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    Clinical Trial Results:
    A randomized, Phase II, placebo controlled study of GDC-0068, an inhibitor to Akt, in combination with fluoropyrimidine plus oxaliplatin in patients with locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma

    Summary
    EudraCT number
    		 2012-002080-10
    Trial protocol
    		 GB   DE   IT   ES  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    09 Jun 2016
    First version publication date
    09 Jun 2016
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    GO28341
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01896531
    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
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    03 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jun 2015
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To estimate the efficacy of ipatasertib (GDC-0068) combined with modified 5-fluorouracil (bolus and infusional), leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy compared with placebo combined with mFOLFOX6 chemotherapy in participants with inoperable locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, as measured by progression-free survival.
    Protection of trial subjects
    This study was conducted in accordance with the United States Food and Drugs Administration regulations, the International Conference on Harmonization (ICH) E6 Good Clinical Practice (GCP), and applicable local, state, and federal laws, as well as other applicable country laws.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Aug 2013
    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: 9
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    United States: 31
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 64
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Singapore: 7
    Country: Number of subjects enrolled
    Taiwan: 9
    Worldwide total number of subjects
    153
    EEA total number of subjects
    36
    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)
    96
    From 65 to 84 years
    56
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Total 153 participants were randomized in this study, of which 152 participants received the treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ipatasertib + mFOLFOX6
    Arm description
    		 Ipatasertib was administered at a dose of 600 milligrams (mg) orally once daily, beginning on Day 1 of Cycle 1 through Day 7 of each 14-day cycle until the participant experienced disease progression or intolerable toxicity. Following ipatasertib administration on Day 1 of each cycle, the participant then received mFOLFOX6 in the following order: oxaliplatin as an 85 milligram per square-meter (mg/m^2) intravenous (IV) infusion on Day 1 every 14 days with co-administration of leucovorin at 400 mg/m^2 or equivalent substitute. The participant then received 5-fluorouracil (5-FU) as a 400 mg/m^2 bolus infusion followed by 5-FU as a 2400 mg/m^2 continuous IV infusion (or 5-FU as a 1200 mg/m^2/day continuous IV infusion). Following Cycle 8, oxaliplatin was discontinued.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ipatasertib
    Investigational medicinal product code
    GDC-0068
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ipatasertib was administered at a dose of 600 mg orally once daily, beginning on Day 1 of Cycle 1 through Day 7 of each 14-day cycle until the participant experienced disease progression or intolerable toxicity.

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxaliplatin was administered as an 85 mg/m^2 IV infusion on Day 1 every 14 days up to Cycle 8 until the participant experienced disease progression or intolerable toxicity.

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Leucovorin was administered at a dose of 400 mg/m^2 as an intravenous infusion on Day 1 every 14 days until the participant experienced disease progression or intolerable toxicity.

    Investigational medicinal product name
    5-fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil (5-FU) was administered as a 400 mg/m^2 bolus infusion followed by 5-FU as a 2400 mg/m^2 continuous IV infusion (or 5-FU as a 1200 mg/m^2/day continuous IV infusion) from Days 1 to 3 of each cycle (over approximately a 46-hour period) until the participant experienced disease progression or intolerable toxicity.

    Arm title
    		 Placebo + mFOLFOX6
    Arm description
    		 Placebo matched to ipatasertib was administered orally once daily, beginning on Day 1 of Cycle 1 through Day 7 of each 14-day cycle until the participant experienced disease progression or intolerable toxicity. Following placebo administration on Day 1 of each cycle, the participant then received mFOLFOX6 in the following order: oxaliplatin as an 85 mg/m^2 IV infusion on Day 1 every 14 days with co-administration of leucovorin at 400 mg/m^2 or equivalent substitute. The participant then received 5-FU as a 400 mg/m^2 bolus infusion followed by 5-FU as a 2400 mg/m^2 continuous IV infusion (or 5-FU as a 1200 mg/m^2/day continuous IV infusion). Following Cycle 8, oxaliplatin was discontinued.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matched to ipatasertib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to ipatasertib was administered orally once daily, beginning on Day 1 of Cycle 1 through Day 7 of each 14-day cycle until the participant experienced disease progression or intolerable toxicity.

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Oxaliplatin was administered as an 85 mg/m^2 IV infusion on Day 1 every 14 days up to Cycle 8 until the participant experienced disease progression or intolerable toxicity.

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Leucovorin was administered at a dose of 400 mg/m^2 as an intravenous infusion on Day 1 every 14 days until the participant experienced disease progression or intolerable toxicity.

    Investigational medicinal product name
    5-fluorouracil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5-fluorouracil (5-FU) was administered as a 400 mg/m^2 bolus infusion followed by 5-FU as a 2400 mg/m^2 continuous IV infusion (or 5-FU as a 1200 mg/m^2/day continuous IV infusion) from Days 1 to 3 of each cycle (over approximately a 46-hour period) until the participant experienced disease progression or intolerable toxicity.

    Number of subjects in period 1
    		Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Started
    71
    82
    Treated
    70
    82
    Completed
    0
    0
    Not completed
    71
    82
         Consent withdrawn by subject
    3
    2
         Death
    40
    29
         Unspecified
    1
    2
         Ongoing in the study
    25
    49
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ipatasertib + mFOLFOX6
    Reporting group description
    		 Ipatasertib was administered at a dose of 600 milligrams (mg) orally once daily, beginning on Day 1 of Cycle 1 through Day 7 of each 14-day cycle until the participant experienced disease progression or intolerable toxicity. Following ipatasertib administration on Day 1 of each cycle, the participant then received mFOLFOX6 in the following order: oxaliplatin as an 85 milligram per square-meter (mg/m^2) intravenous (IV) infusion on Day 1 every 14 days with co-administration of leucovorin at 400 mg/m^2 or equivalent substitute. The participant then received 5-fluorouracil (5-FU) as a 400 mg/m^2 bolus infusion followed by 5-FU as a 2400 mg/m^2 continuous IV infusion (or 5-FU as a 1200 mg/m^2/day continuous IV infusion). Following Cycle 8, oxaliplatin was discontinued.

    Reporting group title
    Placebo + mFOLFOX6
    Reporting group description
    		 Placebo matched to ipatasertib was administered orally once daily, beginning on Day 1 of Cycle 1 through Day 7 of each 14-day cycle until the participant experienced disease progression or intolerable toxicity. Following placebo administration on Day 1 of each cycle, the participant then received mFOLFOX6 in the following order: oxaliplatin as an 85 mg/m^2 IV infusion on Day 1 every 14 days with co-administration of leucovorin at 400 mg/m^2 or equivalent substitute. The participant then received 5-FU as a 400 mg/m^2 bolus infusion followed by 5-FU as a 2400 mg/m^2 continuous IV infusion (or 5-FU as a 1200 mg/m^2/day continuous IV infusion). Following Cycle 8, oxaliplatin was discontinued.

    Reporting group values
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6 Total
    Number of subjects
    		 71 82 153
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.5 ( 11.4 ) 61.3 ( 10.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 19 22 41
        Male
    		 52 60 112

    End points

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    End points reporting groups
    Reporting group title
    Ipatasertib + mFOLFOX6
    Reporting group description
    		 Ipatasertib was administered at a dose of 600 milligrams (mg) orally once daily, beginning on Day 1 of Cycle 1 through Day 7 of each 14-day cycle until the participant experienced disease progression or intolerable toxicity. Following ipatasertib administration on Day 1 of each cycle, the participant then received mFOLFOX6 in the following order: oxaliplatin as an 85 milligram per square-meter (mg/m^2) intravenous (IV) infusion on Day 1 every 14 days with co-administration of leucovorin at 400 mg/m^2 or equivalent substitute. The participant then received 5-fluorouracil (5-FU) as a 400 mg/m^2 bolus infusion followed by 5-FU as a 2400 mg/m^2 continuous IV infusion (or 5-FU as a 1200 mg/m^2/day continuous IV infusion). Following Cycle 8, oxaliplatin was discontinued.

    Reporting group title
    Placebo + mFOLFOX6
    Reporting group description
    		 Placebo matched to ipatasertib was administered orally once daily, beginning on Day 1 of Cycle 1 through Day 7 of each 14-day cycle until the participant experienced disease progression or intolerable toxicity. Following placebo administration on Day 1 of each cycle, the participant then received mFOLFOX6 in the following order: oxaliplatin as an 85 mg/m^2 IV infusion on Day 1 every 14 days with co-administration of leucovorin at 400 mg/m^2 or equivalent substitute. The participant then received 5-FU as a 400 mg/m^2 bolus infusion followed by 5-FU as a 2400 mg/m^2 continuous IV infusion (or 5-FU as a 1200 mg/m^2/day continuous IV infusion). Following Cycle 8, oxaliplatin was discontinued.

    Primary: Percentage of Participants With Disease Progression or Death

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    End point title
    		 Percentage of Participants With Disease Progression or Death [1]
    End point description
    Tumor response was assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Progressive disease (PD): At least a 20 percent (%) increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 millimeter (mm) or progression of non-target lesions. Death on study was defined as death from any cause within 30 days of the last dose of study treatment regimen. Analysis population included all randomized participants. Data were reported for all randomized participants and for participants with phosphatase and tensin homolog (PTEN) loss tumors.
    End point type
    Primary
    End point timeframe
    Screening, at the end of Cycle 4 and every fourth cycle thereafter until disease progression or death, whichever occurred first, assessed up to approximately 1.75 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this end point.
    End point values
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    71 [2]
    82 [3]
    Units: percentage of participants
    number (not applicable)
        All randomized participants
    67.6
    69.5
        Participants with PTEN loss tumors
    73.3
    61.9
    Notes
    [2] - Number of participants analyzed=15 for PTEN loss tumors
    [3] - Number of participants analyzed=21 for PTEN loss tumors
    No statistical analyses for this end point

    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 using RECIST Version 1.1 and assessed by the investigator), or death from any cause on study. PD: At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or progression of non-target lesions. Death on study was defined as death from any cause within 30 days of the last dose of study treatment regimen. Kaplan−Meier estimates were used for evaluation. Analysis population included all randomized participants. Data were reported for all randomized participants and for participants with PTEN loss tumors.
    End point type
    Primary
    End point timeframe
    Screening, at the end of Cycle 4 and every fourth cycle thereafter until disease progression or death, whichever occurred first, assessed up to approximately 1.75 years
    End point values
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    71 [4]
    82 [5]
    Units: months
    median (confidence interval 90%)
        All randomized participants
    6.57 (5.72 to 7.52)
    7.52 (6.24 to 8.11)
        Participants with PTEN loss tumors
    7.1 (5.39 to 9.92)
    7.39 (6.51 to 14.69)
    Notes
    [4] - Number of participants analyzed=15 for PTEN loss tumors
    [5] - Number of participants analyzed=21 for PTEN loss tumors
    Statistical analysis title
    		 PFS: Ipatasertib + mFOLFOX6 vs. Placebo + mFOLFOX6
    Statistical analysis description
    All randomized participants
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.56
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.55
    Notes
    [6] - Unstratified analysis
    Statistical analysis title
    		 PFS: Ipatasertib + mFOLFOX6 vs. Placebo + mFOLFOX6
    Statistical analysis description
    Participants with PTEN loss tumors. Number of participants with PTEN loss tumors in this analysis = 15 (Ipatasertib + mFOLFOX6) + 21 (Placebo + mFOLFOX6) = 36
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.86
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 2.11
    Notes
    [7] - Unstratified analysis

    Secondary: Percentage of Participants Who Died

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    End point title
    		 Percentage of Participants Who Died
    End point description
    Death on study was defined as death from any cause within 30 days of the last dose of study treatment regimen. Analysis population included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Baseline until death (assessed up to approximately 1.75 years)
    End point values
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    71
    82
    Units: percentage of participants
        number (not applicable)
    54.9
    35.4
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS was defined as the time from the date of randomization to the date of death from any cause. Death on study was defined as death from any cause within 30 days of the last dose of study treatment regimen. Kaplan−Meier estimates were used for evaluation. Analysis population included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Baseline until death (assessed up to approximately 1.75 years)
    End point values
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    71
    82
    Units: months
        median (confidence interval 90%)
    12.12 (10.28 to 14.55)
    15.67 (13.54 to 19.81)
    Statistical analysis title
    		 OS: Ipatasertib + mFOLFOX6 vs. Placebo + mFOLFOX6
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.01
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.85
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.23
         upper limit
    		 2.79
    Notes
    [8] - Unstratified analysis

    Secondary: Percentage of Participants with Objective Tumor Response

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    End point title
    		 Percentage of Participants with Objective Tumor Response
    End point description
    Objective Response was defined as the participants achieving either a complete response (CR) or a partial response (PR) based on the investigator assessment using RECIST v 1.1. CR: disappearance of all target lesions and all pathological lymph nodes below 10 mm. Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions. Analysis population included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Screening, at the end of Cycle 4 and every fourth cycle thereafter until disease progression or death, whichever occurred first, assessed up to approximately 1.75 years
    End point values
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: percentage of participants
        number (not applicable)
    Notes
    [9] - Due to primary efficacy endpoints not met, secondary efficacy endpoints were not analyzed.
    [10] - Due to primary efficacy endpoints not met, secondary efficacy endpoints were not analyzed.
    No statistical analyses for this end point

    Secondary: Duration of objective response

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    End point title
    		 Duration of objective response
    End point description
    Duration of objective response in participants with measurable soft tissue 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 Version 1.1. PD: At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or progression of non-target lesions. Analysis population included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Screening, at the end of Cycle 4 and every fourth cycle thereafter until disease progression or death, whichever occurred first, assessed up to approximately 1.75 years
    End point values
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: months
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [11] - Due to primary efficacy endpoints not met, secondary efficacy endpoints were not analyzed.
    [12] - Due to primary efficacy endpoints not met, secondary efficacy endpoints were not analyzed.
    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 Version 1.1. PD: At least a 20% increase in the sum of diameters of target lesions, and the sum must also demonstrate an absolute increase of at least 5 mm or progression of non-target lesions. Analysis population included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Screening, at the end of Cycle 4 and every fourth cycle thereafter until disease progression or death, whichever occurred first, assessed up to approximately 1.75 years
    End point values
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: months
        median (confidence interval 90%)
    ( to )
    ( to )
    Notes
    [13] - Due to primary efficacy endpoints not met, secondary efficacy endpoints were not analyzed.
    [14] - Due to primary efficacy endpoints not met, secondary efficacy endpoints were not analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline until 30 days after the last dose of study treatment or until initiation of another anti-cancer therapy, whichever occurred first (up to approximately 1.75 years)
    Adverse event reporting additional description
    One participant in Ipatasertib + mFOLFOX6 group was randomized prior to site notification of participant's death.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Ipatasertib + mFOLFOX6
    Reporting group description
    		 Ipatasertib was administered at a dose of 600 milligrams (mg) orally once daily, beginning on Day 1 of Cycle 1 through Day 7 of each 14-day cycle until the participant experienced disease progression or intolerable toxicity. Following ipatasertib administration on Day 1 of each cycle, the participant then received mFOLFOX6 in the following order: oxaliplatin as an 85 milligram per square-meter (mg/m^2) intravenous (IV) infusion on Day 1 every 14 days with co-administration of leucovorin at 400 mg/m^2 or equivalent substitute. The participant then received 5-fluorouracil (5-FU) as a 400 mg/m^2 bolus infusion followed by 5-FU as a 2400 mg/m^2 continuous IV infusion (or 5-FU as a 1200 mg/m^2/day continuous IV infusion). Following Cycle 8, oxaliplatin was discontinued.

    Reporting group title
    Placebo + mFOLFOX6
    Reporting group description
    		 Placebo matched to ipatasertib was administered orally once daily, beginning on Day 1 of Cycle 1 through Day 7 of each 14-day cycle until the participant experienced disease progression or intolerable toxicity. Following placebo administration on Day 1 of each cycle, the participant then received mFOLFOX6 in the following order: oxaliplatin as an mg/m^2 IV infusion on Day 1 every 14 days with co-administration of leucovorin at 400 mg/m^2 or equivalent substitute. The participant then received 5-FU as a 400 mg/m^2 bolus infusion followed by 5-FU as a 2400 mg/m^2 continuous IV infusion (or 5-FU as a 1200 mg/m^2/day continuous IV infusion). Following Cycle 8, oxaliplatin was discontinued.

    Serious adverse events
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 70 (54.29%)
    35 / 82 (42.68%)
         number of deaths (all causes)
    39
    29
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Tumour pain
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Venous thrombosis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Obstruction
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 70 (4.29%)
    3 / 82 (3.66%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 70 (0.00%)
    3 / 82 (3.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Chemical peritonitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pyloric stenosis
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral gas embolism
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diabetic hyperosmolar coma
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (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
    1 / 70 (1.43%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 70 (4.29%)
    4 / 82 (4.88%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic pseudo−obstruction
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (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
    5 / 70 (7.14%)
    3 / 82 (3.66%)
         occurrences causally related to treatment / all
    5 / 6
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 70 (1.43%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    2 / 70 (2.86%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jejunal perforation
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    4 / 70 (5.71%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal fistula
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 70 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 70 (5.71%)
    4 / 82 (4.88%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 70 (2.86%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract disorder
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (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 / 70 (0.00%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 70 (1.43%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 70 (0.00%)
    1 / 82 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 70 (4.29%)
    2 / 82 (2.44%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    3 / 70 (4.29%)
    0 / 82 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperosmolar hyperglycaemic state
         subjects affected / exposed
    1 / 70 (1.43%)
    0 / 82 (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 + mFOLFOX6 Placebo + mFOLFOX6
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    70 / 70 (100.00%)
    79 / 82 (96.34%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 70 (7.14%)
    4 / 82 (4.88%)
         occurrences all number
    5
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 70 (20.00%)
    16 / 82 (19.51%)
         occurrences all number
    18
    27
    Catheter site pain
         subjects affected / exposed
    4 / 70 (5.71%)
    5 / 82 (6.10%)
         occurrences all number
    4
    7
    Chest discomfort
         subjects affected / exposed
    6 / 70 (8.57%)
    1 / 82 (1.22%)
         occurrences all number
    7
    2
    Chest pain
         subjects affected / exposed
    4 / 70 (5.71%)
    6 / 82 (7.32%)
         occurrences all number
    5
    8
    Fatigue
         subjects affected / exposed
    43 / 70 (61.43%)
    37 / 82 (45.12%)
         occurrences all number
    110
    81
    Influenza like illness
         subjects affected / exposed
    4 / 70 (5.71%)
    3 / 82 (3.66%)
         occurrences all number
    4
    4
    Mucosal inflammation
         subjects affected / exposed
    13 / 70 (18.57%)
    15 / 82 (18.29%)
         occurrences all number
    46
    20
    Oedema peripheral
         subjects affected / exposed
    7 / 70 (10.00%)
    8 / 82 (9.76%)
         occurrences all number
    10
    13
    Pyrexia
         subjects affected / exposed
    15 / 70 (21.43%)
    9 / 82 (10.98%)
         occurrences all number
    17
    10
    Temperature intolerance
         subjects affected / exposed
    7 / 70 (10.00%)
    11 / 82 (13.41%)
         occurrences all number
    8
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 70 (10.00%)
    10 / 82 (12.20%)
         occurrences all number
    8
    13
    Dyspnoea
         subjects affected / exposed
    10 / 70 (14.29%)
    14 / 82 (17.07%)
         occurrences all number
    16
    20
    Epistaxis
         subjects affected / exposed
    5 / 70 (7.14%)
    5 / 82 (6.10%)
         occurrences all number
    6
    5
    Hiccups
         subjects affected / exposed
    7 / 70 (10.00%)
    5 / 82 (6.10%)
         occurrences all number
    10
    6
    Oropharyngeal pain
         subjects affected / exposed
    4 / 70 (5.71%)
    6 / 82 (7.32%)
         occurrences all number
    5
    7
    Rhinorrhoea
         subjects affected / exposed
    5 / 70 (7.14%)
    4 / 82 (4.88%)
         occurrences all number
    5
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 70 (7.14%)
    3 / 82 (3.66%)
         occurrences all number
    5
    3
    Insomnia
         subjects affected / exposed
    12 / 70 (17.14%)
    13 / 82 (15.85%)
         occurrences all number
    20
    20
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 70 (10.00%)
    6 / 82 (7.32%)
         occurrences all number
    9
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 70 (7.14%)
    10 / 82 (12.20%)
         occurrences all number
    7
    15
    Blood creatinine increased
         subjects affected / exposed
    6 / 70 (8.57%)
    4 / 82 (4.88%)
         occurrences all number
    8
    6
    Blood triglycerides increased
         subjects affected / exposed
    1 / 70 (1.43%)
    5 / 82 (6.10%)
         occurrences all number
    1
    8
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 70 (1.43%)
    5 / 82 (6.10%)
         occurrences all number
    1
    5
    Neutrophil count decreased
         subjects affected / exposed
    5 / 70 (7.14%)
    12 / 82 (14.63%)
         occurrences all number
    7
    18
    Platelet count decreased
         subjects affected / exposed
    6 / 70 (8.57%)
    5 / 82 (6.10%)
         occurrences all number
    11
    18
    Weight decreased
         subjects affected / exposed
    16 / 70 (22.86%)
    10 / 82 (12.20%)
         occurrences all number
    21
    15
    White blood cell count decreased
         subjects affected / exposed
    3 / 70 (4.29%)
    5 / 82 (6.10%)
         occurrences all number
    4
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    15 / 70 (21.43%)
    13 / 82 (15.85%)
         occurrences all number
    18
    19
    Dysgeusia
         subjects affected / exposed
    13 / 70 (18.57%)
    15 / 82 (18.29%)
         occurrences all number
    13
    15
    Headache
         subjects affected / exposed
    6 / 70 (8.57%)
    7 / 82 (8.54%)
         occurrences all number
    19
    14
    Neuropathy peripheral
         subjects affected / exposed
    27 / 70 (38.57%)
    38 / 82 (46.34%)
         occurrences all number
    47
    99
    Paraesthesia
         subjects affected / exposed
    6 / 70 (8.57%)
    6 / 82 (7.32%)
         occurrences all number
    10
    6
    Peripheral sensory neuropathy
         subjects affected / exposed
    10 / 70 (14.29%)
    14 / 82 (17.07%)
         occurrences all number
    17
    23
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 70 (20.00%)
    15 / 82 (18.29%)
         occurrences all number
    27
    22
    Granulocytopenia
         subjects affected / exposed
    4 / 70 (5.71%)
    6 / 82 (7.32%)
         occurrences all number
    6
    10
    Leukopenia
         subjects affected / exposed
    1 / 70 (1.43%)
    6 / 82 (7.32%)
         occurrences all number
    4
    10
    Neutropenia
         subjects affected / exposed
    21 / 70 (30.00%)
    33 / 82 (40.24%)
         occurrences all number
    38
    66
    Thrombocytopenia
         subjects affected / exposed
    8 / 70 (11.43%)
    11 / 82 (13.41%)
         occurrences all number
    14
    22
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    6 / 70 (8.57%)
    2 / 82 (2.44%)
         occurrences all number
    6
    3
    Abdominal distension
         subjects affected / exposed
    9 / 70 (12.86%)
    7 / 82 (8.54%)
         occurrences all number
    10
    8
    Abdominal pain
         subjects affected / exposed
    18 / 70 (25.71%)
    20 / 82 (24.39%)
         occurrences all number
    25
    34
    Abdominal pain upper
         subjects affected / exposed
    10 / 70 (14.29%)
    6 / 82 (7.32%)
         occurrences all number
    11
    9
    Constipation
         subjects affected / exposed
    26 / 70 (37.14%)
    25 / 82 (30.49%)
         occurrences all number
    58
    49
    Diarrhoea
         subjects affected / exposed
    57 / 70 (81.43%)
    34 / 82 (41.46%)
         occurrences all number
    203
    68
    Dry mouth
         subjects affected / exposed
    4 / 70 (5.71%)
    8 / 82 (9.76%)
         occurrences all number
    6
    9
    Dyspepsia
         subjects affected / exposed
    9 / 70 (12.86%)
    17 / 82 (20.73%)
         occurrences all number
    11
    22
    Dysphagia
         subjects affected / exposed
    7 / 70 (10.00%)
    8 / 82 (9.76%)
         occurrences all number
    13
    9
    Flatulence
         subjects affected / exposed
    2 / 70 (2.86%)
    5 / 82 (6.10%)
         occurrences all number
    3
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 70 (8.57%)
    5 / 82 (6.10%)
         occurrences all number
    6
    10
    Nausea
         subjects affected / exposed
    51 / 70 (72.86%)
    51 / 82 (62.20%)
         occurrences all number
    117
    133
    Stomatitis
         subjects affected / exposed
    17 / 70 (24.29%)
    8 / 82 (9.76%)
         occurrences all number
    26
    12
    Vomiting
         subjects affected / exposed
    43 / 70 (61.43%)
    33 / 82 (40.24%)
         occurrences all number
    105
    78
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    13 / 70 (18.57%)
    20 / 82 (24.39%)
         occurrences all number
    13
    22
    Dry skin
         subjects affected / exposed
    5 / 70 (7.14%)
    8 / 82 (9.76%)
         occurrences all number
    7
    10
    Palmar−plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    5 / 70 (7.14%)
    3 / 82 (3.66%)
         occurrences all number
    5
    6
    Pruritus
         subjects affected / exposed
    10 / 70 (14.29%)
    4 / 82 (4.88%)
         occurrences all number
    11
    4
    Rash
         subjects affected / exposed
    20 / 70 (28.57%)
    10 / 82 (12.20%)
         occurrences all number
    34
    18
    Skin discolouration
         subjects affected / exposed
    4 / 70 (5.71%)
    0 / 82 (0.00%)
         occurrences all number
    6
    0
    Skin hyperpigmentation
         subjects affected / exposed
    7 / 70 (10.00%)
    1 / 82 (1.22%)
         occurrences all number
    7
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    5 / 70 (7.14%)
    3 / 82 (3.66%)
         occurrences all number
    7
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 70 (1.43%)
    7 / 82 (8.54%)
         occurrences all number
    3
    9
    Back pain
         subjects affected / exposed
    8 / 70 (11.43%)
    14 / 82 (17.07%)
         occurrences all number
    14
    23
    Flank pain
         subjects affected / exposed
    3 / 70 (4.29%)
    6 / 82 (7.32%)
         occurrences all number
    6
    6
    Muscle spasms
         subjects affected / exposed
    1 / 70 (1.43%)
    5 / 82 (6.10%)
         occurrences all number
    1
    7
    Musculoskeletal pain
         subjects affected / exposed
    6 / 70 (8.57%)
    3 / 82 (3.66%)
         occurrences all number
    6
    3
    Myalgia
         subjects affected / exposed
    4 / 70 (5.71%)
    1 / 82 (1.22%)
         occurrences all number
    8
    1
    Pain in extremity
         subjects affected / exposed
    3 / 70 (4.29%)
    6 / 82 (7.32%)
         occurrences all number
    4
    10
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 70 (10.00%)
    3 / 82 (3.66%)
         occurrences all number
    10
    3
    Urinary tract infection
         subjects affected / exposed
    9 / 70 (12.86%)
    5 / 82 (6.10%)
         occurrences all number
    10
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    41 / 70 (58.57%)
    41 / 82 (50.00%)
         occurrences all number
    117
    92
    Dehydration
         subjects affected / exposed
    5 / 70 (7.14%)
    5 / 82 (6.10%)
         occurrences all number
    5
    6
    Hyperglycaemia
         subjects affected / exposed
    14 / 70 (20.00%)
    15 / 82 (18.29%)
         occurrences all number
    23
    28
    Hyperkalaemia
         subjects affected / exposed
    6 / 70 (8.57%)
    5 / 82 (6.10%)
         occurrences all number
    7
    6
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 70 (5.71%)
    2 / 82 (2.44%)
         occurrences all number
    4
    4
    Hypocalcaemia
         subjects affected / exposed
    4 / 70 (5.71%)
    2 / 82 (2.44%)
         occurrences all number
    5
    2
    Hypokalaemia
         subjects affected / exposed
    11 / 70 (15.71%)
    8 / 82 (9.76%)
         occurrences all number
    14
    11
    Hypomagnesaemia
         subjects affected / exposed
    6 / 70 (8.57%)
    4 / 82 (4.88%)
         occurrences all number
    12
    7
    Hyponatraemia
         subjects affected / exposed
    4 / 70 (5.71%)
    2 / 82 (2.44%)
         occurrences all number
    7
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Mar 2013
    Version 2: Updated information related to the ipatasertib/placebo formulation had been added. Updated safety and clinical data from the Phase Ib study of ipatasertib in combination with chemotherapy, including mFOLFOX6, (Study PAM4983g) had been included. Dose-modification guidelines for the management of adverse events related to mFOLFOX6 chemotherapy and/or to ipatasertib had been updated to improve clarity and consistency. Medical monitor contact information for sites in Europe and Asia had been added.
    26 Aug 2014
    Version 3: The sample size for this study had been increased from approximately 120 participants to approximately 150 patients. The primary reason to increase the sample size was to maintain the target PFS events by accounting for the unexpected discontinuations for surgery and/or radiofrequency ablation in some participants left with minimal disease following treatment on this study. The adjusted increase in sample size enabled a robust estimate of the primary endpoint with the preplanned PFS events for the overall population and for the diagnostic-positive (Dx+) sub-population.

    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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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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