
    4
    Lacrimation increased
         subjects affected / exposed
    4 / 76 (5.26%)
    1 / 75 (1.33%)
         occurrences all number
    5
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    4 / 76 (5.26%)
    1 / 75 (1.33%)
         occurrences all number
    4
    1
    Abdominal Pain
         subjects affected / exposed
    14 / 76 (18.42%)
    6 / 75 (8.00%)
         occurrences all number
    14
    7
    Abdominal pain upper
         subjects affected / exposed
    7 / 76 (9.21%)
    4 / 75 (5.33%)
         occurrences all number
    9
    4
    Constipation
         subjects affected / exposed
    10 / 76 (13.16%)
    16 / 75 (21.33%)
         occurrences all number
    10
    19
    Diarrhoea
         subjects affected / exposed
    66 / 76 (86.84%)
    24 / 75 (32.00%)
         occurrences all number
    194
    45
    Dry mouth
         subjects affected / exposed
    7 / 76 (9.21%)
    6 / 75 (8.00%)
         occurrences all number
    8
    11
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 76 (6.58%)
    8 / 75 (10.67%)
         occurrences all number
    6
    8
    Dyspepsia
         subjects affected / exposed
    12 / 76 (15.79%)
    9 / 75 (12.00%)
         occurrences all number
    12
    9
    Nausea
         subjects affected / exposed
    36 / 76 (47.37%)
    23 / 75 (30.67%)
         occurrences all number
    52
    25
    Stomatitis
         subjects affected / exposed
    5 / 76 (6.58%)
    6 / 75 (8.00%)
         occurrences all number
    6
    7
    Vomiting
         subjects affected / exposed
    17 / 76 (22.37%)
    4 / 75 (5.33%)
         occurrences all number
    21
    5
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    40 / 76 (52.63%)
    40 / 75 (53.33%)
         occurrences all number
    50
    54
    Dermatitis Acneiform
         subjects affected / exposed
    4 / 76 (5.26%)
    3 / 75 (4.00%)
         occurrences all number
    5
    4
    Dry skin
         subjects affected / exposed
    5 / 76 (6.58%)
    3 / 75 (4.00%)
         occurrences all number
    5
    3
    Erythema
         subjects affected / exposed
    5 / 76 (6.58%)
    4 / 75 (5.33%)
         occurrences all number
    6
    9
    Onycholysis
         subjects affected / exposed
    5 / 76 (6.58%)
    2 / 75 (2.67%)
         occurrences all number
    6
    2
    Pruritus
         subjects affected / exposed
    6 / 76 (7.89%)
    10 / 75 (13.33%)
         occurrences all number
    7
    13
    Rash
         subjects affected / exposed
    19 / 76 (25.00%)
    14 / 75 (18.67%)
         occurrences all number
    25
    21
    Rash maculo-papular
         subjects affected / exposed
    4 / 76 (5.26%)
    7 / 75 (9.33%)
         occurrences all number
    7
    11
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 76 (1.32%)
    5 / 75 (6.67%)
         occurrences all number
    1
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 76 (10.53%)
    6 / 75 (8.00%)
         occurrences all number
    10
    7
    Musculoskeletal pain
         subjects affected / exposed
    5 / 76 (6.58%)
    3 / 75 (4.00%)
         occurrences all number
    5
    3
    Myalgia
         subjects affected / exposed
    6 / 76 (7.89%)
    12 / 75 (16.00%)
         occurrences all number
    6
    13
    Pain in extremity
         subjects affected / exposed
    4 / 76 (5.26%)
    7 / 75 (9.33%)
         occurrences all number
    4
    7
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    2 / 76 (2.63%)
    5 / 75 (6.67%)
         occurrences all number
    2
    5
    Folliculitis
         subjects affected / exposed
    5 / 76 (6.58%)
    3 / 75 (4.00%)
         occurrences all number
    5
    3
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 76 (3.95%)
    5 / 75 (6.67%)
         occurrences all number
    3
    6
    Urinary tract infection
         subjects affected / exposed
    8 / 76 (10.53%)
    9 / 75 (12.00%)
         occurrences all number
    13
    10
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 76 (5.26%)
    7 / 75 (9.33%)
         occurrences all number
    4
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 76 (14.47%)
    6 / 75 (8.00%)
         occurrences all number
    14
    7
    Hyperglycaemia
         subjects affected / exposed
    3 / 76 (3.95%)
    5 / 75 (6.67%)
         occurrences all number
    4
    6
    Hypokalaemia
         subjects affected / exposed
    4 / 76 (5.26%)
    2 / 75 (2.67%)
         occurrences all number
    9
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jul 2015
    Request for tumor biopsy had been changed from optional to mandated for patients who are discontinued from study treatment prior to surgery. Evaluation of the patient’s tumor sample for PTEN status by a central laboratory was clarified to indicate that it should occur prior to the initiation of study treatment even though in the absence of archival tissue, fresh tissue biopsy samples will be acceptable for eligibility. Guidance for pathology assessment in the study was added. In situ hybridization (ISH) was added as an additional optional method to study exploratory endpoints.
    19 Jan 2016
    Dosing delay due to treatment-related toxicity had been clarified that when dosing delay to paclitaxel occurs, preferred dosing for ipatasertib/placebo is to align and resume with paclitaxel dosing. Clarified that dose reductions and dose modification(s) for ipatasertib/placebo and paclitaxel are independent. Further guidance and clarification to the management of diarrhea had been provided. Grade ≥ 3 diarrhea and Grade 2 diarrhea that persists for longer than 5 days despite optimal medical management had been added as adverse event of special interest. Data entry requirements for adverse event reporting had been clarified for persistent or recurrent adverse events. A sensitivity analysis that accounts for patients whose pCR assessment cannot be ascertained had been added.

    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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