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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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

200149

ISRCTN number

US NCT number

WHO universal trial number (UTN)

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

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

24 Oct 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Nov 2017

Was the trial ended prematurely?

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

Independent data monitoring committee (IDMC) involvement?

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

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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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.

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 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

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.

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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Reporting group title

Sorafenib+Placebo

Reporting group description

Reporting group title

Sorafenib+Mapatumumab 30 mg/kg

Reporting group description

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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Reporting group title

Sorafenib+Placebo

Reporting group description

Reporting group title

Sorafenib+Mapatumumab 30 mg/kg

Reporting group description

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 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

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 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 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 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

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 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 1

Comparison groups

Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg

Number of subjects included in analysis

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 1

Comparison groups

Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg

Number of subjects included in analysis

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 1

Comparison groups

Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg

Number of subjects included in analysis

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 1

Comparison groups

Sorafenib+Placebo v Sorafenib+Mapatumumab 30 mg/kg

Number of subjects included in analysis

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

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

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

Top of page

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

Top of page

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 name

MedDRA

Dictionary version

21.0

Reporting group title

Sorafenib+Placebo

Reporting group description

Reporting group title

Sorafenib+Mapatumumab 30 mg/kg

Reporting group description

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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Were there any global substantial amendments to the protocol? Yes

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).

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

Secondary: Time to progression-Investigator assessment

Secondary: Time to progression-Investigator assessment

Secondary: Median overall survival

Secondary: Median overall survival

Secondary: Progression free survival-BICR assessment

Secondary: Progression free survival-BICR assessment

Secondary: Progression free survival-Investigator assessment

Secondary: Progression free survival-Investigator assessment

Secondary: Percentage of participants with objective response-BICR assessment

Secondary: Percentage of participants with objective response-BICR assessment

Secondary: Percentage of participants with objective response-Investigator assessment

Secondary: Percentage of participants with objective response-Investigator assessment

Secondary: Percentage of participants with disease control-BICR assessment

Secondary: Percentage of participants with disease control-BICR assessment

Secondary: Percentage of participants with disease control-Investigator assessment

Secondary: Percentage of participants with disease control-Investigator assessment

Secondary: Time to response-BICR assessment

Secondary: Time to response-BICR assessment

Secondary: Duration of response-BICR assessment

Secondary: Duration of response-BICR assessment

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

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

Secondary: Number of participants with severe AEs

Secondary: Number of participants with severe AEs

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

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

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

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

Secondary: Number of participants with anti-mapatumumab antibodies

Secondary: Number of participants with anti-mapatumumab antibodies

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

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

Secondary: Change from Baseline in heart rate

Secondary: Change from Baseline in heart rate

Secondary: Change from Baseline in temperature

Secondary: Change from Baseline in temperature

Secondary: Change from Baseline in respiratory rate

Secondary: Change from Baseline in respiratory rate

Secondary: Change from Baseline in weight

Secondary: Change from Baseline in weight

Secondary: Serum concentration of mapatumumab

Secondary: Serum concentration of mapatumumab

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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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