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    Clinical Trial Results:
    A Randomized, Multi-Center, Blinded, Placebo-Controlled Study of Mapatumumab ([HGS1012], a Fully Human Monoclonal Antibody to TRAIL-R1) in Combination with Sorafenib as a First-Line Therapy in Subjects with Advanced Hepatocellular Carcinoma

    Summary
    EudraCT number
    		 2010-020798-17
    Trial protocol
    		 DE  
    Global end of trial date
    29 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Dec 2018
    First version publication date
    12 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    200149
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.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
    24 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of mapatumumab in combination with sorafenib in subjects with advanced hepatocellular carcinoma.
    Protection of trial subjects
    A suggested pre-medication regimen of diphenhydramine and acetaminophen administered within 1 hour prior to the start of the mapatumumab/placebo dose in order minimize infusion/hypersensitivity reactions.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Romania: 38
    Country: Number of subjects enrolled
    Russian Federation: 20
    Country: Number of subjects enrolled
    Ukraine: 16
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    101
    EEA total number of subjects
    54
    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)
    61
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of mapatumumab in combination with sorafenib in participants with advanced hepatocellular carcinoma.

    Pre-assignment
    Screening details
    		 A total of 217 participants were screened of which 116 were screen failures and 101 participants were randomized in a ratio of 1:1 to any one of the 2 treatment arms. The study was conducted at 29 centers in 6 countries.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sorafenib+Placebo
    Arm description
    		 Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity
    Arm type
    		 Placebo

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was administered at a dose of 400 mg twice daily without food (at least 1 hour before or 2 hours after a meal).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Two hundred and fifty milliliters of normal saline was administered as intravenous infusion. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle.

    Arm title
    		 Sorafenib+Mapatumumab 30 mg/kg
    Arm description
    		 Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mapatumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Mapatumumab was available as a lyophilized formulation in sterile, single-use 10 milliliter (mL) vials containing 100 mg mapatumumab. Mapatumumab was administered at a dose of 30 mg/kg via the intravenous route on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Sorafenib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sorafenib was administered at a dose of 400 mg twice daily without food (at least 1 hour before or 2 hours after a meal).

    Number of subjects in period 1
    		Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Started
    51
    50
    Completed
    30
    31
    Not completed
    21
    19
         Clinical progression
    1
    -
         Adverse event, serious fatal
    4
    7
         Metastatic Hepatocellular Carcinoma
    1
    -
         Physician decision
    6
    1
         Consent withdrawn by subject
    6
    5
         Adverse event, non-fatal
    2
    3
         Lack of compliance
    1
    -
         Sponsor decision
    -
    1
         Lost to follow-up
    -
    1
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sorafenib+Placebo
    Reporting group description
    		 Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity

    Reporting group title
    Sorafenib+Mapatumumab 30 mg/kg
    Reporting group description
    		 Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity.

    Reporting group values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg Total
    Number of subjects
    		 51 50 101
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 28 33 61
        From 65-84 years
    		 23 17 40
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 60.8 ( 13.36 ) 60.0 ( 11.93 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 12 24 36
        Male
    		 39 26 65
    Race/Ethnicity, Customized
    Units: Subjects
        White/Caucasian – European Heritage
    		 48 48 96
        Asian–East Asian Heritage
    		 1 0 1
        Black or African American
    		 2 2 4

    End points

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    End points reporting groups
    Reporting group title
    Sorafenib+Placebo
    Reporting group description
    		 Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity

    Reporting group title
    Sorafenib+Mapatumumab 30 mg/kg
    Reporting group description
    		 Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity.

    Primary: Time to progression-Blinded independent central review (BICR) assessment

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    End point title
    		 Time to progression-Blinded independent central review (BICR) assessment
    End point description
    Time to progression is defined as the time from randomization to radiologic disease progression based on blinded independent review (BICR) of imaging scans using modified Response Evaluation Criteria in Solid Tumors assessment (mRECIST) for hepatocellular carcinoma. The primary analysis was performed using Kaplan Meier methods. The median time to progression is reported with one-sided 90% confidence interval. Analysis was performed on the modified Intent to Treat (mITT) Population which comprised of all randomized participants who received at least part of 1 dose of study agent (mapatumumab/placebo and/or sorafenib) with participants analyzed according to the groups to which they were randomized. 99999 indicates upper limit was not measurable as one-sided confidence interval is presented. Only those participants who had their BICR scans read were included in the analysis.
    End point type
    Primary
    End point timeframe
    Randomization to maximum of 24.1 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    48 [1]
    45 [2]
    Units: Months
        median (confidence interval 90%)
    5.6 (4.3 to 99999)
    4.1 (2.8 to 99999)
    Notes
    [1] - mITT Population
    [2] - mITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio comparing mapatumumab to placebo obtained from Cox proportional hazards model with covariate adjustment for Barcelona Clinic Liver Cancer and ECOG performance status.
    Comparison groups
    Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7382 [3]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.192
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.737
    Notes
    [3] - P-value for comparison of treatment groups obtained from stratified log-rank test-stratified by Barcelona Clinic Liver Cancer and Eastern Cooperative Oncology Group (ECOG) performance status.

    Secondary: Time to progression-Investigator assessment

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    End point title
    		 Time to progression-Investigator assessment
    End point description
    Time to progression is defined as the time from randomization to radiologic disease progression. The primary analysis was performed using Kaplan Meier methods based on application of mRECIST for hepatocellular carcinoma to investigator assessments. The median time to progression is reported with one-sided 90% confidence interval. 99999 indicates upper limit was not measurable as one-sided confidence interval is presented.
    End point type
    Secondary
    End point timeframe
    Randomization to maximum of 52.9 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [4]
    50 [5]
    Units: Months
        median (confidence interval 90%)
    8.3 (5.4 to 99999)
    6.4 (5.4 to 99999)
    Notes
    [4] - mITT Population
    [5] - mITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio comparing mapatumumab to placebo obtained from Cox proportional hazards model with covariate adjustment for Barcelona Clinic Liver Cancer and ECOG performance status.
    Comparison groups
    Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3156 [6]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.922
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.288
    Notes
    [6] - P-value for comparison of treatment groups obtained from stratified log-rank test-stratified by Barcelona Clinic Liver Cancer and Eastern Cooperative Oncology Group (ECOG) performance status.

    Secondary: Median overall survival

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    End point title
    		 Median overall survival
    End point description
    Overall survival is defined as time from randomization to death from any cause. The analysis was performed using Kaplan Meier methods. The median overall survival is reported with one-sided 90% confidence interval. 99999 indicates upper limit was not measurable as one-sided confidence interval is presented.
    End point type
    Secondary
    End point timeframe
    Randomization to maximum of 52.9 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [7]
    50 [8]
    Units: Months
        median (confidence interval 90%)
    10.1 (8.9 to 99999)
    10.0 (7.3 to 99999)
    Notes
    [7] - mITT Population
    [8] - mITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio comparing mapatumumab to placebo obtained from Cox proportional hazards model with covariate adjustment for Barcelona Clinic Liver Cancer and ECOG performance status.
    Comparison groups
    Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6121 [9]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.007
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.346
    Notes
    [9] - P-value for comparison of treatment groups obtained from stratified log-rank test-stratified by Barcelona Clinic Liver Cancer and ECOG performance status.

    Secondary: Progression free survival-BICR assessment

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    End point title
    		 Progression free survival-BICR assessment
    End point description
    Progression free survival is defined as time from randomization to radiologic disease progression or death from any cause. The analysis was performed using Kaplan Meier methods using BICR assessment of imaging scans. The median progression free survival is reported with one-sided 90% confidence interval. 99999 indicates upper limit was not measurable as one-sided confidence interval is presented. Only those participants who had their BICR scans read were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Randomization to maximum of 24.1 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    48 [10]
    45 [11]
    Units: Months
        median (confidence interval 90%)
    4.3 (3.1 to 99999)
    3.2 (2.7 to 99999)
    Notes
    [10] - mITT Population
    [11] - mITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio comparing Mapatumumab to placebo obtained from Cox proportional hazards model with covariate adjustment for Barcelona Clinic Liver Cancer and ECOG performance status.
    Comparison groups
    Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6925 [12]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.066
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.43
    Notes
    [12] - P-value for comparison of treatment groups obtained from stratified log-rank test - stratified by Barcelona Clinic Liver Cancer and ECOG performance status.

    Secondary: Progression free survival-Investigator assessment

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    End point title
    		 Progression free survival-Investigator assessment
    End point description
    Progression free survival is defined as time from randomization to radiologic disease progression or death from any cause. The analysis was performed using Kaplan Meier methods based on application of mRECIST for hepatocellular carcinoma to investigator assessments. The median progression free survival is reported with one-sided 90% confidence interval. 99999 indicates upper limit was not measurable as one-sided confidence interval is presented.
    End point type
    Secondary
    End point timeframe
    Randomization to maximum of 52.9 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [13]
    50 [14]
    Units: Months
        median (confidence interval 90%)
    5.4 (3.6 to 99999)
    4.0 (3.4 to 99999)
    Notes
    [13] - mITT Population
    [14] - mITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio comparing Mapatumumab to placebo obtained from Cox proportional hazards model with covariate adjustment for Barcelona Clinic Liver Cancer and ECOG performance status.
    Comparison groups
    Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3088 [15]
    Method
    		 Stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.909
    Confidence interval
         level
    		 90%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.191
    Notes
    [15] - P-value for comparison of treatment groups obtained from stratified log-rank test - stratified by Barcelona Clinic Liver Cancer and ECOG performance status.

    Secondary: Percentage of participants with objective response-BICR assessment

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    End point title
    		 Percentage of participants with objective response-BICR assessment
    End point description
    Objective response rate is defined as the percentage of participants with complete response+partial response according to mRECIST criteria for hepatocellular carcinoma using BICR assessment of imaging scans. The percentage of participants with objective response is reported along with 95% confidence interval. Only those participants who had their BICR scans read and having available assessment for best response were analyzed.
    End point type
    Secondary
    End point timeframe
    Randomization to maximum of 24.1 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    40 [16]
    39 [17]
    Units: Percentage of participants
        number (confidence interval 95%)
    12.5 (4.2 to 26.8)
    17.9 (7.5 to 33.5)
    Notes
    [16] - mITT Population
    [17] - mITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5458 [18]
    Method
    		 Fisher exact
    Parameter type
    		 Response rate difference
    Point estimate
    5.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.8
         upper limit
    		 26.6
    Notes
    [18] - Nominal P-value for comparison of treatment groups obtained from Fisher's exact test.

    Secondary: Percentage of participants with objective response-Investigator assessment

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    End point title
    		 Percentage of participants with objective response-Investigator assessment
    End point description
    Objective response rate is defined as the percentage of participants with complete response+partial response according to mRECIST criteria for hepatocellular carcinoma to investigator assessments. The percentage of participants with objective response is reported along with 95% confidence interval. Only those participants with available assessment for best response were analyzed.
    End point type
    Secondary
    End point timeframe
    Randomization to maximum of 52.9 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [19]
    48 [20]
    Units: Percentage of participants
        number (confidence interval 95%)
    7.8 (2.2 to 18.9)
    14.6 (6.1 to 27.8)
    Notes
    [19] - mITT Population
    [20] - mITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3479 [21]
    Method
    		 Fisher exact
    Parameter type
    		 Response rate difference
    Point estimate
    6.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 26.2
    Notes
    [21] - Nominal P-value for comparison of treatment groups obtained from Fisher's exact test.

    Secondary: Percentage of participants with disease control-BICR assessment

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    End point title
    		 Percentage of participants with disease control-BICR assessment
    End point description
    Disease control rate is the percentage of participants with complete response+partial response+stable disease according to mRECIST criteria for hepatocellular carcinoma. The end point was based on BICR assessment of imaging scans. The percentage of participants with disease control is presented along with 95% confidence interval. Only those participants who had their BICR scans read and having available assessment for best response were analyzed.
    End point type
    Secondary
    End point timeframe
    Randomization to maximum of 24.1 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    40 [22]
    39 [23]
    Units: Percentage of participants
        number (confidence interval 95%)
    92.5 (79.6 to 98.4)
    71.8 (55.1 to 85.0)
    Notes
    [22] - mITT Population
    [23] - mITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0198 [24]
    Method
    		 Fisher exact
    Parameter type
    		 Disease control rate difference
    Point estimate
    -20.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.8
         upper limit
    		 1.8
    Notes
    [24] - Nominal P-value for comparison of treatment groups obtained from Fisher's exact test.

    Secondary: Percentage of participants with disease control-Investigator assessment

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    End point title
    		 Percentage of participants with disease control-Investigator assessment
    End point description
    Disease control rate is the percentage of participants with complete response+partial response+stable disease according to mRECIST criteria for hepatocellular carcinoma to investigator assessments. The percentage of participants with disease control is presented along with 95% confidence interval. Only those participants with available assessment for best response were analyzed.
    End point type
    Secondary
    End point timeframe
    Randomization to maximum of 52.9 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [25]
    48 [26]
    Units: Percentage of participants
        number (confidence interval 95%)
    74.5 (60.4 to 85.7)
    68.8 (53.7 to 81.3)
    Notes
    [25] - mITT Population
    [26] - mITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6558 [27]
    Method
    		 Fisher exact
    Parameter type
    		 Disease control rate difference
    Point estimate
    -5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.4
         upper limit
    		 13.8
    Notes
    [27] - Nominal P-value for comparison of treatment groups obtained from Fisher's exact test.

    Secondary: Time to response-BICR assessment

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    End point title
    		 Time to response-BICR assessment
    End point description
    Time to response is defined as time from randomization to first partial response or complete response in responders only. Complete Response (CR): Disappearance of intratumoral arterial enhancement in all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions. Only responders were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Randomization to maximum of 24.1 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    5 [28]
    7 [29]
    Units: Days
        median (full range (min-max))
    44 (41 to 85)
    48 (41 to 188)
    Notes
    [28] - mITT Population
    [29] - mITT Population
    No statistical analyses for this end point

    Secondary: Duration of response-BICR assessment

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    End point title
    		 Duration of response-BICR assessment
    End point description
    Duration of response is defined as time from first PR or CR to radiologic disease progression; in responders only. CR: Disappearance of intratumoral arterial enhancement in all target lesions. PR: At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the Baseline sum of the diameters of target lesions. Progressive disease (PD): An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started. Only responders were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Randomization to maximum of 24.1 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    5 [30]
    7 [31]
    Units: Days
        median (full range (min-max))
    123 (55 to 325)
    127 (42 to 372)
    Notes
    [30] - mITT Population
    [31] - mITT Population
    No statistical analyses for this end point

    Secondary: Number of participants with treatment-emergent non-serious adverse events (AEs) and serious adverse events (SAEs)

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    End point title
    		 Number of participants with treatment-emergent non-serious adverse events (AEs) and serious adverse events (SAEs)
    End point description
    An AE is any unfavorable or unintended sign, symptom, or disease that is temporally associated with the use of a study agent but is not necessarily caused by the study agent. An SAE is an adverse event resulting in any of the following outcomes: death, life-threatening, inpatient hospitalization, prolongation of an existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect or other medically important events that may jeopardize the participant or may require intervention to prevent one of the other outcomes mentioned before. A treatment-emergent AE is an AE that emerged during treatment, having been absent pre-treatment, or worsened relative to the pre-treatment state. As-Treated Population comprised of participants who received at least part of 1 dose of study agent analyzed according to the treatment that they actually received.
    End point type
    Secondary
    End point timeframe
    Start of study treatment to maximum of 52.9 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [32]
    50 [33]
    Units: Participants
        Non-serious AEs|
    47
    49
        SAEs|
    27
    21
    Notes
    [32] - As-Treated Population
    [33] - As-Treated Population
    No statistical analyses for this end point

    Secondary: Number of participants with severe AEs

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    End point title
    		 Number of participants with severe AEs
    End point description
    An AE is any unfavorable or unintended sign, symptom, or disease that is temporally associated with the use of a study agent but is not necessarily caused by the study agent. Severity of AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0. Grade 1 represents mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 represents moderate; minimal, local or non-invasive intervention indicated. Grade 3 represents severe or medically significant but not immediately life -threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 represents life –threatening consequences; urgent intervention indicated. Grade 5 represents death related to AE. Severe AE is defined as AEs classified by investigator as severe (causing inability to carry out usual activities), life threatening or fatal using NCI-CTCAE Version 4.0 grading.
    End point type
    Secondary
    End point timeframe
    Start of study treatment to maximum of 52.9 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [34]
    50 [35]
    Units: Participants
    42
    38
    Notes
    [34] - As-Treated Population
    [35] - As-Treated Population
    No statistical analyses for this end point

    Secondary: Number of participants with worst toxicity grade-chemistry parameters

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    End point title
    		 Number of participants with worst toxicity grade-chemistry parameters
    End point description
    Blood samples were collected for the evaluation of following chemistry parameters: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), amylase, bilirubin, gamma glutamyl transferase (GGT), calcium, potassium, magnesium, albumin, sodium and creatinine. Laboratory toxicities were graded based on NCI-CTCAE version 4.0. Grade 1 represents mild; asymptomatic or mild symptoms. Grade 2 represents moderate; minimal, local or non-invasive intervention indicated. Grade 3 represents severe or medically significant but not immediately life -threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 represents life –threatening consequences; urgent intervention indicated. Number of participants with worst toxicity grades for any abnormalities observed in any chemistry parameters during study is presented. Only participants with data available at specified time points were analyzed (indicated by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Enrolment to maximum of 52.9 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [36]
    50 [37]
    Units: Participants
        ALT increased; Grade 0, n=51, 50|
    6
    4
        ALT increased; Grade 1, n=51, 50|
    30
    28
        ALT increased; Grade 2, n=51, 50|
    8
    9
        ALT increased; Grade 3, n=51, 50|
    7
    9
        ALT increased; Grade 4, n=51, 50|
    0
    0
        AST increased; Grade 0, n=51, 50|
    1
    1
        AST increased; Grade 1, n=51, 50|
    23
    20
        AST increased; Grade 2, n=51, 50|
    10
    9
        AST increased; Grade 3, n=51, 50|
    16
    20
        AST increased; Grade 4, n=51, 50|
    1
    0
        ALP increased; Grade 0, n=51, 50|
    4
    8
        ALP increased; Grade 1, n=51, 50|
    31
    26
        ALP increased; Grade 2, n=51, 50|
    11
    11
        ALP increased; Grade 3, n=51, 50|
    5
    5
        ALP increased; Grade 4, n=51, 50|
    0
    0
        Amylase increased; Grade 0, n=51, 50|
    30
    22
        Amylase increased; Grade 1, n=51, 50|
    9
    17
        Amylase increased; Grade 2, n=51, 50|
    5
    8
        Amylase increased; Grade 3, n=51, 50|
    6
    3
        Amylase increased; Grade 4, n=51, 50|
    1
    0
        Bilirubin increased; Grade 0, n=51, 50|
    12
    9
        Bilirubin increased; Grade 1, n=51, 50|
    15
    10
        Bilirubin increased; Grade 2, n=51, 50|
    17
    16
        Bilirubin increased; Grade 3, n=51, 50|
    7
    13
        Bilirubin increased; Grade 4, n=51, 50|
    0
    2
        GGT increased; Grade 0, n=51, 50|
    1
    2
        GGT increased; Grade 1, n=51, 50|
    10
    13
        GGT increased; Grade 2, n=51, 50|
    14
    15
        GGT increased; Grade 3, n=51, 50|
    23
    18
        GGT increased; Grade 4, n=51, 50|
    3
    2
        Hypercalcemia; Grade 0, n=49, 47|
    37
    37
        Hypercalcemia; Grade 1, n=49, 47|
    11
    9
        Hypercalcemia; Grade 2, n=49, 47|
    1
    0
        Hypercalcemia; Grade 3, n=49, 47|
    0
    0
        Hypercalcemia; Grade 4, n=49, 47|
    0
    1
        Hyperkalemia; Grade 0; n=51, 50|
    36
    27
        Hyperkalemia; Grade 1; n=51, 50|
    2
    3
        Hyperkalemia; Grade 2; n=51, 50|
    10
    10
        Hyperkalemia; Grade 3; n=51, 50|
    0
    7
        Hyperkalemia; Grade 4; n=51, 50|
    3
    3
        Hypermagnesemia; Grade 0; n=51, 50|
    29
    28
        Hypermagnesemia; Grade 1; n=51, 50|
    21
    19
        Hypermagnesemia; Grade 2; n=51, 50|
    0
    0
        Hypermagnesemia; Grade 3; n=51, 50|
    1
    3
        Hypermagnesemia; Grade 4; n=51, 50|
    0
    0
        Hypernatremia; Grade 0, n=51, 50|
    18
    18
        Hypernatremia; Grade 1, n=51, 50|
    16
    14
        Hypernatremia; Grade 2, n=51, 50|
    0
    0
        Hypernatremia; Grade 3, n=51, 50|
    16
    15
        Hypernatremia; Grade 4, n=51, 50|
    1
    3
        Hypoalbuminemia; Grade 0, n=51, 50|
    22
    26
        Hypoalbuminemia; Grade 1, n=51, 50|
    10
    9
        Hypoalbuminemia; Grade 2, n=51, 50|
    18
    14
        Hypoalbuminemia; Grade 3, n=51, 50|
    1
    1
        Hypoalbuminemia; Grade 4, n=51, 50|
    0
    0
        Hypocalcemia; Grade 0, n=50, 50|
    16
    15
        Hypocalcemia; Grade 1, n=50, 50|
    8
    14
        Hypocalcemia; Grade 2, n=50, 50|
    18
    19
        Hypocalcemia; Grade 3, n=50, 50|
    6
    2
        Hypocalcemia; Grade 4, n=50, 50|
    2
    0
        Hypokalemia; Grade 0, n=51, 50|
    37
    41
        Hypokalemia; Grade 1, n=51, 50|
    11
    8
        Hypokalemia; Grade 2, n=51, 50|
    0
    0
        Hypokalemia; Grade 3, n=51, 50|
    1
    1
        Hypokalemia; Grade 4, n=51, 50|
    2
    0
        Hypomagnesemia; Grade 0, n=51, 50|
    30
    35
        Hypomagnesemia; Grade 1, n=51, 50|
    19
    13
        Hypomagnesemia; Grade 2, n=51, 50|
    2
    1
        Hypomagnesemia; Grade 3, n=51, 50|
    0
    0
        Hypomagnesemia; Grade 4, n=51, 50|
    0
    1
        Hyponatremia; Grade 0, n=49, 47|
    40
    32
        Hyponatremia; Grade 1, n=49, 47|
    5
    10
        Hyponatremia; Grade 2, n=49, 47|
    2
    3
        Hyponatremia; Grade 3, n=49, 47|
    2
    2
        Hyponatremia; Grade 4, n=49, 47|
    0
    0
        Lipase increased; Grade 0, n=51, 50|
    19
    13
        Lipase increased; Grade 1, n=51, 50|
    5
    6
        Lipase increased; Grade 2, n=51, 50|
    8
    8
        Lipase increased; Grade 3, n=51, 50|
    16
    17
        Lipase increased; Grade 4, n=51, 50|
    3
    6
        Renal: Creatinine increased; Grade 0, n=51, 50|
    36
    34
        Renal: Creatinine increased; Grade 1, n=51, 50|
    7
    12
        Renal: Creatinine increased; Grade 2, n=51, 50|
    8
    3
        Renal: Creatinine increased; Grade 3, n=51, 50|
    0
    1
        Renal: Creatinine increased; Grade 4, n=51, 50|
    0
    0
    Notes
    [36] - As-Treated Population
    [37] - As-Treated Population
    No statistical analyses for this end point

    Secondary: Number of participants with worst toxicity grade-hematology parameters

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    End point title
    		 Number of participants with worst toxicity grade-hematology parameters
    End point description
    Blood samples were collected for assessment of the following hematology parameters: activated partial thromboplastin time (APTT), hemoglobin, international normalized ratio (INR), lymphocytes, neutrophils, platelets and white blood cells (WBC). Laboratory toxicities were graded based on the NCI-CTCAE version 4.0. Grade 1 represents mild; asymptomatic or mild symptoms. Grade 2 represents moderate; minimal, local or non-invasive intervention indicated. Grade 3 represents severe or medically significant but not immediately life -threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 represents life –threatening consequences; urgent intervention indicated. Number of participants with worst toxicity grades for any abnormalities observed in any hematology parameters during the study is presented. Only participants with data available at specified time points were analyzed (indicated by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Enrolment to maximum of 52.9 months
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [38]
    50 [39]
    Units: Participants
        APTT prolonged; Grade 0, n=51, 50|
    24
    22
        APTT prolonged; Grade 1, n=51, 50|
    19
    24
        APTT prolonged; Grade 2, n=51, 50|
    6
    2
        APTT prolonged; Grade 3, n=51, 50|
    2
    2
        APTT prolonged; Grade 4, n=51, 50|
    0
    0
        Anemia; Grade 0, n=51, 50|
    13
    9
        Anemia; Grade 1, n=51, 50|
    23
    22
        Anemia; Grade 2, n=51, 50|
    9
    16
        Anemia; Grade 3, n=51, 50|
    6
    3
        Anemia; Grade 4, n=51, 50|
    0
    0
        Hemoglobin increased; Grade 0, n=46, 44|
    46
    44
        Hemoglobin increased; Grade 1, n=46, 44|
    0
    0
        Hemoglobin increased; Grade 2, n=46, 44|
    0
    0
        Hemoglobin increased; Grade 3, n=46, 44|
    0
    0
        Hemoglobin increased; Grade 4, n=46, 44|
    0
    0
        INR increased; Grade 0, n=51, 50|
    2
    3
        INR increased; Grade 1, n=51, 50|
    35
    30
        INR increased; Grade 2, n=51, 50|
    12
    14
        INR increased; Grade 3, n=51, 50|
    2
    3
        INR increased; Grade 4, n=51, 50|
    0
    0
        Lymphocytes decreased; Grade 0, n=51, 50|
    24
    23
        Lymphocytes decreased; Grade 1, n=51, 50|
    3
    0
        Lymphocytes decreased; Grade 2, n=51, 50|
    16
    18
        Lymphocytes decreased; Grade 3, n=51, 50|
    8
    8
        Lymphocytes decreased; Grade 4, n=51, 50|
    0
    1
        Lymphocytes increased; Grade 0, n=51, 49|
    49
    45
        Lymphocytes increased; Grade 1, n=51, 49|
    0
    0
        Lymphocytes increased; Grade 2, n=51, 49|
    2
    4
        Lymphocytes increased; Grade 3, n=51, 49|
    0
    0
        Lymphocytes increased; Grade 4, n=51, 49|
    0
    0
        Neutrophil count decreased; Grade 0, n=51, 50|
    39
    37
        Neutrophil count decreased; Grade 1, n=51, 50|
    3
    2
        Neutrophil count decreased; Grade 2, n=51, 50|
    8
    7
        Neutrophil count decreased; Grade 3, n=51, 50|
    1
    1
        Neutrophil count decreased; Grade 4, n=51, 50|
    0
    3
        Platelets decreased; Grade 0, n=51, 50|
    21
    21
        Platelets decreased; Grade 1, n=51, 50|
    12
    16
        Platelets decreased; Grade 2, n=51, 50|
    10
    6
        Platelets decreased; Grade 3, n=51, 50|
    7
    5
        Platelets decreased; Grade 4, n=51, 50|
    1
    2
        WBC decreased; Grade 0, n=51, 50|
    33
    30
        WBC decreased; Grade 1, n=51, 50|
    10
    12
        WBC decreased; Grade 2, n=51, 50|
    8
    5
        WBC decreased; Grade 3, n=51, 50|
    0
    3
        WBC decreased; Grade 4, n=51, 50|
    0
    0
    Notes
    [38] - As-Treated Population
    [39] - As-Treated Population
    No statistical analyses for this end point

    Secondary: Number of participants with anti-mapatumumab antibodies

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    End point title
    		 Number of participants with anti-mapatumumab antibodies [40]
    End point description
    Blood samples were collected for the assessment of serum antibodies. The presence of anti-mapatumumab antibodies was assessed using a validated electrochemiluminescent immunoassay. The assay incorporated a tiered testing approach which used screening and confirmation steps. The anti-drug antibody (ADA) confirmed positive participants were separated into transient or persistent antibody positives. Persistent positive refers to positive immunogenic response at 2 or more assessments or at the final assessment. Transient positive refers to positive immunogenic response at only 1 assessment and negative at the final assessment. Only participants with an available immunogenicity assay were analyzed.
    End point type
    Secondary
    End point timeframe
    Randomization to maximum of 24.1 months
    Notes
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only Sorafenib+Mapatumumab 30 mg/kg was included in the analysis.
    End point values
    		 Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    49 [41]
    Units: Participants
        Transient positive|
    6
        Persistent positive|
    7
        Negative|
    36
    Notes
    [41] - As-Treated Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP)

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    End point title
    		 Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP)
    End point description
    SBP and DBP were obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. 99999 indicates data was not available due to insufficient number of participants. Only those participants with data available at specified time points were analyzed (indicated by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [42]
    50 [43]
    Units: Millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        SBP; Cycle 2 Day 1, n=46, 44|
    2.3 ( 14.13 )
    2.2 ( 18.64 )
        SBP; CYCLE 3 DAY 1, n=39, 35|
    6.0 ( 16.81 )
    4.1 ( 13.66 )
        SBP; CYCLE 4; DAY 1; n=33, 32|
    2.1 ( 15.57 )
    5.3 ( 13.52 )
        SBP; CYCLE 5 DAY 1; n=27, 26|
    1.7 ( 13.05 )
    4.9 ( 16.42 )
        SBP; CYCLE 6 DAY 1; n=24, 22|
    1.3 ( 12.14 )
    5.1 ( 13.40 )
        SBP; CYCLE 7 DAY 1; n=24, 22|
    -0.8 ( 11.02 )
    5.0 ( 12.78 )
        SBP; CYCLE 8 DAY 1; n=22, 21|
    -1.6 ( 11.48 )
    5.2 ( 14.83 )
        SBP; CYCLE 9 DAY 1; n=19, 16|
    1.2 ( 16.37 )
    7.8 ( 13.98 )
        SBP; CYCLE 10 DAY 1; n=18, 16|
    1.4 ( 16.57 )
    4.5 ( 16.19 )
        SBP; CYCLE 11 DAY 1; n=16, 15|
    2.4 ( 18.82 )
    5.2 ( 18.32 )
        SBP; CYCLE 12 DAY 1; n=15, 13|
    2.7 ( 12.34 )
    5.2 ( 14.73 )
        SBP; CYCLE 13 DAY 1; n=13, 12|
    2.3 ( 12.26 )
    3.0 ( 14.91 )
        SBP; CYCLE 14 DAY 1; n=12, 12|
    -1.0 ( 10.13 )
    4.0 ( 14.63 )
        SBP; CYCLE 15 DAY 1; n=10, 9|
    1.4 ( 8.21 )
    6.7 ( 21.05 )
        SBP; CYCLE 16 DAY 1; n=10, 9|
    1.8 ( 5.79 )
    7.9 ( 15.28 )
        SBP; CYCLE 17 DAY 1; n=8, 8|
    1.3 ( 11.95 )
    10.1 ( 17.70 )
        SBP; CYCLE 18 DAY 1; n=8, 8|
    -2.0 ( 9.26 )
    9.5 ( 19.41 )
        SBP; CYCLE 19 DAY 1; n=6, 8|
    -4.8 ( 14.93 )
    8.4 ( 20.68 )
        SBP; CYCLE 20 DAY 1; n=6, 8|
    1.2 ( 9.13 )
    5.8 ( 19.33 )
        SBP; CYCLE 21 DAY 1; n=4, 8|
    2.5 ( 8.23 )
    10.0 ( 21.23 )
        SBP; CYCLE 22 DAY 1; n=4, 8|
    6.0 ( 10.55 )
    5.5 ( 14.11 )
        SBP; CYCLE 23 DAY 1; n=4, 8|
    -1.0 ( 10.80 )
    12.9 ( 20.15 )
        SBP; CYCLE 24 DAY 1; n=4, 8|
    -3.0 ( 6.38 )
    5.6 ( 19.86 )
        SBP; CYCLE 25 DAY 1; n=4, 8|
    1.3 ( 12.20 )
    11.3 ( 20.08 )
        SBP; CYCLE 26 DAY 1; n=4, 7|
    6.0 ( 11.89 )
    9.3 ( 22.92 )
        SBP; CYCLE 27 DAY 1; n=4, 5|
    3.3 ( 10.44 )
    8.4 ( 18.04 )
        SBP; CYCLE 28 DAY 1; n=4, 5|
    3.3 ( 7.41 )
    5.2 ( 20.19 )
        SBP; CYCLE 29 DAY 1; n=3, 4|
    -0.7 ( 14.29 )
    3.3 ( 24.27 )
        SBP; CYCLE 30 DAY 1; n=3, 4|
    2.7 ( 6.43 )
    -2.3 ( 13.43 )
        SBP; CYCLE 31 DAY 1; n=3, 4|
    -3.0 ( 11.79 )
    2.0 ( 23.15 )
        SBP; CYCLE 32 DAY 1; n=3, 4|
    5.0 ( 4.58 )
    3.3 ( 16.40 )
        SBP; CYCLE 33 DAY 1; n=2, 4|
    0.0 ( 14.14 )
    -5.3 ( 19.96 )
        SBP; CYCLE 34 DAY 1; n=1, 4|
    13.0 ( 99999 )
    -5.3 ( 10.66 )
        SBP; CYCLE 35 DAY 1; n=0, 4|
    99999 ( 99999 )
    -5.0 ( 15.81 )
        SBP; CYCLE 36 DAY 1; n=0, 4|
    99999 ( 99999 )
    -1.5 ( 13.00 )
        SBP; CYCLE 37 DAY 1; n=0, 3|
    99999 ( 99999 )
    -6.0 ( 23.52 )
        SBP; CYCLE 38 DAY 1; n=0, 3|
    99999 ( 99999 )
    -1.3 ( 18.04 )
        SBP; CYCLE 39 DAY 1; n=0, 3|
    99999 ( 99999 )
    -4.3 ( 21.01 )
        SBP; CYCLE 40 DAY 1; n=0, 2|
    99999 ( 99999 )
    -12.5 ( 10.61 )
        SBP; CYCLE 41 DAY 1; n=0, 2|
    99999 ( 99999 )
    -15.0 ( 21.21 )
        SBP; CYCLE 42 DAY 1; n=0, 2|
    99999 ( 99999 )
    -7.5 ( 17.68 )
        SBP; CYCLE 43 DAY 1; n=0, 2|
    99999 ( 99999 )
    -17.5 ( 17.68 )
        SBP; CYCLE 44 DAY 1; n=0, 2|
    99999 ( 99999 )
    -10.0 ( 14.14 )
        SBP; CYCLE 45 DAY 1; n=0, 2|
    99999 ( 99999 )
    -17.5 ( 17.68 )
        SBP; CYCLE 46 DAY 1; n=0, 2|
    99999 ( 99999 )
    -5.0 ( 21.21 )
        SBP; CYCLE 47 DAY 1; n=0, 2|
    99999 ( 99999 )
    -17.5 ( 17.68 )
        SBP; CYCLE 48 DAY 1; n=0, 2|
    99999 ( 99999 )
    -5.0 ( 21.21 )
        SBP; CYCLE 49 DAY 1; n=0, 2|
    99999 ( 99999 )
    -17.5 ( 17.68 )
        SBP; CYCLE 50 DAY 1; n=0, 2|
    99999 ( 99999 )
    -15.0 ( 21.21 )
        SBP; CYCLE 51 DAY 1; n=0, 2|
    99999 ( 99999 )
    -10.0 ( 21.21 )
        SBP; CYCLE 52 DAY 1; n=0, 2|
    99999 ( 99999 )
    -17.5 ( 17.68 )
        SBP; CYCLE 53 DAY 1; n=0, 2|
    99999 ( 99999 )
    -20.0 ( 14.14 )
        SBP; CYCLE 54 DAY 1; n=0, 2|
    99999 ( 99999 )
    -10.0 ( 14.14 )
        SBP; CYCLE 55 DAY 1; n=0, 1|
    99999 ( 99999 )
    -30.0 ( 99999 )
        SBP; CYCLE 56 DAY 1; n=0, 1|
    99999 ( 99999 )
    -30.0 ( 99999 )
        SBP; CYCLE 57 DAY 1; n=0, 1|
    99999 ( 99999 )
    -30.0 ( 99999 )
        SBP; CYCLE 58 DAY 1; n=0, 1|
    99999 ( 99999 )
    -25.0 ( 99999 )
        SBP; CYCLE 59 DAY 1; n=0, 1|
    99999 ( 99999 )
    -20.0 ( 99999 )
        SBP; CYCLE 60 DAY 1; n=0, 1|
    99999 ( 99999 )
    -30.0 ( 99999 )
        SBP; CYCLE 61 DAY 1; n=0, 1|
    99999 ( 99999 )
    -25.0 ( 99999 )
        SBP; CYCLE 62 DAY 1; n=0, 1|
    99999 ( 99999 )
    -23.0 ( 99999 )
        SBP; CYCLE 63 DAY 1; n=0, 1|
    99999 ( 99999 )
    -28.0 ( 99999 )
        SBP; CYCLE 64 DAY 1; n=0, 1|
    99999 ( 99999 )
    -25.0 ( 99999 )
        SBP; CYCLE 65 DAY 1; n=0, 1|
    99999 ( 99999 )
    -26.0 ( 99999 )
        SBP; CYCLE 66 DAY 1; n=0, 1|
    99999 ( 99999 )
    -32.0 ( 99999 )
        SBP; CYCLE 67 DAY 1; n=0, 1|
    99999 ( 99999 )
    -33.0 ( 99999 )
        SBP; CYCLE 68 DAY 1; n=0, 1|
    99999 ( 99999 )
    -32.0 ( 99999 )
        SBP; CYCLE 69 DAY 1; n=0, 1|
    99999 ( 99999 )
    -31.0 ( 99999 )
        SBP; CYCLE 70 DAY 1; n=0, 1|
    99999 ( 99999 )
    -25.0 ( 99999 )
        SBP; CYCLE 71 DAY 1; n=0, 1|
    99999 ( 99999 )
    -28.0 ( 99999 )
        SBP; CYCLE 72 DAY 1; n=0, 1|
    99999 ( 99999 )
    -30.0 ( 99999 )
        SBP; CYCLE 73 DAY 1; n=0, 1|
    99999 ( 99999 )
    -27.0 ( 99999 )
        SBP; CYCLE 74 DAY 1; n=0, 1|
    99999 ( 99999 )
    -30.0 ( 99999 )
        SBP; CYCLE 75 DAY 1; n=0, 1|
    99999 ( 99999 )
    -28.0 ( 99999 )
        DBP; Cycle 2 Day 1, n=46, 44|
    -0.6 ( 8.51 )
    0.7 ( 9.82 )
        DBP; CYCLE 3 DAY 1, n=39, 35|
    2.1 ( 7.20 )
    1.4 ( 8.90 )
        DBP; CYCLE 4; DAY 1; n=33, 32|
    1.8 ( 10.52 )
    2.4 ( 8.22 )
        DBP; CYCLE 5 DAY 1; n=27, 26|
    0.9 ( 10.00 )
    3.0 ( 15.49 )
        DBP; CYCLE 6 DAY 1; n=24, 22|
    3.5 ( 8.32 )
    1.2 ( 10.21 )
        DBP; CYCLE 7 DAY 1; n=24, 22|
    0.5 ( 8.57 )
    2.0 ( 7.42 )
        DBP; CYCLE 8 DAY 1; n=22, 21|
    0.5 ( 7.37 )
    2.3 ( 8.27 )
        DBP; CYCLE 9 DAY 1; n=19, 16|
    2.7 ( 8.67 )
    4.1 ( 9.15 )
        DBP; CYCLE 10 DAY 1; n=18, 16|
    2.7 ( 9.81 )
    2.4 ( 7.50 )
        DBP; CYCLE 11 DAY 1; n=16, 15|
    -0.1 ( 10.25 )
    0.9 ( 9.49 )
        DBP; CYCLE 12 DAY 1; n=15, 13|
    0.6 ( 7.80 )
    2.1 ( 8.65 )
        DBP; CYCLE 13 DAY 1; n=13, 12|
    -2.2 ( 6.07 )
    -2.7 ( 7.64 )
        DBP; CYCLE 14 DAY 1; n=12, 12|
    0.7 ( 6.87 )
    3.3 ( 11.78 )
        DBP; CYCLE 15 DAY 1; n=10, 9|
    2.1 ( 8.49 )
    1.1 ( 12.97 )
        DBP; CYCLE 16 DAY 1; n=10, 9|
    0.1 ( 7.68 )
    0.1 ( 11.88 )
        DBP; CYCLE 17 DAY 1; n=8, 8|
    -1.5 ( 8.23 )
    5.0 ( 7.15 )
        DBP; CYCLE 18 DAY 1; n=8, 8|
    0.1 ( 6.47 )
    3.4 ( 11.15 )
        DBP; CYCLE 19 DAY 1; n=6, 8|
    -2.5 ( 5.82 )
    5.5 ( 12.17 )
        DBP; CYCLE 20 DAY 1; n=6, 8|
    2.3 ( 3.83 )
    3.5 ( 10.09 )
        DBP; CYCLE 21 DAY 1; n=4, 8|
    0.8 ( 2.99 )
    2.8 ( 11.96 )
        DBP; CYCLE 22 DAY 1; n=4, 8|
    -1.8 ( 3.95 )
    3.8 ( 7.63 )
        DBP; CYCLE 23 DAY 1; n=4, 8|
    2.5 ( 4.20 )
    5.1 ( 12.12 )
        DBP; CYCLE 24 DAY 1; n=4, 8|
    -3.0 ( 11.17 )
    2.5 ( 12.99 )
        DBP; CYCLE 25 DAY 1; n=4, 8|
    3.5 ( 3.11 )
    2.5 ( 15.80 )
        DBP; CYCLE 26 DAY 1; n=4, 7|
    0.0 ( 3.27 )
    4.0 ( 14.57 )
        DBP; CYCLE 27 DAY 1; n=4, 5|
    -3.3 ( 4.72 )
    3.6 ( 11.67 )
        DBP; CYCLE 28 DAY 1; n=4, 5|
    2.0 ( 1.63 )
    4.0 ( 14.21 )
        DBP; CYCLE 29 DAY 1; n=3, 4|
    1.7 ( 10.41 )
    -2.0 ( 7.26 )
        DBP; CYCLE 30 DAY 1; n=3, 4|
    -0.3 ( 4.04 )
    -2.3 ( 6.60 )
        DBP; CYCLE 31 DAY 1; n=3, 4|
    6.7 ( 7.64 )
    0.5 ( 11.45 )
        DBP; CYCLE 32 DAY 1; n=3, 4|
    2.7 ( 7.51 )
    -0.3 ( 7.76 )
        DBP; CYCLE 33 DAY 1; n=2, 4|
    0.5 ( 7.78 )
    -2.5 ( 8.50 )
        DBP; CYCLE 34 DAY 1; n=1, 4|
    -15.0 ( 99999 )
    -1.8 ( 6.99 )
        DBP; CYCLE 35 DAY 1; n=0, 4|
    99999 ( 99999 )
    -3.0 ( 8.12 )
        DBP; CYCLE 36 DAY 1; n=0, 4|
    99999 ( 99999 )
    1.5 ( 3.00 )
        DBP; CYCLE 37 DAY 1; n=0, 3|
    99999 ( 99999 )
    1.7 ( 12.58 )
        DBP; CYCLE 38 DAY 1; n=0, 3|
    99999 ( 99999 )
    -2.3 ( 6.81 )
        DBP; CYCLE 39 DAY 1; n=0, 3|
    99999 ( 99999 )
    0.3 ( 10.50 )
        DBP; CYCLE 40 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.0 ( 0.00 )
        DBP; CYCLE 41 DAY 1; n=0, 2|
    99999 ( 99999 )
    -7.5 ( 3.54 )
        DBP; CYCLE 42 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.0 ( 0.00 )
        DBP; CYCLE 43 DAY 1; n=0, 2|
    99999 ( 99999 )
    -7.5 ( 3.54 )
        DBP; CYCLE 44 DAY 1; n=0, 2|
    99999 ( 99999 )
    -2.5 ( 3.54 )
        DBP; CYCLE 45 DAY 1; n=0, 2|
    99999 ( 99999 )
    -7.5 ( 3.54 )
        DBP; CYCLE 46 DAY 1; n=0, 2|
    99999 ( 99999 )
    -5.0 ( 7.07 )
        DBP; CYCLE 47 DAY 1; n=0, 2|
    99999 ( 99999 )
    -3.0 ( 24.04 )
        DBP; CYCLE 48 DAY 1; n=0, 2|
    99999 ( 99999 )
    -5.0 ( 7.07 )
        DBP; CYCLE 49 DAY 1; n=0, 2|
    99999 ( 99999 )
    -12.5 ( 3.54 )
        DBP; CYCLE 50 DAY 1; n=0, 2|
    99999 ( 99999 )
    -5.0 ( 7.07 )
        DBP; CYCLE 51 DAY 1; n=0, 2|
    99999 ( 99999 )
    -5.0 ( 7.07 )
        DBP; CYCLE 52 DAY 1; n=0, 2|
    99999 ( 99999 )
    -10.0 ( 7.07 )
        DBP; CYCLE 53 DAY 1; n=0, 2|
    99999 ( 99999 )
    -7.5 ( 3.54 )
        DBP; CYCLE 54 DAY 1; n=0, 2|
    99999 ( 99999 )
    -5.0 ( 7.07 )
        DBP; CYCLE 55 DAY 1; n=0, 1|
    99999 ( 99999 )
    -15.0 ( 99999 )
        DBP; CYCLE 56 DAY 1; n=0, 1|
    99999 ( 99999 )
    -10.0 ( 99999 )
        DBP; CYCLE 57 DAY 1; n=0, 1|
    99999 ( 99999 )
    -15.0 ( 99999 )
        DBP; CYCLE 58 DAY 1; n=0, 1|
    99999 ( 99999 )
    -10.0 ( 99999 )
        DBP; CYCLE 59 DAY 1; n=0, 1|
    99999 ( 99999 )
    -10.0 ( 99999 )
        DBP; CYCLE 60 DAY 1; n=0, 1|
    99999 ( 99999 )
    -15.0 ( 99999 )
        DBP; CYCLE 61 DAY 1; n=0, 1|
    99999 ( 99999 )
    -15.0 ( 99999 )
        DBP; CYCLE 62 DAY 1; n=0, 1|
    99999 ( 99999 )
    -13.0 ( 99999 )
        DBP; CYCLE 63 DAY 1; n=0, 1|
    99999 ( 99999 )
    -15.0 ( 99999 )
        DBP; CYCLE 64 DAY 1; n=0, 1|
    99999 ( 99999 )
    -14.0 ( 99999 )
        DBP; CYCLE 65 DAY 1; n=0, 1|
    99999 ( 99999 )
    -15.0 ( 99999 )
        DBP; CYCLE 66 DAY 1; n=0, 1|
    99999 ( 99999 )
    -17.0 ( 99999 )
        DBP; CYCLE 67 DAY 1; n=0, 1|
    99999 ( 99999 )
    -14.0 ( 99999 )
        DBP; CYCLE 68 DAY 1; n=0, 1|
    99999 ( 99999 )
    -15.0 ( 99999 )
        DBP; CYCLE 69 DAY 1; n=0, 1|
    99999 ( 99999 )
    -17.0 ( 999999 )
        DBP; CYCLE 70 DAY 1; n=0, 1|
    99999 ( 99999 )
    -16.0 ( 99999 )
        DBP; CYCLE 71 DAY 1; n=0, 1|
    99999 ( 99999 )
    -15.0 ( 99999 )
        DBP; CYCLE 72 DAY 1; n=0, 1|
    99999 ( 99999 )
    -19.0 ( 99999 )
        DBP; CYCLE 73 DAY 1; n=0, 1|
    99999 ( 99999 )
    -15.0 ( 99999 )
        DBP; CYCLE 74 DAY 1; n=0, 1|
    99999 ( 99999 )
    -14.0 ( 99999 )
        DBP; CYCLE 75 DAY 1; n=0, 1|
    99999 ( 99999 )
    -17.0 ( 99999 )
    Notes
    [42] - As-Treated Population
    [43] - As-Treated Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in heart rate

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    End point title
    		 Change from Baseline in heart rate
    End point description
    Heart rate was obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. 99999 indicates data was not available due to insufficient number of participants. Only those participants with data available at specified time points were analyzed (indicated by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [44]
    50 [45]
    Units: Beats per minute
    arithmetic mean (standard deviation)
        Cycle 2 Day 1, n=46, 44|
    0.7 ( 8.32 )
    -1.8 ( 9.42 )
        CYCLE 3 DAY 1, n=39, 35|
    1.7 ( 7.69 )
    -1.6 ( 6.78 )
        CYCLE 4; DAY 1; n=33, 32|
    1.0 ( 10.09 )
    1.9 ( 7.61 )
        CYCLE 5 DAY 1; n=27, 26|
    1.3 ( 9.45 )
    0.2 ( 10.65 )
        CYCLE 6 DAY 1; n=24, 22|
    0.2 ( 10.37 )
    0.3 ( 8.31 )
        CYCLE 7 DAY 1; n=24, 22|
    2.0 ( 8.40 )
    -1.8 ( 8.80 )
        CYCLE 8 DAY 1; n=22, 21|
    0.5 ( 7.70 )
    -0.4 ( 7.30 )
        CYCLE 9 DAY 1; n=19, 16|
    2.1 ( 8.04 )
    0.3 ( 7.10 )
        CYCLE 10 DAY 1; n=18, 16|
    2.3 ( 8.62 )
    0.5 ( 13.54 )
        CYCLE 11 DAY 1; n=16, 15|
    -0.8 ( 6.51 )
    -2.0 ( 9.88 )
        CYCLE 12 DAY 1; n=15, 13|
    -0.7 ( 4.28 )
    0.2 ( 9.92 )
        CYCLE 13 DAY 1; n=13, 12|
    0.9 ( 5.47 )
    0.9 ( 9.77 )
        CYCLE 14 DAY 1; n=12, 12|
    1.6 ( 7.03 )
    3.1 ( 10.25 )
        CYCLE 15 DAY 1; n=10, 9|
    5.6 ( 12.39 )
    2.2 ( 8.51 )
        CYCLE 16 DAY 1; n=10, 9|
    3.3 ( 7.06 )
    0.7 ( 9.12 )
        CYCLE 17 DAY 1; n=8, 8|
    3.1 ( 7.20 )
    1.6 ( 10.23 )
        CYCLE 18 DAY 1; n=8, 8|
    6.4 ( 8.68 )
    -0.5 ( 6.12 )
        CYCLE 19 DAY 1; n=6, 8|
    -2.5 ( 10.54 )
    0.5 ( 9.78 )
        CYCLE 20 DAY 1; n=6, 8|
    0.3 ( 6.38 )
    0.9 ( 7.36 )
        CYCLE 21 DAY 1; n=4, 8|
    0.5 ( 1.91 )
    -1.4 ( 10.28 )
        CYCLE 22 DAY 1; n=4, 8|
    0.5 ( 1.91 )
    3.0 ( 13.41 )
        CYCLE 23 DAY 1; n=4, 8|
    -3.8 ( 6.02 )
    2.9 ( 9.76 )
        CYCLE 24 DAY 1; n=4, 8|
    -2.5 ( 5.97 )
    2.9 ( 10.92 )
        CYCLE 25 DAY 1; n=4, 8|
    -1.8 ( 2.06 )
    0.3 ( 11.13 )
        CYCLE 26 DAY 1; n=4, 7|
    -0.5 ( 1.91 )
    1.6 ( 11.43 )
        CYCLE 27 DAY 1; n=4, 5|
    -2.0 ( 2.31 )
    2.4 ( 11.70 )
        CYCLE 28 DAY 1; n=4, 5|
    -1.8 ( 5.56 )
    -0.2 ( 13.68 )
        CYCLE 29 DAY 1; n=3, 4|
    0.0 ( 4.00 )
    -3.8 ( 6.45 )
        CYCLE 30 DAY 1; n=3, 4|
    0.3 ( 2.08 )
    -9.3 ( 5.25 )
        CYCLE 31 DAY 1; n=3, 4|
    -2.7 ( 6.43 )
    -0.8 ( 8.77 )
        CYCLE 32 DAY 1; n=3, 4|
    2.0 ( 4.00 )
    -3.8 ( 6.65 )
        CYCLE 33 DAY 1; n=2, 4|
    -2.0 ( 0.00 )
    -5.5 ( 7.55 )
        CYCLE 34 DAY 1; n=1, 4|
    0.0 ( 99999 )
    -3.5 ( 4.43 )
        CYCLE 35 DAY 1; n=0, 4|
    99999 ( 99999 )
    -4.8 ( 4.99 )
        CYCLE 36 DAY 1; n=0, 4|
    99999 ( 99999 )
    -8.0 ( 8.37 )
        CYCLE 37 DAY 1; n=0, 3|
    99999 ( 99999 )
    -9.3 ( 6.11 )
        CYCLE 38 DAY 1; n=0, 3|
    99999 ( 99999 )
    -2.0 ( 6.93 )
        CYCLE 39 DAY 1; n=0, 3|
    99999 ( 99999 )
    -4.7 ( 6.43 )
        CYCLE 40 DAY 1; n=0, 2|
    99999 ( 99999 )
    -4.0 ( 8.49 )
        CYCLE 41 DAY 1; n=0, 2|
    99999 ( 99999 )
    -7.0 ( 9.90 )
        CYCLE 42 DAY 1; n=0, 2|
    99999 ( 99999 )
    -2.0 ( 8.49 )
        CYCLE 43 DAY 1; n=0, 2|
    99999 ( 99999 )
    -6.0 ( 14.14 )
        CYCLE 44 DAY 1; n=0, 2|
    99999 ( 99999 )
    -2.0 ( 14.14 )
        CYCLE 45 DAY 1; n=0, 2|
    99999 ( 99999 )
    -4.0 ( 14.14 )
        CYCLE 46 DAY 1; n=0, 2|
    99999 ( 99999 )
    -3.0 ( 18.38 )
        CYCLE 47 DAY 1; n=0, 2|
    99999 ( 99999 )
    -2.0 ( 14.14 )
        CYCLE 48 DAY 1; n=0, 2|
    99999 ( 99999 )
    -3.0 ( 15.56 )
        CYCLE 49 DAY 1; n=0, 2|
    99999 ( 99999 )
    -9.0 ( 9.90 )
        CYCLE 50 DAY 1; n=0, 2|
    99999 ( 99999 )
    -5.0 ( 9.90 )
        CYCLE 51 DAY 1; n=0, 2|
    99999 ( 99999 )
    -5.0 ( 12.73 )
        CYCLE 52 DAY 1; n=0, 2|
    99999 ( 99999 )
    -8.0 ( 11.31 )
        CYCLE 53 DAY 1; n=0, 2|
    99999 ( 99999 )
    -10.0 ( 2.83 )
        CYCLE 54 DAY 1; n=0, 2|
    99999 ( 99999 )
    -2.0 ( 8.49 )
        CYCLE 55 DAY 1; n=0, 1|
    99999 ( 99999 )
    -10.0 ( 99999 )
        CYCLE 56 DAY 1; n=0, 1|
    99999 ( 99999 )
    -12.0 ( 99999 )
        CYCLE 57 DAY 1; n=0, 1|
    99999 ( 99999 )
    -10.0 ( 99999 )
        CYCLE 58 DAY 1; n=0, 1|
    99999 ( 99999 )
    -8.0 ( 99999 )
        CYCLE 59 DAY 1; n=0, 1|
    99999 ( 99999 )
    -12.0 ( 99999 )
        CYCLE 60 DAY 1; n=0, 1|
    99999 ( 99999 )
    -10.0 ( 99999 )
        CYCLE 61 DAY 1; n=0, 1|
    99999 ( 99999 )
    -12.0 ( 99999 )
        CYCLE 62 DAY 1; n=0, 1|
    99999 ( 99999 )
    -14.0 ( 99999 )
        CYCLE 63 DAY 1; n=0, 1|
    99999 ( 99999 )
    -15.0 ( 99999 )
        CYCLE 64 DAY 1; n=0, 1|
    99999 ( 99999 )
    -10.0 ( 99999 )
        CYCLE 65 DAY 1; n=0, 1|
    99999 ( 99999 )
    -11.0 ( 99999 )
        CYCLE 66 DAY 1; n=0, 1|
    99999 ( 99999 )
    -12.0 ( 99999 )
        CYCLE 67 DAY 1; n=0, 1|
    99999 ( 99999 )
    -9.0 ( 99999 )
        CYCLE 68 DAY 1; n=0, 1|
    99999 ( 99999 )
    -10.0 ( 99999 )
        CYCLE 69 DAY 1; n=0, 1|
    99999 ( 99999 )
    -12.0 ( 99999 )
        CYCLE 70 DAY 1; n=0, 1|
    99999 ( 99999 )
    -9.0 ( 99999 )
        CYCLE 71 DAY 1; n=0, 1|
    99999 ( 99999 )
    -7.0 ( 99999 )
        CYCLE 72 DAY 1; n=0, 1|
    99999 ( 99999 )
    -10.0 ( 99999 )
        CYCLE 73 DAY 1; n=0, 1|
    99999 ( 99999 )
    -9.0 ( 99999 )
        CYCLE 74 DAY 1; n=0, 1|
    99999 ( 99999 )
    -8.0 ( 99999 )
        CYCLE 75 DAY 1; n=0, 1|
    99999 ( 99999 )
    -9.0 ( 99999 )
    Notes
    [44] - As-Treated Population
    [45] - As-Treated Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in temperature

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    End point title
    		 Change from Baseline in temperature
    End point description
    Temperature was obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. 99999 indicates data was not available due to insufficient number of participants. Only those participants with data available at specified time points were analyzed (indicated by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [46]
    50 [47]
    Units: Celsius
    arithmetic mean (standard deviation)
        Cycle 2 Day 1, n=46, 43|
    0.02 ( 0.288 )
    -0.02 ( 0.242 )
        CYCLE 3 DAY 1, n=39, 35|
    -0.01 ( 0.374 )
    -0.11 ( 0.340 )
        CYCLE 4; DAY 1; n=33, 32|
    0.02 ( 0.354 )
    -0.05 ( 0.298 )
        CYCLE 5 DAY 1; n=27, 26|
    0.05 ( 0.374 )
    -0.04 ( 0.218 )
        CYCLE 6 DAY 1; n=23, 22|
    -0.05 ( 0.374 )
    -0.07 ( 0.223 )
        CYCLE 7 DAY 1; n=24, 22|
    0.03 ( 0.334 )
    -0.10 ( 0.408 )
        CYCLE 8 DAY 1; n=21, 21|
    0.01 ( 0.460 )
    0.02 ( 0.161 )
        CYCLE 9 DAY 1; n=19, 16|
    0.04 ( 0.493 )
    0.00 ( 0.171 )
        CYCLE 10 DAY 1; n=18, 16|
    0.05 ( 0.539 )
    0.04 ( 0.200 )
        CYCLE 11 DAY 1; n=16, 15|
    -0.02 ( 0.468 )
    -0.09 ( 0.181 )
        CYCLE 12 DAY 1; n=15, 13|
    0.00 ( 0.270 )
    0.02 ( 0.245 )
        CYCLE 13 DAY 1; n=13, 12|
    0.00 ( 0.354 )
    0.03 ( 0.176 )
        CYCLE 14 DAY 1; n=12, 12|
    0.13 ( 0.380 )
    -0.04 ( 0.219 )
        CYCLE 15 DAY 1; n=10, 9|
    0.11 ( 0.420 )
    -0.13 ( 0.269 )
        CYCLE 16 DAY 1; n=10, 9|
    0.01 ( 0.318 )
    -0.04 ( 0.174 )
        CYCLE 17 DAY 1; n=8, 8|
    0.00 ( 0.227 )
    0.05 ( 0.076 )
        CYCLE 18 DAY 1; n=8, 8|
    -0.14 ( 0.346 )
    -0.09 ( 0.189 )
        CYCLE 19 DAY 1; n=6, 8|
    -0.10 ( 0.456 )
    0.10 ( 0.207 )
        CYCLE 20 DAY 1; n=6, 8|
    -0.02 ( 0.397 )
    0.01 ( 0.146 )
        CYCLE 21 DAY 1; n=4, 8|
    0.13 ( 0.411 )
    -0.01 ( 0.304 )
        CYCLE 22 DAY 1; n=4, 8|
    0.17 ( 0.206 )
    0.00 ( 0.193 )
        CYCLE 23 DAY 1; n=4, 8|
    0.03 ( 0.299 )
    0.13 ( 0.231 )
        CYCLE 24 DAY 1; n=4, 8|
    0.18 ( 0.171 )
    0.06 ( 0.119 )
        CYCLE 25 DAY 1; n=4, 8|
    0.20 ( 0.432 )
    0.00 ( 0.185 )
        CYCLE 26 DAY 1; n=4, 7|
    0.15 ( 0.129 )
    -0.01 ( 0.308 )
        CYCLE 27 DAY 1; n=4, 5|
    0.18 ( 0.171 )
    0.10 ( 0.173 )
        CYCLE 28 DAY 1; n=4, 5|
    0.15 ( 0.208 )
    -0.02 ( 0.179 )
        CYCLE 29 DAY 1; n=3, 4|
    0.13 ( 0.153 )
    -0.02 ( 0.275 )
        CYCLE 30 DAY 1; n=3, 4|
    0.10 ( 0.173 )
    0.00 ( 0.082 )
        CYCLE 31 DAY 1; n=3, 4|
    -0.07 ( 0.351 )
    0.05 ( 0.265 )
        CYCLE 32 DAY 1; n=3, 4|
    0.10 ( 0.173 )
    -0.05 ( 0.265 )
        CYCLE 33 DAY 1; n=2, 4|
    0.30 ( 0.424 )
    -0.07 ( 0.222 )
        CYCLE 34 DAY 1; n=1, 4|
    0.30 ( 99999 )
    -0.20 ( 0.283 )
        CYCLE 35 DAY 1; n=0, 4|
    99999 ( 99999 )
    -0.05 ( 0.058 )
        CYCLE 36 DAY 1; n=0, 4|
    99999 ( 99999 )
    -0.07 ( 0.150 )
        CYCLE 37 DAY 1; n=0, 3|
    99999 ( 99999 )
    -0.30 ( 0.458 )
        CYCLE 38 DAY 1; n=0, 3|
    99999 ( 99999 )
    0.00 ( 0.100 )
        CYCLE 39 DAY 1; n=0, 3|
    99999 ( 99999 )
    -0.07 ( 0.058 )
        CYCLE 40 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.00 ( 0.00 )
        CYCLE 41 DAY 1; n=0, 2|
    99999 ( 99999 )
    -0.10 ( 0.141 )
        CYCLE 42 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.05 ( 0.071 )
        CYCLE 43 DAY 1; n=0, 2|
    99999 ( 99999 )
    -0.05 ( 0.212 )
        CYCLE 44 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.00 ( 0.141 )
        CYCLE 45 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.00 ( 0.283 )
        CYCLE 46 DAY 1; n=0, 2|
    99999 ( 99999 )
    -0.05 ( 0.071 )
        CYCLE 47 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.05 ( 0.212 )
        CYCLE 48 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.00 ( 0.000 )
        CYCLE 49 DAY 1; n=0, 2|
    99999 ( 99999 )
    -0.05 ( 0.212 )
        CYCLE 50 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.00 ( 0.141 )
        CYCLE 51 DAY 1; n=0, 2|
    99999 ( 99999 )
    -0.05 ( 0.071 )
        CYCLE 52 DAY 1; n=0, 2|
    99999 ( 99999 )
    -0.10 ( 0.141 )
        CYCLE 53 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.05 ( 0.071 )
        CYCLE 54 DAY 1; n=0, 2|
    99999 ( 99999 )
    -0.05 ( 0.071 )
        CYCLE 55 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.20 ( 99999 )
        CYCLE 56 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.10 ( 99999 )
        CYCLE 57 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.00 ( 99999 )
        CYCLE 58 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.10 ( 99999 )
        CYCLE 59 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.00 ( 99999 )
        CYCLE 60 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.10 ( 99999 )
        CYCLE 61 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.10 ( 99999 )
        CYCLE 62 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.00 ( 99999 )
        CYCLE 63 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.10 ( 99999 )
        CYCLE 64 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.10 ( 99999 )
        CYCLE 65 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.00 ( 99999 )
        CYCLE 66 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.20 ( 99999 )
        CYCLE 67 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.10 ( 99999 )
        CYCLE 68 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.00 ( 99999 )
        CYCLE 69 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.20 ( 99999 )
        CYCLE 70 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.00 ( 99999 )
        CYCLE 71 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.10 ( 99999 )
        CYCLE 72 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.20 ( 99999 )
        CYCLE 73 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.10 ( 99999 )
        CYCLE 74 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.20 ( 99999 )
        CYCLE 75 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.10 ( 99999 )
    Notes
    [46] - As-Treated Population
    [47] - As-Treated Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in respiratory rate

    		 Close Top of page
    End point title
    		 Change from Baseline in respiratory rate
    End point description
    Respiratory rate was obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. 99999 indicates data was not available due to insufficient number of participants. Only those participants with data available at specified time points were analyzed (indicated by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [48]
    50 [49]
    Units: Breaths per minute
    arithmetic mean (standard deviation)
        CYCLE 2 Day 1, n=46, 44|
    -0.1 ( 1.62 )
    0.1 ( 1.31 )
        CYCLE 3 DAY 1, n=39, 35|
    0.2 ( 2.34 )
    -0.2 ( 1.71 )
        CYCLE 4; DAY 1; n=32, 32|
    0.2 ( 1.79 )
    -0.3 ( 1.45 )
        CYCLE 5 DAY 1; n=26, 26|
    -0.1 ( 1.86 )
    -0.3 ( 1.50 )
        CYCLE 6 DAY 1; n=24, 22|
    0.5 ( 2.15 )
    -0.3 ( 1.88 )
        CYCLE 7 DAY 1; n=24, 22|
    -0.1 ( 2.09 )
    -0.2 ( 1.74 )
        CYCLE 8 DAY 1; n=21, 21|
    0.6 ( 1.78 )
    -0.1 ( 1.59 )
        CYCLE 9 DAY 1; n=19, 16|
    -0.5 ( 1.98 )
    -0.2 ( 2.04 )
        CYCLE 10 DAY 1; n=18, 16|
    -1.7 ( 2.95 )
    -0.4 ( 2.03 )
        CYCLE 11 DAY 1; n=16, 15|
    -0.8 ( 1.97 )
    -0.8 ( 2.21 )
        CYCLE 12 DAY 1; n=15, 13|
    0.0 ( 2.48 )
    -1.0 ( 2.45 )
        CYCLE 13 DAY 1; n=13, 12|
    -0.2 ( 1.69 )
    -0.7 ( 2.67 )
        CYCLE 14 DAY 1; n=12, 12|
    0.4 ( 2.43 )
    -1.0 ( 2.52 )
        CYCLE 15 DAY 1; n=10, 9|
    -0.5 ( 1.65 )
    -0.9 ( 3.06 )
        CYCLE 16 DAY 1; n=10, 9|
    -0.5 ( 1.72 )
    -0.9 ( 2.76 )
        CYCLE 17 DAY 1; n=8, 8|
    0.0 ( 2.20 )
    0.1 ( 1.81 )
        CYCLE 18 DAY 1; n=8, 8|
    -0.4 ( 2.07 )
    0.4 ( 1.60 )
        CYCLE 19 DAY 1; n=6, 8|
    0.7 ( 1.37 )
    0.0 ( 1.51 )
        CYCLE 20 DAY 1; n=6, 8|
    0.2 ( 0.75 )
    0.0 ( 1.60 )
        CYCLE 21 DAY 1; n=4, 8|
    0.8 ( 0.96 )
    -0.1 ( 1.64 )
        CYCLE 22 DAY 1; n=4, 8|
    0.0 ( 0.00 )
    -0.1 ( 1.36 )
        CYCLE 23 DAY 1; n=4, 8|
    0.5 ( 1.00 )
    0.4 ( 1.60 )
        CYCLE 24 DAY 1; n=4, 8|
    -0.3 ( 1.26 )
    0.0 ( 1.20 )
        CYCLE 25 DAY 1; n=4, 8|
    -0.3 ( 0.50 )
    -0.3 ( 1.49 )
        CYCLE 26 DAY 1; n=4, 7|
    -0.5 ( 1.00 )
    0.0 ( 1.63 )
        CYCLE 27 DAY 1; n=4, 5|
    0.0 ( 1.41 )
    0.0 ( 1.00 )
        CYCLE 28 DAY 1; n=4, 5|
    -0.3 ( 0.50 )
    0.2 ( 2.17 )
        CYCLE 29 DAY 1; n=3, 4|
    -0.7 ( 1.53 )
    -0.3 ( 2.22 )
        CYCLE 30 DAY 1; n=3, 4|
    0.0 ( 0.00 )
    -0.3 ( 2.06 )
        CYCLE 31 DAY 1; n=3, 4|
    0.7 ( 0.58 )
    0.3 ( 2.36 )
        CYCLE 32 DAY 1; n=3, 4|
    -0.7 ( 1.53 )
    0.0 ( 2.16 )
        CYCLE 33 DAY 1; n=2, 4|
    -2.0 ( 0.00 )
    -0.8 ( 1.50 )
        CYCLE 34 DAY 1; n=1, 4|
    0.0 ( 99999 )
    0.8 ( 1.50 )
        CYCLE 35 DAY 1; n=0, 4|
    99999 ( 99999 )
    0.0 ( 1.83 )
        CYCLE 36 DAY 1; n=0, 4|
    99999 ( 99999 )
    0.3 ( 1.71 )
        CYCLE 37 DAY 1; n=0, 3|
    99999 ( 99999 )
    -1.0 ( 1.73 )
        CYCLE 38 DAY 1; n=0, 3|
    99999 ( 99999 )
    -0.3 ( 2.52 )
        CYCLE 39 DAY 1; n=0, 3|
    99999 ( 99999 )
    -1.0 ( 1.73 )
        CYCLE 40 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.0 ( 0.00 )
        CYCLE 41 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.0 ( 0.00 )
        CYCLE 42 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.0 ( 0.00 )
        CYCLE 43 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.0 ( 0.00 )
        CYCLE 44 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.0 ( 0.00 )
        CYCLE 45 DAY 1; n=0, 2|
    99999 ( 99999 )
    -1.5 ( 0.71 )
        CYCLE 46 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.0 ( 0.00 )
        CYCLE 47 DAY 1; n=0, 2|
    99999 ( 99999 )
    -0.5 ( 0.71 )
        CYCLE 48 DAY 1; n=0, 2|
    99999 ( 99999 )
    1.0 ( 1.41 )
        CYCLE 49 DAY 1; n=0, 2|
    99999 ( 99999 )
    -1.0 ( 1.41 )
        CYCLE 50 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.0 ( 0.00 )
        CYCLE 51 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.0 ( 0.00 )
        CYCLE 52 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.0 ( 0.00 )
        CYCLE 53 DAY 1; n=0, 2|
    99999 ( 99999 )
    -1.0 ( 1.41 )
        CYCLE 54 DAY 1; n=0, 2|
    99999 ( 99999 )
    0.0 ( 0.00 )
        CYCLE 55 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.0 ( 99999 )
        CYCLE 56 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.0 ( 99999 )
        CYCLE 57 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.0 ( 99999 )
        CYCLE 58 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.0 ( 99999 )
        CYCLE 59 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.0 ( 99999 )
        CYCLE 60 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.0 ( 99999 )
        CYCLE 61 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.0 ( 99999 )
        CYCLE 62 DAY 1; n=0, 1|
    99999 ( 99999 )
    -1.0 ( 99999 )
        CYCLE 63 DAY 1; n=0, 1|
    99999 ( 99999 )
    -1.0 ( 99999 )
        CYCLE 64 DAY 1; n=0, 1|
    99999 ( 99999 )
    -2.0 ( 99999 )
        CYCLE 65 DAY 1; n=0, 1|
    99999 ( 99999 )
    -2.0 ( 99999 )
        CYCLE 66 DAY 1; n=0, 1|
    99999 ( 99999 )
    -1.0 ( 99999 )
        CYCLE 67 DAY 1; n=0, 1|
    99999 ( 99999 )
    -2.0 ( 99999 )
        CYCLE 68 DAY 1; n=0, 1|
    99999 ( 99999 )
    -2.0 ( 99999 )
        CYCLE 69 DAY 1; n=0, 1|
    99999 ( 99999 )
    -1.0 ( 99999 )
        CYCLE 70 DAY 1; n=0, 1|
    99999 ( 99999 )
    -2.0 ( 99999 )
        CYCLE 71 DAY 1; n=0, 1|
    99999 ( 99999 )
    -2.0 ( 99999 )
        CYCLE 72 DAY 1; n=0, 1|
    99999 ( 99999 )
    -2.0 ( 99999 )
        CYCLE 73 DAY 1; n=0, 1|
    99999 ( 99999 )
    -2.0 ( 99999 )
        CYCLE 74 DAY 1; n=0, 1|
    99999 ( 99999 )
    -2.0 ( 99999 )
        CYCLE 75 DAY 1; n=0, 1|
    99999 ( 99999 )
    -2.0 ( 99999 )
    Notes
    [48] - As-Treated Population
    [49] - As-Treated Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in weight

    		 Close Top of page
    End point title
    		 Change from Baseline in weight
    End point description
    Weight was obtained on Day 1 of each cycle. Baseline is the last assessment prior to first dose. Change from Baseline is the value at indicated time point minus the value at Baseline. 99999 indicates data was not available due to insufficient number of participants. Only those participants with data available at specified time points were analyzed (indicated by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and Day 1 of Cycles 2 to 75 (each cycle of 21 days)
    End point values
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    51 [50]
    50 [51]
    Units: Kilograms
    arithmetic mean (standard deviation)
        Cycle 2 Day 1, n=46, 44|
    -1.51 ( 2.192 )
    -1.55 ( 2.405 )
        CYCLE 3 DAY 1, n=39, 35|
    -2.54 ( 2.734 )
    -1.88 ( 2.710 )
        CYCLE 4; DAY 1; n=33, 32|
    -3.02 ( 2.451 )
    -1.86 ( 3.305 )
        CYCLE 5 DAY 1; n=27, 26|
    -3.31 ( 2.521 )
    -2.01 ( 3.301 )
        CYCLE 6 DAY 1; n=24, 22|
    -3.25 ( 3.078 )
    -2.61 ( 4.200 )
        CYCLE 7 DAY 1; n=24, 22|
    -3.75 ( 4.172 )
    -2.14 ( 5.877 )
        CYCLE 8 DAY 1; n=22, 21|
    -3.89 ( 4.384 )
    -2.61 ( 5.016 )
        CYCLE 9 DAY 1; n=19, 16|
    -4.14 ( 5.151 )
    -2.14 ( 4.998 )
        CYCLE 10 DAY 1; n=18, 16|
    -5.50 ( 6.983 )
    -1.99 ( 5.478 )
        CYCLE 11 DAY 1; n=16, 15|
    -5.70 ( 6.045 )
    -1.67 ( 4.681 )
        CYCLE 12 DAY 1; n=15, 13|
    -5.85 ( 5.206 )
    -1.72 ( 4.260 )
        CYCLE 13 DAY 1; n=13, 12|
    -6.54 ( 5.795 )
    -1.11 ( 4.483 )
        CYCLE 14 DAY 1; n=12, 12|
    -7.03 ( 6.500 )
    -1.23 ( 3.899 )
        CYCLE 15 DAY 1; n=10, 9|
    -7.21 ( 7.449 )
    -1.09 ( 4.705 )
        CYCLE 16 DAY 1; n=10, 9|
    -7.59 ( 6.970 )
    -0.93 ( 4.519 )
        CYCLE 17 DAY 1; n=8, 8|
    -8.49 ( 8.606 )
    -1.24 ( 5.205 )
        CYCLE 18 DAY 1; n=8, 8|
    -8.25 ( 9.002 )
    -0.80 ( 4.888 )
        CYCLE 19 DAY 1; n=6, 8|
    -8.78 ( 9.953 )
    -0.19 ( 5.044 )
        CYCLE 20 DAY 1; n=6, 8|
    -9.22 ( 10.752 )
    -0.40 ( 5.986 )
        CYCLE 21 DAY 1; n=4, 8|
    -3.03 ( 7.950 )
    -0.29 ( 6.354 )
        CYCLE 22 DAY 1; n=4, 8|
    -3.50 ( 7.735 )
    -0.32 ( 5.370 )
        CYCLE 23 DAY 1; n=4, 8|
    -4.13 ( 8.189 )
    -0.16 ( 5.297 )
        CYCLE 24 DAY 1; n=4, 7|
    -3.38 ( 7.273 )
    -1.93 ( 1.511 )
        CYCLE 25 DAY 1; n=4, 8|
    -3.88 ( 8.250 )
    0.04 ( 5.789 )
        CYCLE 26 DAY 1; n=4, 7|
    -3.88 ( 6.981 )
    0.54 ( 6.484 )
        CYCLE 27 DAY 1; n=4, 5|
    -4.88 ( 6.408 )
    -2.04 ( 2.308 )
        CYCLE 28 DAY 1; n=4, 5|
    -5.13 ( 6.115 )
    -2.20 ( 1.989 )
        CYCLE 29 DAY 1; n=3, 4|
    -5.50 ( 7.697 )
    -2.18 ( 1.786 )
        CYCLE 30 DAY 1; n=3, 4|
    -5.83 ( 7.286 )
    -3.25 ( 0.379 )
        CYCLE 31 DAY 1; n=3, 4|
    -5.50 ( 7.467 )
    -3.38 ( 0.435 )
        CYCLE 32 DAY 1; n=3, 4|
    -5.50 ( 7.467 )
    -3.05 ( 0.100 )
        CYCLE 33 DAY 1; n=2, 4|
    -1.75 ( 1.061 )
    -3.13 ( 0.150 )
        CYCLE 34 DAY 1; n=1, 4|
    -2.50 ( 99999 )
    -3.18 ( 0.350 )
        CYCLE 35 DAY 1; n=0, 4|
    99999 ( 99999 )
    -3.25 ( 0.379 )
        CYCLE 36 DAY 1; n=0, 4|
    99999 ( 99999 )
    -3.38 ( 0.624 )
        CYCLE 37 DAY 1; n=0, 3|
    99999 ( 99999 )
    -3.17 ( 0.961 )
        CYCLE 38 DAY 1; n=0, 3|
    99999 ( 99999 )
    -2.63 ( 0.814 )
        CYCLE 39 DAY 1; n=0, 3|
    99999 ( 99999 )
    -3.00 ( 0.200 )
        CYCLE 40 DAY 1; n=0, 2|
    99999 ( 99999 )
    -3.40 ( 0.566 )
        CYCLE 41 DAY 1; n=0, 2|
    99999 ( 99999 )
    -2.90 ( 0.141 )
        CYCLE 42 DAY 1; n=0, 2|
    99999 ( 99999 )
    -3.00 ( 0.000 )
        CYCLE 43 DAY 1; n=0, 2|
    99999 ( 99999 )
    -2.90 ( 0.141 )
        CYCLE 44 DAY 1; n=0, 2|
    99999 ( 99999 )
    -3.90 ( 1.273 )
        CYCLE 45 DAY 1; n=0, 2|
    99999 ( 99999 )
    -4.40 ( 1.980 )
        CYCLE 46 DAY 1; n=0, 2|
    99999 ( 99999 )
    -3.90 ( 1.273 )
        CYCLE 47 DAY 1; n=0, 2|
    99999 ( 99999 )
    -3.40 ( 0.566 )
        CYCLE 48 DAY 1; n=0, 2|
    99999 ( 99999 )
    -3.65 ( 0.919 )
        CYCLE 49 DAY 1; n=0, 2|
    99999 ( 99999 )
    -4.40 ( 1.980 )
        CYCLE 50 DAY 1; n=0, 2|
    99999 ( 99999 )
    -4.15 ( 1.626 )
        CYCLE 51 DAY 1; n=0, 2|
    99999 ( 99999 )
    -3.65 ( 0.919 )
        CYCLE 52 DAY 1; n=0, 2|
    99999 ( 99999 )
    -2.90 ( 0.141 )
        CYCLE 53 DAY 1; n=0, 2|
    99999 ( 99999 )
    -4.40 ( 1.980 )
        CYCLE 54 DAY 1; n=0, 2|
    99999 ( 99999 )
    -3.65 ( 0.919 )
        CYCLE 55 DAY 1; n=0, 1|
    99999 ( 99999 )
    -2.80 ( 99999 )
        CYCLE 56 DAY 1; n=0, 1|
    99999 ( 99999 )
    -1.80 ( 99999 )
        CYCLE 57 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.80 ( 99999 )
        CYCLE 58 DAY 1; n=0, 1|
    99999 ( 99999 )
    -1.30 ( 99999 )
        CYCLE 59 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.30 ( 99999 )
        CYCLE 60 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.30 ( 99999 )
        CYCLE 61 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.00 ( 99999 )
        CYCLE 62 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.30 ( 99999 )
        CYCLE 63 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.80 ( 99999 )
        CYCLE 64 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.60 ( 99999 )
        CYCLE 65 DAY 1; n=0, 1|
    99999 ( 99999 )
    -2.80 ( 99999 )
        CYCLE 66 DAY 1; n=0, 1|
    99999 ( 99999 )
    -3.30 ( 99999 )
        CYCLE 67 DAY 1; n=0, 1|
    99999 ( 99999 )
    -3.80 ( 99999 )
        CYCLE 68 DAY 1; n=0, 1|
    99999 ( 99999 )
    -1.30 ( 99999 )
        CYCLE 69 DAY 1; n=0, 1|
    99999 ( 99999 )
    -1.80 ( 99999 )
        CYCLE 70 DAY 1; n=0, 1|
    99999 ( 99999 )
    0.20 ( 99999 )
        CYCLE 71 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.80 ( 99999 )
        CYCLE 72 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.80 ( 99999 )
        CYCLE 73 DAY 1; n=0, 1|
    99999 ( 99999 )
    -1.30 ( 99999 )
        CYCLE 74 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.80 ( 99999 )
        CYCLE 75 DAY 1; n=0, 1|
    99999 ( 99999 )
    -0.30 ( 99999 )
    Notes
    [50] - As-Treated Population
    [51] - As-Treated Population
    No statistical analyses for this end point

    Secondary: Serum concentration of mapatumumab

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    End point title
    		 Serum concentration of mapatumumab [52]
    End point description
    Blood samples were collected for determination of serum mapatumumab concentration at the indicated time points. 99999 indicates standard deviation could not be calculated as only one participant was analyzed at the specified time points. Only those participants with data available at the specified time points were analyzed (indicated by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Day1 pre-dose(Cycle 1,2,4,5,6,8,9,10,12,14,16,17,18,20,22,24,26,28,30,32,34);end of infusion (Cycle 1);Day8 pre-dose(Cycle 1);Day15 pre-dose (Cycle 1,2);Day21(Cycle 2,4,6,8,9,12,14,16,18,20,22,24,26,28,30,32,34);Cycle 99(end of treatment) (21-day cycles)
    Notes
    [52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only Sorafenib+Mapatumumab 30 mg/kg was included in the analysis.
    End point values
    		 Sorafenib+Mapatumumab 30 mg/kg
    Number of subjects analysed
    50 [53]
    Units: Nanograms per milliliter
    arithmetic mean (standard deviation)
        CYCLE 1 Day 1, pre-dose, n=46|
    638.4 ( 2668.01 )
        CYCLE 1 DAY 1,end of infusion, n=46|
    555157.6 ( 260848.85 )
        CYCLE 1; DAY 8, pre-dose; n=40|
    250229.9 ( 89714.76 )
        CYCLE 1 DAY 15, pre-dose; n=1|
    121556.0 ( 99999 )
        CYCLE 2 DAY 1, pre-dose; n=40|
    126588.4 ( 149231.45 )
        CYCLE 2 DAY 15, pre-dose; n=3|
    128839.0 ( 153667.78 )
        CYCLE 2 DAY 21; n=28|
    180606.6 ( 109893.28 )
        CYCLE 4 DAY 1, pre-dose; n=31|
    194936.8 ( 142242.80 )
        CYCLE 4, DAY 21; n=23|
    183754.3 ( 93584.71 )
        CYCLE 5, DAY 1, pre-dose; n=1|
    223681.0 ( 99999 )
        CYCLE 6, DAY 1, pre-dose; n=21|
    160741.5 ( 64893.03 )
        CYCLE 6, DAY 21; n=20|
    201237.7 ( 75352.54 )
        CYCLE 8, DAY 1, pre-dose; n=21|
    246616.5 ( 204363.04 )
        CYCLE 8, DAY 21; n=17|
    187927.6 ( 104803.16 )
        CYCLE 9, DAY 1, pre-dose; n=1|
    136122.0 ( 99999 )
        CYCLE 10, DAY 1, pre-dose; n=16|
    204147.1 ( 103243.21 )
        CYCLE 10, DAY 21; n=15|
    219503.0 ( 105968.15 )
        CYCLE 12, DAY 1, pre-dose; n=12|
    200141.1 ( 93093.68 )
        CYCLE 12, DAY 21; n=11|
    256924.5 ( 111904.82 )
        CYCLE 14, DAY 1, pre-dose; n=9|
    207930.6 ( 84247.04 )
        CYCLE 14, DAY 21 n=9|
    256779.4 ( 127463.67 )
        CYCLE 16, DAY 1, pre-dose; n=9|
    196074.3 ( 100377.45 )
        CYCLE 16, DAY 21; n=8|
    253521.0 ( 87675.77 )
        CYCLE 17, DAY 1, pre-dose; n=1|
    156161.0 ( 99999 )
        CYCLE 18, DAY 1, pre-dose; n=8|
    199379.4 ( 61011.54 )
        CYCLE 18, DAY 21; n=7|
    229539.1 ( 86440.46 )
        CYCLE 20 DAY 1, pre-dose; n=8|
    189486.6 ( 54097.82 )
        CYCLE 20, DAY 21; n=7|
    222443.7 ( 86046.38 )
        CYCLE 22 DAY 1, pre-dose; n=8|
    208485.4 ( 80252.29 )
        CYCLE 22, DAY 21; n=7|
    212481.1 ( 110103.79 )
        CYCLE 24 DAY 1, pre-dose; n=8|
    219439.8 ( 71740.01 )
        CYCLE 24, DAY 21; n=7|
    221249.1 ( 73317.41 )
        CYCLE 26 DAY 1, pre-dose; n=4|
    223427.3 ( 67101.56 )
        CYCLE 26, DAY 21; n=4|
    295941.5 ( 100208.45 )
        CYCLE 28 DAY 1, pre-dose; n=3|
    219802.7 ( 115484.98 )
        CYCLE 28, DAY 21; n=2|
    173018.5 ( 54870.78 )
        CYCLE 30 DAY 1, pre-dose; n=2|
    173200.5 ( 13447.05 )
        CYCLE 30, DAY 21; n=2|
    180484.5 ( 14783.48 )
        CYCLE 32 DAY 1, pre-dose; n=1|
    178275.0 ( 99999 )
        CYCLE 32, DAY 21; n=1|
    177496.0 ( 99999 )
        CYCLE 34 DAY 1, pre-dose; n=1|
    150553.0 ( 99999 )
        CYCLE 34, DAY 21; n=1|
    134781.0 ( 99999 )
        CYCLE 99, end of treatment; n=14|
    86640.1 ( 64981.14 )
    Notes
    [53] - As-Treated Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Start of study treatment up to maximum of 52.9 months
    Adverse event reporting additional description
    Treatment-emergent non-serious AEs and SAEs were collected in the As-Treated Population which comprised of participants who received at least part of 1 dose of study agent analyzed according to the treatment that they actually received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Sorafenib+Placebo
    Reporting group description
    		 Participants received sorafenib 400 milligrams (mg) orally twice daily continuously in each 21-day cycle. Placebo was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity

    Reporting group title
    Sorafenib+Mapatumumab 30 mg/kg
    Reporting group description
    		 Participants received sorafenib 400 mg orally twice daily continuously in each 21-day cycle. Mapatumumab 30 milligrams per kilogram (mg/kg) was administered via the intravenous route on Day 1 of each 21-day cycle. The treatments were administered until radiologic disease progression or unacceptable toxicity

    Serious adverse events
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 51 (52.94%)
    21 / 50 (42.00%)
         number of deaths (all causes)
    40
    39
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    9 / 51 (17.65%)
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 9
    0 / 4
    Hepatic cancer metastatic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Disease progression
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Gastric haemorrhage
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ascites
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sorafenib+Placebo Sorafenib+Mapatumumab 30 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 51 (92.16%)
    49 / 50 (98.00%)
    Investigations
    Weight decreased
         subjects affected / exposed
    22 / 51 (43.14%)
    19 / 50 (38.00%)
         occurrences all number
    41
    34
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 51 (21.57%)
    9 / 50 (18.00%)
         occurrences all number
    37
    25
    Lipase increased
         subjects affected / exposed
    12 / 51 (23.53%)
    17 / 50 (34.00%)
         occurrences all number
    37
    46
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    11 / 51 (21.57%)
    8 / 50 (16.00%)
         occurrences all number
    17
    12
    Blood bilirubin increased
         subjects affected / exposed
    9 / 51 (17.65%)
    5 / 50 (10.00%)
         occurrences all number
    36
    14
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 51 (15.69%)
    7 / 50 (14.00%)
         occurrences all number
    18
    11
    Amylase increased
         subjects affected / exposed
    8 / 51 (15.69%)
    7 / 50 (14.00%)
         occurrences all number
    12
    29
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 51 (9.80%)
    0 / 50 (0.00%)
         occurrences all number
    11
    0
    Platelet count decreased
         subjects affected / exposed
    6 / 51 (11.76%)
    0 / 50 (0.00%)
         occurrences all number
    34
    0
    Transaminases increased
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Weight increased
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    4
    White blood cell count decreased
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 50 (6.00%)
         occurrences all number
    34
    9
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 51 (23.53%)
    16 / 50 (32.00%)
         occurrences all number
    16
    25
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 50 (6.00%)
         occurrences all number
    5
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 51 (19.61%)
    8 / 50 (16.00%)
         occurrences all number
    15
    13
    Thrombocytopenia
         subjects affected / exposed
    5 / 51 (9.80%)
    7 / 50 (14.00%)
         occurrences all number
    9
    13
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 51 (15.69%)
    11 / 50 (22.00%)
         occurrences all number
    12
    26
    Fatigue
         subjects affected / exposed
    15 / 51 (29.41%)
    6 / 50 (12.00%)
         occurrences all number
    24
    10
    Oedema peripheral
         subjects affected / exposed
    9 / 51 (17.65%)
    6 / 50 (12.00%)
         occurrences all number
    12
    7
    Pyrexia
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 50 (10.00%)
         occurrences all number
    3
    8
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    19 / 51 (37.25%)
    16 / 50 (32.00%)
         occurrences all number
    46
    29
    Abdominal pain
         subjects affected / exposed
    9 / 51 (17.65%)
    8 / 50 (16.00%)
         occurrences all number
    22
    11
    Nausea
         subjects affected / exposed
    8 / 51 (15.69%)
    8 / 50 (16.00%)
         occurrences all number
    11
    10
    Vomiting
         subjects affected / exposed
    7 / 51 (13.73%)
    5 / 50 (10.00%)
         occurrences all number
    23
    7
    Ascites
         subjects affected / exposed
    6 / 51 (11.76%)
    0 / 50 (0.00%)
         occurrences all number
    11
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    5
    Haemorrhoids
         subjects affected / exposed
    4 / 51 (7.84%)
    0 / 50 (0.00%)
         occurrences all number
    5
    0
    Stomatitis
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 50 (6.00%)
         occurrences all number
    4
    4
    Constipation
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 50 (6.00%)
         occurrences all number
    4
    5
    Dyspepsia
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 50 (10.00%)
         occurrences all number
    3
    7
    Hepatic pain
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    6
    Jaundice hepatocellular
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 50 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 51 (11.76%)
    0 / 50 (0.00%)
         occurrences all number
    8
    0
    Dysphonia
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    4
    Skin and subcutaneous tissue disorders
    Rash papular
         subjects affected / exposed
    0 / 51 (0.00%)
    9 / 50 (18.00%)
         occurrences all number
    0
    13
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    18 / 51 (35.29%)
    19 / 50 (38.00%)
         occurrences all number
    29
    28
    Hyperkeratosis
         subjects affected / exposed
    0 / 51 (0.00%)
    6 / 50 (12.00%)
         occurrences all number
    0
    7
    Rash
         subjects affected / exposed
    4 / 51 (7.84%)
    6 / 50 (12.00%)
         occurrences all number
    5
    6
    Alopecia
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 50 (8.00%)
         occurrences all number
    3
    4
    Pruritus
         subjects affected / exposed
    3 / 51 (5.88%)
    4 / 50 (8.00%)
         occurrences all number
    3
    4
    Erythema
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    6
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    3 / 51 (5.88%)
    6 / 50 (12.00%)
         occurrences all number
    3
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 51 (23.53%)
    9 / 50 (18.00%)
         occurrences all number
    17
    15
    Hypocalcaemia
         subjects affected / exposed
    9 / 51 (17.65%)
    4 / 50 (8.00%)
         occurrences all number
    32
    15
    Hyponatraemia
         subjects affected / exposed
    7 / 51 (13.73%)
    7 / 50 (14.00%)
         occurrences all number
    9
    9
    Hypokalaemia
         subjects affected / exposed
    6 / 51 (11.76%)
    3 / 50 (6.00%)
         occurrences all number
    20
    6
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 50 (0.00%)
         occurrences all number
    7
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2010
    Amendment 01 - Inclusion criteria: adjusted serum albumin levels to ≥2.8 grams per deciliter (g/dL) or ≥28 grams per liter (g/L) – modified in order to be consistent with criteria for Child Pugh A. - Mapatumumab/placebo will be discontinued for Grade 4 transaminase elevations of any duration if they are considered related to mapatumumab. - Participants requiring a delay of >21 days for hypertension,will discontinue sorafenib, unless in the study investigator’s opinion, the participant may benefit from continued treatment. - Concomitant medications – allowable regimens. - Statistical analysis for primary endpoint – includes testing the hazard ratio for time to progression (TTP) at a 1-sided significance level of 0.01 with a Cox proportional hazards model controlling for the factors stratifying randomization as covariates. - Criteria for protocol specified events revised for transaminases (Grade 4 elevations), lipase or amylase (Grade 4 elevations; Grade 3 elevations associated with clinical/imaging findings of pancreatitis, resulting in chronic damage to the pancreas). - Modified Response Evaluation Criteria in Hepatocellular Carcinoma (mRECIST for HCC) adapted from Lencioni, 2010 for use in this study.
    23 Feb 2011
    Amendment 02 - Exclusion criteria added: History of organ allograft - Prohibited medications– clarified to include any locoregional therapy including embolization, radiofrequency ablation (RFA) or percutaneous ethanol injection.
    15 Jul 2015
    Amendment 03 - The protocol amendment number and version date have been added to the cover page. - A revision chronology page has been added. - The protocol has been modified to allow participants to receive extended access to study drug while receiving the local standard of care for hepatocellular carcinoma (HCC). A new section has been added to clarify assessments required for participants receiving extended access to study drug. - The long term follow up phase of the study has been removed as there is no longer a requirement to follow participants for long term survival since at least 90% of participants have met the survival endpoint. - The protocol has been updated to comply, where applicable, with the GlaxoSmithKline Standard Operating Procedure (GSK SOP), associated guidance and protocol template. - Reference to contacting Human Genome Science to report Adverse Events has been updated to GSK Case Management Group (CMG).

    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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