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    Clinical Trial Results:
    A Randomized, Phase II, Placebo-controlled Study of Ipatasertib (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
    26 Jan 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    10 Feb 2022
    First version publication date
    09 Jun 2016
    Other versions
    		 v1
    Version creation reason

    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
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 61 6878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, 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
    Final
    Date of interim/final analysis
    26 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of the efficacy of ipatasertib in combination with oxaliplatin, 5-fluorouracil, and leucovorin (modified FOLFOX6 [mFOLFOX6]) chemotherapy in participants with advanced or metastatic gastric or gastroesophageal junction (GEJ) cancer.
    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
    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
    26
    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
    		 The study was conducted at 33 centers in 11 countries.

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

    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
    Other name
    GDC-0068
    Pharmaceutical forms
    Tablet, Capsule
    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
    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
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    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
    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
    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.

    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.

    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
         Study Ended by Sponsor
    7
    20
         Death Prior to Treatment
    1
    -
         Death
    57
    59
         Non-compliance
    -
    1
         Lost to follow-up
    3
    -

    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)
    		 57.6 ± 11.4 61.4 ± 11.0 -
    Sex: Female, Male
    Units: Participants
        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: Progression-Free Survival (PFS) in All Randomized Participants and Participants With PTEN Loss Tumors at Primary Analysis

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    End point title
    		 Progression-Free Survival (PFS) in All Randomized Participants and Participants With PTEN Loss Tumors at Primary Analysis
    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. Progressive disease (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. The randomized population was defined as all participants who were randomized in the study. Randomized participants with PTEN loss tumors were also analyzed. For the primary analysis, PTEN loss was defined as the condition "Perc Cells Cytoplasmic Stain Int 0" of greater than or equal to 10. Here 'n' indicates the number analyzed for the specified population.
    End point type
    Primary
    End point timeframe
    Screening, at the end of Cycle 4 (cycle = 14 days) 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
    82
    Units: months
    median (confidence interval 90%)
        All Randomized Participants (n=71,82)
    6.57 (5.72 to 7.52)
    7.52 (6.24 to 8.11)
        Participants With PTEN Loss Tumors (n=15,21)
    7.10 (5.39 to 9.92)
    7.39 (6.51 to 14.69)
    Statistical analysis title
    		 All randomized participants
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    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
    [1] - Unstratified analysis
    Statistical analysis title
    		 Participants with PTEN loss tumors
    Statistical analysis description
    Total number of participants with PTEN loss tumors in this analysis is 36.
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    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
    [2] - Unstratified analysis

    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. Kaplan−Meier estimates were used for evaluation. All randomized participants, randomized participants with PTEN loss tumors and randomized participants who were Akt diagnostic-positive (Akt Dx+) were analyzed. For the final analysis, PTEN loss was defined as the condition "Perc Cells Cytoplasmic Stain Int 0" of greater than 10. Here 'n' indicates the number analyzed for the specified population. '99999' indicates that data point was not estimable due to low number of events.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study (up to approximately 7.5 years)
    End point values
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    71
    82
    Units: months
    median (confidence interval 90%)
        Randomized (n=71,82)
    11.96 (10.28 to 14.55)
    15.31 (13.54 to 16.92)
        PTEN Loss Tumors (n=14,15)
    14.82 (11.99 to 18.40)
    21.78 (14.13 to 99999)
        Akt Dx+ (n=23,23)
    11.66 (9.92 to 18.40)
    17.22 (12.71 to 23.29)
    Statistical analysis title
    		 All randomized participants
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0234
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.52
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.12
         upper limit
    		 2.07
    Notes
    [3] - Unstratified analysis
    Statistical analysis title
    		 Participants with PTEN loss tumors
    Statistical analysis description
    Total number of participants with PTEN loss tumors in this analysis is 29.
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.2867
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.66
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 3.65
    Notes
    [4] - Unstratified analysis
    Statistical analysis title
    		 Participants who are Akt Dx+
    Statistical analysis description
    Total number of participants who are Akt Dx+ in this analysis is 46.
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.1369
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.66
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 2.93
    Notes
    [5] - Unstratified analysis

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    Objective Response Rate was defined as the percentage of 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. All randomized participants, randomized participants with PTEN loss tumors and randomized participants who were Akt diagnostic-positive (Akt Dx+) were analyzed. For the final analysis, PTEN loss was defined as the condition "Perc Cells Cytoplasmic Stain Int 0" of greater than 10. Here ‘n’ indicates the number analyzed for the specified population.
    End point type
    Secondary
    End point timeframe
    Screening, at the end of Cycle 4 (cycle = 14 days) and every fourth cycle thereafter until disease progression or death, whichever occurred first, up to end of study (up to approximately 7.5 years)
    End point values
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    71
    82
    Units: percentage of participants
    number (confidence interval 90%)
        Randomized (n=71,82)
    52.1 (41.74 to 62.35)
    57.3 (48.02 to 66.59)
        PTEN Loss Tumors (n=14,15)
    50.0 (26.36 to 73.64)
    73.3 (50.00 to 87.82)
        Akt Dx+ (n=23,23)
    52.2 (33.51 to 70.39)
    56.5 (38.05 to 72.67)
    Statistical analysis title
    		 All randomized participants
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5202
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    -5.2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -18.46
         upper limit
    		 8.06
    Statistical analysis title
    		 Participants with PTEN loss tumors
    Statistical analysis description
    Total number of participants with PTEN loss tumors in this analysis is 29.
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2035
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    -23.33
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -52.24
         upper limit
    		 5.58
    Statistical analysis title
    		 Participants who are Akt Dx+
    Statistical analysis description
    Total number of participants who are Akt Dx+ in this analysis is 46.
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7697
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    -4.35
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -28.48
         upper limit
    		 19.79

    Secondary: Duration of Objective Tumor Response

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    End point title
    		 Duration of Objective Tumor Response
    End point description
    Duration of objective tumor 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. All randomized participants, randomized participants with PTEN loss tumors and randomized participants who were Akt diagnostic-positive (Akt Dx+) were analyzed. For the final analysis, PTEN loss was defined as the condition "Perc Cells Cytoplasmic Stain Int 0" of greater than 10. '99999' indicates that data point was not estimable due to low number of events. Here ‘n’ indicates the number analyzed for the specified population.
    End point type
    Secondary
    End point timeframe
    Screening, at the end of Cycle 4 (cycle = 14 days) and every fourth cycle thereafter until disease progression or death, whichever occurred first, up to end of study (up to approximately 7.5 years)
    End point values
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    37
    47
    Units: months
    median (confidence interval 90%)
        Randomized (n=37,47)
    4.63 (4.01 to 5.52)
    5.85 (4.47 to 6.90)
        PTEN Loss Tumor (n=7,11)
    4.70 (4.27 to 99999)
    5.98 (4.86 to 10.94)
        Akt Dx+ (n=12,13)
    4.70 (3.84 to 14.78)
    6.80 (4.86 to 10.71)
    Statistical analysis title
    		 All randomized participants
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.5974
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.14
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.73
    Notes
    [6] - Unstratified analysis
    Statistical analysis title
    		 Participants who are Akt Dx+
    Statistical analysis description
    Total number of participants who are Akt Dx+ in this analysis is 25.
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.6097
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 1.75
    Notes
    [7] - Unstratified analysis
    Statistical analysis title
    		 Participants with PTEN loss tumors
    Statistical analysis description
    Total number of participants with PTEN loss tumors in this analysis is 18.
    Comparison groups
    Ipatasertib + mFOLFOX6 v Placebo + mFOLFOX6
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.5385
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 1.79
    Notes
    [8] - Unstratified analysis

    Secondary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs)
    End point description
    An adverse event is any untoward medical occurrence in a subject 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. Death on study was defined as death from any cause within 30 days of the last dose of study treatment regimen. The safety population was defined as all randomized participants who received at least one dose of ipatasertib/placebo or mFOLFOX6, with participants grouped according to the treatment actually received.
    End point type
    Secondary
    End point timeframe
    Baseline until end of study (up to approximately 7.5 years)
    End point values
    		 Ipatasertib + mFOLFOX6 Placebo + mFOLFOX6
    Number of subjects analysed
    70
    82
    Units: participants
    70
    80
    No statistical analyses for this end point

    Secondary: Serum Concentration of Ipatasertib

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    End point title
    		 Serum Concentration of Ipatasertib [9]
    End point description
    The pharmacokinetic (PK) population was defined as all participants with evaluable PK data. Here ‘n’ indicates the number analyzed for the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Day 1 at 1 hour and 4 hours post-dose; Day 5, pre-dose and 2 hours post-dose
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Ipatasertib serum concentrations were only measured in the arm that received ipatasertib.
    End point values
    		 Ipatasertib + mFOLFOX6
    Number of subjects analysed
    64
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1: 1 hour post-dose (n=63)
    506 ± 550
        Day 1: 4 hours post-dose (n=64)
    389 ± 202
        Day 5: pre-dose (n=62)
    90.7 ± 61.0
        Day 5: 2 hours post-dose (n=57)
    557 ± 328
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline until end of study (up to approximately 7.5 years)
    Adverse event reporting additional description
    Safety population included treated participants (i.e., participants who received at least one dose of ipatasertib/placebo or mFOLFOX6), with participants allocated to the treatment arm associated with the regimen that they actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    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 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.

    Serious adverse events
    		 Placebo+mFOLFOX6 Ipatasertib+mFOLFOX6
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 82 (43.90%)
    39 / 70 (55.71%)
         number of deaths (all causes)
    59
    57
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    GASTRIC CANCER
         subjects affected / exposed
    2 / 82 (2.44%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    TUMOUR PAIN
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    VENOUS THROMBOSIS
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    2 / 82 (2.44%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    FATIGUE
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OBSTRUCTION
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    3 / 82 (3.66%)
    3 / 70 (4.29%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    3 / 82 (3.66%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    PLATELET COUNT DECREASED
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    CHEMICAL PERITONITIS
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PELVIC FRACTURE
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIAC ARREST
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nervous system disorders
    CEREBRAL GAS EMBOLISM
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DIABETIC HYPEROSMOLAR COMA
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARAPARESIS
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    ULCERATIVE KERATITIS
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (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
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    4 / 82 (4.88%)
    4 / 70 (5.71%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASCITES
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    3 / 82 (3.66%)
    5 / 70 (7.14%)
         occurrences causally related to treatment / all
    2 / 3
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    2 / 82 (2.44%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTERITIS
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 70 (1.43%)
         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
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC ULCER
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATEMESIS
         subjects affected / exposed
    1 / 82 (1.22%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ILEUS
         subjects affected / exposed
    0 / 82 (0.00%)
    3 / 70 (4.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 82 (1.22%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL PSEUDO-OBSTRUCTION
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JEJUNAL PERFORATION
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINE PERFORATION
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 82 (0.00%)
    4 / 70 (5.71%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OBSTRUCTION GASTRIC
         subjects affected / exposed
    2 / 82 (2.44%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OESOPHAGEAL FISTULA
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    4 / 82 (4.88%)
    3 / 70 (4.29%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILIARY OBSTRUCTION
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JAUNDICE CHOLESTATIC
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATURIA
         subjects affected / exposed
    0 / 82 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYDRONEPHROSIS
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL COLIC
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT DISORDER
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BURSITIS
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FLANK PAIN
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (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
    APPENDICITIS PERFORATED
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHOPULMONARY ASPERGILLOSIS
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARGE INTESTINE INFECTION
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORAL CANDIDIASIS
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PHARYNGITIS
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    2 / 82 (2.44%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY TUBERCULOSIS
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    2 / 82 (2.44%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUBERCULOSIS
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIRAL INFECTION
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (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
    CACHEXIA
         subjects affected / exposed
    1 / 82 (1.22%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DECREASED APPETITE
         subjects affected / exposed
    0 / 82 (0.00%)
    3 / 70 (4.29%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    2 / 82 (2.44%)
    3 / 70 (4.29%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FAILURE TO THRIVE
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 82 (0.00%)
    3 / 70 (4.29%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIC HYPEROSMOLAR NONKETOTIC SYNDROME
         subjects affected / exposed
    0 / 82 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo+mFOLFOX6 Ipatasertib+mFOLFOX6
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    79 / 82 (96.34%)
    70 / 70 (100.00%)
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    5 / 82 (6.10%)
    2 / 70 (2.86%)
         occurrences all number
    5
    2
    HYPERTENSION
         subjects affected / exposed
    5 / 82 (6.10%)
    4 / 70 (5.71%)
         occurrences all number
    5
    4
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    16 / 82 (19.51%)
    13 / 70 (18.57%)
         occurrences all number
    27
    17
    CATHETER SITE PAIN
         subjects affected / exposed
    5 / 82 (6.10%)
    4 / 70 (5.71%)
         occurrences all number
    7
    4
    CHEST DISCOMFORT
         subjects affected / exposed
    2 / 82 (2.44%)
    5 / 70 (7.14%)
         occurrences all number
    3
    6
    CHEST PAIN
         subjects affected / exposed
    6 / 82 (7.32%)
    4 / 70 (5.71%)
         occurrences all number
    8
    5
    FATIGUE
         subjects affected / exposed
    37 / 82 (45.12%)
    44 / 70 (62.86%)
         occurrences all number
    83
    112
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    3 / 82 (3.66%)
    4 / 70 (5.71%)
         occurrences all number
    4
    4
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    15 / 82 (18.29%)
    13 / 70 (18.57%)
         occurrences all number
    20
    46
    OEDEMA PERIPHERAL
         subjects affected / exposed
    8 / 82 (9.76%)
    7 / 70 (10.00%)
         occurrences all number
    13
    10
    PYREXIA
         subjects affected / exposed
    9 / 82 (10.98%)
    15 / 70 (21.43%)
         occurrences all number
    10
    18
    TEMPERATURE INTOLERANCE
         subjects affected / exposed
    11 / 82 (13.41%)
    7 / 70 (10.00%)
         occurrences all number
    12
    8
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    12 / 82 (14.63%)
    7 / 70 (10.00%)
         occurrences all number
    15
    8
    DYSPNOEA
         subjects affected / exposed
    15 / 82 (18.29%)
    10 / 70 (14.29%)
         occurrences all number
    21
    16
    EPISTAXIS
         subjects affected / exposed
    5 / 82 (6.10%)
    5 / 70 (7.14%)
         occurrences all number
    5
    6
    HICCUPS
         subjects affected / exposed
    5 / 82 (6.10%)
    7 / 70 (10.00%)
         occurrences all number
    6
    10
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    6 / 82 (7.32%)
    4 / 70 (5.71%)
         occurrences all number
    7
    5
    RHINORRHOEA
         subjects affected / exposed
    4 / 82 (4.88%)
    6 / 70 (8.57%)
         occurrences all number
    5
    6
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    3 / 82 (3.66%)
    5 / 70 (7.14%)
         occurrences all number
    3
    5
    INSOMNIA
         subjects affected / exposed
    13 / 82 (15.85%)
    12 / 70 (17.14%)
         occurrences all number
    20
    18
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    6 / 82 (7.32%)
    7 / 70 (10.00%)
         occurrences all number
    8
    9
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    10 / 82 (12.20%)
    5 / 70 (7.14%)
         occurrences all number
    15
    7
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    4 / 82 (4.88%)
    6 / 70 (8.57%)
         occurrences all number
    6
    8
    BLOOD TRIGLYCERIDES INCREASED
         subjects affected / exposed
    5 / 82 (6.10%)
    1 / 70 (1.43%)
         occurrences all number
    8
    1
    GLYCOSYLATED HAEMOGLOBIN INCREASED
         subjects affected / exposed
    5 / 82 (6.10%)
    1 / 70 (1.43%)
         occurrences all number
    5
    1
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    12 / 82 (14.63%)
    5 / 70 (7.14%)
         occurrences all number
    18
    7
    PLATELET COUNT DECREASED
         subjects affected / exposed
    5 / 82 (6.10%)
    6 / 70 (8.57%)
         occurrences all number
    18
    10
    WEIGHT DECREASED
         subjects affected / exposed
    9 / 82 (10.98%)
    16 / 70 (22.86%)
         occurrences all number
    13
    21
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    5 / 82 (6.10%)
    3 / 70 (4.29%)
         occurrences all number
    7
    4
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    13 / 82 (15.85%)
    15 / 70 (21.43%)
         occurrences all number
    19
    18
    DYSGEUSIA
         subjects affected / exposed
    8 / 82 (9.76%)
    5 / 70 (7.14%)
         occurrences all number
    8
    5
    HEADACHE
         subjects affected / exposed
    8 / 82 (9.76%)
    7 / 70 (10.00%)
         occurrences all number
    16
    20
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    38 / 82 (46.34%)
    27 / 70 (38.57%)
         occurrences all number
    100
    46
    PARAESTHESIA
         subjects affected / exposed
    6 / 82 (7.32%)
    6 / 70 (8.57%)
         occurrences all number
    6
    10
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    14 / 82 (17.07%)
    10 / 70 (14.29%)
         occurrences all number
    24
    17
    TASTE DISORDER
         subjects affected / exposed
    7 / 82 (8.54%)
    8 / 70 (11.43%)
         occurrences all number
    7
    8
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    15 / 82 (18.29%)
    14 / 70 (20.00%)
         occurrences all number
    22
    27
    GRANULOCYTOPENIA
         subjects affected / exposed
    6 / 82 (7.32%)
    4 / 70 (5.71%)
         occurrences all number
    10
    6
    LEUKOPENIA
         subjects affected / exposed
    6 / 82 (7.32%)
    1 / 70 (1.43%)
         occurrences all number
    10
    4
    NEUTROPENIA
         subjects affected / exposed
    33 / 82 (40.24%)
    21 / 70 (30.00%)
         occurrences all number
    71
    38
    THROMBOCYTOPENIA
         subjects affected / exposed
    11 / 82 (13.41%)
    8 / 70 (11.43%)
         occurrences all number
    22
    14
    Eye disorders
    VISION BLURRED
         subjects affected / exposed
    5 / 82 (6.10%)
    2 / 70 (2.86%)
         occurrences all number
    11
    2
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    3 / 82 (3.66%)
    6 / 70 (8.57%)
         occurrences all number
    5
    6
    ABDOMINAL DISTENSION
         subjects affected / exposed
    7 / 82 (8.54%)
    9 / 70 (12.86%)
         occurrences all number
    9
    10
    ABDOMINAL PAIN
         subjects affected / exposed
    20 / 82 (24.39%)
    19 / 70 (27.14%)
         occurrences all number
    34
    26
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    7 / 82 (8.54%)
    9 / 70 (12.86%)
         occurrences all number
    10
    10
    CONSTIPATION
         subjects affected / exposed
    24 / 82 (29.27%)
    27 / 70 (38.57%)
         occurrences all number
    48
    59
    DIARRHOEA
         subjects affected / exposed
    34 / 82 (41.46%)
    57 / 70 (81.43%)
         occurrences all number
    73
    202
    DRY MOUTH
         subjects affected / exposed
    8 / 82 (9.76%)
    4 / 70 (5.71%)
         occurrences all number
    10
    6
    DYSPEPSIA
         subjects affected / exposed
    17 / 82 (20.73%)
    9 / 70 (12.86%)
         occurrences all number
    22
    11
    DYSPHAGIA
         subjects affected / exposed
    7 / 82 (8.54%)
    7 / 70 (10.00%)
         occurrences all number
    8
    13
    FLATULENCE
         subjects affected / exposed
    5 / 82 (6.10%)
    2 / 70 (2.86%)
         occurrences all number
    6
    3
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    5 / 82 (6.10%)
    6 / 70 (8.57%)
         occurrences all number
    10
    6
    NAUSEA
         subjects affected / exposed
    51 / 82 (62.20%)
    51 / 70 (72.86%)
         occurrences all number
    133
    117
    STOMATITIS
         subjects affected / exposed
    8 / 82 (9.76%)
    17 / 70 (24.29%)
         occurrences all number
    12
    26
    VOMITING
         subjects affected / exposed
    33 / 82 (40.24%)
    43 / 70 (61.43%)
         occurrences all number
    87
    104
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    20 / 82 (24.39%)
    13 / 70 (18.57%)
         occurrences all number
    22
    13
    DRY SKIN
         subjects affected / exposed
    8 / 82 (9.76%)
    5 / 70 (7.14%)
         occurrences all number
    11
    7
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
         subjects affected / exposed
    4 / 82 (4.88%)
    5 / 70 (7.14%)
         occurrences all number
    9
    5
    PRURITUS
         subjects affected / exposed
    6 / 82 (7.32%)
    10 / 70 (14.29%)
         occurrences all number
    6
    11
    RASH
         subjects affected / exposed
    11 / 82 (13.41%)
    20 / 70 (28.57%)
         occurrences all number
    20
    34
    SKIN DISCOLOURATION
         subjects affected / exposed
    0 / 82 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    0
    6
    SKIN HYPERPIGMENTATION
         subjects affected / exposed
    1 / 82 (1.22%)
    7 / 70 (10.00%)
         occurrences all number
    1
    7
    Renal and urinary disorders
    PROTEINURIA
         subjects affected / exposed
    3 / 82 (3.66%)
    5 / 70 (7.14%)
         occurrences all number
    5
    7
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    10 / 82 (12.20%)
    6 / 70 (8.57%)
         occurrences all number
    12
    9
    BACK PAIN
         subjects affected / exposed
    14 / 82 (17.07%)
    8 / 70 (11.43%)
         occurrences all number
    23
    14
    FLANK PAIN
         subjects affected / exposed
    7 / 82 (8.54%)
    3 / 70 (4.29%)
         occurrences all number
    8
    6
    MUSCLE SPASMS
         subjects affected / exposed
    5 / 82 (6.10%)
    1 / 70 (1.43%)
         occurrences all number
    7
    1
    MYALGIA
         subjects affected / exposed
    1 / 82 (1.22%)
    4 / 70 (5.71%)
         occurrences all number
    1
    8
    PAIN IN EXTREMITY
         subjects affected / exposed
    6 / 82 (7.32%)
    3 / 70 (4.29%)
         occurrences all number
    11
    4
    Infections and infestations
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    3 / 82 (3.66%)
    7 / 70 (10.00%)
         occurrences all number
    3
    10
    URINARY TRACT INFECTION
         subjects affected / exposed
    4 / 82 (4.88%)
    10 / 70 (14.29%)
         occurrences all number
    9
    11
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    41 / 82 (50.00%)
    41 / 70 (58.57%)
         occurrences all number
    92
    115
    DEHYDRATION
         subjects affected / exposed
    5 / 82 (6.10%)
    5 / 70 (7.14%)
         occurrences all number
    6
    5
    HYPERGLYCAEMIA
         subjects affected / exposed
    15 / 82 (18.29%)
    14 / 70 (20.00%)
         occurrences all number
    28
    23
    HYPERKALAEMIA
         subjects affected / exposed
    5 / 82 (6.10%)
    6 / 70 (8.57%)
         occurrences all number
    7
    7
    HYPOALBUMINAEMIA
         subjects affected / exposed
    2 / 82 (2.44%)
    4 / 70 (5.71%)
         occurrences all number
    4
    4
    HYPOCALCAEMIA
         subjects affected / exposed
    2 / 82 (2.44%)
    4 / 70 (5.71%)
         occurrences all number
    2
    5
    HYPOKALAEMIA
         subjects affected / exposed
    8 / 82 (9.76%)
    11 / 70 (15.71%)
         occurrences all number
    11
    14
    HYPOMAGNESAEMIA
         subjects affected / exposed
    4 / 82 (4.88%)
    7 / 70 (10.00%)
         occurrences all number
    7
    13
    HYPONATRAEMIA
         subjects affected / exposed
    2 / 82 (2.44%)
    4 / 70 (5.71%)
         occurrences all number
    2
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 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.
    25 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.
    01 Apr 2016
    Version 4: The main purpose of this amendment was to provide a high-level summary of the primary analysis results for Study GO28341 and describe the management plan for ongoing participants. The primary analysis for safety and efficacy showed that ipatasertib+mFOLFOX6, compared with placebo +mFOLFOX6, did not improve progression-free survival (primary endpoint) or overall survival (secondary endpoint) in either the randomized population or the subset of participants who had tumors with loss of the tumor suppressor phosphatase and tensin homolog (PTEN loss) meeting pre-defined criteria by immunohistochemistry prior to the primary analysis. Safety data from this study were consistent with the known safety profiles for ipatasertib and mFOLFOX6 chemotherapy. The overall safety profile and the risks associated with ipatasertib had not changed. As of 11 January 2016, the Sponsor provided all investigators with the unblinded study treatment assignments and a summary of the primary analysis results to allow investigators to share this information and discuss future treatment plans with the 7 ongoing participants in the study. Because of a lack of clinical benefit, the Sponsor recommended discontinuation of ipatasertib/placebo treatment. Allowed for certain laboratory assessments scheduled during the treatment period (glycosylated hemoglobin, fasting lipid profile, coagulation, and urinalysis) to be performed only if clinically indicated, at the discretion of the investigator, for participants who continue to receive ipatasertib with or without mFOLFOX6 treatment in the study. Eliminated exploratory assessments, survival follow-up and assessment of new anti-cancer therapies for all participants.
    26 Oct 2017
    Version 5: GDC-0068 was updated to reflect the international nonproprietary name “ipatasertib”. The Protocol was amended to provide an update on the formulation of ipatasertib (previously capsule; tablet formulation effective no later than March, 2018) and to simplify the study assessment schedule for the 1 ongoing participant in the study (at approximately every 3-4 months, or more frequently if clinically indicated). As of 1 October 2017, the study was unblinded following primary analysis; 1 participant remained on study treatment receiving ipatasertib.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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