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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-controlled Study of AG-120 in Previously-treated Subjects With Nonresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation

    Summary
    EudraCT number
    2015-005117-72
    Trial protocol
    DE   GB   ES   FR   IT  
    Global end of trial date
    17 May 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Jun 2022
    First version publication date
    02 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AG120-C-005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02989857
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier (I.R.I.S.)
    Sponsor organisation address
    50, rue Carnot, Suresnes cedex, France, 92284
    Public contact
    Institut de Recherches Internationales Servier Clinical Studies Department , Institut de Recherches Internationales Servier , +33 155724366, scientificinformation@servier.com
    Scientific contact
    Medical Affairs Servier Pharmaceuticals LLC, Institut de Recherches Internationales Servier , +1 888-788-1735, scientificinformation@servier.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
    17 May 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to demonstrate the efficacy of AG-120 based on Progression Free Survival (PFS) per Independent Radiology Center (IRC) assessment compared to placebo in subjects with nonresectable or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation.
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki, and applicable regulatory requirements. All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 125
    Worldwide total number of subjects
    187
    EEA total number of subjects
    39
    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)
    115
    From 65 to 84 years
    72
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects took part in the study at 49 study sites in France, Italy, Spain, South Korea, the United States, and the United Kingdom from 20 February 2017 to 17 May 2021.

    Pre-assignment
    Screening details
    The final analysis of progression-free survival (PFS) occurred once 131 PFS events had been determined by Investigator assessment. Two subjects were randomised in the study after the data cutoff date (31 January 2019) for the final analysis of PFS.

    Period 1
    Period 1 title
    Randomisation Phase
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    AG-120
    Arm description
    Subjects received AG-120 500 mg, tablet, orally, once daily (QD) in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.
    Arm type
    Active comparator

    Investigational medicinal product name
    AG-120
    Investigational medicinal product code
    Other name
    Ivosidenib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet administered orally.

    Arm title
    Placebo
    Arm description
    Subjects received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Subjects who experienced disease progression and received placebo were allowed to cross over and receive AG-120.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet administered orally.

    Number of subjects in period 1
    AG-120 Placebo
    Started
    126
    61
    Completed
    123
    59
    Not completed
    3
    2
         Not Treated
    3
    2
    Period 2
    Period 2 title
    Cross Over Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    After Crossover to AG-120
    Arm description
    Subjects who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.
    Arm type
    Experimental

    Investigational medicinal product name
    AG-120
    Investigational medicinal product code
    Other name
    Ivosidenib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet administered orally.

    Number of subjects in period 2 [1]
    After Crossover to AG-120
    Started
    43
    Completed
    43
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects who had experienced disease progression and received placebo were allowed to cross over to receive AG-120. Completed = Subjects who completed the protocol defined treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AG-120
    Reporting group description
    Subjects received AG-120 500 mg, tablet, orally, once daily (QD) in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Subjects who experienced disease progression and received placebo were allowed to cross over and receive AG-120.

    Reporting group values
    AG-120 Placebo Total
    Number of subjects
    126 61 187
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.3 ( 10.97 ) 62.9 ( 10.38 ) -
    Gender categorical
    Units: Subjects
        Female
    82 37 119
        Male
    44 24 68
    Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    7 2 9
        Not Hispanic or Latino
    84 40 124
        Not Reported
    0 2 2
        Missing
    35 17 52
    Race, Customized
    Units: Subjects
        American Indian or Alaska Native
    1 0 1
        Asian
    15 8 23
        Black or African American
    1 1 2
        Native Hawaiian or Other Pacific Islander
    1 0 1
        White
    71 35 106
        Other
    1 0 1
        Not Reported
    1 0 1
        Missing
    35 17 52

    End points

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    End points reporting groups
    Reporting group title
    AG-120
    Reporting group description
    Subjects received AG-120 500 mg, tablet, orally, once daily (QD) in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 45 months.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 7 months. Subjects who experienced disease progression and received placebo were allowed to cross over and receive AG-120.
    Reporting group title
    After Crossover to AG-120
    Reporting group description
    Subjects who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 32 months.

    Subject analysis set title
    Randomisation phase AG-120 plus Cross over phase AG-120
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study. Participants who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle.

    Primary: Progression Free Survival (PFS) as Determined by the Independent Radiology Committee (IRC)

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    End point title
    Progression Free Survival (PFS) as Determined by the Independent Radiology Committee (IRC)
    End point description
    PFS is defined as the time from date of randomisation to the date of first documented disease progression as assessed by the IRC using Response Evaluation Criteria in Solid Tumors [RECIST] v1.1, or date of death due to any cause, whichever occurred first. Disease progression was defined as greater than or equal to (≥)20 percent (%) increase in sum of the diameter of target lesions, taking as reference the smallest sum diameter recorded since the treatment started. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 millimetres (mm) or the appearance of 1 or more new lesions. ITT set=all subjects who were randomised, with the treatment group designated according to the randomisation. Number analysed=number of subjects with data available for analyses at the specified time point. Two subjects were excluded from analysis as they were randomised in the study after the data cutoff date (31 January 2019) for the analysis of PFS.
    End point type
    Primary
    End point timeframe
    From the date of randomisation to the date of first documentation of disease progression or death due to any cause (Up to approximately 2 years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    124
    61
    Units: months
        median (confidence interval 95%)
    2.7 (1.6 to 4.2)
    1.4 (1.4 to 1.6)
    Statistical analysis title
    Statistical Analysis for PFS by the IRC
    Statistical analysis description
    Hazard ratio was calculated from stratified Cox regression model with placebo as the denominator, with two-sided 95% confidence interval.
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.25
         upper limit
    0.54
    Notes
    [1] - P-value was calculated from the one-sided stratified log-rank test.

    Secondary: Percentage of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Percentage of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is any untoward medical occurrence associated with the use of a drug in subjects, whether or not considered drug related. An AE or suspected adverse reaction is considered serious (an SAE) if it is fatal, life-threatening, causes in-patient hospitalisation or prolongation of existing hospitalisation, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect in a neonate/infant born to a mother or father exposed to study treatment or is an important medical event. Safety Analysis Set (SAS) included all subjects who had received at least one dose of study drug (AG-120 or Placebo). Treatment-emergent adverse events are reported.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 28 days after last dose for each intervention (Up to approximately 4 Years)
    End point values
    AG-120 After Crossover to AG-120 Placebo
    Number of subjects analysed
    123
    43
    59
    Units: percentage of subjects
    number (not applicable)
        AEs
    97.6
    95.3
    96.6
        SAEs
    35.0
    27.9
    23.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance Status

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    End point title
    Percentage of Subjects With Eastern Cooperative Oncology Group (ECOG) Performance Status
    End point description
    The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score classified subjects according to their functional impairment, with scores ranging from 0 to 4. ECOG PS: 0 = fully active, able to carry on all pre-disease performance without restriction; 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work; 2 = ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours; 3 = capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = completely disabled, cannot carry on any self-care, totally confined to bed or chair. A higher score means a worse functional status. ITT population included all subjects who were randomised, with the treatment group designated according to the randomisation.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    AG-120 Placebo
    Number of subjects analysed
    126
    61
    Units: percentage of subjects
    number (not applicable)
        Score 0
    39.7
    31.1
        Score 1
    59.5
    67.2
        Score 2
    0.0
    1.6
        Score 3
    0.8
    0.0
        Score 4
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Required At Least One Concomitant Medications During the Treatment

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    End point title
    Percentage of Subjects Who Required At Least One Concomitant Medications During the Treatment
    End point description
    Concomitant medications were medications that were ongoing or initiated after the first dose of the study drug but before the last dose plus 28 days. Percentage of subjects who required at least one concomitant medications during the study along with their prescribed study drug (AG-120 or placebo) were reported. SAS included all subjects who had received at least one dose of study drug (AG-120 or Placebo).
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 28 days after last dose (Up to approximately 4 Years)
    End point values
    AG-120 After Crossover to AG-120 Placebo
    Number of subjects analysed
    123
    43
    59
    Units: percentage of subjects
        number (not applicable)
    99.2
    95.3
    98.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events

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    End point title
    Percentage of Subjects With Abnormal Electrocardiogram (ECG) Changes Reported as Adverse Events
    End point description
    SAS included all subjects who had received at least one dose of study drug (AG-120 or Placebo).
    End point type
    Secondary
    End point timeframe
    Pre-dose C1D1, C2D1; Post-dose C1D1, C1D15, C2D1 and Day 1 of C3D1 and all cycles thereafter up to last dose plus 28 days (Up to approximately 4 years)
    End point values
    AG-120 After Crossover to AG-120 Placebo
    Number of subjects analysed
    123
    43
    59
    Units: percentage of subjects
    number (not applicable)
        Electrocardiogram QT Prolonged
    9.8
    2.3
    3.4
        Electrocardiogram Abnormal
    0.8
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival was defined as the time in months from date of randomisation to the date of death due to any cause. Subjects without documentation of death at the time of the final collection were censored at the date the subject was last known to be alive, or the final collection date, whichever is earlier. ITT population included all subjects who were randomised, with the treatment group designated according to the randomisation.
    End point type
    Secondary
    End point timeframe
    From date of randomisation until the date of death due to any cause (Up to approximately 2 years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    126
    61
    Units: months
        median (confidence interval 95%)
    10.3 (7.8 to 12.4)
    7.5 (4.8 to 11.1)
    Statistical analysis title
    Statistical Analysis for OS
    Statistical analysis description
    Hazard ratio was calculated from the stratified Cox regression model with placebo as the comparator, with two-sided 95% CI. Stratification factor was the number of prior line of therapies at randomisation.
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.093 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    1.12
    Notes
    [2] - P-value was calculated from the one-sided stratified log-rank test. Stratification factor is the number of prior line of therapies at randomisation.

    Secondary: Objective Response Rate (ORR) as Assessed by the Investigator RECIST Version 1.1

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    End point title
    Objective Response Rate (ORR) as Assessed by the Investigator RECIST Version 1.1
    End point description
    ORR as assessed by the investigator was defined as the percentage of subjects with a best overall response (BOR) defined as complete response (CR) or partial response (PR) per RECIST v1.1. CR: disappearance of all target and non-target lesions (TLs) and all pathological lymph nodes (LNs) (target and non target), with short axis <10mm. PR: ≥30% decrease in sum of diameters (SOD) from Baseline. ITT population included all subjects who were randomised, with the treatment group designated according to the randomisation. Two participants were excluded from the analysis as they were randomized in the study after the data cutoff date (31 January 2019) for the analysis of tumor response.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation up to confirmed CR or PR (Up to approximately 2 years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    124
    61
    Units: percentage of subjects
        number (confidence interval 95%)
    3.2 (0.9 to 8.1)
    1.6 (0.0 to 8.8)
    Statistical analysis title
    Statistical Analysis for ORR by the Investigator
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.466 [3]
    Method
    Fisher exact
    Confidence interval
    Notes
    [3] - P-value was calculated from 1-sided Fisher exact test.

    Secondary: ORR as Assessed by the IRC Per RECIST v1.1

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    End point title
    ORR as Assessed by the IRC Per RECIST v1.1
    End point description
    ORR as assessed by the IRC was defined as the percentage of subjects with a BOR defined as CR or PR per RECIST v1.1. CR: disappearance of all target and non-target lesions (TLs) and all pathological lymph nodes (LNs) (target and non target), with short axis <10mm. PR: ≥30% decrease in sum of diameters (SOD) from Baseline. ITT population included all subjects who were randomised, with the treatment group designated according to the randomisation. Two participants were excluded from the analysis as they were randomized in the study after the data cutoff date (31 January 2019) for the analysis of tumor response.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation up to confirmed CR or PR (Up to approximately 2 years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    124
    61
    Units: percentage of subjects
        number (confidence interval 95%)
    2.4 (0.5 to 6.9)
    0.0 (0.0 to 5.9)
    Statistical analysis title
    Statistical Analysis for ORR by the IRC
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.299 [4]
    Method
    Fisher exact
    Confidence interval
    Notes
    [4] - P-value was calculated from 1-sided Fisher exact test.

    Secondary: Duration of Response (DOR) as Assessed by the Investigator

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    End point title
    Duration of Response (DOR) as Assessed by the Investigator
    End point description
    DOR was defined as the time in months from date of first documented CR or PR to date of first documented disease progression or death due to any cause, whichever is earlier, as assessed by the Investigator per RECIST v1.1. CR: disappearance of all target and non-target lesions (TLs) and all pathological lymph nodes (LNs) (target and non target), with short axis <10mm. PR: ≥30% decrease in sum of diameters (SOD) from Baseline. Subjects with response and without progression were censored at the last observation. Subjects with CR or PR per investigator assessment by the data cutoff date (31 January 2019) for the analysis of tumor response. 9999=Median, upper and lower limit was not available due to the insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    4
    1
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: DOR as Assessed by the IRC Per RECIST v1.1

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    End point title
    DOR as Assessed by the IRC Per RECIST v1.1
    End point description
    DOR was defined as the time in months from date of first documented CR or PR to date of first documented disease progression or death due to any cause, whichever is earlier, as assessed by the IRC per RECIST v1.1. CR: disappearance of all target and non-target lesions (TLs) and all pathological lymph nodes (LNs) (target and non target), with short axis <10mm. PR: ≥30% decrease in sum of diameters (SOD) from Baseline. Subjects with response and without progression were censored at the last observation. Subjects with CR or PR per investigator assessment by the data cutoff date (31 January 2019) for the analysis of tumor response. 9999=Median, upper and lower limit were not available due to the insufficient number of participants.
    End point type
    Secondary
    End point timeframe
    From the date of first confirmed CR or PR to disease progression or death regardless of cause (Up to approximately 2 years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    3
    0 [5]
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    ( to )
    Notes
    [5] - There were no responders in placebo.
    No statistical analyses for this end point

    Secondary: Time to Response (TTR) as Assessed by the Investigator

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    End point title
    Time to Response (TTR) as Assessed by the Investigator
    End point description
    TTR was defined as the time from date of randomisation to date of first documented CR or PR for responders, as assessed by the Investigator per RECIST v1.1. CR: disappearance of all target and non-target lesions (TLs) and all pathological lymph nodes (LNs) (target and non target), with short axis <10mm. PR: ≥30% decrease in sum of diameters (SOD) from Baseline. Only responders were analysed for this outcome measure. Subjects with CR or PR per investigator assessment by the data cutoff date (31 January 2019) were analysed for tumor response. 9999=Median, upper and lower limit were not available due to the insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation up to the date of first documented CR or PR (Up to approximately 2 years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    4
    1
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: TTR as Assessed by the IRC Per RECIST v1.1

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    End point title
    TTR as Assessed by the IRC Per RECIST v1.1
    End point description
    TTR was defined as the time from date of randomisation to date of first documented CR or PR for responders, as assessed by the IRC per RECIST v1.1. CR: disappearance of all target and non-target lesions (TLs) and all pathological lymph nodes (LNs) (target and non target), with short axis <10mm. PR: ≥30% decrease in sum of diameters (SOD) from Baseline. Only responders were analysed for this outcome measure. Subjects with CR or PR per investigator assessment by the data cutoff date (31 January 2019) were analysed for tumor response. 9999= Median, lower limit, and upper limit were not available due to the insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation up to the date of first documented CR or PR (Up to approximately 2 years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    3
    0 [6]
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    ( to )
    Notes
    [6] - There were no responders in placebo.
    No statistical analyses for this end point

    Secondary: PFS as Determined by Investigator

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    End point title
    PFS as Determined by Investigator
    End point description
    PFS was defined as the time from date of randomisation to the date of first documented disease progression as assessed by the investigator using RECIST v1.1, or date of death due to any cause, whichever occurred first. Disease progression was defined as ≥20% increase in sum of the diameter of target lesions, taking as reference the smallest sum diameter recorded since the treatment started. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm or the appearance of 1 or more new lesions. No progression or death by data cutoff date was censored at the last adequate assessment date. ITT set included all subjects who were randomised, with the treatment group designated according to the randomisation. Two participants were excluded from the analysis as they were randomized in the study after the data cutoff date (31 January 2019) for the analysis of PFS.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation to the date of first documentation of disease progression or death due to any cause (Up to approximately 2 years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    124
    61
    Units: months
        median (confidence interval 95%)
    2.7 (1.6 to 3.6)
    1.4 (1.4 to 2.5)
    Statistical analysis title
    Statistical Analysis for PFS by Investigator
    Statistical analysis description
    Hazard ratio was calculated from the stratified Cox regression model with placebo as the denominator, with two-sided 95% CI. Stratification factor was the number of prior line of therapies at randomisation.
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [7]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.33
         upper limit
    0.68
    Notes
    [7] - P-value was calculated from one-sided stratified log-rank test. Stratification factor was the number of prior line of therapies at randomisation.

    Secondary: Change From Baseline in Health-Related Quality of Life (HRQOL) Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Subscales Scores

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    End point title
    Change From Baseline in Health-Related Quality of Life (HRQOL) Based on European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire- Core 30 Subscales Scores
    End point description
    EORTC-QLQ-C30 is the European Organization for Research and Treatment of Cancer – Quality of Life Questionnaire – Core Questionnaire. For EORTC QLQ-C30, subscales of physical functioning, pain, and appetite loss were assessed. These had 4 response levels (not at all, a little, quite a bit, and very much). For functional scales, higher scores=better QOL (positive change from Baseline=improvement). For symptom scales, lower scores=better QOL (negative change from Baseline=improvement). ITT population included all randomised subjects, with treatment group designated according to the randomization. Number analysed is the number of subjects for a specific category with data available for analysis at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1 and Cycle 3 Day 1
    End point values
    AG-120 Placebo
    Number of subjects analysed
    126
    61
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1: Physical Functioning (n=67,21)
    -2.4 ( 1.75 )
    -13.3 ( 2.95 )
        Cycle 2 Day 1: Pain (n=67,21)
    2.2 ( 2.48 )
    12.5 ( 4.35 )
        Cycle 2 Day 1: Appetite Loss (n=67,21)
    7.9 ( 2.60 )
    4.3 ( 4.55 )
        Cycle 3 Day 1: Physical Functioning (n=50,9)
    -0.2 ( 1.89 )
    -12.6 ( 3.88 )
        Cycle 3 Day 1: Pain (n=50,9)
    -1.2 ( 2.73 )
    -5.3 ( 5.96 )
        Cycle 3 Day 1: Appetite Loss (n=50,9)
    -0.5 ( 2.89 )
    3.2 ( 6.40 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Cycle 2 Day 1: Physical Functioning
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Least-squares mean difference
    Point estimate
    11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.23
         upper limit
    17.73
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Cycle 2 Day 1: Pain
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Least-squares mean difference
    Point estimate
    -10.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.18
         upper limit
    -0.52
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Cycle 2 Day 1: Appetite Loss
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Least-squares mean difference
    Point estimate
    3.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.65
         upper limit
    13.91
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Cycle 3 Day 1: Physical Functioning
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Least-squares mean difference
    Point estimate
    12.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.85
         upper limit
    20.78
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Cycle 3 Day 1: Pain
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Least-squares mean difference
    Point estimate
    4.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.74
         upper limit
    17.04
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Cycle 3 Day 1: Appetite Loss
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Least-squares mean difference
    Point estimate
    -3.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.46
         upper limit
    10.11

    Secondary: Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21)

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    End point title
    Change From Baseline in HRQOL Based on: Quality of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (QLQ-BIL21)
    End point description
    For HRQOL based on QLQ-BIL21, subscales of eating symptoms and pain symptoms were assessed. Each item is a 4-point Likert scale. There are 4 response levels (not at all, a little, quite a bit, and very much). For symptom scales, lower scores=better QOL (negative change from Baseline=improvement). ITT population included all randomised subjects, with treatment group designated according to the randomisation. Number analysed is the number of subjects for a specific category with data available for analysis at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Cycle 2 Day 1 and Cycle 3 Day 1
    End point values
    AG-120 Placebo
    Number of subjects analysed
    126
    61
    Units: score on a scale
    arithmetic mean (standard deviation)
        Cycle 2 Day 1: Pain (n=65,20)
    5.1 ( 1.94 )
    10.1 ( 3.49 )
        Cycle 2 Day 1: Appetite Loss (n=65,20)
    4.3 ( 1.84 )
    3.6 ( 3.19 )
        Cycle 3 Day 1: Pain (n=48,9)
    2.3 ( 2.16 )
    -2.1 ( 4.70 )
        Cycle 3 Day 1: Appetite Loss (n=48,9)
    -2.0 ( 2.02 )
    4.1 ( 4.24 )
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Cycle 2 Day 1: Pain
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Least-squares mean difference
    Point estimate
    -5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.93
         upper limit
    2.8
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Cycle 2 Day 1: Appetite Loss
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Least-squares mean difference
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.56
         upper limit
    7.88
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Cycle 3 Day 1: Pain
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Least-squares mean difference
    Point estimate
    4.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.82
         upper limit
    14.55
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Cycle 3 Day 1: Appetite Loss
    Comparison groups
    AG-120 v Placebo
    Number of subjects included in analysis
    187
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Least-squares mean difference
    Point estimate
    -6.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.34
         upper limit
    3.12

    Secondary: Percentage of Subjects With Change Based on HRQOL: Patient Global Impression of Change (PGI-C)

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    End point title
    Percentage of Subjects With Change Based on HRQOL: Patient Global Impression of Change (PGI-C)
    End point description
    The anchor-based questionnaire PGI-C contains the following 3 items (the overall change in the physical functioning since the start of taking the study medication, the overall change in the appetite since the start of taking the study medication, and the overall change in the pain since the start of taking the study medication). The PGI-C is measured using a 7-point Likert scale, with 1 = very much better, 2 = much better, 3 = a little better, 4 = no change, 5 = a little worse, 6 = much worse, and 7 = very much worse. 9999: The data is not reported as the analyses were limited by small sample sizes available at post-baseline timepoints for PGI-C.
    End point type
    Secondary
    End point timeframe
    Baseline up to Survival follow-up (up to approximately 4 years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    24
    0 [8]
    Units: percentage of subjects
        number (not applicable)
    9999
    Notes
    [8] - Number analysed was 0 at safety follow up.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S)

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    End point title
    Percentage of Subjects With Severity Based on HRQOL: Patient Global Impression of Severity (PGI-S)
    End point description
    The anchor-based questionnaire PGI-S contains the following 3 items (the severity of the physical functioning decline over the past week, the severity of the appetite decrease over the past week, and the severity of the pain over the past week). The PGI-S is measured using a 7-point Likert scale, with 1 = very much better, 2 = much better, 3 = a little better, 4 = no change, 5 = a little worse, 6 = much worse, and 7 = very much worse. 9999: The data is not reported as the analyses were limited by small sample sizes available at post-baseline timepoints for PGI-S.
    End point type
    Secondary
    End point timeframe
    Baseline up to Survival follow up (up to approximately 4 years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    24
    0 [9]
    Units: percentage of subjects
        number (not applicable)
    9999
    Notes
    [9] - Number analysed was 0 at safety follow up.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response

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    End point title
    Percentage of Subjects with Each EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) Dimension Response
    End point description
    The EQ-5D-5L assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. 9999=The data is not reported as the analyses were limited by small sample sizes available at post-baseline timepoints for EQ-5D-5L.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to EOT (Up to approximately 4 Years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    55
    27
    Units: percentage of subjects
        number (not applicable)
    9999
    9999
    No statistical analyses for this end point

    Secondary: Change From Baseline in EQ-5D-5L Visual Analogue Scale (EQ-5D-5L VAS) Score

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    End point title
    Change From Baseline in EQ-5D-5L Visual Analogue Scale (EQ-5D-5L VAS) Score
    End point description
    The EQ-5D-5L VAS records the participant's self-rated health on a vertical visual analogue scale numbered from 100 (best health imagined) to 0 (worst health imagined). 9999= The data is not reported as the analyses were limited by small sample sizes available at post-baseline timepoints for EQ-5D-5L VAS.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to EOT (Up to approximately 4 Years)
    End point values
    AG-120 Placebo
    Number of subjects analysed
    49
    22
    Units: score on a scale
        arithmetic mean (standard deviation)
    9999 ( 9999 )
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of AG-120

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    End point title
    Maximum Observed Plasma Concentration (Cmax) of AG-120
    End point description
    Pharmacokinetic (PK) Analysis Population consisted of all subjects who were enrolled and received at least one dose of study medication (AG-120) with sufficient plasma sample data to assess PK parameters. Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint. Number analysed is the number of subjects with data available for analyses at the specified time point.
    End point type
    Secondary
    End point timeframe
    Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)
    End point values
    Randomisation phase AG-120 plus Cross over phase AG-120
    Number of subjects analysed
    142
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=142)
    4424.0 ( 1808.07 )
        Cycle 2 Day 1 (n=107)
    5050.5 ( 1666.07 )
    No statistical analyses for this end point

    Secondary: Time to Reach Maximal Plasma Concentration (Tmax) of AG-120

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    End point title
    Time to Reach Maximal Plasma Concentration (Tmax) of AG-120
    End point description
    PK Analysis Population consisted of all subjects who were enrolled and received at least one dose of study medication (AG-120) with sufficient plasma sample data to assess PK parameters. Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint. Number analysed is the number of subjects with data available for analyses at the specified time point.
    End point type
    Secondary
    End point timeframe
    Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)
    End point values
    Randomisation phase AG-120 plus Cross over phase AG-120
    Number of subjects analysed
    142
    Units: hours (h)
    median (full range (min-max))
        Cycle 1 Day 1 (n=142)
    2.63 (0.50 to 4.87)
        Cycle 2 Day 1 (n=107)
    2.07 (0.50 to 4.08)
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24)

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    End point title
    Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC0-24)
    End point description
    PK Analysis Population consisted of all subjects who were enrolled and received at least one dose of study medication (AG-120) with sufficient plasma sample data to assess PK parameters. Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint. Number analysed is the number of subjects with data available for analyses at the specified time point.
    End point type
    Secondary
    End point timeframe
    Post-dose Cycle 2 Day 1 (each cycle = 28 days)
    End point values
    Randomisation phase AG-120 plus Cross over phase AG-120
    Number of subjects analysed
    107
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    91219.4 ( 31574.57 )
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4)

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    End point title
    Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours (AUC0-4)
    End point description
    PK Analysis Population consisted of all subjects who were enrolled and received at least one dose of study medication (AG-120) with sufficient plasma sample data to assess PK parameters. Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint. Number analyzed is the number of subjects with data available for analyses at the specified time point.
    End point type
    Secondary
    End point timeframe
    Post-dose of Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)
    End point values
    Randomisation phase AG-120 plus Cross over phase AG-120
    Number of subjects analysed
    141
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=141)
    10972.2 ( 5044.18 )
        Cycle 2 Day 1 (n=106)
    16651.7 ( 5269.96 )
    No statistical analyses for this end point

    Secondary: Accumulation Ratio Based on AUC0-4 (Racc AUC0-4)

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    End point title
    Accumulation Ratio Based on AUC0-4 (Racc AUC0-4)
    End point description
    PK Analysis Population consisted of all subjects who were enrolled and received at least one dose of study medication (AG-120) with sufficient plasma sample data to assess PK parameters. Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint. Number analysed is the number of subjects with data available for analyses at the specified time point.
    End point type
    Secondary
    End point timeframe
    Post-dose Cycle 2 Day 1 (each cycle = 28 days)
    End point values
    Randomisation phase AG-120 plus Cross over phase AG-120
    Number of subjects analysed
    98
    Units: ratio
        arithmetic mean (standard deviation)
    1.6881 ( 0.83303 )
    No statistical analyses for this end point

    Secondary: Accumulation Ratio Based on Cmax (Racc Cmax)

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    End point title
    Accumulation Ratio Based on Cmax (Racc Cmax)
    End point description
    PK Analysis Population consisted of all subjects who were enrolled and received at least one dose of study medication (AG-120) with sufficient plasma sample data to assess PK parameters. Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint. Number analysed is the number of subjects with data available for analyses at the specified time point.
    End point type
    Secondary
    End point timeframe
    Post-dose of Cycle 2 on Days 1 (each cycle = 28 days)
    End point values
    Randomisation phase AG-120 plus Cross over phase AG-120
    Number of subjects analysed
    100
    Units: ratio
        arithmetic mean (standard deviation)
    1.2369 ( 0.50798 )
    No statistical analyses for this end point

    Secondary: Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: B (Baseline Effect Value)

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    End point title
    Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: B (Baseline Effect Value)
    End point description
    B is the Baseline Effect Value. Pharmacodynamic (PD) Analysis Population consisted of all subjects who were enrolled and received any dose of study medication (AG-120) with sufficient plasma sample data to assess pharmacodynamic parameters. Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint. Number analysed is the number of subjects with data available for analyses at the specified time point.
    End point type
    Secondary
    End point timeframe
    Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)
    End point values
    Randomisation phase AG-120 plus Cross over phase AG-120
    Number of subjects analysed
    142
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1
    1107.70 ( 1709.919 )
        Cycle 2 Day 1
    795.09 ( 938.677 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events

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    End point title
    Percentage of Subjects Who Experienced Laboratory Abnormalities Reported as Grade 3 or Higher Adverse Events
    End point description
    The laboratory parameters evaluated by the investigator included hematology and chemistry. Laboratory abnormalities reported in this endpoint are Grade 3 or higher adverse events. Grading categories were determined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. SAS included all subjects who received at least one dose of study drug (AG-120 or Placebo).
    End point type
    Secondary
    End point timeframe
    From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years)
    End point values
    AG-120 After Crossover to AG-120 Placebo
    Number of subjects analysed
    123
    43
    59
    Units: percentage of subjects
    number (not applicable)
        Anaemia
    7.3
    9.3
    0.0
        Platelet Count Decreased
    2.4
    2.3
    0.0
        Neutrophil Count Decreased
    1.6
    0.0
    0.0
        White Blood Cell Count decreased
    1.6
    0.0
    0.0
        Lymphocyte Count Decreased
    0.8
    0.0
    3.4
        Thrombocytopenia
    0.8
    0.0
    0.0
        Blood Loss Anaemia
    0.8
    0.0
    0.0
        Blood Bilirubin Increased
    5.7
    7.0
    1.7
        Hyponatraemia
    5.7
    2.3
    10.2
        Aspartate Aminotransferase Increased
    4.9
    4.7
    1.7
        Hypophosphataemia
    3.3
    4.7
    5.1
        Hyperbilirubinaemia
    3.3
    0.0
    0.0
        Hyperkalaemia
    2.4
    2.3
    3.4
        Blood Alkaline Phosphatase Increased
    2.4
    0.0
    5.1
        Alanine Aminotransferase Increased
    1.6
    2.3
    0.0
        Hypoalbuminaemia
    1.6
    0.0
    1.7
        Gamma-glutamyltransferase Increased
    0.8
    0.0
    1.7
        Hypercalcaemia
    0.8
    0.0
    1.7
        Hyperuricaemia
    0.8
    0.0
    0.0
        Hypokalaemia
    0.8
    2.3
    1.7
        Transaminases Increased
    0.8
    0.0
    0.0
        Blood Uric Acid Increased
    0.0
    0.0
    1.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Clinically Significant Grade 3 or higher Vital Signs AEs

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    End point title
    Percentage of Subjects With Clinically Significant Grade 3 or higher Vital Signs AEs
    End point description
    Clinically significant vital signs were recorded as adverse events; there were some vital signs reported as Grade 3 or higher adverse events. Grading categories were determined by NCI CTCAE, version 4.03.
    End point type
    Secondary
    End point timeframe
    From first dose of the study drug up to end of treatment visit for each intervention (Up to approximately 4 Years)
    End point values
    AG-120 After Crossover to AG-120 Placebo
    Number of subjects analysed
    123
    43
    59
    Units: percentage of subjects
    number (not applicable)
        Pyrexia
    0.8
    2.3
    0.0
        Weight Decreased
    0.8
    0.0
    1.7
        Hypertension
    1.6
    7.0
    1.7
        Hypotension
    1.6
    2.3
    1.7
    No statistical analyses for this end point

    Secondary: Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: AUEC0-4

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    End point title
    Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: AUEC0-4
    End point description
    AUEC0-4 is the area of the response curve from time point zero (predose) up to 4 hr postdose. PD Analysis Population consisted of all subjects who were enrolled and received any dose of study medication (AG-120) with sufficient plasma sample data to assess pharmacodynamic parameters. Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint. Number analysed is the number of subjects with data available for analyses at the specified time point.
    End point type
    Secondary
    End point timeframe
    Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)
    End point values
    Randomisation phase AG-120 plus Cross over phase AG-120
    Number of subjects analysed
    141
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=141)
    3334.3 ( 4785.48 )
        Cycle 2 Day 1 (n=107)
    368.4 ( 278.78 )
    No statistical analyses for this end point

    Secondary: Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BAUEC0-4

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    End point title
    Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BAUEC0-4
    End point description
    %BAUEC0-4 is the percent inhibition for AUEC0-4. PD Analysis Population consisted of all subjects who were enrolled and received any dose of study medication (AG-120) with sufficient plasma sample data to assess pharmacodynamic parameters. Crossover C1D1 and crossover C2D1 visits were combined with C1D1 and C2D1 visits, respectively for the analysis of this endpoint. Number analysed is the number of subjects with data available for analyses at the specified time point.
    End point type
    Secondary
    End point timeframe
    Post-dose Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle = 28 days)
    End point values
    Randomisation phase AG-120 plus Cross over phase AG-120
    Number of subjects analysed
    141
    Units: percent
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=141)
    20.22090 ( 10.13659 )
        Cycle 2 Day 1 (n=107)
    74.9750 ( 22.53852 )
    No statistical analyses for this end point

    Secondary: Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: Rtrough

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    End point title
    Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: Rtrough
    End point description
    Rtrough is the observed response value at the end of a dosing interval. PD Analysis Population consisted of all subjects who were enrolled and received any dose of study medication (AG-120) with sufficient plasma sample data to assess pharmacodynamic parameters. Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint. Number analysed is the number of subjects with data available for analyses at the specified time point.
    End point type
    Secondary
    End point timeframe
    Post-dose Cycle 2 Day 1 (each cycle = 28 days)
    End point values
    Randomisation phase AG-120 plus Cross over phase AG-120
    Number of subjects analysed
    108
    Units: ng/mL
        arithmetic mean (standard deviation)
    97.66 ( 72.838 )
    No statistical analyses for this end point

    Secondary: Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BRtrough

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    End point title
    Plasma 2-hydroxyglutarate (2-HG) Levels of AG-120: %BRtrough
    End point description
    %BRtrough is the percent inhibition for Rtrough. PD Analysis Population consisted of all subjects who were enrolled and received any dose of study medication (AG-120) with sufficient plasma sample data to assess pharmacodynamic parameters. Crossover C2D1 visit was combined with C2D1 visit for the analysis of this endpoint. Number analysed is the number of subjects with data available for analyses at the specified time point.
    End point type
    Secondary
    End point timeframe
    Post-dose Cycle 2 Day 1 (each cycle = 28 days)
    End point values
    Randomisation phase AG-120 plus Cross over phase AG-120
    Number of subjects analysed
    108
    Units: percent
        arithmetic mean (standard deviation)
    73.726 ( 23.3113 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 28 days after last dose for each intervention (Up to approximately 4 years)
    Adverse event reporting additional description
    Safety Analysis Set included all subjects who received at least one dose of study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    AG-120
    Reporting group description
    Subjects received AG-120 500 mg, tablet, orally, once daily (QD) in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up, or the sponsor ended the study for up to approximately 24 months.

    Reporting group title
    After Cross Over to AG-120
    Reporting group description
    Subjects who experienced disease progression and received placebo were allowed to cross over to receive AG-120 500 mg, tablet, orally, QD in each 28-day treatment cycle for up to approximately 24 months.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received AG-120 matched placebo, orally, QD in each 28-day treatment cycle, until occurrence of disease progression, unacceptable toxicity, confirmed pregnancy, death, subject withdrawal, lost to follow-up or the sponsor ended the study for up to approximately 24 months. Subjects who experienced disease progression and received placebo were allowed to cross over and receive AG-120.

    Serious adverse events
    AG-120 After Cross Over to AG-120 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    43 / 123 (34.96%)
    12 / 43 (27.91%)
    14 / 59 (23.73%)
         number of deaths (all causes)
    99
    34
    14
         number of deaths resulting from adverse events
    6
    2
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 43 (2.33%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 123 (1.63%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    2 / 123 (1.63%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 123 (1.63%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arterial injury
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 123 (1.63%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Tachyarrhythmia
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thecal sac compression
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 123 (0.81%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    3 / 123 (2.44%)
    1 / 43 (2.33%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 123 (0.81%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal pseudo-obstruction
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 123 (1.63%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 123 (1.63%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 123 (0.81%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    3 / 123 (2.44%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    1 / 123 (0.81%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 123 (2.44%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    3 / 123 (2.44%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 43 (2.33%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    2 / 123 (1.63%)
    1 / 43 (2.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 123 (3.25%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 123 (3.25%)
    0 / 43 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 123 (0.81%)
    1 / 43 (2.33%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 43 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    AG-120 After Cross Over to AG-120 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    118 / 123 (95.93%)
    36 / 43 (83.72%)
    56 / 59 (94.92%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    11 / 123 (8.94%)
    3 / 43 (6.98%)
    1 / 59 (1.69%)
         occurrences all number
    16
    5
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    13 / 123 (10.57%)
    3 / 43 (6.98%)
    3 / 59 (5.08%)
         occurrences all number
    23
    6
    3
    Blood creatinine increased
         subjects affected / exposed
    7 / 123 (5.69%)
    1 / 43 (2.33%)
    3 / 59 (5.08%)
         occurrences all number
    8
    1
    6
    Blood bilirubin increased
         subjects affected / exposed
    12 / 123 (9.76%)
    2 / 43 (4.65%)
    4 / 59 (6.78%)
         occurrences all number
    16
    4
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    11 / 123 (8.94%)
    4 / 43 (9.30%)
    6 / 59 (10.17%)
         occurrences all number
    14
    5
    8
    Electrocardiogram QT prolonged
         subjects affected / exposed
    11 / 123 (8.94%)
    1 / 43 (2.33%)
    2 / 59 (3.39%)
         occurrences all number
    27
    3
    2
    Platelet count decreased
         subjects affected / exposed
    7 / 123 (5.69%)
    2 / 43 (4.65%)
    3 / 59 (5.08%)
         occurrences all number
    14
    5
    4
    White blood cell count decreased
         subjects affected / exposed
    9 / 123 (7.32%)
    2 / 43 (4.65%)
    1 / 59 (1.69%)
         occurrences all number
    26
    3
    1
    Weight decreased
         subjects affected / exposed
    10 / 123 (8.13%)
    6 / 43 (13.95%)
    3 / 59 (5.08%)
         occurrences all number
    17
    8
    7
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 123 (8.94%)
    4 / 43 (9.30%)
    2 / 59 (3.39%)
         occurrences all number
    16
    9
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 123 (5.69%)
    4 / 43 (9.30%)
    1 / 59 (1.69%)
         occurrences all number
    8
    6
    1
    Headache
         subjects affected / exposed
    16 / 123 (13.01%)
    2 / 43 (4.65%)
    4 / 59 (6.78%)
         occurrences all number
    24
    2
    5
    Neuropathy peripheral
         subjects affected / exposed
    8 / 123 (6.50%)
    0 / 43 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    11
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    23 / 123 (18.70%)
    7 / 43 (16.28%)
    3 / 59 (5.08%)
         occurrences all number
    47
    8
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    17 / 123 (13.82%)
    5 / 43 (11.63%)
    7 / 59 (11.86%)
         occurrences all number
    25
    8
    10
    Chills
         subjects affected / exposed
    8 / 123 (6.50%)
    1 / 43 (2.33%)
    3 / 59 (5.08%)
         occurrences all number
    8
    1
    3
    Fatigue
         subjects affected / exposed
    38 / 123 (30.89%)
    10 / 43 (23.26%)
    10 / 59 (16.95%)
         occurrences all number
    42
    17
    13
    Gait disturbance
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 43 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    3
    Oedema peripheral
         subjects affected / exposed
    17 / 123 (13.82%)
    9 / 43 (20.93%)
    6 / 59 (10.17%)
         occurrences all number
    25
    12
    7
    Pyrexia
         subjects affected / exposed
    16 / 123 (13.01%)
    2 / 43 (4.65%)
    6 / 59 (10.17%)
         occurrences all number
    23
    4
    6
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    10 / 123 (8.13%)
    4 / 43 (9.30%)
    2 / 59 (3.39%)
         occurrences all number
    16
    4
    2
    Abdominal pain
         subjects affected / exposed
    30 / 123 (24.39%)
    7 / 43 (16.28%)
    9 / 59 (15.25%)
         occurrences all number
    46
    9
    12
    Abdominal discomfort
         subjects affected / exposed
    4 / 123 (3.25%)
    3 / 43 (6.98%)
    0 / 59 (0.00%)
         occurrences all number
    5
    4
    0
    Abdominal distension
         subjects affected / exposed
    13 / 123 (10.57%)
    2 / 43 (4.65%)
    5 / 59 (8.47%)
         occurrences all number
    13
    4
    6
    Dyspepsia
         subjects affected / exposed
    7 / 123 (5.69%)
    1 / 43 (2.33%)
    3 / 59 (5.08%)
         occurrences all number
    7
    1
    3
    Dry mouth
         subjects affected / exposed
    3 / 123 (2.44%)
    1 / 43 (2.33%)
    4 / 59 (6.78%)
         occurrences all number
    4
    1
    4
    Diarrhoea
         subjects affected / exposed
    43 / 123 (34.96%)
    12 / 43 (27.91%)
    10 / 59 (16.95%)
         occurrences all number
    67
    22
    18
    Constipation
         subjects affected / exposed
    20 / 123 (16.26%)
    5 / 43 (11.63%)
    11 / 59 (18.64%)
         occurrences all number
    26
    5
    11
    Gastrooesophageal reflux disease
         subjects affected / exposed
    9 / 123 (7.32%)
    1 / 43 (2.33%)
    2 / 59 (3.39%)
         occurrences all number
    11
    1
    2
    Ascites
         subjects affected / exposed
    25 / 123 (20.33%)
    5 / 43 (11.63%)
    7 / 59 (11.86%)
         occurrences all number
    59
    9
    10
    Nausea
         subjects affected / exposed
    52 / 123 (42.28%)
    12 / 43 (27.91%)
    17 / 59 (28.81%)
         occurrences all number
    76
    18
    26
    Vomiting
         subjects affected / exposed
    28 / 123 (22.76%)
    5 / 43 (11.63%)
    11 / 59 (18.64%)
         occurrences all number
    38
    6
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 123 (25.20%)
    5 / 43 (11.63%)
    5 / 59 (8.47%)
         occurrences all number
    38
    5
    6
    Dyspnoea
         subjects affected / exposed
    12 / 123 (9.76%)
    4 / 43 (9.30%)
    10 / 59 (16.95%)
         occurrences all number
    14
    5
    15
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    4 / 123 (3.25%)
    1 / 43 (2.33%)
    3 / 59 (5.08%)
         occurrences all number
    6
    1
    3
    Rash
         subjects affected / exposed
    10 / 123 (8.13%)
    2 / 43 (4.65%)
    0 / 59 (0.00%)
         occurrences all number
    13
    2
    0
    Pruritus
         subjects affected / exposed
    7 / 123 (5.69%)
    3 / 43 (6.98%)
    3 / 59 (5.08%)
         occurrences all number
    8
    4
    4
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    4 / 123 (3.25%)
    2 / 43 (4.65%)
    3 / 59 (5.08%)
         occurrences all number
    5
    2
    5
    Insomnia
         subjects affected / exposed
    12 / 123 (9.76%)
    3 / 43 (6.98%)
    3 / 59 (5.08%)
         occurrences all number
    13
    4
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 123 (11.38%)
    5 / 43 (11.63%)
    6 / 59 (10.17%)
         occurrences all number
    17
    7
    7
    Back pain
         subjects affected / exposed
    16 / 123 (13.01%)
    2 / 43 (4.65%)
    7 / 59 (11.86%)
         occurrences all number
    23
    2
    10
    Muscular weakness
         subjects affected / exposed
    1 / 123 (0.81%)
    4 / 43 (9.30%)
    2 / 59 (3.39%)
         occurrences all number
    1
    4
    2
    Muscle spasms
         subjects affected / exposed
    6 / 123 (4.88%)
    4 / 43 (9.30%)
    1 / 59 (1.69%)
         occurrences all number
    8
    6
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 123 (3.25%)
    3 / 43 (6.98%)
    0 / 59 (0.00%)
         occurrences all number
    10
    3
    0
    Urinary tract infection
         subjects affected / exposed
    7 / 123 (5.69%)
    1 / 43 (2.33%)
    1 / 59 (1.69%)
         occurrences all number
    10
    1
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    9 / 123 (7.32%)
    2 / 43 (4.65%)
    1 / 59 (1.69%)
         occurrences all number
    10
    4
    2
    Hypercalcaemia
         subjects affected / exposed
    2 / 123 (1.63%)
    1 / 43 (2.33%)
    7 / 59 (11.86%)
         occurrences all number
    2
    1
    7
    Decreased appetite
         subjects affected / exposed
    30 / 123 (24.39%)
    6 / 43 (13.95%)
    11 / 59 (18.64%)
         occurrences all number
    41
    7
    13
    Hyponatraemia
         subjects affected / exposed
    14 / 123 (11.38%)
    1 / 43 (2.33%)
    6 / 59 (10.17%)
         occurrences all number
    25
    1
    9
    Hypomagnesaemia
         subjects affected / exposed
    9 / 123 (7.32%)
    1 / 43 (2.33%)
    3 / 59 (5.08%)
         occurrences all number
    9
    2
    3
    Hypokalaemia
         subjects affected / exposed
    10 / 123 (8.13%)
    2 / 43 (4.65%)
    4 / 59 (6.78%)
         occurrences all number
    15
    2
    4
    Hypoalbuminaemia
         subjects affected / exposed
    8 / 123 (6.50%)
    3 / 43 (6.98%)
    4 / 59 (6.78%)
         occurrences all number
    14
    5
    4
    Hypophosphataemia
         subjects affected / exposed
    6 / 123 (4.88%)
    3 / 43 (6.98%)
    3 / 59 (5.08%)
         occurrences all number
    7
    5
    6
    Hyperkalaemia
         subjects affected / exposed
    6 / 123 (4.88%)
    2 / 43 (4.65%)
    3 / 59 (5.08%)
         occurrences all number
    9
    2
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Aug 2016
    The major changes included in Amendment 1 version 2.0: • The primary endpoint of PFS will be based on Independent Radiology center assessment instead of Investigator assessment. • The secondary endpoint of PFS was adjusted to be assessed by the Investigator versus the IRC, and the secondary response endpoints will be assessed by the Investigator and IRC. • The adjustment of statistical assumptions results in an increase in the number of subjects to be enrolled, and an increase in the statistical power to detect a significant difference. The number of study centers is slightly increased to account for the increase in the sample size. • The exact IDH mutation variants to be tested for eligibility were listed to account for assay specifications. • The screening window for baseline scans was shortened from within 28 days to within 21 days prior to C1D1. • After 54 weeks (approximately 1 year), scans will be performed every 8 weeks instead of every 9 weeks, which will be the schedule for PFS and QOL assessments in follow-up as well. In addition to the above, minor formatting changes and clarifications were made that are not reflected in this document.
    05 Oct 2016
    The major changes included in Amendment 2 version 3.0: • Per FDA feedback, dose re-escalation will not be permitted in the event of life threatening Grade 4 AG-120 related toxicities. • Added clarification around qualifications for subjects who continue study treatment beyond disease progression, also per FDA feedback. • Other clarifications and corrections as outlined below were implemented for consistency. In addition to the above, minor formatting changes and clarifications were made that are not reflected in this document.
    01 Sep 2017
    The substantial changes in Amendment 3 version 4.0 included : • Added the Patient Global Impression of Change (PGI C) and the Patient Global Impression of Severity (PGI-S) as additional health related quality of life (HRQOL) measures throughout the protocol, per FDA’s request to ask some anchor based questions in addition to the European Organisation for Research and Treatment of Cancer - Quality Of Life Questionnaire – Core Questionnaire (EORTC QLQ C30) and the European Organisation for Research and Treatment of Cancer - Quality Of Life Questionnaire - Cholangiocarcinoma and Gallbladder Cancer Module (EORTC QLQ BIL21). • Added the following caveat to exclusion criterion 17 per the Agios Clinical Science Department: “Subjects with chronic HBV that is adequately suppressed per institutional practice will be permitted.” • Added exclusion criterion 20 per Germany’s request: “The exclusion of persons who have been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities is missing, cf. § 40 par. 1 cl. 3 no. 4 of the AMG.” • Added exclusion criterion 21 per Germany’s request: “The exclusion of persons dependent on the sponsor, investigator, or study site is missing, cf. § 40 par. 1 cl. 3 no. 3 b) and c) of the AMG in conjunction with section 1.61 of the ICH/GCP guideline topic E6.” • Updated text about taking the tablets with food per Agios’s updated, approved food language.
    04 Apr 2018
    The substantial changes included in Amendment 4 version 5.0: • Palliative radiotherapy to treat symptomatic non target lesions that cannot otherwise be medically managed will be permitted after disease progression has been verified and unblinding has occurred, and in the setting of continuation of AG-120 beyond disease progression, with Medical Monitor approval. • Information on drug-drug interactions has been revised, consistent with the AG-120 Investigator’s Brochure, Version 7.0. • As updated in the AG-120 Investigator’s Brochure, Version 7.0, AG-120 does not inhibit P-gp at clinically relevant concentrations. Therefore, exclusion criterion 10, excluding subjects who are taking P-gp transporter-sensitive substrate medications with a narrow therapeutic window, unless they can be transferred to other medications within ≥5 half-lives prior to administration of study treatment, has been removed. • Hematology, serum chemistry, circulating tumor DNA, and exploratory biomarker assessments are required at both the end of treatment (EOT) visit and at the cross over Cycle 1 Day 1 (C1D1) visit. If the cross over C1D1 visit occurs within 3 days of the EOT visit, these laboratory assessments need not be repeated. • The list of medications known to prolong the QT interval was expanded and updated.
    01 Mar 2019
    The substantial changes included in Amendment 5 version 6.0: • Added language to outline the management of subjects following study unblinding. • Added an exclusion criterion to exclude subjects with a known medical history of PML. • Added new Section 11.3 (Other Potential Risks) describing leukoencephalopathy and sensorimotor neuropathy/polyneuropathy as other potential risks associated with AG 120.

    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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