Clinical trial NCT01258608
Conditions: Carcinoma, Hepatocellular
Keywords: advanced hepatocellular carcinoma Mapatumumab HGS1012 sorafenib
Sponsor: Human Genome Sciences Inc., a GSK Company
Start date: 2011-02-08; Completion date: 2017-11-29
Enrollment: 101 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Mapatumumab is a fully human, agonist monoclonal antibody that activates the cell death pathway in tumor cells by specifically binding to TRAIL-R1 with high affinity. Sorafenib, a multikinase inhibitor, is the standard of care for treatment of patients with advanced hepatocellular carcinoma (HCC). The mechanisms of sorafenib and mapatumumab action suggest that these agents could interact synergistically. This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of mapatumumab in combination with sorafenib in subjects with advanced hepatocellular carcinoma.

Detailed description:

Arms: arm 1: Mapatumumab 30 milligrams (mg)/kilogram (kg) intravenously on Day 1 of each cycle (i.e. every 21 days) plus sorafenib 400 mg orally twice daily continuously in each cycle until radiologic disease progression or unacceptable toxicity arm 2: Placebo intravenously on Day 1 of each cycle (i.e. every 21 days) plus sorafenib 400 mg orally twice daily continuously in each cycle until radiologic disease progression or unacceptable toxicity
Interventions: intervention 1: Mapatumumab intervention 2: Placebo intervention 3: Sorafenib
Intervention descriptions: intervention 1: Mapatumumab will be supplied as a lyophilized formulation in 10 mL vials containing 100 mg mapatumumab for intravenous infusion at the dose of 30 mg/kg. intervention 2: Normal saline solution for intravenous infusion will be administered as placebo for mapatumumab intervention 3: Sorafenib will be supplied as tablets, each containing 274 mg sorafenib tosylate, equivalent to 200 mg of sorafenib, to be administered 400 mg (2 x 200 mg tablets) orally twice daily.

Protocol documents:
Prot_000.pdf: 
CLINICAL PROTOCOL HGS1012-C1103
Protocol Amendment: 03
Date: 15 July 2015
TITLE OF STUDY:
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
STUDY SPONSOR:
Human Genome Sciences, Inc.
14200 Shady Grove Road
Rockville, Maryland 20850
EudraCT Number:
2010-020798-17
Confidentiality
This document contains proprietary and confidential information of Human Genome Sciences, Inc. Acceptance 
of this document constitutes agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without prior written approval from Human Genome Sciences, Inc., except that this 
document may be disclosed to study personnel under your supervision who need to know the contents for 
conducting the study and appropriate Institutional Review Boards and Independent Ethics Committee under the 
condition that they are requested to keep it confidential. The foregoing shall not apply to disclosure required by 
governmental regulations or laws however; Human Genome Sciences, Inc. must be promptly informed of any 
such disclosure.
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REVISION CHRONOLOGY FOR HGS1012-C1103 (200149)
Date
Document*
Global
14 September 2010
Original
Global
21 December 2010
Amendment No 01
Global
23 February 2011
Amendment No 02
Global
DNG 2013N166298_03
15 July 2015
Amendment No 03
Global
DNG 2013N166298_04
15 July 2015
Re Publishing Amendment No 03
*A Summary of Modifications which provides a detailed list of changes for the amendment is 
included in Appendix 9.
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Investigator Agreement
I will provide copies of the protocol, any subsequent amendments and access to all 
information furnished by the sponsor to study personnel under my supervision. I will discuss 
this material with them to ensure that they are fully informed about the investigational study 
agent and the study protocol. I agree to conduct this clinical trial according to the protocol 
described herein, except when mutually agreed to in writing with the sponsor. I also agree to 
conduct this study in compliance with Good Clinical Practice standards as defined by the 
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice, all 
applicable national, state, and local regulations, as well as the requirements of the appropriate 
Institutional Review Board/Independent Ethics Committee and any other institutional 
requirements.
Principal Investigator:
Signature
Date
Name (please type or print)
Institution
Address


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Study Synopsis
Study Number: HGS1012-C1103
Title of the Study: 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
Clinical Development Phase: 2
Objectives:
Primary:
•
To evaluate the efficacy of mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma.
Secondary:
•
To evaluate the safety of the mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma.
•
To determine serum mapatumumab concentrations.
Diagnosis & Inclusion Criteria:
Subjects enrolled in the study must meet the following inclusion criteria:
1. Child-Pugh Class A (see Appendix 1).
2. Barcelona Clinic Liver Cancer (BCLC) advanced stage (C) hepatocellular carcinoma, or 
BCLC intermediate stage (B) hepatocellular carcinoma if treatment with transarterial 
chemoembolization is not considered appropriate (see Appendix 2).
3. Measurable disease demonstrating intratumoral arterial enhancement by contrast enhanced 
computerized tomography (CT), with use of multislice scanners, or contrast enhanced 
dynamic magnetic resonance imaging (MRI), with at least 1 tumor lesion that meets the 
following criteria:
-
Located in the liver.
-
Can be accurately measured in at least 1 dimension.
-
Well delineated area of viable, hypervascular (contrast enhancement in the arterial 
phase) tumor that is > 2 cm in the axial plane.
-
Suitable for repeat measurement.
-
Not previously treated with locoregional or systemic treatment unless the lesion shows 
a well-delineated area of viable (contrast enhancement in the arterial phase) tumor that 
is > 2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical 
enhancement as a result of the previous intervention, then it cannot be selected as a 
target lesion).


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4. Radiologic eligibility (measurable disease) must be confirmed by the blinded, 
independent, central read (BICR) prior to randomization.
5. Adequate bone marrow, renal and liver function:
-
Absolute neutrophil count ≥ 1.5 x 109 /L or ≥ 1500 /mm3.
-
Platelet count ≥ 50 x 109 /L or ≥ 50,000 /mm3.
-
Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L) without growth factor support or transfusional 
support.
-
Serum creatinine level ≤ 2.0 mg/dL or ≤ 176.8 µmol/L.
-
Total bilirubin < 3.0 mg/dL or < 51.3 µmol/L.
-
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5.0 x upper limit of 
normal.
-
Amylase and lipase ≤ 1.5 x upper limit of normal.
-
Serum albumin ≥ 2.8 g/dL or ≥ 28 g/L.
-
International normalized ratio ≤ 1.5.
6. Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) 
Scale (see Appendix 3).
7. Age 18 years or older.
8. Have the ability to understand the requirements of the study, provide written informed
consent (including consent for the use and disclosure of research-related health 
information), and comply with the study and follow-up procedures.
Exclusion Criteria:
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria:
1. Any co-morbid condition that in the judgment of the investigator renders the subject at 
high risk of treatment complications or reduces the possibility of assessing clinical effect.
2. Received prior investigational or non-investigational cytotoxic chemotherapy, hormonal 
therapy, biological therapy (including but not limited to monoclonal antibodies, small 
molecules or other immunotherapy) to treat hepatocellular carcinoma.
3. History of organ allograft.
4. Previously received mapatumumab and/or sorafenib.
5. Underwent resection, radiofrequency ablation, radiation or chemoembolization within 
4 weeks before enrollment or not recovered from such treatments.
6. Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy, 
immunotherapy, radiofrequency ablation) or other investigational agents during the study 
treatment period.
7. Major surgery (ie, the opening of a major body cavity, requiring the use of general 
anesthesia) within 4 weeks before enrollment; minor surgery (except for insertion of 
vascular access device) within 2 weeks before enrollment; or not yet recovered from the 
effects of the surgery.
8. Systemic steroids within 1 week before enrollment except steroids used as part of an 
antiemetic regimen or maintenance-dose steroids for non-cancerous disease.
9. Hepatic encephalopathy, per the investigator’s evaluation.
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10. History of clinically significant gastrointestinal bleeding requiring procedural intervention 
(eg, variceal banding, transjugular intrahepatic portosystemic shunt procedure, arterial 
embolization, topical coagulation therapy) within 4 weeks before enrollment.
11. Gastrointestinal disease resulting in an inability to take oral medication or a requirement 
for intravenous hyperalimentation.
12. History of any infection requiring hospitalization or intravenous antibiotics within 2 weeks 
before enrollment.
13. Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) 
with no evidence of progression and neurologically stable off anticonvulsants and steroids.
14. Known human immunodeficiency virus infection.
15. Unstable angina, myocardial infarction, cerebrovascular accident, ≥ Class II congestive 
heart failure according to the New York Heart Association Classification for Congestive 
Heart Failure (see Appendix 4) within 6 months before enrollment.
16. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin.
17. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure 
> 90 mmHg despite optimal medical management).
18. Using and unable to discontinue use of concomitant strong CYP3A4 inducers 
(eg, including but not limited to St. John’s Wort, dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, phenobarbital).
19. Pregnant female or nursing mother. All females with an intact uterus (unless amenorrheic 
for the 24 months before enrollment) must have a negative serum pregnancy test at 
screening. All non-sterile or non-postmenopausal females must practice a medically 
accepted method of contraception over the course of the study and for 60 days after the 
last dose of study agent.
20. Males who do not agree to use effective contraception during the study and for a period of 
60 days following the final dose of study agent.
21. Subject is currently enrolled in or has not yet completed at least 30 days since ending 
other investigational device or drug study(s) or subject is receiving other investigational 
agents.
22. Acute or chronic severe renal insufficiency (glomoerular filtration rate 
< 30 mL/min/1.73 m2) or acute renal insufficiency of any severity due to 
the hepato-renal syndrome.
23. Hepatitis B virus DNA levels > 2,000 IU/mL.
Study Design and Schedule:
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma. In addition to receiving sorafenib, subjects will be 
randomly assigned to 1 of 2 treatment groups in a 1:1 ratio to receive 30 mg/kg 
mapatumumab or placebo.
Randomization will be stratified according to BCLC advanced stage C vs BCLC intermediate 
stage B and ECOG performance status (0 vs 1, 2). 


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Approximately 100 advanced HCC subjects will be randomized/enrolled.  
Study Treatment:
Mapatumumab will be supplied in open label vials and third party unblinding will be 
employed. The study agent will be reconstituted by the unblinded site pharmacist or unblinded 
designee. The unblinded site pharmacist or unblinded designee will also be the person 
responsible for receiving and dispensing study agent but independent of all other study 
activities. All other study personnel, the subject, the Sponsor will remain blinded to the study 
agent received. Separate monitors will be responsible for the clinical (blinded monitor) and 
study agent (unblinded monitor) aspects of the study.
Subjects will receive treatment every 21 days (ie, a cycle) as outlined below:
Arm A: 
Sorafenib 400 mg orally twice daily continuously in each cycle + placebo 
intravenously on Day 1 of each cycle.
Arm B:
Sorafenib 400 mg orally twice daily continuously + mapatumumab (30 mg/kg) 
intravenously on Day 1 of each cycle.
Subjects will continue to receive study treatment(s) until radiologic disease progression or 
unacceptable toxicity. Subjects unable to tolerate sorafenib may continue to receive 
mapatumumab/placebo every 21 days until radiographic progression. Subjects unable to 
tolerate mapatumumab/placebo may continue to receive sorafenib until radiographic 
progression. Subjects who completed more than 24 months of study treatment with sorafenib 
with or without mapatumumab and who in the opinion of the investigator obtain clinical 
benefit from treatment, will be allowed to continue treatment with sorafenib with or without 
unblinded mapatumumab in the clinical trial.  This extension of treatment will continue until 
the subject’s disease progresses or they withdraw from study. In addition extension of 
treatment with mapatumumab will not extend beyond the expiry date of the drug batch 
(March 2016).
All subjects will have an end of treatment visit at least 30 days after the last dose of sorafenib 
and/or mapatumumab/placebo whichever is later, for scheduled safety follow-up assessments. 
During the Extended Access phase, subjects will have regular visits for assessment of disease 
response at least every 3 months or as per standard of care, whichever is sooner. In addition,
BP will be monitored every 6 weeks and recorded in the eCRF. Serious AEs will continue to 
be collected during this Extended Access phase according to Section 8. Study drug 
administration and inventory/accountability will continue to be recorded during this period 
according to Section 5.
Disease Assessments:
Radiologic disease assessments along with assessment of alpha fetoprotein will be performed 
at the end of every two 21-day cycles (ie, Cycles 2, 4, 6 and every 2 cycles thereafter). The 
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disease assessment will be performed and documented no earlier than 5 days before the start 
of the next cycle. Clinical responses will be evaluated according to mRECIST for HCC (see 
Section 6.8 and Appendix 5). The same assessment method will be used throughout the study 
for each subject. If disease progression is based only on new lesions or is equivocal, images 
will be provided to the blinded, independent, central reader (BICR) for confirmation of 
disease progression. Partial response (PR) and complete response (CR) will be confirmed at 
the next scheduled disease assessment (no fewer than 4 weeks after the initial documentation 
of PR or CR). All imaging scans used for disease assessments will be made available for 
independent radiology review by the Sponsor or designee.
During the Extended Access phase, subjects will have regular visits for assessment of disease 
response at least every 3 months or as per standard of care, whichever is sooner, until disease 
progression is documented. Independent radiological review for confirmation of disease 
progression is not required.
Safety Assessments:
The safety of sorafenib and mapatumumab will be assessed by evaluation of the type, 
frequency, and severity of adverse events (ie, according to the NCI-CTCAE Version 4.0
grading) and changes in clinical laboratory tests (hematology and clinical chemistry) and 
immunogenicity over time. In the event that an adverse event does not have an NCI-CTCAE 
Version 4.0 grading, the severity grades in Section 8.6 will be used. Adverse events (including 
serious adverse events) will be captured from the start of study agent administration (sorafenib 
and/or mapatumumab/placebo) through at least 30 days following the last dose of sorafenib 
and/or mapatumumab/placebo, whichever is later. Laboratory assessments will be performed 
at screening, and during each study visit outlined in the study calendar found in Section 6.3.
During the Extended Access phase, laboratory assessments will be performed as per standard 
of care; SAEs will continue to be collected according to Section 8.
The Human Genome Sciences Review Committeee (HGSRC) is comprised of the Department 
Heads of Biostatistics, Regulatory Affairs and Drug Development. The HGSRC will review 
safety data after: (1) 10 subjects have completed 1 cycle; and (2) 30 subjects have completed 
1 cycle. HGSRC reviews of safety data will be conducted approximately every 4 months 
thereafter, until 90% of subjects have reached radiologic progression. The HGSRC may 
conduct additional reviews at their own request and/or at the request of the Medical Monitor. 
The HGSRC may request the unblinding of treatment assignment for a subject and/or 
treatment groups. If treatment assignments are unblinded, the rationale for the unblinding will 
be documented.
Immunogenicity:
Blood samples for serum antibodies to mapatumumab will be obtained as outlined in Table 6-
1.
Dose Modification/Delay:
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Dose modifications will not be allowed for mapatumumab/placebo. Dose modifications of 
sorafenib for toxicity will be made according to the guidelines provided in the treatment 
section (Section 5.2.3) of the protocol.
Details regarding pre-treatment and management of hypersensitivity reactions related to 
mapatumumab are provided in Section 5.1.5 and Appendix 8.
Pharmacokinetics:
Multiple blood specimens will be obtained from subjects for serum mapatumumab 
concentration determinations as outlined in Table 6-1.
Pharmacodynamics:
Subjects will be given the option to participate in a biomarker research sub-study. Consenting 
subjects will be asked to provide a historically obtained biopsy sample, if available, and 
several blood samples. In addition, samples will be requested from subjects who undergo a 
biopsy during the treatment period.
To examine biomarkers present peripherally, blood will be drawn during Cycles 1 and 2, from 
which DNA and serum proteins will be isolated. The biomarker sub-study is detailed in 
Appendix 6.
Exploratory Assessments:
Blood samples will be collected for quantification of B and T lymphocyte subsets on Day 1 
(prior to dosing) and Day 15 of Cycles 1 and 2.
Study Endpoints:
The following will be evaluated (these endpoints and the respective analyses are defined in 
Section 9):
Primary:
•
Time to progression (TTP).
Secondary:
•
Overall survival.
•
Progression-free survival.
•
Objective response (complete response [CR] + partial response [PR]).
•
Disease control (CR + PR + stable disease [SD]).
•
Response duration and time to response in responders.
•
Frequency and severity of treatment-emergent adverse events.
•
Laboratory parameters.


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•
Serum mapatumumab concentrations for use in a population pharmacokinetic analysis.
Statistical Methods:
Sample Size:
A total of approximately 100 subjects will be randomly assigned to 1 of 2 arms and treated 
with either sorafenib + placebo or the 2-agent combination of sorafenib and mapatumumab at 
30 mg/kg in a 1:1 ratio. A sample size of 50 subjects randomized and treated in each group is 
sufficient to estimate the median time to progression with a precision of approximately -1.9 M 
to +2.6 M relative to the observed median. In addition, a sample size of 50 patients per arm 
will provide 80% power to detect an improvement in TTP from 5.5 to 8.9 M with at a 
one-sided significance level of 0.10.
Statistical Analysis:
The primary analysis will be an estimate of median time to progression in each arm using 
Kaplan Meier methods, reported with 95% confidence intervals, along with testing the 
hazard ratio for time to progression at a 1-sided significance level of 0.10 with a Cox 
proportional hazards model controlling for the factors stratifying the randomization as 
covariates. Secondary analyses include estimates, using Kaplan Meier methods, of median 
progression-free survival (PFS) and median overall survival (OS) along with associated 
logrank testing. In addition, estimates of overall response rate (CR+PR) and disease control 
rate (CR+PR+SD) will be reported with 95% confidence intervals and an estimate of the 
difference in response rates and disease control rates between groups will be reported and 
tested for significance with a Pearson chi-square test (or Fisher’s exact test). For frequency 
and severity of adverse events and laboratory toxicity grading, counts and rates will be 
presented.
Study Calendar:
The study calendar is located in Section 6.3 of the protocol.
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Table of Contents
Revision Chronology for HGS1012-C1103 (200149)................................................................ 2
Study Synopsis ........................................................................................................................... 4
Table of Contents...................................................................................................................... 11
List of Tables............................................................................................................................ 14
List of Abbreviations................................................................................................................ 15
1
Background......................................................................................................................... 17
1.1
Hepatocellular Carcinoma........................................................................................ 17
1.2
Treatment Options for Patients with Hepatocellular Carcinoma.............................. 17
1.3
The Role of the TRAIL Pathway in HCC ................................................................ 17
1.3.1
TRAIL and TRAIL Receptors...................................................................... 17
1.3.2
TRAIL and HBV/HCV Infection ................................................................. 18
1.4
Mapatumumab.......................................................................................................... 18
1.4.1
Mapatumumab Pharmacology...................................................................... 18
1.4.2
Non-Clinical Mapatumumab Safety Studies ................................................ 19
1.4.3
Clinical Experience with Mapatumumab ..................................................... 20
1.5
Rationale for the Evaluation of Mapatumumab in Combination with Sorafenib 
in Hepatocellular Carcinoma.................................................................................... 21
1.6
Rationale for Dose Selection.................................................................................... 22
2
Study Objectives................................................................................................................. 23
2.1
Primary Objective..................................................................................................... 23
2.2
Secondary Objective................................................................................................. 23
3
Study Design....................................................................................................................... 23
3.1
Basic Design Characteristics .................................................................................... 23
4
Inclusion and Exclusion Criteria ........................................................................................ 25
4.1
Inclusion Criteria...................................................................................................... 25
4.2
Exclusion Criteria..................................................................................................... 26
5
Study Treatment Regimen.................................................................................................. 27
5.1
Mapatumumab and Placebo...................................................................................... 27
5.1.1
Formulation .................................................................................................. 27
5.1.2
Packaging, Labeling, Preparation, and Storage............................................ 27
5.1.3
Mapatumumab/Placebo Dose, Route of Administration and Schedule ....... 28
5.1.4
Mapatumumab/Placebo Dose Toxicity/Delay.............................................. 28
5.1.5
Management of Allergic/Hypersensitivity Reactions to 
Mapatumumab/Placebo ................................................................................ 29
5.2
Sorafenib................................................................................................................... 30
5.2.1
Packaging, Labeling, Preparation, and Storage............................................ 30


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5.2.2
Anticipated Toxicities with Sorafenib.......................................................... 30
5.2.3
Alteration of Sorafenib Dose/Schedule Due to Toxicity.............................. 30
5.3
Concurrent Medications and Therapies.................................................................... 33
5.3.1
Allowable Regimens..................................................................................... 33
5.3.2
Prohibited Medications................................................................................. 34
5.3.3
Prohibited Therapies..................................................................................... 34
6
Study Procedures ................................................................................................................ 34
6.1
Screening Procedures ............................................................................................... 34
6.2
Study Enrollment/Randomization Procedures.......................................................... 35
6.3
On-treatment Study Procedures................................................................................ 36
6.4
Extended Access to Study Drug............................................................................... 39
6.5
Safety Follow-up ...................................................................................................... 39
6.6
Withdrawal of Subjects from Treatment .................................................................. 39
6.7
Withdrawal of Subjects from Study ......................................................................... 40
6.8
Disease Response Assessments................................................................................ 40
6.8.1
Disease Response Assessments for Subjects in the Extended Access 
Phase............................................................................................................. 41
6.9
Treatment after the end of the Study ........................................................................ 41
7
Pharmacokinetic, Immunogenicity, Pharmacodynamic and Exploratory Assessments..... 41
7.1
Pharmacokinetic Assessments.................................................................................. 41
7.2
Immunogenicity........................................................................................................ 41
7.3
Pharmacodynamic Assessments............................................................................... 41
7.4
Exploratory Assessments (B and T Lymphocyte Subsets)....................................... 42
7.4.1
Rationale for B and T Lymphocyte Analysis ............................................... 42
7.4.2
Collection of Samples for B and T Lymphocyte Analysis........................... 42
8
Adverse Event Reporting.................................................................................................... 42
8.1
Definitions ................................................................................................................ 42
8.2
Reporting Adverse Events to the Sponsor or Designee............................................ 43
8.3
Laboratory Abnormalities as Adverse Events.......................................................... 43
8.4
Other Events Requiring Rapid Reporting................................................................. 44
8.5
Reporting a Pregnancy.............................................................................................. 44
8.6
Investigator Evaluation of Adverse Events .............................................................. 44
8.7
Follow-up of Adverse Events................................................................................... 46
8.8
Regulatory Reporting Requirements for SAEs ........................................................ 46
8.9
Reporting Serious Adverse Events to the Institutional Review Board/Ethics 
Committee ................................................................................................................ 46
9
Endpoints and Statistical Analysis ..................................................................................... 47


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9.1
General Statistical Considerations............................................................................ 47
9.2
Sample Size Rationale.............................................................................................. 47
9.3
Efficacy..................................................................................................................... 47
9.3.1
Primary Efficacy Endpoint........................................................................... 47
9.3.2
Primary Efficacy Analysis............................................................................ 47
9.3.3
Secondary Efficacy Endpoints...................................................................... 47
9.3.4
Secondary Efficacy Analyses ....................................................................... 48
9.4
Safety........................................................................................................................ 48
9.4.1
Definition of Safety Variables...................................................................... 48
9.4.2
Human Genome Sciences Safety Review Committee.................................. 48
9.4.3
Analysis of Safety Variables ........................................................................ 48
9.5
Pharmacokinetics...................................................................................................... 49
9.5.1
Definition of Pharmacokinetic Evaluation ................................................... 49
9.5.2
Analysis of Pharmacokinetics ...................................................................... 49
9.6
Pharmacodynamics................................................................................................... 49
10 Study Administration.......................................................................................................... 49
10.1 Informed Consent ..................................................................................................... 49
10.2 Institutional Review Board Review/Independent Ethics Committee Review and 
Approval ................................................................................................................... 50
10.3 Protocol Compliance ................................................................................................ 50
10.4 Protocol Revisions.................................................................................................... 50
10.5 Data Collection and Management ............................................................................ 50
10.6 Study Monitoring...................................................................................................... 51
10.7 Drug Accountability ................................................................................................. 51
10.8 Retention of Records ................................................................................................ 52
10.9 Financial Disclosure ................................................................................................. 52
10.10 Publication Policy..................................................................................................... 52
10.11 Study or Study Site Termination .............................................................................. 52
11 References .......................................................................................................................... 54
List of Appendices.................................................................................................................... 61


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List of Tables
Table 5-1
Sorafenib dose levels........................................................................................ 31
Table 5-2
Dose modifications of sorafenib for skin toxicity ............................................ 31
Table 5-3
Dose modifications of sorafenib for hypertension ........................................... 32
Table 5-4
Dose modifications of sorafenib for sorafenib-associated toxicity .................. 33
Table 6-1
Study calendar .................................................................................................. 36


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List of Abbreviations
AE
adverse event
AFP
α - fetoprotein
ALT
alanine transaminase
AST
aspartate transaminase
BCLC
Barcelona Clinic Liver Cancer
BICR
blinded independent central read
CR
complete response
CT
computerized tomography
dL
deciliter
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
ECOG
Eastern Cooperative Oncology Group
Fc
heavy chain constant region or fragment of antibody
GGT
gamma-glutamyl transpeptidase
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HGS
Human Genome Sciences
HGSRC
Human Genome Sciences Review Committee
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
International normalized ratio
IR
incomplete response
IRB
Institutional Review Board
kg
kilogram
mg
milligram
mL
milliliter
mm
millimeter
mmHg
millimeters of mercury
mRECIST
modified RECIST assessment for HCC
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
ng
nanogram
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OS
overall survival
PD
progressive disease
PK
pharmacokinetics
PPT
partial thromboplastin time
PR
partial response
PS 
performance status
PT
prothrombin time


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RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
SAE
serious adverse event
SD
stable disease
TNF
tumor necrosis factor
TRAIL
tumor necrosis factor-related apoptosis-inducing ligand
TRAIL-R1
TRAIL receptor 1
TRAIL-R2
TRAIL receptor 2
TTP
time to progression


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1 Background
1.1
Hepatocellular Carcinoma
Hepatocellular carcinoma is the 5th most common cancer worldwide accounting for 2% of all 
malignancies. It is the 3rd leading cause of cancer-related death globally with 1 million new 
cases a year (WHO, 2002; IACR, 2002; Ferlay et al, 2004; Lopez et al, 2006).
Hepatocellular carcinoma is more prevalent in males with a male:female ratio as high as 8:1. 
Depending on the endemic risk factors, hepatocellular carcinoma is diagnosed during the 
4th through 6th decades of life. The reported incidence of  hepatocellular carcinoma is 
increasing because of a better ability to diagnose the disease and because of the long-term 
consequences of hepatitis C virus (HCV) and hepatitis B virus (HBV) infection (Ries et al, 
2006). Worldwide the most common cause of hepatocellular carcinoma is chronic HBV 
infection (El-Serag et al, 2003). Endemic areas thus include China, South Asia and 
South Africa where the incidence of hepatocellular carcinoma can be as high as 120 cases 
per 100,000. In the United States, where HCV and alcohol are the main risk factors, 
the age-adjusted incidence rates have increased from 1.4 cases per 100,000 in 1980 to a 
current incidence of 4 cases per 100,000. This equates to about 8500-11,000 new cases 
diagnosed each year (IACR, 2002; Ferlay et al, 2004; Pawlik et al, 2004; Edwards, et al, 2005; 
Jemal et al, 2007; Bosch et al, 2004).
1.2
Treatment Options for Patients with Hepatocellular Carcinoma
Surgery, including transplantation, is the only curative modality for hepatocellular carcinoma 
(Venook, 1994; Cha et al, 2003). The 5-year survival rate for patients with unresectable 
hepatocellular carcinoma is 11% in the US (ACS, 2007), < 8% in Europe (Capocaccia et al, 
2007), and < 10% in Asia (Teo and Fock, 2001). Symptomatic hepatocellular carcinoma has a 
very poor prognosis with a median survival of 1–8 months (Forner et al, 2006; Llovet et al, 
1999a, Llovet et al, 1999b).
Sorafenib, a multikinase inhibitor, is the 1st systemic therapy to significantly impact survival 
in patients with advanced hepatocellular carcinoma, as demonstrated in an international, 
multicenter Phase 3, placebo-controlled trial (Llovet et al, 2008). Sorafenib was approved in 
the United States and European Union for the 1st-line treatment of advanced hepatocellular 
carcinoma in late 2007 and the 2008 National Comprehensive Cancer Network guidelines 
have been updated with the addition of sorafenib as a treatment option for hepatocellular 
carcinoma patients. The updated Barcelona Clinic Liver Cancer (BCLC) guidelines 
recommend sorafenib for hepatocellular carcinoma patients with BCLC Advanced Stage (C) 
(Forner et al, 2010).
1.3
The Role of the TRAIL Pathway in HCC
1.3.1
TRAIL and TRAIL Receptors
TRAIL is a member of the tumor necrosis factor (TNF) ligand superfamily, with homology 
to Fas/Apo1 ligand (Pitti et al, 1996; Wiley et al, 1995). TRAIL induces programmed 
cell death primarily in tumor cells through activation of TRAIL death receptors, TRAIL-R1 


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(death receptor 4) or TRAIL-R2 (death receptor 5) (Ashkenazi et al, 1999; Evdokiou et al, 
2002; Kothny-Wilkes et al, 1998; Lawrence et al, 2001; Pitti et al, 1996; Walczak et al, 1999; 
Wiley et al, 1995).
TRAIL-R1, the target of mapatumumab, is detectable on tumor cells derived from colon, lung, 
liver, gastric, pancreas, uterus and esophagus and in tissue sections from various tumors of the 
colon, lung, pancreas, liver and stomach without significant expression in parallel normal 
tissues (Halpern et al, 2004; Roach et al, 2004).
1.3.2
TRAIL and HBV/HCV Infection
Acutely infected tissues, including the liver, utilize the TRAIL pathway to eliminate virally 
and bacterially infected cells (Herr et al, 2007). In viral hepatitis, TRAIL and 1 of its 
receptors, TRAIL-R2, are upregulated and contribute to the elimination of infected 
hepatocytes associated with viral hepatitis (Bantel and Schulze-Osthoff, 2003; Lin et al, 2002; 
Matsuda et al, 2005). In addition to HBV and HCV infection, steatosis, exposure to bile acids 
and chronic alcohol exposure induce increased expression of TRAIL and TRAIL-R2, but not 
TRAIL-R1, in human hepatocytes (Dunn et al, 2007; Mundt et al, 2005). Cell surface 
expression of TRAIL-R2, but not TRAIL-R1, was altered and responsible for sensitization to 
TRAIL in hepatocytes exposed to bile acids (Higuchi et al, 2001; Malhi et al, 2007). These 
findings have been reproduced in preclinical models. Non-virally infected hepatocytes are 
refractory to TRAIL and TRAIL-R agonists but exposure of HCV-infected hepatocytes to 
TRAIL leads to a significant level of apoptosis (Volkmann et al, 2007). Inhibition of the 
TRAIL pathway may protect infected cells from apoptosis and allow for chronic infection 
(Mundt et al, 2003). Recent non-clinical observations demonstrated that natural killer cells 
expressing the ligand TRAIL, are enriched in the livers of patients with chronic HBV 
infection, and TRAIL is overexpressed in the livers of patients with HCV-associated steatosis 
(Mundt et al, 2005). 
In summary, preclinical data suggest that mapatumumab may promote apoptosis of cancer 
cells, including hepatocellular carcinoma cells. Whether viral infection, including HBV or 
HCV infection, will attenuate or modulate the effects of mapatumumab on hepatocytes is not 
yet known, but experience to date in a Phase 1b trial of mapatumumab in combination with 
sorafenib in subjects with advanced hepatocellular carcinoma who are positive for hepatitis B 
surface antigen or hepatitis C antibody indicates that the safety experience is consistent with 
underlying disease and known sorafenib toxicities (see Section 1.2).
1.4
Mapatumumab
1.4.1
Mapatumumab Pharmacology
Mapatumumab is a fully human, agonist monoclonal antibody that activates the cell death 
pathway in tumor cells by specifically binding to TRAIL-R1 with high affinity. 
Mapatumumab efficiently induces apoptosis in human cancer cell lines expressing the 
TRAIL-R1 protein on the cell surface. Nonclinical studies have demonstrated that 
mapatumumab can induce cytotoxicity in multiple tumor cell lines representing both solid and 
hematological malignancies, including cancers of the biliary tract, colon, lung, breast, 


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pancreas, esophagus, ovary, kidney, uterus, as well as lymphoma and various leukemias. 
Mapatumumab has also demonstrated anti-tumor activity as a single agent, preventing 
tumor growth and in some cases causing regression of tumors in xenograft tumor models of 
multiple human malignancies, including lung, colon, kidney, and uterus (Camidge, 2007; 
Georgakis et al, 2005; Jin et al, 2007; Humphreys, 2004; Marini et al, 2006; Menoret et al, 
2006; Pukac et al, 2005).
The relationship between receptor expression and response to therapy with mapatumumab 
remains unclear. In vitro studies of cell lines have shown that TRAIL-R1 expression level is 
not a consistent predictor of response to mapatumumab. Although both TRAIL-R1 expression 
and apoptosis in response to mapatumumab are increased in many tumor cell lines as 
compared with normal diploid cells, there are examples of mapatumumab cytotoxicity on cell 
lines with very low levels of detectable receptor, and conversely, mapatumumab resistant cell 
lines that have relatively high levels of TRAIL-R1 cell surface expression.
Tumor cell cytotoxic activity can be enhanced when mapatumumab is administered in 
combination with chemotherapeutics or other anti-neoplastic agents. Enhanced apoptotic 
signaling, in vitro cell killing and in vivo anti-tumor activity have been observed when 
mapatumumab has been combined with various types of therapeutic agents and treatments 
including microtubule poisons, anti metabolites, topoisomerase inhibitors, proteosome 
inhibitors, platinum agents and radiation. Both the level and spectrum of activity of 
mapatumumab is enhanced in in vitro cytotoxicity and in vivo xenograft studies in 
combination with various chemotherapeutic and anti-neoplastic agents, including a xenograft 
model of hepatocellular carcinoma in combination with cisplatin and gemcitabine 
(Camidge, 2007; Pukac et al, 2005; Georgakis et al, 2005; Humphreys, 2004; Jin et al, 2007; 
Human Genome Sciences data on file).
Please refer to the mapatumumab Investigator’s Brochure for detailed information regarding 
the nonclinical pharmacology, toxicology, and PK of mapatumumab.
1.4.2
Non-Clinical Mapatumumab Safety Studies
To assess the nonclinical safety of mapatumumab, a 6-month toxicity study, with a 4-month 
recovery period, was conducted in chimpanzees. Mapatumumab was administered 
intravenously at up to 40 mg/kg every 10 days. No mapatumumab-specific toxicity was 
identified and no anti-mapatumumab antibodies were detected.
To assess its off-target effects, mapatumumab was administered intravenously weekly to 
cynomolgus monkeys, whose TRAIL R1 homolog does not bind mapatumumab. 
Mapatumumab was well tolerated at doses of up to 50 mg/kg and was not highly 
immunogenic: of the 40 monkeys treated, 1 developed anti-mapatumumab antibodies. The 
positive response was observed in an animal in the high dose (50 mg/kg) group.
In vitro, mapatumumab was found to decrease viability of normal human hepatocytes, 
although the observed effect was less than that observed with TRAIL. This effect was variable 
across donors and did not amplify with increasing concentrations of mapatumumab. It should 


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be noted that in clinical studies, plasma mapatumumab concentrations have been achieved that 
are > 1100–fold greater than the minimum exposure resulting in reduced in vitro hepatocyte 
viability. Despite this, the clinical results do not reveal evidence of hepatotoxicity in those 
studies. Hence it appears that the in vitro hepatocyte viability assay is not predictive of 
mapatumumab effects in vivo.
1.4.3
Clinical Experience with Mapatumumab
Over 400 subjects have received mapatumumab in clinical trials to date. Preliminary clinical 
data are available from 218 subjects who received mapatumumab as a single agent at doses 
ranging from 0.01 to 20 mg/kg across 6 clinical trials.
Based on available data, mapatumumab appears to be well tolerated and no significant safety 
issues have been observed. Adverse events have generally been mild to moderate in severity, 
manageable, and do not appear related to dose. The most frequently reported treatment-related 
adverse events occurring in > 10% of subjects were fatigue, hypotension, nausea and pyrexia. 
Severe events have been uncommon and generally judged not related to mapatumumab. 
Severe events judged at least possibly related to mapatumumab have been observed and a 
complete list can be found in the mapatumumab Investigator’s Brochure. Grade 3 or Grade 4 
hematologic, renal, or hepatic laboratory abnormalities also have been relatively uncommon 
with no significant trend or dose-response evident. Lymphopenia was the most commonly 
observed laboratory abnormality, but tended to be intermittent and reversible and was not 
associated with infectious events.
In subjects with solid tumors, stable disease has been the best response observed with 
mapatumumab as a single-agent. However, 2 complete responses (CRs) and 1 partial response 
(PR) were observed in subjects with follicular lymphoma.
In addition, preliminary clinical data are available from 234 subjects who received 
mapatumumab at doses ranging from 1 to 30 mg/kg every 21 days in combination with 
chemotherapy in 5 clinical trials (carboplatin/paclitaxel [N = 100], gemcitabine/cisplatin 
[N = 49], bortezomib [n = 69], or sorafenib [n = 16]. Mapatumumab has been generally well 
tolerated; adverse events and laboratory abnormalities have been consistent with those 
expected with underlying disease or chemotherapy. A listing of severe events considered at 
least possibly related to mapatumumab can be found in the mapatumumab Investigator’s 
Brochure. The most commonly occurring laboratory abnormalities have been hematologic 
(ie, anemia, neutropenia, thrombocytopenia, and leukopenia), as expected with chemotherapy. 
Grade 3/4 laboratory abnormalities have been relatively uncommon. Higher frequencies of 
Grade 3/4 neutropenia, leukopenia, lymphopenia, and thrombocytopenia have been observed. 
Data from randomized Phase 2 studies in combination with chemotherapy suggest that 
mapatumumab may increase rates of lymphopenia.
One subject receiving mapatumumab in combination with carboplatin/paclitaxel has 
achieved a CR. Twenty-two subjects receiving mapatumumab in combination with 
paclitaxel/carboplatin and 12 subjects receiving mapatumumab in combination with 
gemcitabine/cisplatin have achieved PRs. Three subjects receiving mapatumumab in 


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combination with bortezomib achieved CRs; 25 subjects receiving mapatumumab in 
combination with bortezomib achieved a PR.  
1.5
Rationale for the Evaluation of Mapatumumab in Combination with 
Sorafenib in Hepatocellular Carcinoma
Sorafenib is the standard of care for treatment of patients with advanced hepatocellular 
carcinoma. Sorafenib is a multikinase inhibitor that targets the Raf/mitogen-activated protein 
kinase/extracellular signal-regulated kinase signaling pathway, blocks tumor angiogenesis and 
induces apoptosis (Panka et al, 2006; Rahmani et al, 2005; Yu et al, 2005; Wilhelm et al, 
2004). Sorafenib was approved by the European Medicines Agency and the Food and Drug 
Administration in 2007 for treatment of patients with hepatocellular carcinoma based on the 
demonstration of improved overall survival in the 602 patient randomized, placebo-controlled, 
Phase 3 “Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol” (SHARP)
trial. Approximately half the 602 patients had either hepatitis C virus or hepatitis B virus as 
underlying etiology and 26% had alcohol-related cirrhosis. The median overall survival was 
10.7 months for patients in the sorafenib arm compared with 7.0 months for patients in the 
placebo arm (hazard ratio in the sorafenib group, 0.69 95% confidence interval, 0.55 to 0.87; 
p < 0.001). The median time to radiologic progression was 5.5 months in the sorafenib arm, 
compared with 2.8 months in the placebo arm (p < 0.0001) (Llovet et al, 2008). Seven patients 
in the sorafenib group (2%) and 2 patients in the placebo group (1%) had a PR; no patients 
had a CR.
A 2nd randomized, placebo-controlled Phase 3 trial was conducted in the Asia-Pacific region 
(Cheng et al, 2009). The 226 patients randomly assigned to sorafenib or placebo in this trial 
appeared to have more advanced disease than those in the SHARP trial, with a higher 
frequency of extrahepatic spread, poorer ECOG PS, and higher levels of AFP, but still showed 
a benefit from treatment with sorafenib. The majority (73%) had hepatitis B virus as an 
underlying etiology. The median overall survival was 6.5 months for patients in the sorafenib 
arm, compared with 4.2 months in the placebo group (hazard ratio, 0.68, 95% confidence 
interval, 0.50-0.93; p = 0.014). The median time to progression was 2.8 months in the 
sorafenib group, compared with 1.4 months in the placebo group (hazard ratio, 0.57, 95% 
confidence interval 0.42-0.79; p = 0.0005).
The mechanisms of sorafenib and mapatumumab action suggest that these agents could 
interact synergistically. Sorafenib sensitizes human cancer cell lines, including cell lines 
derived from hepatocellular carcinoma, to apoptotic stimuli by reducing expression of 
apoptotic regulatory proteins; Mcl-1, Bcl-xL, and FLIP (Kim et al ,2008; Koehler et al, 2009; 
Rosato et al, 2007; Liu et al, 2006; Rahmani et al, 2005; Yu et al, 2005). Mcl-1, Bcl-xL 
and FLIP have also been shown to mediate sensitivity of a wide range of tumor cell lines 
to TRAIL receptor agonists (Meng et al, 2007; Rosato et al, 2007; Llobet et al 2010;
Blechacz et al, 2009; Katz et al, 2009; Huang and Sincrope, 2010; and Menoret et al, 2006). 
Recent studies demonstrated the combination of sorafenib with TRAIL or TRAIL receptor 
antibodies has significant activity in hepatocellular carcinoma cell lines (Koehler et al, 2009) 
and colon tumor xenografts (Ricci et al, 2007) that were resistant to TRAIL and an antibody 
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Mapatumumab activity has been evaluated preclinically in hepatocellular carcinoma cell lines 
by in vitro cytotoxicity assays both as a single agent and in combination with doxorubicin, 
cisplatin, gemcitabine or sorafenib. Single agent mapatumumab activity was observed in 4 of 
10 hepatocellular carcinoma cell lines. Increased in vitro cytotoxicity, including examples of 
synergy, were observed in 8 of 10 cell lines when mapatumumab was combined with 
doxorubicin or cisplatin or the combination of cisplatin and gemcitabine (Humphreys et al, 
2008). Two of these hepatocellular carcinoma cell lines were evaluated for in vitro 
cytotoxicity of mapatumumab in combination with sorafenib. One displayed an increase in 
cytotoxicity from 30% to 60% when treated with a combination of sorafenib and 
mapatumumab. Importantly, treatment of a primary human hepatocyte cell line did not induce 
any apoptosis at doses of mapatumumab that were cytotoxic to hepatocellular carcinoma cell 
lines (Abdulghani et al, 2008). Therefore, collectively, the expression of TRAIL-R1 in 
hepatocellular carcinoma and preclinical activity observed with combinations of 
mapatumumab with chemotherapy or sorafenib supports the rationale that this combination 
may be able to effectively target hepatocellular carcinoma.
1.6
Rationale for Dose Selection
As 
of 
June 
2010, 
mapatumumab 
has 
been 
administered 
with 
chemotherapy 
(ie, carboplatin/paclitaxel, gemcitabine/cisplatin, bortezomib, or sorafenib) to 234 subjects, 
including 61 subjects who received 20 mg/kg and 50 subjects who received 30 mg/kg 
mapatumumab. Based on available data, mapatumumab in combination with chemotherapy is 
generally well tolerated at dose levels up to and including 30 mg/kg, and no significant safety 
issues have been observed in the course of the clinical trials even at the higher doses.  
Preliminary PK data are available for subjects who received 1, 10, 20 or 30 mg/kg 
mapatumumab in combination with gemcitabine and cisplatin (n = 49), 10 or 30 mg/kg 
mapatumumab in combination with paclitaxel and carboplatin (n = 73), and 3, 10, or 
30 mg/kg mapatumumab in combination with sorafenib (n = 17). Serum or plasma 
mapatumumab concentrations are consistently within the range of expected concentrations 
predicted from Phase 1 study results in solid tumor patients administered mapatumumab as 
monotherapy. Mapatumumab PK is linear and not affected by the addition of therapeutic 
agents. As expected, the observed peak and trough levels of mapatumumab at 30 mg/kg are 
2 to 3 times higher than those observed at 10 mg/kg. Exposure appears to increase in 
proportion to dose and exposures for a given dose are similar across studies. 
A Phase 1b dose escalation study of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma who are positive for hepatitis B surface antigen or 
hepatitis C antibody is being conducted. Safety observations have been consistent with the 
underlying disease and known sorafenib toxicities. As of June 2010, 6 subjects have received 
3 mg/kg, 9 subjects have received 10 mg/kg, and 1 subject has received 30 mg/kg 
mapatumumab. The number of cycles completed ranges from 1 to 20; 4/16 (25.0%) of 
subjects have completed 11 or more cycles. Adverse events have generally been consistent 
with published reports of the toxicities associated with sorafenib and previous experience 
with mapatumumab, as well as underlying disease. The most frequently occurring 
treatment-emergent adverse events, regardless of severity or attribution of causality, 


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include diarrhea (10/16, 62.5%), fatigue (9/16, 56.3%), nausea (9/16, 56.3%), and vomiting 
(7/16, 43.8%). Serious adverse events, regardless of attribution of causality, include 
hypertension, upper respiratory tract infection, atrial fibrillation, hyperbilirubinemia, 
hypoglycemia, and hepatic pain. Severe adverse events considered at least possibly related to 
mapatumumab or its interaction with sorafenib include elevated lipase (3/16, 18.8%), hepatic 
pain (1/16, 6.3%), and thrombocytopenia (1/16, 6.3%). Laboratory abnormalities have 
generally been mild or moderate in severity, manageable, and/or consistent with those 
expected with chemotherapy or the underlying disease. The most frequent Grade 3 or Grade 4 
laboratory abnormalities include elevated total bilirubin (Grade 3, 4/16, 25.0%; Grade 4, 
1/16, 6.3%) and lymphopenia (Grade 3, 3/16, 18.8%; Grade 4, 2/16, 12.5%). Additional 
information on the safety experience can be found in the mapatumumab Investigators’ 
Brochure.
Based on the information currently available, the safety profile continues to be favorable, 
supporting continued evaluation of mapatumumab in combination with chemotherapy, 
including sorafenib. The maximum tolerated dose has not been reached in any of the Phase 1 
or Phase 2 trials conducted to date. Thus, further evaluation of the 30 mg/kg dose is 
warranted.
The dose of sorafenib for this study, 400 mg twice daily, is the approved dose for the 
treatment of unresectable hepatocellular carcinoma.
2 Study Objectives
2.1
Primary Objective
•
To evaluate the efficacy of mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma.
2.2
Secondary Objective
•
To evaluate the safety of the mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma.
•
To determine serum mapatumumab concentrations.
3 Study Design
3.1
Basic Design Characteristics
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma.  
In addition to receiving sorafenib, subjects will be randomly assigned to 1 of 2 treatment 
groups in a 1:1 ratio: 30 mg/kg mapatumumab or placebo.


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Mapatumumab will be supplied in open label vials and 3rd party unblinding will be employed. 
The study agent will be reconstituted by the unblinded site pharmacist or unblinded designee.
The unblinded site pharmacist or unblinded designee will also be the person responsible for 
receiving and dispensing study agent, but independent of all other study activities. All other 
study site personnel, the subject, and the Sponsor will remain blinded to the study agent 
received. Separate monitors will be responsible for the clinical (blinded monitor) and study 
agent (unblinded monitor) aspects of the study.
Number of Subjects:
Approximately 100 subjects with advanced HCC will be randomized/enrolled.
Treatment Groups:
Subjects will receive treatment every 21 days (ie, a cycle) as outlined below:
Arm A:
Sorafenib 400 mg orally twice daily continuously in each cycle + placebo 
intravenously on Day 1 of each cycle
Arm B: 
Sorafenib 400 mg orally twice daily continuously in each cycle + mapatumumab 
(30 mg/kg) intravenously on Day 1 of each cycle
Randomization
Randomization will be stratified according to BCLC advanced stage C vs BCLC intermediate 
stage B and ECOG performance status (0 vs 1, 2).
Estimated Study Duration:
The study is estimated to occur over approximately 24 months. Subjects will continue to 
receive sorafenib with or without mapatumumab/placebo until radiologic disease progression 
or unacceptable toxicity. Estimated median length of subject treatment is 6-8 months. Subjects 
who completed more than 24 months of study treatment with mapatumumab and/or sorafenib 
and who in the opinion of the investigator obtain clinical benefit from treatment, will be 
allowed to continue treatment with unblinded mapatumumab and/or sorafenib in the clinical 
trial.  This extension of treatment will continue until the subject’s disease progresses or they 
withdraw from study. In addition extension of treatment with mapatumumab will not extend 
beyond the expiry date of the drug batch (March 2016).
All subjects will have an End of Treatment visit at least 30 days after the last dose of 
sorafenib and/or mapatumumab/placebo, whichever is later, for scheduled safety follow-up 
assessments.
During the Extended Access phase, subjects will have regular visits for disease assessments 
according to local standard of care. The response assessment will be performed and 
documented at 12 week intervals (± 6 days). In addition BP will be monitored every 6 weeks 
and recorded in the eCRF. Serious AEs will continue to be collected during this Extended 
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Access phase according to Section 8. Study drug administration and inventory/accountability 
will continue to be recorded during this period according to Section 5.
4 Inclusion and Exclusion Criteria
4.1
Inclusion Criteria
Subjects enrolled in the study must meet the following inclusion criteria:
1. Child-Pugh Class A (see Appendix 1).
2. Barcelona Clinic Liver Cancer (BCLC) advanced stage (C) hepatocellular carcinoma, or 
BCLC intermediate stage (B) hepatocellular carcinoma if treatment with transarterial 
chemoembolization is not considered appropriate (see Appendix 2).
3. Measurable disease demonstrating intratumoral arterial enhancement by contrast enhanced 
computerized tomography (CT), with use of multislice scanners, or contrast enhanced 
dynamic magnetic resonance imaging (MRI), with at least 1 tumor lesion that meets the 
following criteria:
-
Located in the liver.
-
Can be accurately measured in at least 1 dimension.
-
Well delineated area of viable, hypervascular (contrast enhancement in the arterial 
phase) tumor that is > 2 cm in the axial plane.
-
Suitable for repeat measurement.
-
Not previously treated with locoregional or systemic treatment unless the lesion shows 
a well-delineated area of viable (contrast enhancement in the arterial phase) tumor that 
is > 2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical 
enhancement as a result of the previous intervention, then it cannot be selected as a 
target lesion).
4. Radiologic eligibility (measurable disease) must be must be confirmed by the BICR prior 
to randomization.
5. Adequate bone marrow, renal and liver function:
-
Absolute neutrophil count ≥ 1.5 x 109 /L or ≥ 1500 /mm3.
-
Platelet count ≥ 50 x 109 /L or ≥ 50,000 /mm3.
-
Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L) without growth factor support or transfusional 
support.
-
Serum creatinine level ≤ 2.0 mg/dL or ≤ 176.8 µmol/L.
-
Total bilirubin < 3.0 mg/dL or < 51.3 µmol/L.
-
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5.0 x upper limit of 
normal.
-
Amylase and lipase ≤ 1.5 x upper limit of normal.
-
Serum albumin ≥ 2.8 g/dL or ≥ 28 g/L.
-
International normalized ratio ≤ 1.5.
6. Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) 
Scale (see Appendix 3).
7. Age 18 years or older.
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8. Have the ability to understand the requirements of the study, provide written informed 
consent (including consent for the use and disclosure of research-related health 
information), and comply with the study and follow-up procedures.
4.2
Exclusion Criteria
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria:
1. Any co-morbid condition that in the judgment of the investigator renders the subject at 
high risk of treatment complications or reduces the possibility of assessing clinical effect.
2. Received prior investigational or non-investigational cytotoxic chemotherapy, hormonal 
therapy, biological therapy (including but not limited to monoclonal antibodies, small 
molecules or other immunotherapy) to treat hepatocellular carcinoma.
3. History of organ allograft.
4. Previously received mapatumumab or sorafenib.
5. Underwent resection, radiofrequency ablation, radiation or chemoembolization within 
4 weeks before enrollment or not recovered from such treatments.
6. Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy, 
immunotherapy, radiofrequency ablation) or other investigational agents during the study 
treatment period.
7. Major surgery (ie, the opening of a major body cavity, requiring the use of general 
anesthesia) within 4 weeks before enrollment; minor surgery (except for insertion of 
vascular access device) within 2 weeks before enrollment; or not yet recovered from the 
effects of the surgery.
8. Systemic steroids within 1 week before enrollment except steroids used as part of an 
antiemetic regimen or maintenance-dose steroids for non-cancerous disease.
9. Hepatic encephalopathy, per the investigator’s evaluation.
10. History of clinically significant gastrointestinal bleeding requiring procedural intervention 
(eg, variceal banding, transjugular intrahepatic portosystemic shunt procedure, arterial 
embolization, topical coagulation therapy) within 4 weeks before enrollment.
11. Gastrointestinal disease resulting in an inability to take oral medication or a requirement 
for intravenous hyperalimentation.
12. History of any infection requiring hospitalization or intravenous antibiotics within 2 weeks 
before enrollment.
13. Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) 
with no evidence of progression and neurologically stable off anticonvulsants and steroids.
14. Known human immunodeficiency virus infection.
15. Unstable angina, myocardial infarction, cerebrovascular accident, ≥ Class II congestive 
heart failure according to the New York Heart Association Classification for Congestive 
Heart Failure (see Appendix 4) within 6 months before enrollment.
16. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin.
17. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure 
> 90 mmHg despite optimal medical management).
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18. Using and unable to discontinue use of concomitant strong CYP3A4 inducers 
(eg, including but not limited to St. John’s Wort, dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, phenobarbital).
19. Pregnant female or nursing mother. All females with an intact uterus (unless amenorrheic 
for the 24 months before enrollment) must have a negative serum pregnancy test at 
screening. All non-sterile or non-postmenopausal females must practice a medically 
accepted method of contraception over the course of the study and for 60 days after the 
last dose of study agent.
20. Males who do not agree to use effective contraception during the study and for a period of 
60 days following the final dose of study agent.
21. Subject is currently enrolled in or has not yet completed at least 30 days since ending 
other investigational device or drug study(s) or subject is receiving other investigational 
agents.
22. Acute or chronic severe renal insufficiency (glomoerular filtration rate 
< 30 mL/min/1.73 m2) or acute renal insufficiency of any severity due to 
the hepato-renal syndrome.
23. Hepatitis B virus DNA levels > 2,000 IU/mL.
5 Study Treatment Regimen
Sorafenib will be administered at a dose of 400 mg twice daily without food (at least 1 hour 
before or 2 hours after a meal). On days when both sorafenib and mapatumumab/placebo are 
administered together, the sorafenib should be taken at the same time as any other calendar 
day.
5.1
Mapatumumab and Placebo
5.1.1
Formulation
Mapatumumab will be supplied as a lyophilized formulation in sterile, single-use 10 mL vials 
containing 100 mg mapatumumab. Upon reconstitution with 5.0 mL of sterile water for 
injection, each vial will contain 20 mg/mL mapatumumab in 0.13 mg/mL citric acid, 
2.8 mg/mL sodium citrate, 19 mg/mL glycine, 5 mg/mL sucrose, 0.2 mg/mL polysorbate 80, 
pH 6.5.
Two hundred-fifty mL normal saline solution for intravenous infusion will be administered as 
placebo for mapatumumab.
5.1.2
Packaging, Labeling, Preparation, and Storage
The Pharmacy Manual will provide instructions for preparation and storage of study agent. 
The product will be securely stored at 2-8ºC.
The study agent label will contain, at a minimum, the following information:
•
Product name
•
Concentration


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•
Lot number
•
Storage instructions
•
Investigational drug statement
•
Manufacturer’s name and address
Study agent inventory/accountability forms will be examined and reconciled by the unblinded 
study monitor or designee. At the end of the study, all used and unused investigational study 
agent will be accounted for on a study agent accountability form provided to the investigator 
by the Sponsor or designee. Please refer to the HGS1012-C1103 Pharmacy Manual for more 
details regarding storage, handling and drug accountability.
5.1.3
Mapatumumab/Placebo Dose, Route of Administration and Schedule
The dose of mapatumumab is 30 mg/kg. Mapatumumab dose calculations will be based upon 
the subject’s weight measured on Day 1 or within 3 days before Day 1 of each cycle. The 
planned duration of each treatment cycle will be 21 days. Mapatumumab/placebo will be 
administered on Day 1 of each cycle.
After reconstitution with sterile water for injection, the calculated mapatumumab dose to be 
administered to the subject will be further diluted in normal saline to a total volume of 
250 mL for intravenous infusion. After adding the reconstituted product, the bag will be 
gently inverted to mix the solution. Following reconstitution and/or dilution in normal saline, 
mapatumumab will be stored at 2-8ºC. The product will be administered to the subject within 
8 hours of reconstitution. Refer to the HGS1012-C1103 Pharmacy Manual for instructions on 
admixing and administering study agent. 
Two hundred-fifty mL normal saline solution for intravenous infusion will be administered as 
placebo for mapatumumab.
Mapatumumab/placebo will be infused at a constant rate over 1 hour.
Infusion and hypersensitivity reactions may occur. A suggested pre-medication regimen for 
mapatumumab/placebo consists of diphenhydramine and acetaminophen administered within 
1 hour prior to the start of the mapatumumab/placebo dose. Use of a pre-medication regimen 
and alternatives to this regimen are at the investigator’s discretion.
Subjects will be monitored closely during and after infusion for any sign of acute adverse 
reaction. If an allergic reaction occurs, see Section 5.1.5 and Appendix 8 for suggested 
medical management.
5.1.4
Mapatumumab/Placebo Dose Toxicity/Delay
Mapatumumab/placebo will be discontinued for Grade 4 transaminase elevations of any 
duration if they are considered related to mapatumumab.
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Mapatumumab/placebo may be delayed up to 2 weeks for toxicities considered related to 
mapatumumab as described below or if the investigator believes that a delay in dosing is 
warranted in the interest of subject safety.
The National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE, Version 4.0) will be used to grade AEs.
•
Grade 4 neutropenia for > 7 consecutive days or febrile neutropenia.
•
Grade 4 thrombocytopenia.
•
Grade 3 or greater non-hematologic AEs except transient transaminase, amylase and 
lipase abnormalities for which the following criteria will apply:
-
Grade 3 or Grade 4 elevations in transaminases that do not resolve to baseline or 
Grade 1 before the next cycle.
-
Grade 3 elevations in lipase or amylase associated with clinical/imaging findings of 
pancreatitis, or resulting in chronic damage to the pancreas. 
-
Any Grade 4 elevations in lipase or amylase for > 4 consecutive days.
If mapatumumab/placebo is delayed for toxicity and the toxicity does not resolve (≤Grade 1) 
or return to baseline within 2 weeks after the delayed dose was originally scheduled (based on 
a 21-day treatment cycle), the subject will be withdrawn from further treatment with 
mapatumumab/placebo. If mapatumumab/placebo is delayed because the investigator believes 
a delay is warranted in the interest of subject safety and dosing of mapatumumab/placebo is 
not resumed within 2 weeks after the delayed dose was originally scheduled (based on a 
21-day treatment cycle), the subject will be withdrawn from future treatment with 
mapatumumab/placebo. Sorafenib dosing will continue while mapatumumab/placebo dosing 
is held. The subject will continue receiving sorafenib until radiologic progressive disease or 
an unacceptable toxicity occurs, at the discretion of the Investigator. 
Doses of mapatumumab may not be altered.
5.1.5
Management of Allergic/Hypersensitivity Reactions to 
Mapatumumab/Placebo
The administration of any recombinant protein has the potential to induce local or system 
immunologic reactions; subjects could experience, for example, acute allergic reactions. To 
date, 2 such SAEs have been reported which were considered related to mapatumumab 
(hypersensitivity and angioedema/facial edema). In the event of allergic/hypersensitivity 
reactions, investigators will institute treatment measures according to best medical and 
nursing practice. Guidelines for treatment are provided in Appendix 8.
For a NCI-CTCAE Version 4.0 Grade 3 or Grade 4 hypersensitivity reaction, treatment with 
mapatumumab/placebo will be discontinued.
If mapatumumab/placebo is discontinued for Grade 3 or Grade 4 hypersensitivity reactions, 
the subject will continue to receive sorafenib, until radiologic progression or unacceptable 
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5.2
Sorafenib
5.2.1
Packaging, Labeling, Preparation, and Storage
Sorafenib is supplied as tablets, each containing 274 mg sorafenib tosylate, equivalent to 
200 mg of sorafenib.
The recommended daily dose of sorafenib is 400 mg (2 x 200 mg tablets) taken orally twice 
daily without food (at least 1 hour before or 2 hours after a meal).
Sorafenib will be stored at room temperature (15-30°C, 59-86°F) in a dry place.
For country-specific formulation and packaging information, please refer to the instructions 
provided in the sorafenib product labeling.
Supplier: Commercially available.
5.2.2
Anticipated Toxicities with Sorafenib
Toxicities anticipated with the use of sorafenib include the following:
•
Cardiac: Cardiac ischemia and/or infarction, hypertension.
•
Dermatologic: Hand-foot skin reaction, rash/desquamation.
•
Hemorrhagic: Increased risk of bleeding.
•
Gastrointestinal: Gastrointestinal perforation.
•
Other: Wound-healing complications, fatigue, weight-loss, alopecia, pruritis, dry skin, 
diarrhea, anorexia, nausea, vomiting, constipation, liver dysfunction and abdominal pain.
Laboratory abnormalities observed in hepatocellular carcinoma patients treated with sorafenib 
include hypophosphatemia, lipase elevations, amylase elevations, hypoalbuminemia, 
international normalized ratio elevations, lymphopenia and thrombocytopenia.
Refer to the product labeling accompanying the product for information approved in your 
country.
5.2.3
Alteration of Sorafenib Dose/Schedule Due to Toxicity
Sorafenib may be reduced or delayed for toxicities considered related to sorafenib as 
described below, or if the investigator believes that a reduction in dose is warranted in the 
interest of subject safety. When a dose reduction is necessary, sorafenib dose may be 
reduced to 400 mg once daily. If an additional dose reduction is required, sorafenib may be 
reduced to a single 400 mg dose every other day (see Table 5-1). A maximum of 2 dose 
reductions of sorafenib will be allowed per subject. Additional dose reductions not mentioned 
in Table 5-1 will need to be discussed with the medical monitor.


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Table 5-1
Sorafenib dose levels
Dose Levels
Sorafenib
0
400 mg twice daily
-1
400 mg once daily
-2
400 mg once every other day
Skin toxicity and hypertension are associated with sorafenib. Guidelines for the management 
of these events are provided in Table 5-2 and Table 5-3, respectively.
Skin Toxicity
Hand-foot skin reaction and rash are common in subjects treated with sorafenib. Management 
may include topical therapies for symptomatic relief, temporary treatment interruption and/or 
dose modification, or in severe or persistent cases, permanent discontinuation. Skin toxicities 
will be managed according to Table 5-2.
Table 5-2
Dose modifications of sorafenib for skin toxicity
Skin Toxicity Grade
Occurrence
Suggested Dose Modification
Grade 1: 
Numbness, dysesthesia, parethesia, 
tingling, painless swelling, erythema or 
discomfort of the hands or feet which does 
not disrupt the subject’s normal activities.
Any occurrence
Continue treatment with sorafenib 
and consider topical therapy for 
symptomatic relief.
Grade 2: 
Painful erythema and swelling of the hands 
or feet and/or discomfort affecting the 
subject’s normal activities.
1st occurrence
Continue treatment with sorafenib
and consider topical therapy for 
symptomatic relief. If no improvement 
within 7 days, see below.
No improvement within 
7 days or 2nd or 3rd
occurrence
Interrupt sorafenib treatment 
until toxicity resolves to Grade 0-1.
When resuming treatment, decrease
sorafenib dose by 1 dose level 
(400 mg daily or 400 mg every 
other day).
4th occurrence
Discontinue sorafenib treatment.
Grade 3: 
Moist desquamation, ulceration, blistering 
or severe pain of the hands or feet, or 
severe discomfort that causes the subject 
to be unable to work or perform activities of 
daily living.
1st or 2nd occurrence
Interrupt sorafenib treatment 
until toxicity resolves to Grade 0-1.
When resuming treatment, decrease 
sorafenib dose by 1 dose level 
(400 mg daily or 400 mg every 
other day).
3rd occurrence
Discontinue sorafenib treatment.


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Hypertension
Hypertension is a known and potentially serious adverse event associated with sorafenib 
treatment. Subjects will have their blood pressure monitored and recorded. If the subject’s 
blood pressure is elevated at any time (> 150/100 mmHg), even outside clinic visits, they will 
contact their study investigator. Guidelines for the management of hypertension are provided 
in Table 5-3.
Table 5-3
Dose modifications of sorafenib for hypertension
Grade
(CTCAE v3.0)
Antihypertensive Therapy
Blood Pressure 
Monitoring
Sorafenib 
Dose
Grade 1
None
Routine
No change
Grade 2
(asymptomatic)
Initiate monotherapy
(suggest dihydropyridine
calcium channel blocker)
Increase frequency and monitor by 
a health professional every 2 days
until stabilized.
No change
Grade 2 
(symptomatic/ 
persistent)
OR
diastolic BP 
> 110 mm Hg
OR
Grade 3
Add agent(s):
calcium channel blocker
(if not already used),
K+ channel opener
(angiotensin blockers), 
beta-blocker,
thiazide diuretic
Increase frequency and monitor by 
health professional every 2 days 
until stabilized; continue monitoring 
every 2 days to stabilization after 
dosing restarted.
Hold* sorafenib until 
symptoms resolve 
and
diastolic BP 
< 100 mm/Hg
Resume treatment 
at 1 dose level 
lower**
Grade 4
Discontinue sorafenib
Discontinue sorafenib
Discontinue 
sorafenib
*Subjects requiring a delay of > 21 days will discontinue sorafenib, unless in the study investigator’s opinion, 
the subject may benefit from continued treatment.
**Subjects requiring > 2 dose reductions will discontinue sorafenib.
BP = Blood pressure.
Refer to NCI-CTCAE v4.0 for grade definitions.
(concluded)
Guidelines 
for 
the 
management 
of 
other 
non-hematologic 
and 
hematologic 
sorafenib-associated toxicities are provided in Table 5-4. Those toxicities that are at least 
possibly related to an interaction with mapatumumab/placebo will have the mapatumumab 
toxicity guidelines in Section 5.1.4 applied.
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Table 5-4
Dose modifications of sorafenib for sorafenib-associated toxicity
Toxicity
Grade 1
Grade 2
Grade 3*
Grade 4*
Non-
hematologic
Continue at 
the same dose 
level
Continue at 
the same dose 
level
Withhold dose until toxicity is 
Grade ≤ 1, then resume 
treatment at the same dose 
level. If subject experiences 
a 2nd Grade 3 toxicity, 
withhold dose until toxicity is 
Grade ≤  1, then reduce 
dose to 400 mg orally daily 
and resume treatment.
Withhold dose until toxicity 
is Grade ≤ 1, then reduce 
dose to 400 mg daily and 
resume treatment, or 
discontinue at the 
discretion of the principal 
investigator after 
discussion with study 
sponsor.
Hematologic
Continue at 
the same dose 
level
Continue at 
the same dose 
level
Withhold dose until toxicity is 
Grade ≤ 2, then resume 
treatment at the same dose 
level. If subject experiences 
a 2nd Grade 3 toxicity, 
withhold dose until toxicity is 
Grade ≤  2, then reduce 
dose to 400 mg orally daily 
and resume treatment.
Withhold dose until toxicity 
is Grade ≤ 2, then reduce 
dose to 400 mg daily and 
resume treatment, or 
discontinue at the 
discretion of the principal 
investigator after 
discussion with study 
sponsor.
See Table 5-2 and Table 5-3 for dose modifications due to skin toxicity and hypertension respectively.
*Subjects who develop Grade 3 fever/chills, Grade 3 elevation of hepatic transaminases with ALT and AST 
< 10X upper limit of normal, Grade 3 hyperlipasemia or hyperamylasemia without clinical or other evidence of 
pancreatitis, Grade 3 leukopenia, or Grade 3/Grade 4 lymphopenia may continue sorafenib treatment without 
interruption at the discretion of the investigator.
Sorafenib Discontinuation
Temporary or permanent discontinuation of sorafenib will be considered in subjects who 
develop cardiac ischemia and/or infarction or severe or persistent hypertension despite 
institution of antihypertensive therapy. If a subject experiences a bleeding event that 
necessitates medical intervention or a gastrointestinal perforation, sorafenib will be 
permanently discontinued. Subjects, who undergo a surgical procedure or intervention to 
decrease portal hypertension, including transjugular intrahepatic portosystemic shunt, will 
discontinue sorafenib.
If the subject is withdrawn from further treatment with sorafenib, the subject may continue to 
receive mapatumumab/placebo alone every 21 days until radiologic progression or 
unacceptable toxicity.
5.3
Concurrent Medications and Therapies
5.3.1
Allowable Regimens
Subjects may continue their baseline medication(s). The daily dose of each medication will be 
maintained throughout the study if possible. If for any reason deemed necessary by the 
investigator, a subject requires additional medication(s), the medication(s) route of 
administration and the indication for which it was given must be recorded in the source 
documents. All concomitant medications will be recorded on the appropriate case report form.
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Systemic, inhaled and topical steroids used as part of an antiemetic regimen or 
maintenance-dose for non-cancerous disease are permitted.
5.3.2
Prohibited Medications
Subjects who require the use of strong CYP3A4 inducers (eg, including but not limited to 
St. John’s 
Wort, 
dexamethasone, 
phenytoin, 
carbamazepine, 
rifampin, 
rifabutin, 
phenobarbital) are not eligible for this study and use of these agents is prohibited as long as 
the subject is receiving sorafenib in this study.
Subjects will not receive any investigational or noninvestigational cytotoxic chemotherapy, 
hormonal therapy, biological therapy (including monoclonal antibodies), immunotherapy or 
any locoregional therapy (such as embolization, RFA or percutaneous ethanol injection) to 
treat hepatocellular carcinoma during the treatment period. Alternative anticancer therapies 
may be administered after radiologic disease progression has been documented, but will be 
avoided if possible during the 30 day safety follow up period after the last dose of study agent 
(mapatumumab/placebo and/or sorafenib) whichever is last. These medications are allowed in 
the long-term follow-up period after the 30 day safety follow-up period and documentation of 
radiologic disease progression.
5.3.3
Prohibited Therapies
Subjects will not undergo major or elective surgery during the treatment period of the study; if 
surgery is required, the subject will be withdrawn from study treatment.
6 Study Procedures
6.1
Screening Procedures
The nature of this study and the potential risks and benefits associated with participation in the 
study will be explained to all potential study subjects. Written informed consent (including 
consent for the use and disclosure of research-related health information) must be obtained 
before any screening procedures are performed that are not considered standard of care.
All of the following assessments must be performed within 28 days prior to enrollment:
•
Obtain written informed consent for participation in the study.
•
Obtain informed consent for participation in the optional biomarker sub-study.
-
If consented, obtain tissue block/slides or cell pellet from diagnostic histologic/ 
cytologic sample.
•
Record demographics.
•
Obtain medical history, to include history of all treatments used to treat the current cancer 
and all prior cancer treatments.
•
Perform baseline complete physical examination including body weight and height.
•
Assess vital signs (blood pressure, heart rate, respiratory rate and temperature).
•
Evaluate performance status (ECOG scale; see Appendix 3).
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•
Draw blood for laboratory tests (see Appendix 7): complete blood count with differential, 
chemistry, hepatitis B surface antigen, Hepatitis B virus DNA, hepatitis C antibody and 
testing for serum pregnancy (all females with an intact uterus [unless amenorrheic for the 
previous 24 months] regardless of age).
•
Obtain radiologic disease and AFP assessments. The method of disease assessment, as per 
mRECIST for HCC (see Appendix 5), will be consistent throughout the study. 
•
Obtain electrocardiogram.
•
Record medications used within 28 days before enrollment.
•
Confirm that subject meets all inclusion/exclusion criteria.
6.2
Study Enrollment/Randomization Procedures
Subjects that meet the eligibility criteria will be randomly assigned treatment by a 
central interactive voice response system in a 1:1 ratio to 1 of 2 treatment arms. The 
randomization will be stratified according to BCLC advanced stage C vs BCLC intermediate 
stage B and ECOG performance status (0 vs 1, 2). The 1st planned dose of sorafenib and
mapatumumab/placebo will be administered no more than 3 days following randomization 
and not prior to randomization. All study site personnel (with the exception of the unblinded 
site pharmacist or unblinded designee), the subject, and the Sponsor will remain blinded to the 
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6.3
On-treatment Study Procedures
Table 6-1
Study calendar
Cycle 1
Cycle 2
Additional 
Cycles13
Extended 
Access 
Phase
Safety Follow-up 
Phase
Procedure
Footnotes
Screen 
Phase
Day 
1
Day 
2
Day 
3
Day 
8
Day 
15
Day 
1
Day 
3
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
≥ 30 days following last 
dose
Informed consent
X
X
Laboratory
CBC with differential;
Coagulation 
parameters
1
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
1
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy
2
X
X
Hepatitis
1
X
B and T lymphocyte 
subsets
3
X
X
X
X
Immunogenicity 
4
X
X
X
Pharmacokinetics
5
X
X
X
X
Biomarkers
6
X
X
X
X
X
X
X
X
X
Study Agent Admin
Sorafenib
7
Twice daily
X
Mapatumumab/ 
Placebo
7
X
X
X
X
Physical/Clinical
Med Hx / Phys.Exam
-
X
Vital signs
8
X
X
X
X
X
X
X
X
X
Body weight
9
X
X
X
X
Performance Status
10
X
X
X
X
Record AEs/ 
11
X
<----------------Throughout the study---------------->
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Table 6-1
Study calendar
Cycle 1
Cycle 2
Additional 
Cycles13
Extended 
Access 
Phase
Safety Follow-up 
Phase
Procedure
Footnotes
Screen 
Phase
Day 
1
Day 
2
Day 
3
Day 
8
Day 
15
Day 
1
Day 
3
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
≥ 30 days following last 
dose
Conmeds
Disease Assessments 
12
X
Performed at the end of every 2 cycles (ie, Cycles 2, 4, 6) and every 2 cycles thereafter 
until radiologic PD is documented.
X
α – Fetoprotein (AFP)
12
X
Performed at the end of every 2 cycles (ie Cycles 2, 4, 6) and every 2 cycles thereafter 
until radiographic PD is documented.
ECG
-
X
Repeat as clinically indicated
AE = adverse event; CBC = complete blood count; CT = computerized tomography; ECG -= electrocardiogram; PD = progressive disease.
1
Safety Labs: Day 1 (complete blood count with differential, coagulation parameters [INR, PT, PTT] and chemistry) must be performed within 3 days prior to dosing on Day 1 of each cycle.  
See Appendix 7 for a detailed list of required laboratory assessments.
2
Pregnancy: Serum test at screening, urine test pre-dose Cycle 1 Day 1; must be negative to receive treatment.
3
B and T lymphocyte subsets: Blood samples for quantification of B and T lymphocytes will be obtained in Cycles 1 and 2 only. Samples will be obtained on Day 1 (prior to dosing) and 
Day 15 of Cycles 1 and 2.
4
Immunogenicity: Obtain prior to dosing on Day 1 of Cycles 1, 2, 4, 6, every 2 cycles thereafter and at the end of treatment visit (at least 30 days after the last dose). On days when 
immunogenicity and pharmacokinetic samples are collected they will be collected together.
5
Pharmacokinetics: Blood specimens will be collected for determination of serum mapatumumab concentrations from subjects as follows:  Cycle 1 (on Day 1 prior to the administration 
mapatumumab/placebo and at the completion of the mapatumumab/placebo infusion, and on Day 8), Cycles 2, 4 and 6 and thereafter on each even cycle (prior to dosing on Day 1), on 
the day of each disease assessment, and at the end of treatment visit (at least 30 days after the last dose). On days when immunogenicity and pharmacokinetic samples are collected 
they will be collected together.  
6
Biomarkers: For subjects participating in the optional biomarker sub-study, historical biopsy samples will be collected, if available, and samples will be collected if obtained during the 
treatment period in Cycle 1 Days 1 (pre-dose mapatumumab), 2, 3, 8 and 15 and Cycle 2 Days 1 (pre-dose mapatumumab), 3, 8 and 15. In addition, blood samples will be obtained as 
follows: blood for isolation of DNA will be collected once, preferably in Cycle 1. Blood for isolation of serum will be collected in Cycles 1 and 2 (pre-dose on the day of 
mapatumumab/placebo dosing). Further details on the biomarker sub-study are outlined in Appendix 6.
7
Study Agent Administration:  Sorafenib will be administered at a dose of 400 mg twice daily without food (at least 1 hour before or 2 hours after a meal). On days when both sorafenib and 
mapatumumab/placebo are administered together, sorafenib should be taken at the same time as any other calendar day.
8
Vital Signs: Blood pressure will be monitored weekly for the first 6 weeks. Vital signs will be obtained within 30 minutes prior to administration of mapatumumab/placebo and at the end of 
infusion on Day 1 of each cycle. For subjects in the Extended Access Phase, only BP is required to be monitored and this should be performed every 6 weeks (± 3 days).
9
Body Weight: To be obtained on the day of or within 3 days before dosing on Day 1 of each cycle.
10
Performance Status: Obtained prior to dosing on Day 1 of each cycle.
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11
Adverse Events: (S)AE collection begins with the start of 1st study agent administration. Concurrent medications will be recorded within 28 days prior to Cycle 1 Day 1. For subjects in 
the Extended Access Phase, only SAEs will be recorded.
12
Disease and α – Fetoprotein (AFP) Assessments: Radiologic and AFP assessments will be performed at the end of every 2 cycles (ie, Cycles 2, 4, 6, etc). For subjects discontinuing 
treatment prior to documentation of radiologic disease progression, disease assessments will be performed every 6 weeks (± 3 days), starting 6 weeks after the previous disease 
assessment while on study, until radiologic disease progression is documented. If disease progression is based only on new lesions or is equivocal, images will be provided to the 
blinded, independent reader for confirmation of disease progression. All imaging scans used for disease assessments will be made available for independent radiology review by the 
Sponsor or designee. For subjects in the Extended Access Phase, disease assessments will be performed as at least every 3 months or as per standard of care, whichever is sooner, 
until disease progression is documented. Independent radiological review of response or for confirmation of disease progression is not required.
13
Subjects who discontinue mapatumumab/placebo will complete the current cycle assessments per the study calendar. Subsequently, for subjects in the Extended Access Phase, 
subjects receiving sorafenib alone will be assessed as per local standard of care and will return at least every 6 weeks for BP monitoring. Serious adverse events will be recorded 
throughout the study
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6.4
Extended Access to Study Drug
Subjects who completed more than 24 months of study treatment sorafenib with or without 
mapatumumab and who in the opinion of the investigator obtain clinical benefit from 
treatment, will be allowed to continue treatment with sorafenib with or without unblinded 
mapatumumab in the clinical trial.  Prior to continuing into the Extended Access phase, 
subjects will be re-consented to agree to the study assessments and a local re-review of their 
pathology/cytology. This extension of treatment will continue until the subject’s disease 
progresses (Section 6.8) or they withdraw from study (Section 6.7). In addition extension of 
treatment with mapatumumab will not extend beyond the expiry date of the drug batch 
(March 2016).
During the Extended Access phase, subjects will have regular visits for disease assessments at 
least every 3 months or as per standard of care, whichever is sooner, until disease progression 
is documented. In addition BP will be monitored every 6 weeks and recorded in the eCRF. 
Serious AEs will continue to be collected during this Extended Access phase according to 
Section 8. Study drug administration and inventory/accountability will continue to be 
recorded during this period according to Section 5. Laboratory assessments will be performed 
as per the standard of care.
6.5
Safety Follow-up
After discontinuation of study treatment, all subjects will return at least 30 days after the last 
dose of sorafenib and/or mapatumumab/placebo, for scheduled safety follow-up assessments 
as outlined in Table 6-1.
6.6
Withdrawal of Subjects from Treatment
Subjects will be free to withdraw from treatment at any time, for any reason, or they may be 
withdrawn/removed, if necessary, to protect their health (see reasons for withdrawal below). It 
is understood by all concerned that an excessive rate of withdrawals can render the study 
uninterpretable; therefore, unnecessary withdrawal of subjects will be avoided.
Subjects may be withdrawn from treatment for any of the following reasons:
•
Radiologic disease progression.
•
Continued unacceptable toxicities despite optimal treatment or dose reduction.
•
Intercurrent illness, at the investigator’s discretion.
•
Withdrawal of consent.
•
Non-compliance/Lost to follow-up.
•
Pregnancy.
•
Termination of the study by the sponsor.
Following subject withdrawal, every effort will be made to collect safety information on each 
subject through 30 days following the last dose of study treatment, unless the subject 
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withdraws consent and refuses to comply with the protocol stipulated safety follow-up or 
share information obtained after the date of withdrawal of consent.
6.7
Withdrawal of Subjects from Study
Subjects may be withdrawn from the study for any of the following reasons:
•
Withdrawal of consent.
•
Non-compliance/Lost to follow-up.
•
Termination of the study by the sponsor.
6.8
Disease Response Assessments
Imaging endpoints will be determined using the modified RECIST criteria for HCC proposed 
by Lencioni 2010 mRECIST for HCC is a joint guideline of the American Association for the 
Study of Liver Diseases and the Journal of the National Cancer Institute. 
Lesions which manifest typical imaging characteristics for HCC demonstrate intratumoral 
arterial contrast on CT and MRI images. mRECIST accounts for newer therapies which may 
impact tumor vascularity and may not yield a typical cytotoxic decrease in tumor size by 
incorporating changes in vascularity into the criteria for target lesion response. Diligence in 
obtaining images during the hepatic arterial contrast enhancement phase is a requirement at 
baseline and all subsequent scans. The same imaging method must be used at baseline and 
during follow up.
As in conventional RECIST, overall response is the result of the combined assessment of 
target, nontarget, and new lesions. There are also specifications for incorporating portal vein 
thrombosis, portal hepatic lymph nodes, and pleural effusions/ascites into the response 
assessment. As with conventional RECIST, the appearance of any new lesion overrides any 
existing lesion response, resulting in classification as progressive disease (PD). Key aspects of 
mRECIST as adapted for this study are summarized in Appendix 4.
Baseline images will be provided to the BICR for confirmation of radiologic eligibility 
(measurable disease). Confirmation of radiologic eligibility for the study will be provided to 
the site by the BICR within 72 hours of receipt of images and will be required for 
randomization.
Disease assessments and an assessment of α -fetoprotein will be performed at the end of every 
2 cycles (ie, Cycles 2, 4, 6 and every 2 cycles thereafter). The response assessment will be 
performed and documented no more than 5 days before the start of the next cycle. All images 
will be provided to the BICR following each disease assessment.
If disease progression is based only on new lesions or is equivocal, images will be provided to 
the BICR for confirmation of radiologic disease progression prior to discontinuing study 
treatment. PR and CR will be confirmed at the next scheduled disease assessment (no fewer 
than 4 weeks after the initial documentation of PR or CR).
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6.8.1
Disease Response Assessments for Subjects in the Extended Access 
Phase
During the Extended Access phase, subjects will have regular visits for disease assessments at 
least every 3 months or as per standard of care, whichever is sooner, until disease progression 
is documented. Independent radiological review for confirmation of disease progression is not 
required.
6.9
Treatment after the end of the Study
The investigator is responsible for ensuring that consideration has been given to the post-study 
care of the subject’s medical condition, whether or not GSK is providing specific post-study 
treatment
7 Pharmacokinetic, Immunogenicity, Pharmacodynamic and 
Exploratory Assessments
7.1
Pharmacokinetic Assessments
For determination of mapatumumab concentration, serum samples will be collected as 
outlined in Table 6-1.
A manual will be provided regarding how to obtain blood samples, process samples, collect 
serum from the blood samples, and how to store and ship the serum samples. Bioanalysis will 
be carried out at Human Genome Sciences to determine mapatumumab concentration in each 
serum sample.
7.2
Immunogenicity
Blood samples for serum antibodies to mapatumumab will be obtained as outlined in 
Table 6-1. 
7.3
Pharmacodynamic Assessments
Subjects will be given the option to participate in an exploratory biomarker research 
sub-study. Consenting subjects will be asked to provide a historically obtained biopsy sample, 
if available, and blood samples. In addition, samples will be requested from subjects who 
undergo a biopsy during the treatment period.
To examine and quantify biomarkers present peripherally, blood will be drawn during 
Cycles 1 and 2, from which DNA and serum proteins will be isolated. The parameters 
evaluated may include, but may not be limited to, M30, TNFα, sTRAIL, soluble Fas ligand, 
interferon-α, 
interferon-γ, 
interleukin-2, 
interleukin-6, 
interleukin-8, 
interleukin-10, 
interleukin-12, and FC gamma receptor and interleukin-6 gene polymorphisms. The 
biomarker sub-study is detailed in Appendix 6.
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7.4
Exploratory Assessments (B and T Lymphocyte Subsets)
7.4.1
Rationale for B and T Lymphocyte Analysis
Over 400 subjects have received mapatumumab in doses ranging from 0.01 to 30 mg/kg 
across multiple Phase 1 and Phase 2 clinical trials in subjects with solid and hematologic 
malignancies. While there is no evidence to date that mapatumumab exacerbates adverse 
events associated with chemotherapy, the most commonly observed laboratory abnormality 
associated with mapatumumab has been lymphopenia. The lymphopenia has been intermittent 
and reversible and was not associated with infectious events. However, the lymphocyte 
subpopulation(s) affected have not been characterized.
The evaluation of lymphocytes will include complete blood count/differential and lymphocyte 
subpopulation analysis (numbers and percentages of T and B cells) by flow cytometry at a 
central laboratory. Blood samples will be examined by flow cytometry for levels of T helper 
(CD4+), T cytotoxic (CD8+) and mature B cells (CD19+).
7.4.2
Collection of Samples for B and T Lymphocyte Analysis
Blood samples will be collected for quantification of B and T lymphocyte subsets on Day 1 
(prior to dosing) and Day 15 of Cycles 1 and 2 as outlined in Table 6-1.
8 Adverse Event Reporting
8.1
Definitions
ADVERSE EVENT (EXPERIENCE) - 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. This includes worsening (eg, increase in frequency or severity) of 
pre-existing conditions.
SERIOUS ADVERSE EVENT – an adverse event resulting in any of the following outcomes:
•
death
•
is life threatening (ie, an immediate threat to life)
•
inpatient hospitalization
•
prolongation of an existing hospitalization
•
persistent or significant disability / incapacity
•
congenital anomaly / birth defect
•
is Medically Important*
*Medical and scientific judgment will be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or result in hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other outcomes listed above. These should also 
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Note: Hospitalizations not associated with an adverse event, for example, for administration 
of chemotherapy or hydration for chemotherapy administration, are not considered serious 
adverse events.
UNEXPECTED ADVERSE EVENT - An adverse event, the nature or severity of which is 
not consistent with the applicable product information (eg, Investigator’s Brochure for an 
unapproved investigational product or package insert/summary of product characteristics for 
an approved product). Expected means that the event has previously been observed with the 
study agent and is identified and/or described in the applicable product information. It does 
not mean that the event is expected with the underlying disease(s) or concomitant 
medications.
8.2
Reporting Adverse Events to the Sponsor or Designee
The investigator and their designees are responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a Human Genome Science product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact.
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 
However, if the investigator learns of any SAE, including a death, at any time after a subject 
has been discharged from the study, and he/she considers the event reasonably related to the 
study treatment or study participation, the investigator must promptly notify GSK CMG.
All adverse events (AEs) that are identified from the start of any study agent administration 
through the specified study follow-up period (through 30 days following administration of the 
final study agent dose) will be recorded on the paper/electronic Adverse Event Case Report 
Form (AE case report form). All data fields on the AE case report form will be completed.
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE Worksheet and emailed 
to GSK CMG at 
 (fax backup: 
within 24 hours of site 
personnel becoming aware of a SAE, regardless of expectedness. All pages of the SAE 
Worksheet will be completed, but the SAE worksheet will not be held until all information is 
available. Additional information and corrections will be provided on subsequent SAE 
Worksheets as described in the Study Procedure Manual. 
8.3
Laboratory Abnormalities as Adverse Events
A laboratory abnormality will be reported as an adverse event if it is associated with an 
intervention. Intervention includes, but is not limited to, discontinuation of treatment, dose 
reduction/delay, additional assessments (excluding follow-up labs), or concomitant therapy. In 
addition, any medically important laboratory abnormality may be reported as an adverse event 
at the discretion of the investigator. This includes laboratory abnormalities for which there is 
no intervention but the abnormal value(s) suggests a disease or organ toxicity. If clinical 
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sequelae are associated with a laboratory abnormality, the diagnosis or medical condition will 
be reported (eg, renal failure, hematuria) not the laboratory abnormality (eg, elevated 
creatinine, urine red blood cells increased).
8.4
Other Events Requiring Rapid Reporting
Protocol Specified Events are additional events [toxicities] specifically identified in this 
protocol that must be reported to GSK CMG or designee in an expedited manner. Protocol 
Specified Events may or may not be SAEs as defined in this protocol. They are SAEs if they 
meet one or more of the criteria for an SAE (see Section 8.1). Protocol Specified Events are 
recorded on SAE Worksheets and sent to GSK CMG within 24 hours of site personnel 
becoming aware of the event.
The Protocol Specified Events for the study:
•
Grade 4 neutropenia for > 7 consecutive days or febrile neutropenia.
•
Grade 4 thrombocytopenia.
•
Grade 3 or greater non-hematologic AEs except transaminase, amylase and lipase 
abnormalities for which the following criteria apply:
•
Grade 4 elevations in transaminases.
•
Grade 4 elevations in lipase or amylase.
•
Grade 3 elevations in lipase or amylase associated with clinical/imaging findings of 
pancreatitis, resulting in chronic damage to the pancreas.
•
Any adverse event that results in discontinuation of treatment if that event is assessed as 
possibly, probably, or definitely related to mapatumumab or sorafenib.
8.5
Reporting a Pregnancy
Any pregnancy in a female participant or a female partner of a male participant must be 
reported to GSK CMG as soon as the site becomes aware of the pregnancy. All pregnancies 
are reported up to 30 days following the last study agent treatment. GSK CMG sends an 
acknowledgement memorandum to the principal investigator along with a Pregnancy 
Assessment Form. Additional Pregnancy Assessment Forms will be sent to the site every 3 
months for reporting of follow-up information. Pregnancy assessment forms must be 
completed by the investigator until live birth, elective termination of the pregnancy, or 
miscarriage. The site is responsible for following the subject’s pregnancy to final outcome.
Pregnancies are not considered adverse events. Complications or medical problems associated 
with a pregnancy are considered AEs and may be SAEs. Complications or medical problems 
are reported as AEs/SAEs according to the procedure described in Section 8.2.
8.6
Investigator Evaluation of Adverse Events
The Investigator will evaluate all adverse events with respect to seriousness (criteria listed in 
Section 8.1 above), severity (intensity or grade) and causality (relationship to study agent) 
according to the following guidelines listed below.
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SEVERITY
Severity will be graded using the NCI-CTCAE, Version 4.0. The NCI-CTCAE may 
be downloaded 
from 
the 
Cancer 
Treatment 
Evaluation 
Program 
website 
(http://ctep.info.nih.gov/reporting/ctc.html). In the event that an AE does not have an 
NCI-CTCAE code, the following severity classifications will be used:
Mild 
causing no limitation of usual activities
Moderate
causing some limitation of usual activities
Severe
causing inability to carry out usual activities
Life Threatening* potentially life threatening or disabling 
*Note – a severity assessment of life threatening is not necessarily the same as life threatening 
as a “Serious” criterion. The latter means that the event is an immediate threat to life as 
opposed to a potential threat to life.
CAUSALITY
Definitely Related
reasonable temporal relationship to study agent administration
follows a known response pattern (eg, drug is known to cause this AE)
there is no alternative etiology
Probably Related
reasonable temporal relationship
follows a suspected response pattern (eg, based on similar drugs)
no evidence for a more likely alternative etiology
Possibly Related
reasonable temporal relationship
little evidence for a more likely alternative etiology
Probably Not Related does not have a reasonable temporal relationship, OR
good evidence for a more likely alternative etiology
Not Related
does not have a temporal relationship, OR
definitely due to alternative etiology 
ICH guidelines (March, 1995) clarify “reasonable causal relationship” to mean “that there are 
facts [evidence] or arguments to suggest a causal relationship”.
The causality assessment must be made by the investigator based on information available at 
the time that the SAE worksheet is completed. The initial causality assessment may be revised 
as new information becomes available.
*Note - If there is evidence that mapatumumab/placebo contributed to or exacerbated an 
event related to sorafenib; the event will be recorded as possibly, probably or definitely 
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8.7
Follow-up of Adverse Events
Adverse events that occur during the course of the study are followed until final outcome is 
known or until the end of the safety follow-up period (30 days following the final dose of any 
study agent). Adverse events that have not resolved by the end of the safety follow-up period 
are recorded as ongoing.
SAEs that have not resolved by the end of the follow-up period are followed until final 
outcome of recovered or recovered with sequelae is achieved. If it is not possible to obtain a 
final outcome for a SAE (eg, the subject is lost to follow up), the reason a final outcome could 
not be obtained will be documented by the investigator.
8.8
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to Human Genome Science of SAEs and non-serious 
AEs related to study treatment (even for non-interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of subjects 
and the safety of a product under clinical investigation are met. 
GSK CMG has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK CMG will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Human Genome Science policy and are 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK CMG will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.9
Reporting Serious Adverse Events to the Institutional Review 
Board/Ethics Committee
All SAEs that are considered unexpected and related to the study agent will be reported by 
GSK CMG or its designee as expedited (ie, 15-Day) reports to the appropriate regulatory 
authorities AND to all participating investigators. Each investigator must notify the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) responsible for 
reviewing the study at their site of all expedited reports. In addition, GSK CMG or its 
designee will follow all applicable local and national regulatory requirements regarding safety 
reporting. Each investigator must also comply with the applicable regulatory requirements 
related to the reporting of SAEs to the IRB/IEC responsible for reviewing the study at their 
site, as well as the regulatory authority(ies) (if applicable).
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9 Endpoints and Statistical Analysis
9.1
General Statistical Considerations
Analyses will be applied to a modified intention-to-treat population unless stated otherwise. 
This population is defined as the set of all randomized subjects who receive at least 1 dose of 
study treatment (mapatumumab/placebo and/or sorafenib) with subjects analyzed according to 
the groups they are randomized to, regardless of the treatment they subsequently receive. 
Additional analyses may be performed on the as-treated population, defined as the set of 
subjects receiving at least 1 dose of study medication analyzed according to the treatment that 
they actually receive.
Analyses will be performed using the SAS System™, WinNonlin Enterprise Edition™, 
StatXact™, and the R statistical package.
9.2
Sample Size Rationale
A total of approximately 100 subjects will be randomly assigned to 1 of 2 arms and treated 
with either sorafenib + placebo or the 2-agent combination of sorafenib and mapatumumab at 
30 mg/kg in a 1:1 ratio. A sample size of 50 subjects randomized and treated in each group is 
sufficient to estimate the median time to progression with a precision of approximately -1.9 M 
to +2.6 M relative to the observed median. In addition, a sample size of 50 patients per arm 
will provide 80% power to detect an improvement in TTP from 5.5 to 8.9 M with at a 
one-sided significance level of 0.10.
9.3
Efficacy
9.3.1
Primary Efficacy Endpoint
The primary endpoint is time to progression (TTP) defined as the time from randomization to 
radiologic disease progression based on blinded independent review of imaging scans. 
9.3.2
Primary Efficacy Analysis
The primary analysis will be an estimate of median time to progression in each arm using 
Kaplan Meier methods, reported with 95% confidence intervals, along with testing the hazard 
ratio for time to progression at a 1-sided significance level of 0.10 with a Cox proportional 
hazards model controlling for the factors stratifying the randomization as covariates.
9.3.3
Secondary Efficacy Endpoints
Secondary endpoints include progression-free survival, overall response, disease control, 
overall survival, time to response, and duration of response (for responders) as defined below:
•
OS: time from randomization to death from any cause.
•
PFS: time from randomization to disease progression or death from any cause.
•
Objective response (CR+PR according to mRECIST for HCC).
•
Disease control (CR+PR+SD according to mRECIST for HCC).
•
Time to response: time from randomization to 1st PR or CR in responders only.
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•
Duration of response: time from 1st PR or CR to disease progression; in responders only.
All secondary endpoints will be based on blinded independent review of imaging scans.
9.3.4
Secondary Efficacy Analyses
Secondary analyses include estimates, using Kaplan Meier methods, of median PFS and 
median OS along with associated logrank testing. In addition, estimates of overall response 
rate (CR+PR) and disease control rate (CR+PR+SD) will be reported with 95% confidence 
intervals and an estimate of the difference in response rates and disease control rates between 
groups will be reported and tested for significance with a Pearson chi-square test (or Fisher’s 
exact test). 
9.4
Safety
9.4.1
Definition of Safety Variables
The safety parameters assessed are given by the following:
•
Frequency, and severity of adverse events (AEs):
-
All AEs will be classified by System Organ Class and Preferred Term under the 
Medical Dictionary for Regulatory Activities (MedDRA) system of classification with 
a severity assigned according to the NCI-CTCAE (Version 4.0, 29 May 2009), or the 
rules specified in Section 8.6.
-
Laboratory parameters as presented in Appendix 7.
-
Laboratory toxicities will be graded based on the NCI-CTCAE (Version 4.0, 
29 May 2009).
•
Anti-mapatumumab antibody response.
•
Vital signs.
•
For frequency and severity of adverse events and laboratory toxicity grading, counts and 
rates will be presented.
9.4.2
Human Genome Sciences Safety Review Committee
The Human Genome Sciences Review Committeee (HGSRC) is comprised of the Department 
Heads of Biostatistics, Regulatory Affairs and Drug Development. The HGSRC will review 
safety data after: (1) 10 subjects have completed 1 cycle; and (2) 30 subjects have completed 
1 cycle. HGSRC reviews of safety data will be conducted approximately every 4 months 
thereafter, until 90% of subjects have reached radiologic progression. The HGSRC may 
conduct additional reviews at their own request and/or at the request of the Medical Monitor. 
The HGSRC may request the unblinding of treatment assignment for a subject and/or 
treatment groups. If treatment assignments are unblinded, the rationale for the unblinding will 
be documented.
9.4.3
Analysis of Safety Variables
The safety analysis will consist of a presentation of rates of AEs observed. Specific AEs will 
be counted once for each subject for calculating rates, but will be presented in total in subject 


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listings. In addition, if the same AE occurs multiple times within a particular subject, the 
highest severity and level of causality observed will be reported. If any associations of interest 
between AEs and baseline characteristics are observed, additional stratified results may be 
presented. All treatment-emergent AEs will be summarized overall, as well as categorized by 
the MedDRA system of classification. AEs will be presented overall, by severity, by relation 
to mapatumumab/placebo, and by relation to sorafenib.
9.5
Pharmacokinetics
9.5.1
Definition of Pharmacokinetic Evaluation
Serum mapatumumab concentration data obtained from this study will be pooled with data 
obtained from other studies for use in a population PK analysis, which will be reported 
separately.
9.5.2
Analysis of Pharmacokinetics
The serum mapatumumab concentration will be determined by enzyme-linked immunosorbent 
assay. Serum mapatumumab concentration results for this study will be presented using 
appropriate graphic and tabular summaries.
9.6
Pharmacodynamics
Expression of biomarkers in tumor tissue and peripheral blood will be correlated with clinical 
outcomes and may be reported separately from the clinical study report. 
10 Study Administration
10.1
Informed Consent
A copy of the proposed informed consent document(s) must be submitted to the sponsor or 
designee for review and comment prior to submission to the reviewing IRB/IEC. The consent 
form must be approved by the IRB/IEC and contain all elements required by national, state, 
local, and institutional regulations or requirements.
It is the responsibility of the investigator to provide each subject with full and adequate verbal 
and written information using the IRB/IEC approved informed consent document(s), 
including the objective and procedures of the study and the possible risks involved before 
inclusion in the study. Each subject must voluntarily provide written informed consent 
(including consent for the use and disclosure of research-related health information). The 
consent must be obtained prior to performing any study-related procedures that are not part of 
normal patient care, including screening and changes in medications including any washout of 
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10.2
Institutional Review Board Review/Independent Ethics Committee 
Review and Approval
The investigator or sponsor (as appropriate per national regulations) shall assure that an 
IRB/IEC, constituted in accordance with ICH Good Clinical Practices, will provide initial and 
continuing review of the study.
Prior to shipment of the study agent and enrollment of study subjects, documented IRB/IEC 
approval of the protocol, informed consent form, and any advertisement for subject 
recruitment must be obtained and provided to the sponsor or designee.
The IRB/IEC must also be informed of all protocol amendments prior to implementation. The 
investigator must provide reports of any change in research activity (ie, the completion, 
termination, or discontinuation of a study) to the IRB/IEC.
10.3
Protocol Compliance
Except for a change that is intended to eliminate an apparent immediate hazard to a study 
subject, the protocol shall be conducted as described. Any such change must be reported 
immediately to the sponsor and to the IRB/IEC.
10.4
Protocol Revisions
Protocol amendments will be prepared and approved by the sponsor. All protocol amendments 
will be signed by the investigator and submitted to the IRB/IEC for review prior to 
implementation. Documentation of IRB/IEC approval must be forwarded to the sponsor or 
designee. If an amendment significantly alters the study design, increases potential risk to the 
subject or otherwise affects statements in the informed consent form, the informed consent 
form must be revised accordingly and submitted to the IRB/IEC for review and approval. The 
approved consent form must be used to obtain informed consent from new subjects prior to 
enrollment and must be used to obtain informed consent from subjects already enrolled if they 
are affected by the amendment.
10.5
Data Collection and Management
Data collected for each study subject are recorded electronically on case report forms 
provided or approved by the sponsor. 
The investigator is responsible for maintaining accurate, complete, and up-to-date records for 
each subject. The investigator is also responsible for maintaining any source documents 
related to the study, including any films, tracings, computer discs, or tapes. The investigator 
must promptly review the completed case report forms for each subject. As the person 
ultimately responsible for the accuracy of all data, the investigator must sign the Investigator's 
Statement in each subject's case report form.
The anonymity of participating subjects must be maintained. Subjects are identified by an 
assigned subject number on case report forms and other documents submitted to the sponsor. 
Documents that identify the subject beyond subject number are not submitted to the sponsor 


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(ie, the signed informed consent document) and must be maintained in strict confidence by the 
investigator, except to the extent necessary to allow auditing by the regulatory authorities, 
study monitor, or sponsor representatives.
Sites enter subject data directly into the electronic data capture (EDC) system and the EDC
system automatically generates queries resulting from computer checks embedded into the 
system, so as to ensure accuracy, quality, consistency, and completeness of the database. 
Manual queries resulting from review by monitors, medical coders, and other Data 
Management staff are also generated from within the EDC system, where they are tracked. 
Sites resolve the queries and correct the entered data when necessary. Every change to data is 
captured in the EDC system audit trail. At study end, each site is provided with a compact 
disk containing the electronic case report forms for each of their subjects.
Upon completion of the study, or after reaching a pre-specified point in the study, Data 
Management locks the database and generates the SAS datasets necessary for data analysis 
and reporting.
10.6
Study Monitoring
The study sponsor, Human Genome Sciences, Inc., or designee, will monitor the study. Study 
monitors representing the sponsor will visit study sites routinely throughout the trial. The 
sponsor will review the paper subject diaries and electronic case report forms and compare 
them with source documents to verify accurate and complete collection of data and confirm 
that the study is being conducted according to the protocol. Auditors representing the sponsor 
may also similarly evaluate the study and its monitors. For these purposes, the investigator 
will make paper subject diaries and electronic case report forms and source documents 
available when requested.
In addition, the study may be evaluated by representatives of the national regulatory 
authorities, who will also be allowed access to study documents. The investigators will 
promptly notify Human Genome Sciences of any audits they have scheduled with any 
regulatory authority.
10.7
Drug Accountability
Upon receipt, the designated unblinded pharmacy personnel at the study site are responsible 
for taking an inventory of the study agent, including any buffers or diluents. A record of this 
inventory must be kept and usage must be documented on study agent inventory forms 
provided by the sponsor.
Study agent inventory forms will be examined and reconciled by an unblinded Clinical 
Research Associate, or designee. At the end of the study, all used and unused study agent 
must be accounted for on a study agent accountability form provided to the investigator by 
Human Genome Sciences or its designee.


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10.8
Retention of Records
The investigator shall retain all records and source documents pertaining to the study, 
including any films, tracings, computer discs, or tapes. They will be retained for the longer of 
the maximum period required by the country and institution in which the study is conducted, 
or the period specified by the sponsor at the time the study is completed, terminated, or 
discontinued.
If the investigator leaves the institution, the records shall be transferred to an appropriate 
designee who accepts the responsibility for record retention. Notice of such transfer shall be 
documented in writing and provided to the sponsor.
10.9
Financial Disclosure
The investigator will provide Human Genome Sciences sufficient and accurate information on 
financial interests (proprietary or equity interests, payments exclusive of clinical trial costs) to 
allow complete disclosure to regulatory authorities. The investigator shall promptly update 
this information if any relevant changes occur during the course of the investigation and for a 
period of 1 year following study completion.
10.10 Publication Policy
This study is being conducted as part of a multi-center clinical study. Data from all sites 
participating in the multi-center clinical study will be pooled and analyzed. The investigator 
acknowledges that an independent, joint publication is anticipated to be authored by the 
investigators of the multi-center study and sponsor’s representatives. Neither institution nor 
principal investigator shall independently publish or present the results of the study prior to 
the publication of the multi-center study publication. The investigator agrees that the sponsor 
will be the coordinator and arbitrator of all multi-center study publications. For multi-center 
trials, no investigator will be authorized to publish study results from an individual center 
until the earlier of the multi-center trial results are published or 12 months after the end or 
termination of the multi-center trial at all sites.
The investigator shall submit a copy of any proposed publication, manuscript, abstract, 
presentation or other document with respect to this study to the sponsor for review and 
comment at least 60 days prior to its submission for publication or presentation. No 
publication or presentation with respect to the study shall be made unless and until the entire
sponsor’s comments on the proposed publication or presentation have been considered and 
any information determined by sponsor to be confidential information has been removed. 
If requested in writing by the sponsor, the investigator shall withhold material from 
submission for publication or presentation for an additional 60 days to allow for the filing of a 
patent application or the taking of other measures to establish and preserve the sponsor’s 
proprietary rights.
10.11 Study or Study Site Termination
If Human Genome Sciences, the investigator, IRB/IEC, or a regulatory authority discovers 
conditions arising during the study that indicate that the study should be halted or that the 


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study center should be terminated, this action may be taken after appropriate consultation 
between Human Genome Sciences and the investigator. Conditions that may warrant 
termination of the study include, but are not limited to, the following:
•
The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study.
•
A decision on the part of Human Genome Sciences to suspend or discontinue testing, 
evaluation, or development of the product.
The study site may warrant termination under the following conditions:
•
Failure of the investigator to enroll subjects into the study at an acceptable rate.
•
Failure of the investigator to comply with pertinent regulatory authority regulations.
•
Submission of knowingly false information from the research facility to Human Genome 
Sciences, study monitor, or the regulatory authority.
•
Insufficient adherence to protocol requirements.


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List of Appendices
Appendix 1
Child-Pugh Classification................................................................................. 62
Appendix 2
BCLC Staging and Treatment Strategy............................................................ 63
Appendix 3
Eastern Cooperative Oncology Group (ECOG) Performance Status............... 64
Appendix 4
New York Heart Association Classification for Congestive Heart Failure...... 65
Appendix 5
Modified Response Evaluation Criteria in Hepatocellular Carcinoma 
(mRECIST for HCC)........................................................................................ 66
Appendix 6
Exploratory Biomarker Sub-study.................................................................... 69
Appendix 7
Laboratory Tests............................................................................................... 72
Appendix 8
Treatment of Allergic/Hypersensitivity Reactions........................................... 73
Appendix 9
Summary of Modifications and Rationale for Amendment 3 .......................... 75
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Appendix 1
Child-Pugh Classification
(Zimmermann H and Reichen J, 2000)
No. of Points
Factor
1
2
3
Bilirubin (mg/dL)
< 2
2–3
> 3
Albumin (g/dL)
> 3.5
2.8–3.5
< 2.8
Prothrombin time (increased seconds)
1–3
4–6
> 6
Ascites
None
Slight
Moderate
Encephalopathy
None
Minimal
Advanced
Grade
Score
A
5 – 6
B
7 – 9
C
10 – 15


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Appendix 2
BCLC Staging and Treatment Strategy
Forner et al, 2010


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Appendix 3
Eastern Cooperative Oncology Group (ECOG) 
Performance Status
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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Appendix 4
New York Heart Association Classification for Congestive 
Heart Failure
(The Criteria Committee of the New York Heart Association; Little, Brown & Co. 1994)
Class
New York Heart Association Classification for Congestive Heart Failure
1
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
2
Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
3
Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable 
at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain.
4
Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. 
Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased.


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Appendix 5
Modified Response Evaluation Criteria in Hepatocellular 
Carcinoma (mRECIST for HCC)
(Adapted from Lencioni, 2010 for use in this study)
Measurable disease: The presence of at least 1 target lesion, by contrast enhanced 
computerized tomography (CT) with use of multislice scanners, or contrast enhanced dynamic 
magnetic resonance imaging (MRI).
Target lesion: Meets all the following criteria:
-
Located in the liver.
-
Can be accurately measured in at least 1 dimension.
-
Well-delineated area of viable, hypervascular (contrast enhancement in the arterial phase) 
tumor that is > 2 cm in the axial plane.
-
Suitable for repeat measurement.
-
Not previously treated with locoregional or systemic treatment unless the lesion shows a 
well-delineated area of viable (contrast enhancement in the arterial phase) tumor that is 
> 2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical 
enhancement as a result of the previous intervention, then it cannot be selected as a target 
lesion).
A maximum of 5 target lesions may be selected.
Nontarget lesion: Other lesions, including small lesions (≤2 cm in the axial plane). Note that
malignant portal vein thrombosis should be considered a nonmeasurable, and therefore
nontarget, lesion. Lymph nodes at the portal hepatic can be considered as malignant if the
lymph node short axis is at least 2 cm. Selection of effusion, including ascities, as a nontarget 
lesion is prohibited. Similarly, bone lesions or any other lesion outside the CT or MRI of the 
abdomen or obtained by other modality, may not be selected as nontarget lesions.
Measurement of lesions: Imaging studies will be by contrast enhanced CT, with use of 
multislice scanners, or contrast enhanced MRI. The same method must be used at baseline and 
during follow up. Note that the longest diameter of the viable tumor is not necessarily located 
in the same scan plane in which the baseline diameter was measured. The measurement of the 
viable tumor diameter should not include any major intervening areas of necrosis. (Please see 
the HGS1012-C1103 Radiographic Data Collection Manual).
Evaluation of target lesions:
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.
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Stable Disease (SD): Any cases that do not qualify for CR, PR or PD.
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.
Evaluation of nontarget lesions:
Complete Response (CR): Disappearance of intratumoral arterial enhancement.
Incomplete Response/Stable Disease (IR/SD): Persistence of intratumoral arterial 
enhancement in 1 or more nontarget lesions.
Progressive Disease (PD): Unequivocal progression of existing nontarget lesions.  
Evaluation of new lesions: A newly detected hepatic nodule will be classified as evidence of 
progression when its longest diameter is ≥ 1 cm and the nodule shows the 
hypervascularization in the arterial phase with washout in the portal venous or late venous 
phase.  
Liver lesions ≥ 1 cm that do not show a typical vascular pattern can be diagnosed as HCC by 
evidence of at least a 1 cm-interval growth in subsequent scans. 
An individual radiologic event will be adjudicated in retrospect as progression at the time it 
was 1st detected by imaging techniques, even if strict criteria were fulfilled only on subsequent 
radiologic testing.
Images by another modality may be obtained, as clinically indicated post-baseline. Sites may 
conclude that post-baseline images based on another modality that indicate disease are 
evidence of radiologic progression if: (1) there was no imaging done at baseline; (2) if there 
was imaging done at baseline showing no disease present at that time; or (3) if there was 
imagine done at baseline indicating that the on-treatment assessment represents unequivocal 
worsening. In these cases the disease will be reported as ‘new lesions’.
All images obtained on study will be provided the BICR for the independent efficacy read, or 
for confirmation of progression if required or requested.
Evaluation of Overall Response: The overall response is determined at each assessment and 
is a result of the combined assessment of target lesions, nontarget lesions and new lesions.


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Overall Response Assessment
Target Lesions
Nontarget Lesions
New Lesions
Overall Response*
CR
CR
No
CR
CR
IR/SD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
*AFP is not included in assessment of overall response.
Best Overall Response:
The best overall response is the best response recorded from the start of treatment until 
disease progression. To be assigned a best overall response of CR or PR, changes in tumor 
measurements must be confirmed at the next scheduled disease assessment (no fewer than 
4 weeks after the initial documentation of PR or CR).


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Appendix 6
Exploratory Biomarker Sub-study
1. Background
Mapatumumab is a targeted therapy. Presently, the relationship between expression of the 
target, TRAIL-R1, and the anti-tumor activity of the antibody is incompletely understood. 
Studies conducted with cell lines derived from human tumors have suggested that the 
relationship between receptor expression and mapatumumab-induced tumor cell death may be 
complex. However, studies of human tumor cells in vitro and transplanted into animals may 
not accurately reflect the relationship between receptor expression and response to 
mapatumumab that may be observed in patients with cancer. One feature of this biomarker 
study is to compare TRAIL-R1 expression from available biopsy material. This could allow 
for a greater understanding of patterns of TRAIL-R1 expression in advanced hepatocellular 
carcinoma.
It is also likely that other factors involved in TRAIL-R1 signaling could critically affect 
response to mapatumumab treatment. A 2nd goal of this biomarker study is to evaluate 
biomarkers that may be potential indicators or modifiers of response to mapatumumab. To 
identify factors that may indicate that a patient is responding to treatment, serum-based 
markers will be compared before and after treatment. To explore factors that are associated 
with the outcome of therapy and could be used prior to treatment to predict which patients 
will respond, somatic (inherited) differences that modify a patient’s drug response will be 
examined.
The information generated from this sub-study will be used solely for research purposes to 
improve future treatment with mapatumumab. It will not be used to change diagnoses or alter 
therapy. Participation in this sub-study is optional.
2. Study Objectives and Design
2.1.
Indicators of Response
2.1.1.
Serum-Based Markers of Response
Induction of cell death in tumor cells can elicit the release of certain biomarkers into the 
serum. These markers can be quantified to evaluate treatment effect. To assess release of 
biomarkers associated with cell death, serum-based assays will be conducted, including, but 
not limited to, assessments of M30, a fragment of cytokeratin 18 that is generated by 
induction of programmed cell death in epithelial tissues. Other examples of markers of tumor 
cell death that will be examined include the cytokines TRAIL, TNFα, soluble Fas ligand, 
interferonα, interferonγ, interleukin-2, interleukin-6, interleukin-8, interleukin-10, and 
interleukin-12. The levels of these factors will be examined before and after treatment to see if 
they correlate with response to treatment.
Serum will be isolated and the level of cytokines and other markers like M30 will be 
characterized. Collection, processing and handling of these samples are described in the 
laboratory manual.


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Samples collected in this study will be stored for up to 15 years and may be analyzed with 
samples collected in other studies, but will only be used for mapatumumab-related research.
2.2.
Modifiers of Response
2.2.1.
Neoplastic Modifiers of Response
Historically collected tumor biopsy material, if available, will be collected from subjects 
during Cycle 1. Samples will also be obtained from subjects who undergo a biopsy during the 
treatment period. Samples of resected tumor tissue that has been formalin-fixed and embedded 
in paraffin is acceptable; either tissue blocks or slides may be provided. Frozen samples of 
tumor tissue may also be provided. Biopsy material collected from fine needle aspirates may 
be provided; either cell pellets or cytological slides are acceptable.
Levels of TRAIL receptors will be assessed in biopsy material using immunohistochemical 
techniques if samples are available as formalin-fixed/paraffin-embedded tissue blocks or 
slides. Historically obtained biopsy material or biopsy material obtained during the treatment 
period that is in the form of fresh frozen tissue or cell pellet samples will be utilized to isolate 
RNA for analysis of TRAIL receptor gene expression.
Similar techniques will be used to evaluate other potential biomarkers and factors that may 
influence mapatumumab response. These may include but are not limited to caspase 8, AKT 
and Mcl-1.
See the laboratory manual for collection, processing and handling of these samples.
Samples collected in this study will be stored for up to 15 years and may be analyzed with 
samples collected in other studies, but will only be used for mapatumumab-related research.
2.2.2.
Somatic Modifiers of Response
Inherited differences in the genes that code for drug targets or components of signaling 
pathways related to the target can dramatically influence the effect of pharmacotherapy. 
Variations in genes that could potentially impact mapatumumab’s activity, including 
polymorphic changes in the Fc gamma receptor and interleukin-6 promoter and K-Ras gene 
mutations, will be examined to see if they correlate with response to treatment.
DNA will be isolated from the blood and polymorphisms and mutations in specific 
response-related genes will be characterized. Collection, processing and handling of these 
samples are described in the laboratory manual.
Samples collected in this study will be stored for up to 15 years and may be analyzed with 
samples collected in other studies, but will only be used for mapatumumab-related research.


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3. Statistical Analysis
Associations will be assessed between candidate biomarkers and treatment outcomes captured 
in the clinical database. Statistical tests to be performed may include Pearson chi-square 
testing, Fisher’s exact test, ANOVA and ANCOVA. Results of the biomarker sub-study may 
be reported independent of the results of HGS1012-C1103.
4. Subject Selection and Withdrawal
Subjects enrolled in the HGS1012-C1103 research study are given the option to participate in 
the Biomarkers Sub-study. A subject may withdraw from the sub-study at any time by 
contacting their Study Investigator, who will contact the sponsor. The sponsor will destroy 
any remaining sample materials and will send a letter back to the Investigator confirming 
sample destruction. Any data or analysis generated from the sample prior to the request for 
destruction will not be destroyed. However, no new information will be generated from the 
sample and no new analysis will be performed.
5. Confidentiality
Information about sub-study subjects will be kept confidential and managed according to the 
requirements of local privacy regulations. Information obtained from samples will not be 
returned to subjects and will not be placed in the subject’s medical record.
6. Ethical Considerations
All subjects enrolled in the HGS1012-C1103 research study who agree to participate in the 
Biomarker Sub-study will be asked to sign a separate Biomarker Informed Consent. Choosing 
to not participate in this sub-study will not affect the subject’s ability to participate in the main 
clinical trial. The Biomarker Informed Consent will be submitted along with the main 
research study informed consent for review by the Institutional Review Board/Ethical 
Committee.
7. Publication of Biomarker Results
Any significant findings, based upon the analysis of aggregate data collected from this 
sub-study may be published by Human Genome Sciences. Personal identifiers will not be 
used in any publication resulting from this sub-study.


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Appendix 7
Laboratory Tests
CBC with Differential
Chemistry
Total white blood cell (WBC) count differential:
Electrolytes:
Neutrophils
Sodium
Bands 
Potassium
Lymphocytes 
Magnesium
Monocytes
Chloride
Eosinophils
Carbon dioxide/bicarbonate*
Basophils
Calcium
       
Hemoglobin
Enzymes:
Hematocrit
SGOT (AST)
Red blood cell count
SGPT (ALT)
Platelet count
Alkaline phosphatase
Absolute Neutrophil Count
Amylase
Total white blood cell count
Lipase
Gamma glutamyl transferase (GGT)
Prothrombin time (PT)
Partial thromboplastin time (PTT)
Other:
International normalized ratio (INR)
Creatinine
Blood Urea Nitrogen
Other:
Total bilirubin
Serum and Urine pregnancy
Total protein
Hepatitis B surface antigen
Albumin
Hepatitis C antibody
B and T lymphocytes
HCV RNA 
HBV DNA
HBsAb
*To be collected if included in routine automated serum chemistry panel.
Refer to Section 6 (Study Procedures) for laboratory test collection schedule.


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Appendix 8
Treatment of Allergic/Hypersensitivity Reactions
In the event of allergic/hypersensitivity reactions to mapatumumab/placebo, investigators will 
institute treatment measures according to best medical and nursing practice. The grading is 
based upon the NCI-CTCAE Version 4.0.0.
The following treatment guidelines will be employed:
•
If chills and fever occur, the infusion will be interrupted. Subjects may be treated 
symptomatically and the infusion will be restarted at 50% of the original rate.
Grade 1 allergic/hypersensitivity reaction (transient flushing or rash, drug fever < 38°C):
•
Decrease infusion rate by 50% and monitor for worsening condition. If the reaction 
worsens, stop the infusion.
Grade 2 allergic/hypersensitivity reaction (rash, flushing, urticaria, dyspnea, drug fever 
< 38°C):
•
Stop the infusion.
•
Administer bronchodilators, oxygen, acetaminophen, etc as medically indicated.
•
Resume infusion at 50% of previous rate once reaction has decreased to ≤ Grade 1 in 
severity. Monitor closely for any worsening. If the reaction recurs, stop the infusion.
Re-treatment following Grade 1 or Grade 2 allergic/hypersensitivity reactions:
•
Once the infusion rate has been decreased due to an allergic/hypersensitivity reaction, it 
will remain decreased for all subsequent infusions.
•
If the subject has a 2nd reaction at the lower infusion rate, the infusion will be stopped and 
the subject will receive no further treatment with mapatumumab/placebo.
•
If the subject experiences a Grade 3 or Grade 4 allergic/hypersensitivity reaction at any 
time, the subject will receive no further treatment with mapatumumab/placebo.
•
If there are questions concerning whether an observed reaction is an 
allergic/hypersensitivity of Grades 1-4, the medical monitor will be contacted immediately 
to assist with grading the reaction.
Grade 3 or Grade 4 allergic/hypersensitivity reaction:
•
A Grade 3 hypersensitivity reaction consists of symptomatic bronchospasm requiring 
parenteral medications with or without urticaria, allergy-related edema/angioedema, or 
asymptomatic hypotension not requiring treatment.
•
A Grade 4 hypersensitivity reaction (ie, anaphylaxis) is a life-threatening event 
characterized by the same symptoms as in a Grade 3 reaction but also complicated by 
symptomatic hypotension or oxygen saturation of 90% or less.


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Treatment of Grade 3 or Grade 4 allergic/hypersensitivity reaction:
•
Stop the infusion immediately and disconnect infusion tubing from the subject.
•
Administer epinephrine, bronchodilators, antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, etc, as medically indicated.
Contact GSK CMG to report an SAE and email SAE worksheet.


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Appendix 9
Summary of Modifications and Rationale for Amendment 3
1. The protocol amendment number and version date have been added to the cover page.
2. A revision chronology page has been added.
3. The protocol has been modified to allow subjects to receive extended access to study drug 
while receiving the local standard of care for HCC. A new section has been added to 
clarify assessments required for subjects receiving extended access to study drug. 
4. The long term follow up phase of the study has been removed as there is no longer a 
requirement to follow subjects for long term survival since at least 90% of subjects have 
met the survival endpoint.
5. The protocol has been updated to comply, where applicable, with the GSK SOP-54825, 
associated guidance and protocol template v3.1.
6. Reference to contacting Human Genome Science to report Adverse Events has been 
updated to GSK CMG. 
Associated Protocol Modifications: 
Text which has been added to the protocol is indicated by bold typeface (except if the section 
is new in its entirety). Text which has been deleted from the protocol is indicated by strike 
through format.
Cover page:
Formerly:  
Protocol Amendment: 02
23 February 2011
Modified to:
Protocol Amendment: 03
15 July 2015
Added: A Revision Chronology page has been added.
Revision Chronology for HGS1012-C1103 (200149)
Date
Document*
Global
14 September 2010
Original
Global
21 December 2010
Amendment No 01
AM03
15Jul15


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Date
Document*
Global
23 February 2011
Amendment No 02
Global
DNG 2013N166298_03
15 July 2015
Amendment No 03
Study Synopsis: Study Design and Schedule, paragraph 3 
Formerly:
Subjects will continue to receive study treatment(s) until radiologic disease progression or 
unacceptable toxicity. Subjects unable to tolerate sorafenib may continue to receive 
mapatumumab/placebo every 21 days until radiographic progression. Subjects unable to 
tolerate mapatumumab/placebo may continue to receive sorafenib until radiographic 
progression. All subjects will have an end of treatment visit at least 30 days after the last dose 
of sorafenib and/or mapatumumab/placebo whichever is later. After discontinuation of 
treatment, subjects will continue to be followed for radiologic disease assessments every 
6 weeks, starting 6 weeks after the previous disease assessment while on treatment, until 
documented radiologic disease progression (if not previously documented) and then every 
3 months thereafter for survival until at least 90% of the subjects have met the survival 
endpoint.
Disease Assessments:
Radiologic disease assessments along with assessment of alpha fetoprotein will be performed 
at the end of every two 21-day cycles (ie, Cycles 2, 4, 6 and every 2 cycles thereafter). The 
disease assessment will be performed and documented no earlier than 5 days before the start 
of the next cycle. Clinical responses will be evaluated according to mRECIST for HCC (see 
Section 6.7 and Appendix 5). The same assessment method will be used throughout the study 
for each subject. If disease progression is based only on new lesions or is equivocal, images 
will be provided to the blinded, independent, central reader (BICR) for confirmation of 
disease progression. Partial response (PR) and complete response (CR) will be confirmed at 
the next scheduled disease assessment (no fewer than 4 weeks after the initial documentation 
of PR or CR). All imaging scans used for disease assessments will be made available for 
independent radiology review by the Sponsor or designee.
Safety Assessments:
The safety of sorafenib and mapatumumab will be assessed by evaluation of the type, 
frequency, and severity of adverse events (ie, according to the NCI-CTCAE Version 4.0 
grading) and changes in clinical laboratory tests (hematology and clinical chemistry) and 
immunogenicity over time. In the event that an adverse event does not have an NCI CTCAE 
Version 4.0 grading, the severity grades in Section 8.6 will be used. Adverse events (including 


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serious adverse events) will be captured from the start of study agent administration (sorafenib 
and/or mapatumumab/placebo) through at least 30 days following the last dose of sorafenib 
and/or mapatumumab/placebo, whichever is later. Laboratory assessments will be performed 
at screening, and during each study visit outlined in the study calendar found in Section 6.3.
Modified to:
Subjects will continue to receive study treatment(s) until radiologic disease progression or 
unacceptable toxicity. Subjects unable to tolerate sorafenib may continue to receive 
mapatumumab/placebo every 21 days until radiographic progression. Subjects unable to 
tolerate mapatumumab/placebo may continue to receive sorafenib until radiographic 
progression. Subjects who completed more than 24 months of study treatment with 
sorafenib with or without mapatumumab and who in the opinion of the investigator 
obtain clinical benefit from treatment, will be allowed to continue treatment with 
sorafenib with or without unblinded mapatumumab in the clinical trial.  This extension 
of treatment will continue until the subject’s disease progresses or they withdraw from 
study. In addition extension of treatment with mapatumumab will not extend beyond the 
expiry date of the drug batch (March 2016).  
All subjects will have an end of treatment visit at least 30 days after the last dose of sorafenib 
and/or mapatumumab/placebo whichever is later. . After discontinuation of treatment, subjects 
will continue to be followed for radiologic disease assessments every 6 weeks, starting 6 
weeks after the previous disease assessment while on treatment, until documented radiologic 
disease progression (if not previously documented) and then every 3 months thereafter for 
survival until at least 90% of the subjects have met the survival endpoint.
During the Extended Access phase, subjects will have regular visits for assessment of 
disease response at least every 3 months or as per standard of care, whichever is sooner. 
In addition, BP will be monitored every 6 weeks and recorded in the eCRF. Serious AEs 
will continue to be collected during this Extended Access phase according to Section 8. 
Study drug administration and inventory/accountability will continue to be recorded 
during this period according to Section 5. 
Disease Assessments:
Radiologic disease assessments along with assessment of alpha fetoprotein will be performed 
at the end of every two 21-day cycles (ie, Cycles 2, 4, 6 and every 2 cycles thereafter). The 
disease assessment will be performed and documented no earlier than 5 days before the start 
of the next cycle. Clinical responses will be evaluated according to mRECIST for HCC (see 
Section 6.7 and Appendix 5). The same assessment method will be used throughout the study 
for each subject. If disease progression is based only on new lesions or is equivocal, images 
will be provided to the blinded, independent, central reader (BICR) for confirmation of 
disease progression. Partial response (PR) and complete response (CR) will be confirmed at 
the next scheduled disease assessment (no fewer than 4 weeks after the initial documentation 
of PR or CR). All imaging scans used for disease assessments will be made available for 
independent radiology review by the Sponsor or designee.


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During the Extended Access phase, subjects will have regular visits for assessment of 
disease response at least every 3 months or as per standard of care, whichever is sooner, 
until disease progression is documented. Independent radiological review for 
confirmation of disease progression is not required.
Safety Assessments:
The safety of sorafenib and mapatumumab will be assessed by evaluation of the type, 
frequency, and severity of adverse events (ie, according to the NCI-CTCAE Version 4.0 
grading) and changes in clinical laboratory tests (hematology and clinical chemistry) and 
immunogenicity over time. In the event that an adverse event does not have an NCI CTCAE 
Version 4.0 grading, the severity grades in Section 8.6 will be used. Adverse events (including 
serious adverse events) will be captured from the start of study agent administration (sorafenib 
and/or mapatumumab/placebo) through at least 30 days following the last dose of sorafenib 
and/or mapatumumab/placebo, whichever is later. Laboratory assessments will be performed 
at screening, and during each study visit outlined in the study calendar found in Section 6.3. 
During the Extended Access phase, laboratory assessments will be performed as per 
standard of care; SAEs will continue to be collected according to Section 8.
Section 3.1 Basic Design Characteristics
Formerly:
Estimated Study Duration:
The study is estimated to occur over approximately 24 months. Subjects will continue to 
receive sorafenib with or without mapatumumab/placebo until radiologic disease progression 
or unacceptable toxicity. Estimated median length of subject treatment is 6-8 months. All 
subjects will have an End of Treatment visit at least 30 days after the last dose of sorafenib 
and/or mapatumumab/placebo, whichever is later. After discontinuation of treatment, subjects 
will continue to be followed for radiologic disease assessments every 6 weeks (± 3 days), 
starting 6 weeks after the previous disease assessment while on treatment, until documented 
radiologic disease progression (if not previously documented). Thereafter, subjects will be 
followed every 3 months for survival until at least 90% of subjects have met the survival 
endpoint.
Modified to:
The study is estimated to occur over approximately 24 months. Subjects will continue to 
receive sorafenib with or without mapatumumab/placebo until radiologic disease progression 
or unacceptable toxicity. Estimated median length of subject treatment is 6-8 months. 
Subjects who completed more than 24 months of study treatment with mapatumumab 
and/or sorafenib and who in the opinion of the investigator obtain clinical benefit from 
treatment, will be allowed to continue treatment with unblinded mapatumumab and/or 
sorafenib in the clinical trial.  This extension of treatment will continue until the 
subject’s disease progresses or they withdraw from study. In addition extension of 


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treatment with mapatumumab will not extend beyond the expiry date of the drug batch 
(March 2016).
All subjects will have an End of Treatment visit at least 30 days after the last dose of 
sorafenib and/or mapatumumab/placebo, whichever is later for scheduled safety follow-up 
assessments. After discontinuation of treatment, subjects will continue to be followed for 
radiologic disease assessments every 6 weeks (± 3 days), starting 6 weeks after the previous 
disease assessment while on treatment, until documented radiologic disease progression (if 
not previously documented). Thereafter, subjects will be followed every 3 months for survival 
until at least 90% of subjects have met the survival endpoint.
During the Extended Access phase, subjects will have regular visits for disease 
assessments according to local standard of care. The response assessment will be 
performed and documented at 12 week intervals (± 6 days). In addition BP will be 
monitored every 6 weeks and recorded in the eCRF. Serious AEs will continue to be 
collected during this Extended Access phase according to Section 8. Study drug 
administration and inventory/accountability will continue to be recorded during this 
period according to Section 5.
Section 6.3 On-treatment Study Procedures
Formerly:


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Table 6-1
Study calendar
Cycle 1
Cycle 2
Additional 
Cycles14
Safety Follow-up Phase
Long-
Term 
Follow-up
Procedure
Footnotes
Screen 
Phase
Day 
1
Day 
2
Day 
3
Day 
8
Day 
15
Day 
1
Day 
3
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 22 of 
last cycle on 
treatment
≥ 30 days 
following 
last dose
Informed consent
X
Laboratory
CBC with differential;
Coagulation 
parameters
1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy
2
X
X
Hepatitis
1
X
B and T lymphocyte 
subsets
3
X
X
X
X
Immunogenicity 
4
X
X
X
X
Pharmacokinetics
5
X
X
X
X
X
Biomarkers
6
X
X
X
X
X
X
X
X
X
Study Agent Admin
Sorafenib
7
Twice daily
Mapatumumab/ 
Placebo
7
X
X
X
Physical/Clinical
Med Hx / Phys.Exam
-
X
Vital signs
8
X
X
X
X
X
X
X
X
Body weight
9
X
X
X
X
Performance Status
10
X
X
X
X
X
Record AEs/ 
Conmeds
11
X
<----------------Throughout the study---------------->


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Table 6-1
Study calendar
Cycle 1
Cycle 2
Additional 
Cycles14
Safety Follow-up Phase
Long-
Term 
Follow-up
Procedure
Footnotes
Screen 
Phase
Day 
1
Day 
2
Day 
3
Day 
8
Day 
15
Day 
1
Day 
3
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 22 of 
last cycle on 
treatment
≥ 30 days 
following 
last dose
Disease Assessments 
12
X
Performed at the end of every 2 cycles (ie, Cycles 2, 4, 6) and every 2 cycles thereafter until radiologic PD is documented.
X
α – Fetoprotein (AFP)
12
X
Performed at the end of every 2 cycles (ie Cycles 2, 4, 6) and every 2 cycles thereafter until radiographic PD is 
documented.
X
ECG
-
X
Repeat as clinically indicated
Survival
13
X
AE = adverse event; CBC = complete blood count; CT = computerized tomography; ECG -= electrocardiogram; PD = progressive disease.
1
Safety Labs: Day 1 (complete blood count with differential, coagulation parameters [INR, PT, PTT] and chemistry) must be performed within 3 days prior to dosing on Day 1 of each cycle.  
See Appendix 7 for a detailed list of required laboratory assessments.
2
Pregnancy: Serum test at screening, urine test pre-dose Cycle 1 Day 1; must be negative to receive treatment.
3
B and T lymphocyte subsets: Blood samples for quantification of B and T lymphocytes will be obtained in Cycles 1 and 2 only. Samples will be obtained on Day 1 (prior to dosing) and 
Day 15 of Cycles 1 and 2.
4
Immunogenicity: Obtain prior to dosing on Day 1 of Cycles 1, 2, 4, 6, every 2 cycles thereafter and at the end of treatment visit (at least 30 days after the last dose). On days when 
immunogenicity and pharmacokinetic samples are collected they will be collected together.
5
Pharmacokinetics: Blood specimens will be collected for determination of serum mapatumumab concentrations from subjects as follows:  Cycle 1 (on Day 1 prior to the administration 
mapatumumab/placebo and at the completion of the mapatumumab/placebo infusion, and on Day 8), Cycles 2, 4 and 6 and thereafter on each even cycle (prior to dosing on Day 1), on 
the day of each disease assessment, and at the end of treatment visit (at least 30 days after the last dose). On days when immunogenicity and pharmacokinetic samples are collected 
they will be collected together.  
6
Biomarkers: For subjects participating in the optional biomarker sub-study, historical biopsy samples will be collected, if available, and samples will be collected if obtained during the 
treatment period in Cycle 1 Days 1 (pre-dose mapatumumab), 2, 3, 8 and 15 and Cycle 2 Days 1 (pre-dose mapatumumab), 3, 8 and 15. In addition, blood samples will be obtained as 
follows: blood for isolation of DNA will be collected once, preferably in Cycle 1. Blood for isolation of serum will be collected in Cycles 1 and 2 (pre-dose on the day of 
mapatumumab/placebo dosing). Further details on the biomarker sub-study are outlined in Appendix 6.
7
Study Agent Administration:  Sorafenib will be administered at a dose of 400 mg twice daily without food (at least 1 hour before or 2 hours after a meal). On days when both sorafenib and 
mapatumumab/placebo are administered together, sorafenib should be taken at the same time as any other calendar day.
8
Vital Signs: Blood pressure will be monitored weekly for the first 6 weeks. Vital signs will be obtained within 30 minutes prior to administration of mapatumumab/placebo and at the end of 
infusion on Day 1 of each cycle.
9
Body Weight: To be obtained on the day of or within 3 days before dosing on Day 1 of each cycle.
10
Performance Status: Obtained prior to dosing on Day 1 of each cycle.
11
Adverse Events: AE collection begins with the start of 1st study agent administration. Concurrent medications will be recorded within 28 days prior to Cycle 1 Day 1.


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12
Disease and α – Fetoprotein (AFP) Assessments: Radiologic and AFP assessments will be performed at the end of every 2 cycles (ie, Cycles 2, 4, 6, etc). For subjects discontinuing 
treatment prior to documentation of radiologic disease progression, disease assessments will be performed every 6 weeks (± 3 days), starting 6 weeks after the previous disease 
assessment while on study, until radiologic disease progression is documented. If disease progression is based only on new lesions or is equivocal, images will be provided to the 
blinded, independent reader for confirmation of disease progression. All imaging scans used for disease assessments will be made available for independent radiology review by the 
Sponsor or designee.
13
Survival: Contact will be made with the subject every 3 months to document survival until at least 90% of subjects have met the survival endpoint.
14
Subjects who discontinue mapatumumab/placebo will complete the current cycle assessments per the study calendar. Subsequently, subjects receiving sorafenib alone will return at 
least every 21 days and on additional days as clinically indicated for safety labs (CBC with differential, chemistry and coagulation parameters) for the duration of treatment. Disease 
assessments must be performed every 6 weeks until radiologic disease progression. Adverse events and concomitant medications will be recorded throughout the study.
(concluded)


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Modified to:


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Table 6-1
Study calendar
Cycle 1
Cycle 2
Additional 
Cycles13
Extended 
Access 
Phase
Safety Follow-up 
Phase
Procedure
Footnotes
Screen 
Phase
Day 
1
Day 
2
Day 
3
Day 
8
Day 
15
Day 
1
Day 
3
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
≥ 30 days following last 
dose
Informed consent
X
X
Laboratory
CBC with differential;
Coagulation 
parameters
1
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
1
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy
2
X
X
Hepatitis
1
X
B and T lymphocyte 
subsets
3
X
X
X
X
Immunogenicity 
4
X
X
X
Pharmacokinetics
5
X
X
X
X
Biomarkers
6
X
X
X
X
X
X
X
X
X
Study Agent Admin
Sorafenib
7
Twice daily
X
Mapatumumab/ 
Placebo
7
X
X
X
X
Physical/Clinical
Med Hx / Phys.Exam
-
X
Vital signs
8
X
X
X
X
X
X
X
X
X
Body weight
9
X
X
X
X
Performance Status
10
X
X
X
X
Record AEs/ 
Conmeds
11
X
<----------------Throughout the study---------------->
Disease Assessments 
12
X
Performed at the end of every 2 cycles (ie, Cycles 2, 4, 6) and every 2 cycles thereafter 
X
AM03
15Jul15


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Table 6-1
Study calendar
Cycle 1
Cycle 2
Additional 
Cycles13
Extended 
Access 
Phase
Safety Follow-up 
Phase
Procedure
Footnotes
Screen 
Phase
Day 
1
Day 
2
Day 
3
Day 
8
Day 
15
Day 
1
Day 
3
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
≥ 30 days following last 
dose
until radiologic PD is documented.
α – Fetoprotein (AFP)
12
X
Performed at the end of every 2 cycles (ie Cycles 2, 4, 6) and every 2 cycles thereafter 
until radiographic PD is documented.
ECG
-
X
Repeat as clinically indicated
AE = adverse event; CBC = complete blood count; CT = computerized tomography; ECG -= electrocardiogram; PD = progressive disease.
1
Safety Labs: Day 1 (complete blood count with differential, coagulation parameters [INR, PT, PTT] and chemistry) must be performed within 3 days prior to dosing 
on Day 1 of each cycle.  See Appendix 7 for a detailed list of required laboratory assessments.
2
Pregnancy: Serum test at screening, urine test pre-dose Cycle 1 Day 1; must be negative to receive treatment.
3
B and T lymphocyte subsets: Blood samples for quantification of B and T lymphocytes will be obtained in Cycles 1 and 2 only. Samples will be obtained on Day 1 (prior to dosing) and 
Day 15 of Cycles 1 and 2.
4
Immunogenicity: Obtain prior to dosing on Day 1 of Cycles 1, 2, 4, 6, every 2 cycles thereafter and at the end of treatment visit (at least 30 days after the last dose). On days when 
immunogenicity and pharmacokinetic samples are collected they will be collected together.
5
Pharmacokinetics: Blood specimens will be collected for determination of serum mapatumumab concentrations from subjects as follows:  Cycle 1 (on Day 1 prior to the administration 
mapatumumab/placebo and at the completion of the mapatumumab/placebo infusion, and on Day 8), Cycles 2, 4 and 6 and thereafter on each even cycle (prior to dosing on Day 1), 
on the day of each disease assessment, and at the end of treatment visit (at least 30 days after the last dose). On days when immunogenicity and pharmacokinetic samples are 
collected they will be collected together.  
6
Biomarkers: For subjects participating in the optional biomarker sub-study, historical biopsy samples will be collected, if available, and samples will be collected if obtained during the 
treatment period in Cycle 1 Days 1 (pre-dose mapatumumab), 2, 3, 8 and 15 and Cycle 2 Days 1 (pre-dose mapatumumab), 3, 8 and 15. In addition, blood samples will be obtained 
as follows: blood for isolation of DNA will be collected once, preferably in Cycle 1. Blood for isolation of serum will be collected in Cycles 1 and 2 (pre-dose on the day of 
mapatumumab/placebo dosing). Further details on the biomarker sub-study are outlined in Appendix 6.
7
Study Agent Administration:  Sorafenib will be administered at a dose of 400 mg twice daily without food (at least 1 hour before or 2 hours after a meal). On days when both sorafenib 
and mapatumumab/placebo are administered together, sorafenib should be taken at the same time as any other calendar day.
8
Vital Signs: Blood pressure will be monitored weekly for the first 6 weeks. Vital signs will be obtained within 30 minutes prior to administration of mapatumumab/placebo and at the 
end of infusion on Day 1 of each cycle. For subjects in the Extended Access Phase, only BP is required to be monitored and this should be performed every 6 weeks (± 3 
days).
9
Body Weight: To be obtained on the day of or within 3 days before dosing on Day 1 of each cycle.
10
Performance Status: Obtained prior to dosing on Day 1 of each cycle.
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11
Adverse Events: (S)AE collection begins with the start of 1st study agent administration. Concurrent medications will be recorded within 28 days prior to Cycle 1 Day 1. For subjects 
in the Extended Access Phase, only SAEs will be recorded.
12
Disease and α – Fetoprotein (AFP) Assessments: Radiologic and AFP assessments will be performed at the end of every 2 cycles (ie, Cycles 2, 4, 6, etc). For subjects discontinuing 
treatment prior to documentation of radiologic disease progression, disease assessments will be performed every 6 weeks (± 3 days), starting 6 weeks after the previous disease 
assessment while on study, until radiologic disease progression is documented. If disease progression is based only on new lesions or is equivocal, images will be provided to the 
blinded, independent reader for confirmation of disease progression. All imaging scans used for disease assessments will be made available for independent radiology review by the 
Sponsor or designee. For subjects in the Extended Access Phase, disease assessments will be performed as at least every 3 months or as per standard of care, whichever 
is sooner, until disease progression is documented. Independent radiological review of response or for confirmation of disease progression is not required.
13
Subjects who discontinue mapatumumab/placebo will complete the current cycle assessments per the study calendar. Subsequently, for subjects in the Extended Access Phase, 
subjects receiving sorafenib alone will be assessed as per local standard of care and will return at least every 6 weeks for BP monitoring. Serious adverse events will be 
recorded throughout the study
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Section 6 Study Procedures
Added:
Section 6.4 Extended Access to Study Drug
Subjects who completed more than 24 months of study treatment sorafenib with or without 
mapatumumab and who in the opinion of the investigator obtain clinical benefit from 
treatment, will be allowed to continue treatment with sorafenib with or without unblinded 
mapatumumab in the clinical trial.  Prior to continuing into the Extended Access phase, 
subjects will be re-consented to agree to the study assessments and a local re-review of their 
pathology/cytology. This extension of treatment will continue until the subject’s disease 
progresses (Section 6.8) or they withdraw from study (Section 6.7). In addition extension of 
treatment with mapatumumab will not extend beyond the expiry date of the drug batch 
(March 2016).
During the Extended Access phase, subjects will have regular visits for disease assessments at 
least every 3 months or as per standard of care, whichever is sooner, until disease progression 
is documented. In addition BP will be monitored every 6 weeks and recorded in the eCRF. 
Serious AEs will continue to be collected during this Extended Access phase according to 
Section 8. Study drug administration and inventory/accountability will continue to be 
recorded during this period according to Section 5. Laboratory assessments will be performed 
as per the standard of care.
Section 6.4 Follow-up Procedures, header
Deleted 
Section 6.4.1 Safety Follow-up, header
Formerly:
After discontinuation of study treatment, all subjects will return 1 day after cycle completion 
(approximately Day 22) and at least 30 days after the last dose of sorafenib and/or 
mapatumumab/placebo, for scheduled safety follow-up assessments as outlined in Table 6-1.
Modified to:
Section 6.5 Safety Follow-up
After discontinuation of study treatment, all subjects will return 1 day after cycle completion 
(approximately Day 22) at least 30 days after the last dose of sorafenib and/or mapatumumab, 
for scheduled safety follow-up assessments as outlined in Table 6-1.


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Section 6.4.2 Long-term Follow-up
Formerly:
For subjects discontinuing treatment prior to documentation of radiologic disease progression, 
and for subjects who experience stable disease or a response (PR, CR) but are no longer 
receiving treatment, radiologic disease assessments will be performed at 6 week intervals 
(± 3 days), starting 6 weeks after the previous radiologic disease assessment while on 
treatment, until radiologic disease progression is documented. Thereafter, subjects will be 
followed every 3 months for survival until at least 90% of subjects have met the survival 
endpoint.
Deleted.
Section 6.5 Withdrawal of Subjects from Treatment, paragraph 3
Formerly:
Subjects who withdraw are to be followed for radiologic progression as outlined in 
Section 6.4.2. In addition, every effort will be made to collect safety information on each 
subject through 30 days following the last dose of study treatment, unless the subject 
withdraws consent and refuses to comply with the protocol stipulated safety follow-up and 
radiologic disease progression assessments, or share information obtained after the date of 
withdrawal of consent.
Modified to:
Subjects who withdraw are to be followed for radiologic progression as outlined in 
Section 6.4.2. In addition Following subject withdrawal, every effort will be made to collect 
safety information on each subject through 30 days following the last dose of study treatment, 
unless the subject withdraws consent and refuses to comply with the protocol stipulated safety 
follow-up and radiologic disease progression assessments, or share information obtained after 
the date of withdrawal of consent.
Section 6.6 Withdrawal of Subjects from Study, paragraph 2
Formerly:
Every effort will be made to collect follow-up information on subjects in the long-term 
follow-up period of the study, unless the subject withdraws consent and refuses to share 
information obtained during the long-term follow-up period obtained after the date of 
withdrawal of consent.


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Deleted
Section 6.7 Disease Response Assessments
Modified to: 
Section 6.8 Disease Response Assessments
Added:
Section 6.8.1. Disease Response Assessments for Subjects in the Extended Access Phase
During the Extended Access phase, subjects will have regular visits for disease assessments at 
least every 3 months or as per standard of care, whichever is sooner, until disease progression 
is documented. Independent radiological review for confirmation of disease progression is not 
required.
Section 6.9 Treatment after the end of the Study
The investigator is responsible for ensuring that consideration has been given to the post-study 
care of the subject’s medical condition, whether or not GSK is providing specific post-study 
treatment
Section 8.2 Reporting Adverse Events to the Sponsor or Designee
Added:
The investigator and their designees are responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a Human Genome Science product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact.
Investigators are not obligated to actively seek AEs or SAEs in former study subjects. 
However, if the investigator learns of any SAE, including a death, at any time after a subject 
has been discharged from the study, and he/she considers the event reasonably related to the 
study treatment or study participation, the investigator must promptly notify GSK CMG.
Formerly:
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE Worksheet and sent to 
HGS within 24 hours of site personnel becoming aware of a SAE, regardless of expectedness. 
All pages of the SAE Worksheet will be completed, but the SAE worksheet will not be held 
until all information is available. Additional information and corrections will be provided on 
subsequent SAE Worksheets as described in the Study Procedure Manual. SAE Worksheets 


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will be sent by facsimile to the Drug Safety Department at HGS using the fax number listed 
below.
FAX #:
Modified to:
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE Worksheet and sent to 
HGS emailed to GSK CMG at 
 (fax backup: 
 within 
24 hours of site personnel becoming aware of a SAE, regardless of expectedness. All pages of 
the SAE Worksheet will be completed, but the SAE worksheet will not be held until all 
information is available. Additional information and corrections will be provided on 
subsequent SAE Worksheets as described in the Study Procedure Manual. SAE Worksheets 
will be sent by facsimile to the Drug Safety Department at HGS using the fax number listed 
below.
FAX #:
Section 8.8 Serious Adverse Events Assessed During Long-term Follow-up
Formerly:
SAEs that occur after the safety follow-up period (30 days following the final dose of study 
agent) that are assessed by the investigator as possibly, probably, or definitely related to study 
agent must be reported to Human Genome Sciences on an SAE worksheet, as described in 
Section 8.2. Post-study SAEs will not be documented on the AE case report form.
Deleted.
Section 8.8 Serious Adverse Events Assessed During Long-Term Follow-up
Section Deleted.
Added:
Section 8.8 Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to Human Genome Science of SAEs and non-serious 
AEs related to study treatment (even for non-interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of subjects 
and the safety of a product under clinical investigation are met. 
GSK CMG has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK CMG will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
and investigators.
PPD
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Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Human Genome Science policy and are 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK CMG will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements.


 
 
 
CLINICAL PROTOCOL HGS1012-C1103 
Protocol Amendment: 02 
Date: 23 February 2011 
 
 
TITLE OF STUDY: 
 
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 
 
 
 
STUDY SPONSOR: 
Human Genome Sciences, Inc. 
 
14200 Shady Grove Road 
 
Rockville, Maryland 20850 
 
 
 
EudraCT Number: 
2010-020798-17 
 
 
 
 
 
Confidentiality 
This document contains proprietary and confidential information of Human Genome Sciences, Inc. Acceptance 
of this document constitutes agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without prior written approval from Human Genome Sciences, Inc., except that this 
document may be disclosed to study personnel under your supervision who need to know the contents for 
conducting the study and appropriate Institutional Review Boards and Independent Ethics Committee under the 
condition that they are requested to keep it confidential. The foregoing shall not apply to disclosure required by 
governmental regulations or laws however; Human Genome Sciences, Inc. must be promptly informed of any 
such disclosure. 
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Investigator Agreement 
I will provide copies of the protocol, any subsequent amendments and access to all 
information furnished by the sponsor to study personnel under my supervision. I will discuss 
this material with them to ensure that they are fully informed about the investigational study 
agent and the study protocol. I agree to conduct this clinical trial according to the protocol 
described herein, except when mutually agreed to in writing with the sponsor. I also agree to 
conduct this study in compliance with Good Clinical Practice standards as defined by the 
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice, all 
applicable national, state, and local regulations, as well as the requirements of the appropriate 
Institutional Review Board/Independent Ethics Committee and any other institutional 
requirements. 
 
 
Principal Investigator: 
 
 
 
Signature  
 
 
 
 
 
 
 
Date 
 
 
 
Name (please type or print) 
 
 
 
Institution 
 
 
 
Address 
 
 
 


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Study Synopsis 
Study Number: HGS1012-C1103 
Title of the Study: 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 
Clinical Development Phase: 2 
Objectives: 
Primary: 
• To evaluate the efficacy of mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma. 
 
Secondary: 
• To evaluate the safety of the mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma. 
• To determine serum mapatumumab concentrations. 
 
Diagnosis & Inclusion Criteria: 
Subjects enrolled in the study must meet the following inclusion criteria: 
1. Child-Pugh Class A (see Appendix 1). 
2. Barcelona Clinic Liver Cancer (BCLC) advanced stage (C) hepatocellular carcinoma, or 
BCLC intermediate stage (B) hepatocellular carcinoma if treatment with transarterial 
chemoembolization is not considered appropriate (see Appendix 2). 
3. Measurable disease demonstrating intratumoral arterial enhancement by contrast enhanced 
computerized tomography (CT), with use of multislice scanners, or contrast enhanced 
dynamic magnetic resonance imaging (MRI), with at least 1 tumor lesion that meets the 
following criteria: 
- 
Located in the liver. 
- 
Can be accurately measured in at least 1 dimension. 
- 
Well delineated area of viable, hypervascular (contrast enhancement in the arterial 
phase) tumor that is > 2 cm in the axial plane. 
- 
Suitable for repeat measurement. 
- 
Not previously treated with locoregional or systemic treatment unless the lesion shows 
a well-delineated area of viable (contrast enhancement in the arterial phase) tumor that 
is > 2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical 
enhancement as a result of the previous intervention, then it cannot be selected as a 
target lesion). 


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4. Radiologic eligibility (measurable disease) must be confirmed by the blinded, 
independent, central read (BICR) prior to randomization. 
5. Adequate bone marrow, renal and liver function: 
- 
Absolute neutrophil count ≥ 1.5 x 109 /L or ≥ 1500 /mm3. 
- 
Platelet count ≥ 50 x 109 /L or ≥ 50,000 /mm3. 
- 
Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L) without growth factor support or transfusional 
support. 
- 
Serum creatinine level ≤ 2.0 mg/dL or ≤ 176.8 µmol/L. 
- 
Total bilirubin < 3.0 mg/dL or < 51.3 µmol/L. 
- 
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5.0 x upper limit of 
normal. 
- 
Amylase and lipase ≤ 1.5 x upper limit of normal. 
- 
Serum albumin ≥ 2.8 g/dL or ≥ 28 g/L. 
- 
International normalized ratio ≤ 1.5. 
6. Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) 
Scale (see Appendix 3). 
7. Age 18 years or older. 
8. Have the ability to understand the requirements of the study, provide written informed 
consent (including consent for the use and disclosure of research-related health 
information), and comply with the study and follow-up procedures. 
 
Exclusion Criteria: 
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria: 
1. Any co-morbid condition that in the judgment of the investigator renders the subject at 
high risk of treatment complications or reduces the possibility of assessing clinical effect. 
2. Received prior investigational or non-investigational cytotoxic chemotherapy, hormonal 
therapy, biological therapy (including but not limited to monoclonal antibodies, small 
molecules or other immunotherapy) to treat hepatocellular carcinoma. 
3. History of organ allograft. 
4. Previously received mapatumumab and/or sorafenib. 
5. Underwent resection, radiofrequency ablation, radiation or chemoembolization within 
4 weeks before enrollment or not recovered from such treatments. 
6. Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy, 
immunotherapy, radiofrequency ablation) or other investigational agents during the study 
treatment period. 
7. Major surgery (ie, the opening of a major body cavity, requiring the use of general 
anesthesia) within 4 weeks before enrollment; minor surgery (except for insertion of 
vascular access device) within 2 weeks before enrollment; or not yet recovered from the 
effects of the surgery. 
8. Systemic steroids within 1 week before enrollment except steroids used as part of an 
antiemetic regimen or maintenance-dose steroids for non-cancerous disease. 
9. Hepatic encephalopathy, per the investigator’s evaluation. 
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10. History of clinically significant gastrointestinal bleeding requiring procedural intervention 
(eg, variceal banding, transjugular intrahepatic portosystemic shunt procedure, arterial 
embolization, topical coagulation therapy) within 4 weeks before enrollment. 
11. Gastrointestinal disease resulting in an inability to take oral medication or a requirement 
for intravenous hyperalimentation. 
12. History of any infection requiring hospitalization or intravenous antibiotics within 2 weeks 
before enrollment. 
13. Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) 
with no evidence of progression and neurologically stable off anticonvulsants and steroids. 
14. Known human immunodeficiency virus infection. 
15. Unstable angina, myocardial infarction, cerebrovascular accident, ≥ Class II congestive 
heart failure according to the New York Heart Association Classification for Congestive 
Heart Failure (see Appendix 4) within 6 months before enrollment. 
16. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. 
17. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure 
> 90 mmHg despite optimal medical management). 
18. Using and unable to discontinue use of concomitant strong CYP3A4 inducers 
(eg, including but not limited to St. John’s Wort, dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, phenobarbital). 
19. Pregnant female or nursing mother. All females with an intact uterus (unless amenorrheic 
for the 24 months before enrollment) must have a negative serum pregnancy test at 
screening. All non-sterile or non-postmenopausal females must practice a medically 
accepted method of contraception over the course of the study and for 60 days after the 
last dose of study agent. 
20. Males who do not agree to use effective contraception during the study and for a period of 
60 days following the final dose of study agent. 
21. Subject is currently enrolled in or has not yet completed at least 30 days since ending 
other investigational device or drug study(s) or subject is receiving other investigational 
agents. 
22. Acute or chronic severe renal insufficiency (glomoerular filtration rate 
< 30 mL/min/1.73 m2) or acute renal insufficiency of any severity due to 
the hepato-renal syndrome. 
23. Hepatitis B virus DNA levels > 2,000 IU/mL. 
 
Study Design and Schedule: 
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma. In addition to receiving sorafenib, subjects will be 
randomly assigned to 1 of 2 treatment groups in a 1:1 ratio to receive 30 mg/kg 
mapatumumab or placebo. 
Randomization will be stratified according to BCLC advanced stage C vs BCLC intermediate 
stage B and ECOG performance status (0 vs 1, 2).  
Approximately 100 advanced HCC subjects will be randomized/enrolled.   


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Study Treatment: 
Mapatumumab will be supplied in open label vials and third party unblinding will be 
employed. The study agent will be reconstituted by the unblinded site pharmacist or unblinded 
designee. The unblinded site pharmacist or unblinded designee will also be the person 
responsible for receiving and dispensing study agent but independent of all other study 
activities. All other study personnel, the subject, the Sponsor will remain blinded to the study 
agent received. Separate monitors will be responsible for the clinical (blinded monitor) and 
study agent (unblinded monitor) aspects of the study. 
Subjects will receive treatment every 21 days (ie, a cycle) as outlined below: 
Arm A:  
Sorafenib 400 mg orally twice daily continuously in each cycle + placebo 
intravenously on Day 1 of each cycle. 
Arm B: 
Sorafenib 400 mg orally twice daily continuously + mapatumumab (30 mg/kg) 
intravenously on Day 1 of each cycle. 
Subjects will continue to receive study treatment(s) until radiologic disease progression or 
unacceptable toxicity. Subjects unable to tolerate sorafenib may continue to receive 
mapatumumab/placebo every 21 days until radiographic progression. Subjects unable to 
tolerate mapatumumab/placebo may continue to receive sorafenib until radiographic 
progression. All subjects will have an end of treatment visit at least 30 days after the last dose 
of sorafenib and/or mapatumumab/placebo whichever is later. After discontinuation of 
treatment, subjects will continue to be followed for radiologic disease assessments every 
6 weeks, starting 6 weeks after the previous disease assessment while on treatment, until 
documented radiologic disease progression (if not previously documented) and then every 
3 months thereafter for survival until at least 90% of the subjects have met the survival 
endpoint. 
Disease Assessments: 
Radiologic disease assessments along with assessment of alpha fetoprotein will be performed 
at the end of every two 21-day cycles (ie, Cycles 2, 4, 6 and every 2 cycles thereafter). The 
disease assessment will be performed and documented no earlier than 5 days before the start 
of the next cycle. Clinical responses will be evaluated according to mRECIST for HCC (see 
Section 6.7 and Appendix 5). The same assessment method will be used throughout the study 
for each subject. If disease progression is based only on new lesions or is equivocal, images 
will be provided to the blinded, independent, central reader (BICR) for confirmation of 
disease progression. Partial response (PR) and complete response (CR) will be confirmed at 
the next scheduled disease assessment (no fewer than 4 weeks after the initial documentation 
of PR or CR). All imaging scans used for disease assessments will be made available for 
independent radiology review by the Sponsor or designee. 


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Safety Assessments: 
The safety of sorafenib and mapatumumab will be assessed by evaluation of the type, 
frequency, and severity of adverse events (ie, according to the NCI-CTCAE Version 4.0 
grading) and changes in clinical laboratory tests (hematology and clinical chemistry) and 
immunogenicity over time. In the event that an adverse event does not have an NCI-CTCAE 
Version 4.0 grading, the severity grades in Section 8.6 will be used. Adverse events (including 
serious adverse events) will be captured from the start of study agent administration (sorafenib 
and/or mapatumumab/placebo) through at least 30 days following the last dose of sorafenib 
and/or mapatumumab/placebo, whichever is later. Laboratory assessments will be performed 
at screening, and during each study visit outlined in the study calendar found in Section 6.3. 
The Human Genome Sciences Review Committeee (HGSRC) is comprised of the Department 
Heads of Biostatistics, Regulatory Affairs and Drug Development. The HGSRC will review 
safety data after: (1) 10 subjects have completed 1 cycle; and (2) 30 subjects have completed 
1 cycle. HGSRC reviews of safety data will be conducted approximately every 4 months 
thereafter, until 90% of subjects have reached radiologic progression. The HGSRC may 
conduct additional reviews at their own request and/or at the request of the Medical Monitor. 
The HGSRC may request the unblinding of treatment assignment for a subject and/or 
treatment groups. If treatment assignments are unblinded, the rationale for the unblinding will 
be documented. 
Immunogenicity: 
Blood samples for serum antibodies to mapatumumab will be obtained as outlined in  
Table 6-1. 
Dose Modification/Delay: 
Dose modifications will not be allowed for mapatumumab/placebo. Dose modifications of 
sorafenib for toxicity will be made according to the guidelines provided in the treatment 
section (Section 5.2.3) of the protocol. 
Details regarding pre-treatment and management of hypersensitivity reactions related to 
mapatumumab are provided in Section 5.1.5 and Appendix 8. 
Pharmacokinetics: 
Multiple blood specimens will be obtained from subjects for serum mapatumumab 
concentration determinations as outlined in Table 6-1. 
Pharmacodynamics: 
Subjects will be given the option to participate in a biomarker research sub-study. Consenting 
subjects will be asked to provide a historically obtained biopsy sample, if available, and 
several blood samples. In addition, samples will be requested from subjects who undergo a 
biopsy during the treatment period. 


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To examine biomarkers present peripherally, blood will be drawn during Cycles 1 and 2, from 
which DNA and serum proteins will be isolated. The biomarker sub-study is detailed in 
Appendix 6. 
Exploratory Assessments: 
Blood samples will be collected for quantification of B and T lymphocyte subsets on Day 1 
(prior to dosing) and Day 15 of Cycles 1 and 2. 
Study Endpoints: 
The following will be evaluated (these endpoints and the respective analyses are defined in 
Section 9): 
Primary: 
• Time to progression (TTP). 
 
Secondary: 
• Overall survival. 
• Progression-free survival. 
• Objective response (complete response [CR] + partial response [PR]). 
• Disease control (CR + PR + stable disease [SD]). 
• Response duration and time to response in responders. 
• Frequency and severity of treatment-emergent adverse events. 
• Laboratory parameters. 
• Serum mapatumumab concentrations for use in a population pharmacokinetic analysis. 
 
Statistical Methods: 
Sample Size: 
A total of approximately 100 subjects will be randomly assigned to 1 of 2 arms and treated 
with either sorafenib + placebo or the 2-agent combination of sorafenib and mapatumumab at 
30 mg/kg in a 1:1 ratio. A sample size of 50 subjects randomized and treated in each group is 
sufficient to estimate the median time to progression with a precision of approximately -1.9 M 
to +2.6 M relative to the observed median. In addition, a sample size of 50 patients per arm 
will provide 80% power to detect an improvement in TTP from 5.5 to 8.9 M with at a 
one-sided significance level of 0.10. 
Statistical Analysis: 
The primary analysis will be an estimate of median time to progression in each arm using 
Kaplan Meier methods, reported with 95% confidence intervals, along with testing the 
hazard ratio for time to progression at a 1-sided significance level of 0.10 with a Cox 
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proportional hazards model controlling for the factors stratifying the randomization as 
covariates. Secondary analyses include estimates, using Kaplan Meier methods, of median 
progression-free survival (PFS) and median overall survival (OS) along with associated 
logrank testing. In addition, estimates of overall response rate (CR+PR) and disease control 
rate (CR+PR+SD) will be reported with 95% confidence intervals and an estimate of the 
difference in response rates and disease control rates between groups will be reported and 
tested for significance with a Pearson chi-square test (or Fisher’s exact test). For frequency 
and severity of adverse events and laboratory toxicity grading, counts and rates will be 
presented. 
Study Calendar: 
The study calendar is located in Section 6.3 of the protocol. 
 
 


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Table of Contents 
Study Synopsis ........................................................................................................................... 3 
Table of Contents...................................................................................................................... 10 
List of Tables............................................................................................................................ 13 
List of Abbreviations................................................................................................................ 14 
1 Background......................................................................................................................... 16 
1.1 
Hepatocellular Carcinoma........................................................................................ 16 
1.2 
Treatment Options for Patients with Hepatocellular Carcinoma.............................. 16 
1.3 
The Role of the TRAIL Pathway in HCC ................................................................ 16 
1.3.1 TRAIL and TRAIL Receptors...................................................................... 16 
1.3.2 TRAIL and HBV/HCV Infection ................................................................. 17 
1.4 
Mapatumumab.......................................................................................................... 17 
1.4.1 Mapatumumab Pharmacology...................................................................... 17 
1.4.2 Non-Clinical Mapatumumab Safety Studies................................................ 18 
1.4.3 Clinical Experience with Mapatumumab ..................................................... 19 
1.5 
Rationale for the Evaluation of Mapatumumab in Combination with Sorafenib 
in Hepatocellular Carcinoma.................................................................................... 20 
1.6 
Rationale for Dose Selection.................................................................................... 21 
2 Study Objectives................................................................................................................. 22 
2.1 
Primary Objective..................................................................................................... 22 
2.2 
Secondary Objective................................................................................................. 22 
3 Study Design....................................................................................................................... 22 
3.1 
Basic Design Characteristics .................................................................................... 22 
4 Inclusion and Exclusion Criteria ........................................................................................ 23 
4.1 
Inclusion Criteria...................................................................................................... 23 
4.2 
Exclusion Criteria..................................................................................................... 24 
5 Study Treatment Regimen.................................................................................................. 26 
5.1 
Mapatumumab and Placebo...................................................................................... 26 
5.1.1 Formulation .................................................................................................. 26 
5.1.2 Packaging, Labeling, Preparation, and Storage............................................ 26 
5.1.3 Mapatumumab/Placebo Dose, Route of Administration and Schedule ....... 26 
5.1.4 Mapatumumab/Placebo Dose Toxicity/Delay.............................................. 27 
5.1.5 Management of Allergic/Hypersensitivity Reactions to 
Mapatumumab/Placebo ................................................................................ 28 
5.2 
Sorafenib................................................................................................................... 28 
5.2.1 Packaging, Labeling, Preparation, and Storage............................................ 28 
5.2.2 Anticipated Toxicities with Sorafenib.......................................................... 28 
5.2.3 Alteration of Sorafenib Dose/Schedule Due to Toxicity.............................. 29 


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5.3 
Concurrent Medications and Therapies.................................................................... 32 
5.3.1 Allowable Regimens..................................................................................... 32 
5.3.2 Prohibited Medications................................................................................. 32 
5.3.3 Prohibited Therapies..................................................................................... 32 
6 Study Procedures................................................................................................................ 32 
6.1 
Screening Procedures ............................................................................................... 32 
6.2 
Study Enrollment/Randomization Procedures.......................................................... 33 
6.3 
On-treatment Study Procedures................................................................................ 34 
6.4 
Follow-up Procedures............................................................................................... 37 
6.4.1 Safety Follow-up .......................................................................................... 37 
6.4.2 Long-term Follow-up ................................................................................... 37 
6.5 
Withdrawal of Subjects from Treatment .................................................................. 37 
6.6 
Withdrawal of Subjects from Study ......................................................................... 37 
6.7 
Disease Response Assessments................................................................................ 38 
7 Pharmacokinetic, Immunogenicity, Pharmacodynamic and Exploratory Assessments..... 39 
7.1 
Pharmacokinetic Assessments.................................................................................. 39 
7.2 
Immunogenicity........................................................................................................ 39 
7.3 
Pharmacodynamic Assessments............................................................................... 39 
7.4 
Exploratory Assessments (B and T Lymphocyte Subsets)....................................... 39 
7.4.1 Rationale for B and T Lymphocyte Analysis............................................... 39 
7.4.2 Collection of Samples for B and T Lymphocyte Analysis........................... 40 
8 Adverse Event Reporting.................................................................................................... 40 
8.1 
Definitions ................................................................................................................ 40 
8.2 
Reporting Adverse Events to the Sponsor or Designee............................................ 40 
8.3 
Laboratory Abnormalities as Adverse Events.......................................................... 41 
8.4 
Other Events Requiring Rapid Reporting................................................................. 41 
8.5 
Reporting a Pregnancy.............................................................................................. 42 
8.6 
Investigator Evaluation of Adverse Events .............................................................. 42 
8.7 
Follow-up of Adverse Events................................................................................... 43 
8.8 
Serious Adverse Events Assessed During Long-Term Follow-up........................... 43 
8.9 
Reporting Serious Adverse Events to the Institutional Review Board/Ethics 
Committee ................................................................................................................ 44 
9 Endpoints and Statistical Analysis ..................................................................................... 44 
9.1 
General Statistical Considerations............................................................................ 44 
9.2 
Sample Size Rationale.............................................................................................. 44 
9.3 
Efficacy..................................................................................................................... 44 
9.3.1 Primary Efficacy Endpoint........................................................................... 44 
9.3.2 Primary Efficacy Analysis............................................................................ 44 


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9.3.3 Secondary Efficacy Endpoints...................................................................... 45 
9.3.4 Secondary Efficacy Analyses....................................................................... 45 
9.4 
Safety........................................................................................................................ 45 
9.4.1 Definition of Safety Variables...................................................................... 45 
9.4.2 Human Genome Sciences Safety Review Committee.................................. 46 
9.4.3 Analysis of Safety Variables ........................................................................ 46 
9.5 
Pharmacokinetics...................................................................................................... 46 
9.5.1 Definition of Pharmacokinetic Evaluation ................................................... 46 
9.5.2 Analysis of Pharmacokinetics ...................................................................... 46 
9.6 
Pharmacodynamics................................................................................................... 46 
10 Study Administration.......................................................................................................... 46 
10.1 Informed Consent ..................................................................................................... 46 
10.2 Institutional Review Board Review/Independent Ethics Committee Review and 
Approval................................................................................................................... 47 
10.3 Protocol Compliance ................................................................................................ 47 
10.4 Protocol Revisions.................................................................................................... 47 
10.5 Data Collection and Management ............................................................................ 47 
10.6 Study Monitoring...................................................................................................... 48 
10.7 Drug Accountability ................................................................................................. 48 
10.8 Retention of Records ................................................................................................ 49 
10.9 Financial Disclosure ................................................................................................. 49 
10.10 Publication Policy..................................................................................................... 49 
10.11 Study or Study Site Termination .............................................................................. 50 
11 References .......................................................................................................................... 51 
List of Appendices.................................................................................................................... 58 
 
 


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List of Tables 
Table 5-1 
Sorafenib dose levels........................................................................................ 29 
Table 5-2 
Dose modifications of sorafenib for skin toxicity ............................................ 30 
Table 5-3 
Dose modifications of sorafenib for hypertension ........................................... 30 
Table 5-4 
Dose modifications of sorafenib for sorafenib-associated toxicity .................. 31 
Table 6-1 
Study calendar .................................................................................................. 34 
 
 
 


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List of Abbreviations 
AE 
adverse event 
AFP 
α - fetoprotein 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BCLC 
Barcelona Clinic Liver Cancer 
BICR 
blinded independent central read 
CR 
complete response 
CT 
computerized tomography 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
Fc 
heavy chain constant region or fragment of antibody 
GGT 
gamma-glutamyl transpeptidase 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HGS 
Human Genome Sciences 
HGSRC 
Human Genome Sciences Review Committee 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IR 
incomplete response 
IRB 
Institutional Review Board 
kg 
kilogram 
mg 
milligram 
mL 
milliliter 
mm 
millimeter 
mmHg 
millimeters of mercury 
mRECIST 
modified RECIST assessment for HCC 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
ng 
nanogram 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OS 
overall survival 
PD 
progressive disease 
PK 
pharmacokinetics 
PPT 
partial thromboplastin time 
PR 
partial response 
PS  
performance status 
PT 
prothrombin time 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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RNA 
ribonucleic acid 
SAE 
serious adverse event 
SD 
stable disease 
TNF 
tumor necrosis factor 
TRAIL 
tumor necrosis factor-related apoptosis-inducing ligand 
TRAIL-R1 
TRAIL receptor 1 
TRAIL-R2 
TRAIL receptor 2 
TTP 
time to progression 
 
 
 
 
 


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1 Background 
1.1 
Hepatocellular Carcinoma 
Hepatocellular carcinoma is the 5th most common cancer worldwide accounting for 2% of all 
malignancies. It is the 3rd leading cause of cancer-related death globally with 1 million new 
cases a year (WHO, 2007; IACR, 2002; Ferlay et al, 2004; Lopez et al, 2006). 
Hepatocellular carcinoma is more prevalent in males with a male:female ratio as high as 8:1. 
Depending on the endemic risk factors, hepatocellular carcinoma is diagnosed during the 
4th through 6th decades of life. The reported incidence of  hepatocellular carcinoma is 
increasing because of a better ability to diagnose the disease and because of the long-term 
consequences of hepatitis C virus (HCV) and hepatitis B virus (HBV) infection (Reis et al, 
2006). Worldwide the most common cause of hepatocellular carcinoma is chronic HBV 
infection (El-Serag et al, 2003). Endemic areas thus include China, South Asia and 
South Africa where the incidence of hepatocellular carcinoma can be as high as 120 cases 
per 100,000. In the United States, where HCV and alcohol are the main risk factors, 
the age-adjusted incidence rates have increased from 1.4 cases per 100,000 in 1980 to a 
current incidence of 4 cases per 100,000. This equates to about 8500-11,000 new cases 
diagnosed each year (IACR, 2002; Ferlay et al, 2004; Pawlik et al, 2004; Edwards, et al, 2005; 
Jemal et al, 2007; Bosch et al, 2004). 
1.2 
Treatment Options for Patients with Hepatocellular Carcinoma 
Surgery, including transplantation, is the only curative modality for hepatocellular carcinoma 
(Venook, 1994; Cha et al, 2003). The 5-year survival rate for patients with unresectable 
hepatocellular carcinoma is 11% in the US (ACS, 2007), < 8% in Europe (Capocaccia et al, 
2007), and < 10% in Asia (Teo and Fock, 2001). Symptomatic hepatocellular carcinoma has a 
very poor prognosis with a median survival of 1–8 months (Former et al, 2006; Llovet et al, 
1999a, b). 
Sorafenib, a multikinase inhibitor, is the 1st systemic therapy to significantly impact survival 
in patients with advanced hepatocellular carcinoma, as demonstrated in an international, 
multicenter Phase 3, placebo-controlled trial (Llovet et al, 2007). Sorafenib was approved in 
the United States and European Union for the 1st-line treatment of advanced hepatocellular 
carcinoma in late 2007 and the 2008 National Comprehensive Cancer Network guidelines 
have been updated with the addition of sorafenib as a treatment option for hepatocellular 
carcinoma patients. The updated Barcelona Clinic Liver Cancer (BCLC) guidelines 
recommend sorafenib for hepatocellular carcinoma patients with BCLC Advanced Stage (C) 
(Forner et al, 2010). 
1.3 
The Role of the TRAIL Pathway in HCC 
1.3.1 
TRAIL and TRAIL Receptors 
TRAIL is a member of the tumor necrosis factor (TNF) ligand superfamily, with homology 
to Fas/Apo1 ligand (Pitti et al, 1996; Wiley et al, 1995). TRAIL induces programmed 
cell death primarily in tumor cells through activation of TRAIL death receptors, TRAIL-R1 
(death receptor 4) or TRAIL-R2 (death receptor 5) (Ashkenazi et al, 1999; Evdokiou et al, 


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2002; Kothny-Wilkes et al, 1998; Lawrence et al, 2001; Pitti et al, 1996; Walczak et al, 1999; 
Wiley et al, 1995). 
TRAIL-R1, the target of mapatumumab, is detectable on tumor cells derived from colon, lung, 
liver, gastric, pancreas, uterus and esophagus and in tissue sections from various tumors of the 
colon, lung, pancreas, liver and stomach without significant expression in parallel normal 
tissues (Halpern et al, 2004; Roach et al, 2004). 
1.3.2 
TRAIL and HBV/HCV Infection 
Acutely infected tissues, including the liver, utilize the TRAIL pathway to eliminate virally 
and bacterially infected cells (Herr et al, 2007). In viral hepatitis, TRAIL and 1 of its 
receptors, TRAIL-R2, are upregulated and contribute to the elimination of infected 
hepatocytes associated with viral hepatitis (Bantel and Schulze-Osthoff, 2003; Lin et al, 2002; 
Matsuda et al, 2005). In addition to HBV and HCV infection, steatosis, exposure to bile acids 
and chronic alcohol exposure induce increased expression of TRAIL and TRAIL-R2, but not 
TRAIL-R1, in human hepatocytes (Dunn et al, 2007; Mundt et al, 2005). Cell surface 
expression of TRAIL-R2, but not TRAIL-R1, was altered and responsible for sensitization to 
TRAIL in hepatocytes exposed to bile acids (Higuchi et al, 2001; Malhi et al, 2007). These 
findings have been reproduced in preclinical models. Non-virally infected hepatocytes are 
refractory to TRAIL and TRAIL-R agonists but exposure of HCV-infected hepatocytes to 
TRAIL leads to a significant level of apoptosis (Volkmann et al, 2007). Inhibition of the 
TRAIL pathway may protect infected cells from apoptosis and allow for chronic infection 
(Mundt et al, 2003). Recent non-clinical observations demonstrated that natural killer cells 
expressing the ligand TRAIL, are enriched in the livers of patients with chronic HBV 
infection, and TRAIL is overexpressed in the livers of patients with HCV-associated steatosis 
(Mundt et al, 2005).  
In summary, preclinical data suggest that mapatumumab may promote apoptosis of cancer 
cells, including hepatocellular carcinoma cells. Whether viral infection, including HBV or 
HCV infection, will attenuate or modulate the effects of mapatumumab on hepatocytes is not 
yet known, but experience to date in a Phase 1b trial of mapatumumab in combination with 
sorafenib in subjects with advanced hepatocellular carcinoma who are positive for hepatitis B 
surface antigen or hepatitis C antibody indicates that the safety experience is consistent with 
underlying disease and known sorafenib toxicities (see Section 1.2). 
1.4 
Mapatumumab 
1.4.1 
Mapatumumab Pharmacology 
Mapatumumab is a fully human, agonist monoclonal antibody that activates the cell death 
pathway in tumor cells by specifically binding to TRAIL-R1 with high affinity. 
Mapatumumab efficiently induces apoptosis in human cancer cell lines expressing the 
TRAIL-R1 protein on the cell surface. Nonclinical studies have demonstrated that 
mapatumumab can induce cytotoxicity in multiple tumor cell lines representing both solid and 
hematological malignancies, including cancers of the biliary tract, colon, lung, breast, 
pancreas, esophagus, ovary, kidney, uterus, as well as lymphoma and various leukemias. 
Mapatumumab has also demonstrated anti-tumor activity as a single agent, preventing 


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tumor growth and in some cases causing regression of tumors in xenograft tumor models of 
multiple human malignancies, including lung, colon, kidney, and uterus (Camidge, 2007; 
Georgakis et al, 2005; Jin et al, 2007; Humphreys, 2004; Marini et al, 2006; Menoret et al, 
2006; Pukac et al, 2005). 
The relationship between receptor expression and response to therapy with mapatumumab 
remains unclear. In vitro studies of cell lines have shown that TRAIL-R1 expression level is 
not a consistent predictor of response to mapatumumab. Although both TRAIL-R1 expression 
and apoptosis in response to mapatumumab are increased in many tumor cell lines as 
compared with normal diploid cells, there are examples of mapatumumab cytotoxicity on cell 
lines with very low levels of detectable receptor, and conversely, mapatumumab resistant cell 
lines that have relatively high levels of TRAIL-R1 cell surface expression. 
Tumor cell cytotoxic activity can be enhanced when mapatumumab is administered in 
combination with chemotherapeutics or other anti-neoplastic agents. Enhanced apoptotic 
signaling, in vitro cell killing and in vivo anti-tumor activity have been observed when 
mapatumumab has been combined with various types of therapeutic agents and treatments 
including microtubule poisons, anti metabolites, topoisomerase inhibitors, proteosome 
inhibitors, platinum agents and radiation. Both the level and spectrum of activity of 
mapatumumab is enhanced in in vitro cytotoxicity and in vivo xenograft studies in 
combination with various chemotherapeutic and anti-neoplastic agents, including a xenograft 
model of hepatocellular carcinoma in combination with cisplatin and gemcitabine 
(Camidge, 2007; Pukac et al, 2005; Georgakis et al, 2005; Humphreys, 2004; Jin et al, 2007; 
Human Genome Sciences data on file). 
Please refer to the mapatumumab Investigator’s Brochure for detailed information regarding 
the nonclinical pharmacology, toxicology, and PK of mapatumumab. 
1.4.2 
Non-Clinical Mapatumumab Safety Studies 
To assess the nonclinical safety of mapatumumab, a 6-month toxicity study, with a 4-month 
recovery period, was conducted in chimpanzees. Mapatumumab was administered 
intravenously at up to 40 mg/kg every 10 days. No mapatumumab-specific toxicity was 
identified and no anti-mapatumumab antibodies were detected. 
To assess its off-target effects, mapatumumab was administered intravenously weekly to 
cynomolgus monkeys, whose TRAIL R1 homolog does not bind mapatumumab. 
Mapatumumab was well tolerated at doses of up to 50 mg/kg and was not highly 
immunogenic: of the 40 monkeys treated, 1 developed anti-mapatumumab antibodies. The 
positive response was observed in an animal in the high dose (50 mg/kg) group. 
In vitro, mapatumumab was found to decrease viability of normal human hepatocytes, 
although the observed effect was less than that observed with TRAIL. This effect was variable 
across donors and did not amplify with increasing concentrations of mapatumumab. It should 
be noted that in clinical studies, plasma mapatumumab concentrations have been achieved that 
are > 1100–fold greater than the minimum exposure resulting in reduced in vitro hepatocyte 
viability. Despite this, the clinical results do not reveal evidence of hepatotoxicity in those 


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studies. Hence it appears that the in vitro hepatocyte viability assay is not predictive of 
mapatumumab effects in vivo. 
1.4.3 
Clinical Experience with Mapatumumab 
Over 400 subjects have received mapatumumab in clinical trials to date. Preliminary clinical 
data are available from 218 subjects who received mapatumumab as a single agent at doses 
ranging from 0.01 to 20 mg/kg across 6 clinical trials. 
Based on available data, mapatumumab appears to be well tolerated and no significant safety 
issues have been observed. Adverse events have generally been mild to moderate in severity, 
manageable, and do not appear related to dose. The most frequently reported treatment-related 
adverse events occurring in > 10% of subjects were fatigue, hypotension, nausea and pyrexia. 
Severe events have been uncommon and generally judged not related to mapatumumab. 
Severe events judged at least possibly related to mapatumumab have been observed and a 
complete list can be found in the mapatumumab Investigator’s Brochure. Grade 3 or Grade 4 
hematologic, renal, or hepatic laboratory abnormalities also have been relatively uncommon 
with no significant trend or dose-response evident. Lymphopenia was the most commonly 
observed laboratory abnormality, but tended to be intermittent and reversible and was not 
associated with infectious events. 
In subjects with solid tumors, stable disease has been the best response observed with 
mapatumumab as a single-agent. However, 2 complete responses (CRs) and 1 partial response 
(PR) were observed in subjects with follicular lymphoma. 
In addition, preliminary clinical data are available from 234 subjects who received 
mapatumumab at doses ranging from 1 to 30 mg/kg every 21 days in combination with 
chemotherapy in 5 clinical trials (carboplatin/paclitaxel [N = 100], gemcitabine/cisplatin 
[N = 49], bortezomib [n = 69], or sorafenib [n = 16]. Mapatumumab has been generally well 
tolerated; adverse events and laboratory abnormalities have been consistent with those 
expected with underlying disease or chemotherapy. A listing of severe events considered at 
least possibly related to mapatumumab can be found in the mapatumumab Investigator’s 
Brochure. The most commonly occurring laboratory abnormalities have been hematologic 
(ie, anemia, neutropenia, thrombocytopenia, and leukopenia), as expected with chemotherapy. 
Grade 3/4 laboratory abnormalities have been relatively uncommon. Higher frequencies of 
Grade 3/4 neutropenia, leukopenia, lymphopenia, and thrombocytopenia have been observed. 
Data from randomized Phase 2 studies in combination with chemotherapy suggest that 
mapatumumab may increase rates of lymphopenia. 
One subject receiving mapatumumab in combination with carboplatin/paclitaxel has 
achieved a CR. Twenty-two subjects receiving mapatumumab in combination with 
paclitaxel/carboplatin and 12 subjects receiving mapatumumab in combination with 
gemcitabine/cisplatin have achieved PRs. Three subjects receiving mapatumumab in 
combination with bortezomib achieved CRs; 25 subjects receiving mapatumumab in 
combination with bortezomib achieved a PR.   


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1.5 
Rationale for the Evaluation of Mapatumumab in Combination with 
Sorafenib in Hepatocellular Carcinoma 
Sorafenib is the standard of care for treatment of patients with advanced hepatocellular 
carcinoma. Sorafenib is a multikinase inhibitor that targets the Raf/mitogen-activated protein 
kinase/extracellular signal-regulated kinase signaling pathway, blocks tumor angiogenesis and 
induces apoptosis (Panka et al, 2006; Rahmani et al, 205; Yu et al, 2005; Wilhelm et al, 
2004). Sorafenib was approved by the European Medicines Agency and the Food and Drug 
Administration in 2007 for treatment of patients with hepatocellular carcinoma based on the 
demonstration of improved overall survival in the 602 patient randomized, placebo-controlled, 
Phase 3 “Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol” (SHARP) 
trial. Approximately half the 602 patients had either hepatitis C virus or hepatitis B virus as 
underlying etiology and 26% had alcohol-related cirrhosis. The median overall survival was 
10.7 months for patients in the sorafenib arm compared with 7.0 months for patients in the 
placebo arm (hazard ratio in the sorafenib group, 0.69 95% confidence interval, 0.55 to 0.87; 
p < 0.001). The median time to radiologic progression was 5.5 months in the sorafenib arm, 
compared with 2.8 months in the placebo arm (p < 0.0001) (Llovet et al, 2008). Seven patients 
in the sorafenib group (2%) and 2 patients in the placebo group (1%) had a PR; no patients 
had a CR. 
A 2nd randomized, placebo-controlled Phase 3 trial was conducted in the Asia-Pacific region 
(Cheng et al, 2009). The 226 patients randomly assigned to sorafenib or placebo in this trial 
appeared to have more advanced disease than those in the SHARP trial, with a higher 
frequency of extrahepatic spread, poorer ECOG PS, and higher levels of AFP, but still showed 
a benefit from treatment with sorafenib. The majority (73%) had hepatitis B virus as an 
underlying etiology. The median overall survival was 6.5 months for patients in the sorafenib 
arm, compared with 4.2 months in the placebo group (hazard ratio, 0.68, 95% confidence 
interval, 0.50-0.93; p = 0.014). The median time to progression was 2.8 months in the 
sorafenib group, compared with 1.4 months in the placebo group (hazard ratio, 0.57, 95% 
confidence interval 0.42-0.79; p = 0.0005). 
The mechanisms of sorafenib and mapatumumab action suggest that these agents could 
interact synergistically. Sorafenib sensitizes human cancer cell lines, including cell lines 
derived from hepatocellular carcinoma, to apoptotic stimuli by reducing expression of 
apoptotic regulatory proteins; Mcl-1, Bcl-xL, and FLIP (Kim et al,2008; Koehler et al, 2009; 
Rosato et al, 2007; Liu et al, 2006; Rahmani et al, 2005; Yu et al, 2005). Mcl-1, Bcl-xL 
and FLIP have also been shown to mediate sensitivity of a wide range of tumor cell lines 
to TRAIL receptor agonists (Meng et al, 2007; Rosato et al, 2007; Llobet et al 2010; 
Blechacz et al, 2009; Katz et al, 2009; Huang and Sincrope, 2010; and Menoret et al, 2006). 
Recent studies demonstrated the combination of sorafenib with TRAIL or TRAIL receptor 
antibodies has significant activity in hepatocellular carcinoma cell lines (Koehler et al, 2009) 
and colon tumor xenografts (Ricci et al, 2007) that were resistant to TRAIL and an antibody 
against TRAIL-R2. 
Mapatumumab activity has been evaluated preclinically in hepatocellular carcinoma cell lines 
by in vitro cytotoxicity assays both as a single agent and in combination with doxorubicin, 
cisplatin, gemcitabine or sorafenib. Single agent mapatumumab activity was observed in 4 of 


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10 hepatocellular carcinoma cell lines. Increased in vitro cytotoxicity, including examples of 
synergy, were observed in 8 of 10 cell lines when mapatumumab was combined with 
doxorubicin or cisplatin or the combination of cisplatin and gemcitabine (Humphreys et al, 
2008). Two of these hepatocellular carcinoma cell lines were evaluated for in vitro 
cytotoxicity of mapatumumab in combination with sorafenib. One displayed an increase in 
cytotoxicity from 30% to 60% when treated with a combination of sorafenib and 
mapatumumab. Importantly, treatment of a primary human hepatocyte cell line did not induce 
any apoptosis at doses of mapatumumab that were cytotoxic to hepatocellular carcinoma cell 
lines (
 and 
 [personal communication], 2008; Abdulghani et al, 2008). 
Therefore, collectively, the expression of TRAIL-R1 in hepatocellular carcinoma and 
preclinical activity observed with combinations of mapatumumab with chemotherapy or 
sorafenib supports the rationale that this combination may be able to effectively target 
hepatocellular carcinoma. 
1.6 
Rationale for Dose Selection 
As 
of 
June 
2010, 
mapatumumab 
has 
been 
administered 
with 
chemotherapy 
(ie, carboplatin/paclitaxel, gemcitabine/cisplatin, bortezomib, or sorafenib) to 234 subjects, 
including 61 subjects who received 20 mg/kg and 50 subjects who received 30 mg/kg 
mapatumumab. Based on available data, mapatumumab in combination with chemotherapy is 
generally well tolerated at dose levels up to and including 30 mg/kg, and no significant safety 
issues have been observed in the course of the clinical trials even at the higher doses.   
Preliminary PK data are available for subjects who received 1, 10, 20 or 30 mg/kg 
mapatumumab in combination with gemcitabine and cisplatin (n = 49), 10 or 30 mg/kg 
mapatumumab in combination with paclitaxel and carboplatin (n = 73), and 3, 10, or 
30 mg/kg mapatumumab in combination with sorafenib (n = 17). Serum or plasma 
mapatumumab concentrations are consistently within the range of expected concentrations 
predicted from Phase 1 study results in solid tumor patients administered mapatumumab as 
monotherapy. Mapatumumab PK is linear and not affected by the addition of therapeutic 
agents. As expected, the observed peak and trough levels of mapatumumab at 30 mg/kg are 
2 to 3 times higher than those observed at 10 mg/kg. Exposure appears to increase in 
proportion to dose and exposures for a given dose are similar across studies.  
A Phase 1b dose escalation study of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma who are positive for hepatitis B surface antigen or 
hepatitis C antibody is being conducted. Safety observations have been consistent with the 
underlying disease and known sorafenib toxicities. As of June 2010, 6 subjects have received 
3 mg/kg, 9 subjects have received 10 mg/kg, and 1 subject has received 30 mg/kg 
mapatumumab. The number of cycles completed ranges from 1 to 20; 4/16 (25.0%) of 
subjects have completed 11 or more cycles. Adverse events have generally been consistent 
with published reports of the toxicities associated with sorafenib and previous experience 
with mapatumumab, as well as underlying disease. The most frequently occurring 
treatment-emergent adverse events, regardless of severity or attribution of causality, 
include diarrhea (10/16, 62.5%), fatigue (9/16, 56.3%), nausea (9/16, 56.3%), and vomiting 
(7/16, 43.8%). Serious adverse events, regardless of attribution of causality, include 
hypertension, upper respiratory tract infection, atrial fibrillation, hyperbilirubinemia, 
PPD
PPD


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hypoglycemia, and hepatic pain. Severe adverse events considered at least possibly related to 
mapatumumab or its interaction with sorafenib include elevated lipase (3/16, 18.8%), hepatic 
pain (1/16, 6.3%), and thrombocytopenia (1/16, 6.3%). Laboratory abnormalities have 
generally been mild or moderate in severity, manageable, and/or consistent with those 
expected with chemotherapy or the underlying disease. The most frequent Grade 3 or Grade 4 
laboratory abnormalities include elevated total bilirubin (Grade 3, 4/16, 25.0%; Grade 4, 
1/16, 6.3%) and lymphopenia (Grade 3, 3/16, 18.8%; Grade 4, 2/16, 12.5%). Additional 
information on the safety experience can be found in the mapatumumab Investigators’ 
Brochure. 
Based on the information currently available, the safety profile continues to be favorable, 
supporting continued evaluation of mapatumumab in combination with chemotherapy, 
including sorafenib. The maximum tolerated dose has not been reached in any of the Phase 1 
or Phase 2 trials conducted to date. Thus, further evaluation of the 30 mg/kg dose is 
warranted. 
The dose of sorafenib for this study, 400 mg twice daily, is the approved dose for the 
treatment of unresectable hepatocellular carcinoma. 
2 Study Objectives 
2.1 
Primary Objective 
• To evaluate the efficacy of mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma. 
 
2.2 
Secondary Objective 
• To evaluate the safety of the mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma. 
• To determine serum mapatumumab concentrations. 
 
3 Study Design 
3.1 
Basic Design Characteristics 
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma.   
In addition to receiving sorafenib, subjects will be randomly assigned to 1 of 2 treatment 
groups in a 1:1 ratio: 30 mg/kg mapatumumab or placebo. 
Mapatumumab will be supplied in open label vials and 3rd party unblinding will be employed. 
The study agent will be reconstituted by the unblinded site pharmacist or unblinded designee. 
The unblinded site pharmacist or unblinded designee will also be the person responsible for 
receiving and dispensing study agent, but independent of all other study activities. All other 
study site personnel, the subject, and the Sponsor will remain blinded to the study agent 


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received. Separate monitors will be responsible for the clinical (blinded monitor) and study 
agent (unblinded monitor) aspects of the study. 
Number of Subjects: 
Approximately 100 subjects with advanced HCC will be randomized/enrolled. 
Treatment Groups: 
Subjects will receive treatment every 21 days (ie, a cycle) as outlined below: 
Arm A: 
Sorafenib 400 mg orally twice daily continuously in each cycle + placebo 
intravenously on Day 1 of each cycle 
Arm B:  
Sorafenib 400 mg orally twice daily continuously in each cycle + mapatumumab 
(30 mg/kg) intravenously on Day 1 of each cycle 
Randomization 
Randomization will be stratified according to BCLC advanced stage C vs BCLC intermediate 
stage B and ECOG performance status (0 vs 1, 2). 
Estimated Study Duration: 
The study is estimated to occur over approximately 24 months. Subjects will continue to 
receive sorafenib with or without mapatumumab/placebo until radiologic disease progression 
or unacceptable toxicity. Estimated median length of subject treatment is 6-8 months. All 
subjects will have an End of Treatment visit at least 30 days after the last dose of sorafenib 
and/or mapatumumab/placebo, whichever is later. After discontinuation of treatment, subjects 
will continue to be followed for radiologic disease assessments every 6 weeks (± 3 days), 
starting 6 weeks after the previous disease assessment while on treatment, until documented 
radiologic disease progression (if not previously documented). Thereafter, subjects will be 
followed every 3 months for survival until at least 90% of subjects have met the survival 
endpoint. 
4 Inclusion and Exclusion Criteria 
4.1 
Inclusion Criteria 
Subjects enrolled in the study must meet the following inclusion criteria: 
1. Child-Pugh Class A (see Appendix 1). 
2. Barcelona Clinic Liver Cancer (BCLC) advanced stage (C) hepatocellular carcinoma, or 
BCLC intermediate stage (B) hepatocellular carcinoma if treatment with transarterial 
chemoembolization is not considered appropriate (see Appendix 2). 
3. Measurable disease demonstrating intratumoral arterial enhancement by contrast enhanced 
computerized tomography (CT), with use of multislice scanners, or contrast enhanced 


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dynamic magnetic resonance imaging (MRI), with at least 1 tumor lesion that meets the 
following criteria: 
- 
Located in the liver. 
- 
Can be accurately measured in at least 1 dimension. 
- 
Well delineated area of viable, hypervascular (contrast enhancement in the arterial 
phase) tumor that is > 2 cm in the axial plane. 
- 
Suitable for repeat measurement. 
- 
Not previously treated with locoregional or systemic treatment unless the lesion shows 
a well-delineated area of viable (contrast enhancement in the arterial phase) tumor that 
is > 2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical 
enhancement as a result of the previous intervention, then it cannot be selected as a 
target lesion). 
4. Radiologic eligibility (measurable disease) must be must be confirmed by the BICR prior 
to randomization. 
5. Adequate bone marrow, renal and liver function: 
- 
Absolute neutrophil count ≥ 1.5 x 109 /L or ≥ 1500 /mm3. 
- 
Platelet count ≥ 50 x 109 /L or ≥ 50,000 /mm3. 
- 
Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L) without growth factor support or transfusional 
support. 
- 
Serum creatinine level ≤ 2.0 mg/dL or ≤ 176.8 µmol/L. 
- 
Total bilirubin < 3.0 mg/dL or < 51.3 µmol/L. 
- 
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5.0 x upper limit of 
normal. 
- 
Amylase and lipase ≤ 1.5 x upper limit of normal. 
- 
Serum albumin ≥ 2.8 g/dL or ≥ 28 g/L. 
- 
International normalized ratio ≤ 1.5. 
6. Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) 
Scale (see Appendix 3). 
7. Age 18 years or older. 
8. Have the ability to understand the requirements of the study, provide written informed 
consent (including consent for the use and disclosure of research-related health 
information), and comply with the study and follow-up procedures. 
 
4.2 
Exclusion Criteria 
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria: 
1. Any co-morbid condition that in the judgment of the investigator renders the subject at 
high risk of treatment complications or reduces the possibility of assessing clinical effect. 
2. Received prior investigational or non-investigational cytotoxic chemotherapy, hormonal 
therapy, biological therapy (including but not limited to monoclonal antibodies, small 
molecules or other immunotherapy) to treat hepatocellular carcinoma. 
3. History of organ allograft. 
4. Previously received mapatumumab or sorafenib. 
5. Underwent resection, radiofrequency ablation, radiation or chemoembolization within 
4 weeks before enrollment or not recovered from such treatments. 
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6. Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy, 
immunotherapy, radiofrequency ablation) or other investigational agents during the study 
treatment period. 
7. Major surgery (ie, the opening of a major body cavity, requiring the use of general 
anesthesia) within 4 weeks before enrollment; minor surgery (except for insertion of 
vascular access device) within 2 weeks before enrollment; or not yet recovered from the 
effects of the surgery. 
8. Systemic steroids within 1 week before enrollment except steroids used as part of an 
antiemetic regimen or maintenance-dose steroids for non-cancerous disease. 
9. Hepatic encephalopathy, per the investigator’s evaluation. 
10. History of clinically significant gastrointestinal bleeding requiring procedural intervention 
(eg, variceal banding, transjugular intrahepatic portosystemic shunt procedure, arterial 
embolization, topical coagulation therapy) within 4 weeks before enrollment. 
11. Gastrointestinal disease resulting in an inability to take oral medication or a requirement 
for intravenous hyperalimentation. 
12. History of any infection requiring hospitalization or intravenous antibiotics within 2 weeks 
before enrollment. 
13. Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) 
with no evidence of progression and neurologically stable off anticonvulsants and steroids. 
14. Known human immunodeficiency virus infection. 
15. Unstable angina, myocardial infarction, cerebrovascular accident, ≥ Class II congestive 
heart failure according to the New York Heart Association Classification for Congestive 
Heart Failure (see Appendix 4) within 6 months before enrollment. 
16. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. 
17. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure 
> 90 mmHg despite optimal medical management). 
18. Using and unable to discontinue use of concomitant strong CYP3A4 inducers 
(eg, including but not limited to St. John’s Wort, dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, phenobarbital). 
19. Pregnant female or nursing mother. All females with an intact uterus (unless amenorrheic 
for the 24 months before enrollment) must have a negative serum pregnancy test at 
screening. All non-sterile or non-postmenopausal females must practice a medically 
accepted method of contraception over the course of the study and for 60 days after the 
last dose of study agent. 
20. Males who do not agree to use effective contraception during the study and for a period of 
60 days following the final dose of study agent. 
21. Subject is currently enrolled in or has not yet completed at least 30 days since ending 
other investigational device or drug study(s) or subject is receiving other investigational 
agents. 
22. Acute or chronic severe renal insufficiency (glomoerular filtration rate 
< 30 mL/min/1.73 m2) or acute renal insufficiency of any severity due to 
the hepato-renal syndrome. 
23. Hepatitis B virus DNA levels > 2,000 IU/mL. 
 


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5 Study Treatment Regimen 
Sorafenib will be administered at a dose of 400 mg twice daily without food (at least 1 hour 
before or 2 hours after a meal). On days when both sorafenib and mapatumumab/placebo are 
administered together, the sorafenib should be taken at the same time as any other calendar 
day. 
5.1 
Mapatumumab and Placebo 
5.1.1 
Formulation 
Mapatumumab will be supplied as a lyophilized formulation in sterile, single-use 10 mL vials 
containing 100 mg mapatumumab. Upon reconstitution with 5.0 mL of sterile water for 
injection, each vial will contain 20 mg/mL mapatumumab in 0.13 mg/mL citric acid, 
2.8 mg/mL sodium citrate, 19 mg/mL glycine, 5 mg/mL sucrose, 0.2 mg/mL polysorbate 80, 
pH 6.5. 
Two hundred-fifty mL normal saline solution for intravenous infusion will be administered as 
placebo for mapatumumab. 
5.1.2 
Packaging, Labeling, Preparation, and Storage 
The Pharmacy Manual will provide instructions for preparation and storage of study agent. 
The product will be securely stored at 2-8ºC. 
The study agent label will contain, at a minimum, the following information: 
• Product name 
• Concentration 
• Lot number 
• Storage instructions 
• Investigational drug statement 
• Manufacturer’s name and address 
 
Study agent inventory/accountability forms will be examined and reconciled by the unblinded 
study monitor or designee. At the end of the study, all used and unused investigational study 
agent will be accounted for on a study agent accountability form provided to the investigator 
by the Sponsor or designee. Please refer to the HGS1012-C1103 Pharmacy Manual for more 
details regarding storage, handling and drug accountability. 
5.1.3 
Mapatumumab/Placebo Dose, Route of Administration and Schedule 
The dose of mapatumumab is 30 mg/kg. Mapatumumab dose calculations will be based upon 
the subject’s weight measured on Day 1 or within 3 days before Day 1 of each cycle. The 
planned duration of each treatment cycle will be 21 days. Mapatumumab/placebo will be 
administered on Day 1 of each cycle. 


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After reconstitution with sterile water for injection, the calculated mapatumumab dose to be 
administered to the subject will be further diluted in normal saline to a total volume of 
250 mL for intravenous infusion. After adding the reconstituted product, the bag will be 
gently inverted to mix the solution. Following reconstitution and/or dilution in normal saline, 
mapatumumab will be stored at 2-8ºC. The product will be administered to the subject within 
8 hours of reconstitution. Refer to the HGS1012-C1103 Pharmacy Manual for instructions on 
admixing and administering study agent.  
Two hundred-fifty mL normal saline solution for intravenous infusion will be administered as 
placebo for mapatumumab. 
Mapatumumab/placebo will be infused at a constant rate over 1 hour. 
Infusion and hypersensitivity reactions may occur. A suggested pre-medication regimen for 
mapatumumab/placebo consists of diphenhydramine and acetaminophen administered within 
1 hour prior to the start of the mapatumumab/placebo dose. Use of a pre-medication regimen 
and alternatives to this regimen are at the investigator’s discretion. 
Subjects will be monitored closely during and after infusion for any sign of acute adverse 
reaction. If an allergic reaction occurs, see Section 5.1.5 and Appendix 8 for suggested 
medical management. 
5.1.4 
Mapatumumab/Placebo Dose Toxicity/Delay 
Mapatumumab/placebo will be discontinued for Grade 4 transaminase elevations of any 
duration if they are considered related to mapatumumab. 
Mapatumumab/placebo may be delayed up to 2 weeks for toxicities considered related to 
mapatumumab as described below or if the investigator believes that a delay in dosing is 
warranted in the interest of subject safety. 
The National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE, Version 4.0) will be used to grade AEs. 
• Grade 4 neutropenia for > 7 consecutive days or febrile neutropenia. 
• Grade 4 thrombocytopenia. 
• Grade 3 or greater non-hematologic AEs except transient transaminase, amylase and 
lipase abnormalities for which the following criteria will apply: 
- 
Grade 3 or Grade 4 elevations in transaminases that do not resolve to baseline or 
Grade 1 before the next cycle. 
- 
Grade 3 elevations in lipase or amylase associated with clinical/imaging findings of 
pancreatitis, or resulting in chronic damage to the pancreas.  
- 
Any Grade 4 elevations in lipase or amylase for > 4 consecutive days. 
 
If mapatumumab/placebo is delayed for toxicity and the toxicity does not resolve (≤ Grade 1) 
or return to baseline within 2 weeks after the delayed dose was originally scheduled (based on 
a 21-day treatment cycle), the subject will be withdrawn from further treatment with 
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mapatumumab/placebo. If mapatumumab/placebo is delayed because the investigator believes 
a delay is warranted in the interest of subject safety and dosing of mapatumumab/placebo is 
not resumed within 2 weeks after the delayed dose was originally scheduled (based on a 
21-day treatment cycle), the subject will be withdrawn from future treatment with 
mapatumumab/placebo. Sorafenib dosing will continue while mapatumumab/placebo dosing 
is held. The subject will continue receiving sorafenib until radiologic progressive disease or 
an unacceptable toxicity occurs, at the discretion of the Investigator.  
Doses of mapatumumab may not be altered. 
5.1.5 
Management of Allergic/Hypersensitivity Reactions to 
Mapatumumab/Placebo 
The administration of any recombinant protein has the potential to induce local or system 
immunologic reactions; subjects could experience, for example, acute allergic reactions. To 
date, 2 such SAEs have been reported which were considered related to mapatumumab 
(hypersensitivity and angioedema/facial edema). In the event of allergic/hypersensitivity 
reactions, investigators will institute treatment measures according to best medical and 
nursing practice. Guidelines for treatment are provided in Appendix 8. 
For a NCI-CTCAE Version 4.0 Grade 3 or Grade 4 hypersensitivity reaction, treatment with 
mapatumumab/placebo will be discontinued. 
If mapatumumab/placebo is discontinued for Grade 3 or Grade 4 hypersensitivity reactions, 
the subject will continue to receive sorafenib, until radiologic progression or unacceptable 
toxicity. 
5.2 
Sorafenib 
5.2.1 
Packaging, Labeling, Preparation, and Storage 
Sorafenib is supplied as tablets, each containing 274 mg sorafenib tosylate, equivalent to 
200 mg of sorafenib. 
The recommended daily dose of sorafenib is 400 mg (2 x 200 mg tablets) taken orally twice 
daily without food (at least 1 hour before or 2 hours after a meal). 
Sorafenib will be stored at room temperature (15-30°C, 59-86°F) in a dry place. 
For country-specific formulation and packaging information, please refer to the instructions 
provided in the sorafenib product labeling. 
Supplier: Commercially available. 
5.2.2 
Anticipated Toxicities with Sorafenib 
Toxicities anticipated with the use of sorafenib include the following: 
• Cardiac: Cardiac ischemia and/or infarction, hypertension. 


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• Dermatologic: Hand-foot skin reaction, rash/desquamation. 
• Hemorrhagic: Increased risk of bleeding. 
• Gastrointestinal: Gastrointestinal perforation. 
• Other: Wound-healing complications, fatigue, weight-loss, alopecia, pruritis, dry skin, 
diarrhea, anorexia, nausea, vomiting, constipation, liver dysfunction and abdominal pain. 
 
Laboratory abnormalities observed in hepatocellular carcinoma patients treated with sorafenib 
include hypophosphatemia, lipase elevations, amylase elevations, hypoalbuminemia, 
international normalized ratio elevations, lymphopenia and thrombocytopenia. 
Refer to the product labeling accompanying the product for information approved in your 
country. 
5.2.3 
Alteration of Sorafenib Dose/Schedule Due to Toxicity 
Sorafenib may be reduced or delayed for toxicities considered related to sorafenib as 
described below, or if the investigator believes that a reduction in dose is warranted in the 
interest of subject safety. When a dose reduction is necessary, sorafenib dose may be 
reduced to 400 mg once daily. If an additional dose reduction is required, sorafenib may be 
reduced to a single 400 mg dose every other day (see Table 5-1). A maximum of 2 dose 
reductions of sorafenib will be allowed per subject. Additional dose reductions not mentioned 
in Table 5-1 will need to be discussed with the medical monitor. 
Table 5-1 
Sorafenib dose levels 
Dose Levels 
Sorafenib 
0 
400 mg twice daily 
-1 
400 mg once daily 
-2 
400 mg once every other day 
 
Skin toxicity and hypertension are associated with sorafenib. Guidelines for the management 
of these events are provided in Table 5-2 and Table 5-3, respectively. 
Skin Toxicity 
Hand-foot skin reaction and rash are common in subjects treated with sorafenib. Management 
may include topical therapies for symptomatic relief, temporary treatment interruption and/or 
dose modification, or in severe or persistent cases, permanent discontinuation. Skin toxicities 
will be managed according to Table 5-2. 
 
 


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Table 5-2 
Dose modifications of sorafenib for skin toxicity 
Skin Toxicity Grade 
Occurrence 
Suggested Dose Modification 
Grade 1:  
Numbness, dysesthesia, parethesia, 
tingling, painless swelling, erythema or 
discomfort of the hands or feet which does 
not disrupt the subject’s normal activities. 
Any occurrence 
Continue treatment with sorafenib 
and consider topical therapy for 
symptomatic relief. 
1st occurrence 
Continue treatment with sorafenib 
and consider topical therapy for 
symptomatic relief. If no improvement 
within 7 days, see below. 
No improvement within 
7 days or 2nd or 3rd 
occurrence 
Interrupt sorafenib treatment  
until toxicity resolves to Grade 0-1. 
When resuming treatment, decrease 
sorafenib dose by 1 dose level  
(400 mg daily or 400 mg every  
other day). 
Grade 2:  
Painful erythema and swelling of the hands 
or feet and/or discomfort affecting the 
subject’s normal activities. 
4th occurrence 
Discontinue sorafenib treatment. 
1st or 2nd occurrence 
Interrupt sorafenib treatment  
until toxicity resolves to Grade 0-1. 
When resuming treatment, decrease 
sorafenib dose by 1 dose level  
(400 mg daily or 400 mg every  
other day). 
Grade 3:  
Moist desquamation, ulceration, blistering 
or severe pain of the hands or feet, or 
severe discomfort that causes the subject 
to be unable to work or perform activities of 
daily living. 
3rd occurrence 
Discontinue sorafenib treatment. 
 
Hypertension 
Hypertension is a known and potentially serious adverse event associated with sorafenib 
treatment. Subjects will have their blood pressure monitored and recorded. If the subject’s 
blood pressure is elevated at any time (> 150/100 mmHg), even outside clinic visits, they will 
contact their study investigator. Guidelines for the management of hypertension are provided 
in Table 5-3. 
Table 5-3 
Dose modifications of sorafenib for hypertension 
Grade 
(CTCAE v3.0) 
Antihypertensive Therapy 
Blood Pressure  
Monitoring 
Sorafenib  
Dose 
Grade 1 
None 
Routine 
No change 
Grade 2 
(asymptomatic) 
Initiate monotherapy 
(suggest dihydropyridine 
calcium channel blocker) 
Increase frequency and monitor by 
a health professional every 2 days 
until stabilized. 
No change 
Grade 2 
(symptomatic/ 
persistent) 
OR 
diastolic BP  
> 110 mm Hg 
OR 
Grade 3 
Add agent(s): 
calcium channel blocker 
(if not already used), 
K+ channel opener 
(angiotensin blockers),  
beta-blocker, 
thiazide diuretic 
Increase frequency and monitor by 
health professional every 2 days 
until stabilized; continue monitoring 
every 2 days to stabilization after 
dosing restarted. 
Hold* sorafenib until 
symptoms resolve 
and 
diastolic BP  
< 100 mm/Hg 
 
Resume treatment 
at 1 dose level 
lower** 


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Table 5-3 
Dose modifications of sorafenib for hypertension 
Grade 
(CTCAE v3.0) 
Antihypertensive Therapy 
Blood Pressure  
Monitoring 
Sorafenib  
Dose 
Grade 4 
Discontinue sorafenib 
Discontinue sorafenib 
Discontinue 
sorafenib 
*Subjects requiring a delay of > 21 days will discontinue sorafenib, unless in the study investigator’s opinion, 
the subject may benefit from continued treatment. 
**Subjects requiring > 2 dose reductions will discontinue sorafenib. 
BP = Blood pressure. 
Refer to NCI-CTCAE v4.0 for grade definitions. 
(concluded) 
 
Guidelines 
for 
the 
management 
of 
other 
non-hematologic 
and 
hematologic 
sorafenib-associated toxicities are provided in Table 5-4. Those toxicities that are at least 
possibly related to an interaction with mapatumumab/placebo will have the mapatumumab 
toxicity guidelines in Section 5.1.4 applied. 
Table 5-4 
Dose modifications of sorafenib for sorafenib-associated toxicity 
Toxicity 
Grade 1 
Grade 2 
Grade 3* 
Grade 4* 
Non-
hematologic 
Continue at 
the same dose 
level 
Continue at 
the same dose 
level 
Withhold dose until toxicity is 
Grade ≤ 1, then resume 
treatment at the same dose 
level. If subject experiences 
a 2nd Grade 3 toxicity, 
withhold dose until toxicity is 
Grade ≤  1, then reduce 
dose to 400 mg orally daily 
and resume treatment. 
Withhold dose until toxicity 
is Grade ≤ 1, then reduce 
dose to 400 mg daily and 
resume treatment, or 
discontinue at the 
discretion of the principal 
investigator after 
discussion with study 
sponsor. 
Hematologic 
Continue at 
the same dose 
level 
Continue at 
the same dose 
level 
Withhold dose until toxicity is 
Grade ≤ 2, then resume 
treatment at the same dose 
level. If subject experiences 
a 2nd Grade 3 toxicity, 
withhold dose until toxicity is 
Grade ≤  2, then reduce 
dose to 400 mg orally daily 
and resume treatment. 
Withhold dose until toxicity 
is Grade ≤ 2, then reduce 
dose to 400 mg daily and 
resume treatment, or 
discontinue at the 
discretion of the principal 
investigator after 
discussion with study 
sponsor. 
See Table 5-2 and Table 5-3 for dose modifications due to skin toxicity and hypertension respectively. 
*Subjects who develop Grade 3 fever/chills, Grade 3 elevation of hepatic transaminases with ALT and AST 
< 10X upper limit of normal, Grade 3 hyperlipasemia or hyperamylasemia without clinical or other evidence of 
pancreatitis, Grade 3 leukopenia, or Grade 3/Grade 4 lymphopenia may continue sorafenib treatment without 
interruption at the discretion of the investigator. 
 
Sorafenib Discontinuation 
Temporary or permanent discontinuation of sorafenib will be considered in subjects who 
develop cardiac ischemia and/or infarction or severe or persistent hypertension despite 
institution of antihypertensive therapy. If a subject experiences a bleeding event that 
necessitates medical intervention or a gastrointestinal perforation, sorafenib will be 
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permanently discontinued. Subjects, who undergo a surgical procedure or intervention to 
decrease portal hypertension, including transjugular intrahepatic portosystemic shunt, will 
discontinue sorafenib. 
If the subject is withdrawn from further treatment with sorafenib, the subject may continue to 
receive mapatumumab/placebo alone every 21 days until radiologic progression or 
unacceptable toxicity. 
5.3 
Concurrent Medications and Therapies 
5.3.1 
Allowable Regimens 
Subjects may continue their baseline medication(s). The daily dose of each medication will be 
maintained throughout the study if possible. If for any reason deemed necessary by the 
investigator, a subject requires additional medication(s), the medication(s) route of 
administration and the indication for which it was given must be recorded in the source 
documents. All concomitant medications will be recorded on the appropriate case report form. 
Systemic, inhaled and topical steroids used as part of an antiemetic regimen or 
maintenance-dose for non-cancerous disease are permitted. 
5.3.2 
Prohibited Medications 
Subjects who require the use of strong CYP3A4 inducers (eg, including but not limited to 
St. John’s 
Wort, 
dexamethasone, 
phenytoin, 
carbamazepine, 
rifampin, 
rifabutin, 
phenobarbital) are not eligible for this study and use of these agents is prohibited as long as 
the subject is receiving sorafenib in this study. 
Subjects will not receive any investigational or noninvestigational cytotoxic chemotherapy, 
hormonal therapy, biological therapy (including monoclonal antibodies), immunotherapy or 
any locoregional therapy (such as embolization, RFA or percutaneous ethanol injection) to 
treat hepatocellular carcinoma during the treatment period. Alternative anticancer therapies 
may be administered after radiologic disease progression has been documented, but will be 
avoided if possible during the 30 day safety follow up period after the last dose of study agent 
(mapatumumab/placebo and/or sorafenib) whichever is last. These medications are allowed in 
the long-term follow-up period after the 30 day safety follow-up period and documentation of 
radiologic disease progression. 
5.3.3 
Prohibited Therapies 
Subjects will not undergo major or elective surgery during the treatment period of the study; if 
surgery is required, the subject will be withdrawn from study treatment. 
6 Study Procedures 
6.1 
Screening Procedures 
The nature of this study and the potential risks and benefits associated with participation in the 
study will be explained to all potential study subjects. Written informed consent (including 
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consent for the use and disclosure of research-related health information) must be obtained 
before any screening procedures are performed that are not considered standard of care. 
All of the following assessments must be performed within 28 days prior to enrollment: 
• Obtain written informed consent for participation in the study. 
• Obtain informed consent for participation in the optional biomarker sub-study. 
- 
If consented, obtain tissue block/slides or cell pellet from diagnostic histologic/ 
cytologic sample. 
• Record demographics. 
• Obtain medical history, to include history of all treatments used to treat the current cancer 
and all prior cancer treatments. 
• Perform baseline complete physical examination including body weight and height. 
• Assess vital signs (blood pressure, heart rate, respiratory rate and temperature). 
• Evaluate performance status (ECOG scale; see Appendix 3). 
• Draw blood for laboratory tests (see Appendix 7): complete blood count with differential, 
chemistry, hepatitis B surface antigen, Hepatitis B virus DNA, hepatitis C antibody and 
testing for serum pregnancy (all females with an intact uterus [unless amenorrheic for the 
previous 24 months] regardless of age). 
• Obtain radiologic disease and AFP assessments. The method of disease assessment, as per 
mRECIST for HCC (see Appendix 5), will be consistent throughout the study.  
• Obtain electrocardiogram. 
• Record medications used within 28 days before enrollment. 
• Confirm that subject meets all inclusion/exclusion criteria. 
 
6.2 
Study Enrollment/Randomization Procedures 
Subjects that meet the eligibility criteria will be randomly assigned treatment by a 
central interactive voice response system in a 1:1 ratio to 1 of 2 treatment arms. The 
randomization will be stratified according to BCLC advanced stage C vs BCLC intermediate 
stage B and ECOG performance status (0 vs 1, 2). The 1st planned dose of sorafenib and 
mapatumumab/placebo will be administered no more than 3 days following randomization 
and not prior to randomization. All study site personnel (with the exception of the unblinded 
site pharmacist or unblinded designee), the subject, and the Sponsor will remain blinded to the 
study agent received. 
 


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6.3 
On-treatment Study Procedures 
Table 6-1 
Study calendar 
 
 
 
Cycle 1 
Cycle 2 
Additional 
Cycles
14 
Safety Follow-up Phase 
Long-
Term 
Follow-up 
Procedure 
Footnotes 
Screen
Phase 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 22 of 
last cycle on 
treatment 
≥ 30 days 
following 
last dose 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
 
 
CBC with differential; 
Coagulation 
parameters 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy 
2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis 
1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B and T lymphocyte 
subsets 
3 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
 
 
 
 
Immunogenicity  
4 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Pharmacokinetics 
5 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
Biomarkers 
6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Study Agent Admin 
 
 
Sorafenib 
7 
 
Twice daily 
 
 
 
Mapatumumab/ 
Placebo 
7 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Physical/Clinical 
 
 
Med Hx / Phys.Exam 
- 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
8 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
Body weight 
9 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Performance Status 
10 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 


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Table 6-1 
Study calendar 
 
 
 
Cycle 1 
Cycle 2 
Additional 
Cycles
14 
Safety Follow-up Phase 
Long-
Term 
Follow-up 
Procedure 
Footnotes 
Screen
Phase 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 22 of 
last cycle on 
treatment 
≥ 30 days 
following 
last dose 
 
Record AEs/ 
Conmeds 
11 
X 
<----------------Throughout the study----------------> 
 
Disease Assessments  
12 
X 
Performed at the end of every 2 cycles (ie, Cycles 2, 4, 6) and every 2 cycles thereafter until radiologic PD is documented. 
X 
α – Fetoprotein (AFP) 
12 
X 
Performed at the end of every 2 cycles (ie Cycles 2, 4, 6) and every 2 cycles thereafter until radiographic PD is 
documented. 
X 
ECG 
- 
X 
Repeat as clinically indicated 
 
Survival 
13 
 
 
X 
AE = adverse event; CBC = complete blood count; CT = computerized tomography; ECG -= electrocardiogram; PD = progressive disease. 
1 
Safety Labs: Day 1 (complete blood count with differential, coagulation parameters [INR, PT, PTT] and chemistry) must be performed within 3 days prior to dosing on Day 1 of each 
cycle.  See Appendix 7 for a detailed list of required laboratory assessments. 
2 
Pregnancy: Serum test at screening, urine test pre-dose Cycle 1 Day 1; must be negative to receive treatment. 
3 
B and T lymphocyte subsets: Blood samples for quantification of B and T lymphocytes will be obtained in Cycles 1 and 2 only. Samples will be obtained on Day 1 (prior to dosing) and 
Day 15 of Cycles 1 and 2. 
4 
Immunogenicity: Obtain prior to dosing on Day 1 of Cycles 1, 2, 4, 6, every 2 cycles thereafter and at the end of treatment visit (at least 30 days after the last dose). On days when 
immunogenicity and pharmacokinetic samples are collected they will be collected together. 
5 
Pharmacokinetics: Blood specimens will be collected for determination of serum mapatumumab concentrations from subjects as follows:  Cycle 1 (on Day 1 prior to the administration 
mapatumumab/placebo and at the completion of the mapatumumab/placebo infusion, and on Day 8), Cycles 2, 4 and 6 and thereafter on each even cycle (prior to dosing on Day 1), 
on the day of each disease assessment, and at the end of treatment visit (at least 30 days after the last dose). On days when immunogenicity and pharmacokinetic samples are 
collected they will be collected together.   
6 
Biomarkers: For subjects participating in the optional biomarker sub-study, historical biopsy samples will be collected, if available, and samples will be collected if obtained during the 
treatment period in Cycle 1 Days 1 (pre-dose mapatumumab), 2, 3, 8 and 15 and Cycle 2 Days 1 (pre-dose mapatumumab), 3, 8 and 15. In addition, blood samples will be obtained 
as follows: blood for isolation of DNA will be collected once, preferably in Cycle 1. Blood for isolation of serum will be collected in Cycles 1 and 2 (pre-dose on the day of 
mapatumumab/placebo dosing). Further details on the biomarker sub-study are outlined in Appendix 6. 
7 
Study Agent Administration:  Sorafenib will be administered at a dose of 400 mg twice daily without food (at least 1 hour before or 2 hours after a meal). On days when both sorafenib 
and mapatumumab/placebo are administered together, sorafenib should be taken at the same time as any other calendar day. 
8 
Vital Signs: Blood pressure will be monitored weekly for the first 6 weeks. Vital signs will be obtained within 30 minutes prior to administration of mapatumumab/placebo and at the end 
of infusion on Day 1 of each cycle. 
9 
Body Weight: To be obtained on the day of or within 3 days before dosing on Day 1 of each cycle. 


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Table 6-1 
Study calendar 
 
 
 
Cycle 1 
Cycle 2 
Additional 
Cycles
14 
Safety Follow-up Phase 
Long-
Term 
Follow-up 
Procedure 
Footnotes 
Screen
Phase 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 22 of 
last cycle on 
treatment 
≥ 30 days 
following 
last dose 
 
10 
Performance Status: Obtained prior to dosing on Day 1 of each cycle. 
11 
Adverse Events: AE collection begins with the start of 1
st study agent administration. Concurrent medications will be recorded within 28 days prior to Cycle 1 Day 1. 
12 
Disease and α – Fetoprotein (AFP) Assessments: Radiologic and AFP assessments will be performed at the end of every 2 cycles (ie, Cycles 2, 4, 6, etc). For subjects discontinuing 
treatment prior to documentation of radiologic disease progression, disease assessments will be performed every 6 weeks (± 3 days), starting 6 weeks after the previous disease 
assessment while on study, until radiologic disease progression is documented. If disease progression is based only on new lesions or is equivocal, images will be provided to the 
blinded, independent reader for confirmation of disease progression. All imaging scans used for disease assessments will be made available for independent radiology review by the 
Sponsor or designee. 
13 
Survival: Contact will be made with the subject every 3 months to document survival until at least 90% of subjects have met the survival endpoint. 
14 
Subjects who discontinue mapatumumab/placebo will complete the current cycle assessments per the study calendar.  Subsequently, subjects receiving sorafenib alone will return at 
least every 21 days and on additional days as clinically indicated for safety labs (CBC with differential, chemistry and coagulation parameters) for the duration of treatment. Disease 
assessments must be performed every 6 weeks until radiologic disease progression.  Adverse events and concomitant medications will be recorded throughout the study. 
(concluded) 
 


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6.4 
Follow-up Procedures 
6.4.1 
Safety Follow-up 
After discontinuation of study treatment, all subjects will return 1 day after cycle completion 
(approximately Day 22) and at least 30 days after the last dose of sorafenib and/or 
mapatumumab/placebo, for scheduled safety follow-up assessments as outlined in Table 6-1. 
6.4.2 
Long-term Follow-up 
For subjects discontinuing treatment prior to documentation of radiologic disease progression, 
and for subjects who experience stable disease or a response (PR, CR) but are no longer 
receiving treatment, radiologic disease assessments will be performed at 6 week intervals 
(± 3 days), starting 6 weeks after the previous radiologic disease assessment while on 
treatment, until radiologic disease progression is documented. Thereafter, subjects will be 
followed every 3 months for survival until at least 90% of subjects have met the survival 
endpoint. 
6.5 
Withdrawal of Subjects from Treatment 
Subjects will be free to withdraw from treatment at any time, for any reason, or they may be 
withdrawn/removed, if necessary, to protect their health (see reasons for withdrawal below). It 
is understood by all concerned that an excessive rate of withdrawals can render the study 
uninterpretable; therefore, unnecessary withdrawal of subjects will be avoided. 
Subjects may be withdrawn from treatment for any of the following reasons: 
• Radiologic disease progression. 
• Continued unacceptable toxicities despite optimal treatment or dose reduction. 
• Intercurrent illness, at the investigator’s discretion. 
• Withdrawal of consent. 
• Non-compliance/Lost to follow-up. 
• Pregnancy. 
• Termination of the study by the sponsor. 
 
Subjects who withdraw are to be followed for radiologic progression as outlined in 
Section 6.4.2. In addition, every effort will be made to collect safety information on each 
subject through 30 days following the last dose of study treatment, unless the subject 
withdraws consent and refuses to comply with the protocol stipulated safety follow-up and 
radiologic disease progression assessments, or share information obtained after the date of 
withdrawal of consent. 
6.6 
Withdrawal of Subjects from Study 
Subjects may be withdrawn from the study for any of the following reasons: 
• Withdrawal of consent. 


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• Non-compliance/Lost to follow-up. 
• Termination of the study by the sponsor. 
 
Every effort will be made to collect follow-up information on subjects in the long-term 
follow-up period of the study, unless the subject withdraws consent and refuses to share 
information obtained during the long-term follow-up period obtained after the date of 
withdrawal of consent. 
6.7 
Disease Response Assessments 
Imaging endpoints will be determined using the modified RECIST criteria for HCC proposed 
by Lencioni and Llovet (2010; mRECIST). mRECIST for HCC is a joint guideline of the 
American Association for the Study of Liver Diseases and the Journal of the National Cancer 
Institute.  
Lesions which manifest typical imaging characteristics for HCC demonstrate intratumoral 
arterial contrast on CT and MRI images. mRECIST accounts for newer therapies which may 
impact tumor vascularity and may not yield a typical cytotoxic decrease in tumor size by 
incorporating changes in vascularity into the criteria for target lesion response. Diligence in 
obtaining images during the hepatic arterial contrast enhancement phase is a requirement at 
baseline and all subsequent scans. The same imaging method must be used at baseline and 
during follow up. 
As in conventional RECIST, overall response is the result of the combined assessment of 
target, nontarget, and new lesions. There are also specifications for incorporating portal vein 
thrombosis, portal hepatic lymph nodes, and pleural effusions/ascites into the response 
assessment. As with conventional RECIST, the appearance of any new lesion overrides any 
existing lesion response, resulting in classification as progressive disease (PD). Key aspects of 
mRECIST as adapted for this study are summarized in Appendix 4. 
Baseline images will be provided to the BICR for confirmation of radiologic eligibility 
(measurable disease). Confirmation of radiologic eligibility for the study will be provided to 
the site by the BICR within 72 hours of receipt of images and will be required for 
randomization. 
Disease assessments and an assessment of α -fetoprotein will be performed at the end of every 
2 cycles (ie, Cycles 2, 4, 6 and every 2 cycles thereafter). The response assessment will be 
performed and documented no more than 5 days before the start of the next cycle. All images 
will be provided to the BICR following each disease assessment. 
If disease progression is based only on new lesions or is equivocal, images will be provided to 
the BICR for confirmation of radiologic disease progression prior to discontinuing study 
treatment. PR and CR will be confirmed at the next scheduled disease assessment (no fewer 
than 4 weeks after the initial documentation of PR or CR). 


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7 Pharmacokinetic, Immunogenicity, Pharmacodynamic and 
Exploratory Assessments 
7.1 
Pharmacokinetic Assessments 
For determination of mapatumumab concentration, serum samples will be collected as 
outlined in Table 6-1. 
A manual will be provided regarding how to obtain blood samples, process samples, collect 
serum from the blood samples, and how to store and ship the serum samples. Bioanalysis will 
be carried out at Human Genome Sciences to determine mapatumumab concentration in each 
serum sample. 
7.2 
Immunogenicity 
Blood samples for serum antibodies to mapatumumab will be obtained as outlined in  
Table 6-1.  
7.3 
Pharmacodynamic Assessments 
Subjects will be given the option to participate in an exploratory biomarker research 
sub-study. Consenting subjects will be asked to provide a historically obtained biopsy sample, 
if available, and blood samples. In addition, samples will be requested from subjects who 
undergo a biopsy during the treatment period. 
To examine and quantify biomarkers present peripherally, blood will be drawn during 
Cycles 1 and 2, from which DNA and serum proteins will be isolated. The parameters 
evaluated may include, but may not be limited to, M30, TNFα, sTRAIL, soluble Fas ligand, 
interferon-α, 
interferon-γ, 
interleukin-2, 
interleukin-6, 
interleukin-8, 
interleukin-10, 
interleukin-12, and FC gamma receptor and interleukin-6 gene polymorphisms. The 
biomarker sub-study is detailed in Appendix 6.  
7.4 
Exploratory Assessments (B and T Lymphocyte Subsets) 
7.4.1 
Rationale for B and T Lymphocyte Analysis 
Over 400 subjects have received mapatumumab in doses ranging from 0.01 to 30 mg/kg 
across multiple Phase 1 and Phase 2 clinical trials in subjects with solid and hematologic 
malignancies. While there is no evidence to date that mapatumumab exacerbates adverse 
events associated with chemotherapy, the most commonly observed laboratory abnormality 
associated with mapatumumab has been lymphopenia. The lymphopenia has been intermittent 
and reversible and was not associated with infectious events. However, the lymphocyte 
subpopulation(s) affected have not been characterized. 
The evaluation of lymphocytes will include complete blood count/differential and lymphocyte 
subpopulation analysis (numbers and percentages of T and B cells) by flow cytometry at a 
central laboratory. Blood samples will be examined by flow cytometry for levels of T helper 
(CD4+), T cytotoxic (CD8+) and mature B cells (CD19+). 


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7.4.2 
Collection of Samples for B and T Lymphocyte Analysis 
Blood samples will be collected for quantification of B and T lymphocyte subsets on Day 1 
(prior to dosing) and Day 15 of Cycles 1 and 2 as outlined in Table 6-1. 
8 Adverse Event Reporting 
8.1 
Definitions 
ADVERSE EVENT (EXPERIENCE) - 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. This includes worsening (eg, increase in frequency or severity) of 
pre-existing conditions. 
SERIOUS ADVERSE EVENT – an adverse event resulting in any of the following outcomes: 
• death 
• is life threatening (ie, an immediate threat to life) 
• inpatient hospitalization 
• prolongation of an existing hospitalization 
• persistent or significant disability / incapacity 
• congenital anomaly / birth defect 
• is Medically Important* 
 
*Medical and scientific judgment will be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or result in hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other outcomes listed above. These should also 
usually be considered serious. (ICH guidelines, March 1995) 
Note: Hospitalizations not associated with an adverse event, for example, for administration 
of chemotherapy or hydration for chemotherapy administration, are not considered serious 
adverse events. 
UNEXPECTED ADVERSE EVENT - An adverse event, the nature or severity of which is 
not consistent with the applicable product information (eg, Investigator’s Brochure for an 
unapproved investigational product or package insert/summary of product characteristics for 
an approved product). Expected means that the event has previously been observed with the 
study agent and is identified and/or described in the applicable product information. It does 
not mean that the event is expected with the underlying disease(s) or concomitant 
medications. 
8.2 
Reporting Adverse Events to the Sponsor or Designee 
All adverse events (AEs) that are identified from the start of any study agent administration 
through the specified study follow-up period (through 30 days following administration of the 


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final study agent dose) will be recorded on the paper/electronic Adverse Event Case Report 
Form (AE case report form). All data fields on the AE case report form will be completed. 
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE Worksheet and sent to 
HGS within 24 hours of site personnel becoming aware of a SAE, regardless of expectedness. 
All pages of the SAE Worksheet will be completed, but the SAE worksheet will not be held 
until all information is available. Additional information and corrections will be provided on 
subsequent SAE Worksheets as described in the Study Procedure Manual. SAE Worksheets 
will be sent by facsimile to the Drug Safety Department at HGS using the fax number listed 
below. 
FAX #: 
 
8.3 
Laboratory Abnormalities as Adverse Events 
A laboratory abnormality will be reported as an adverse event if it is associated with an 
intervention. Intervention includes, but is not limited to, discontinuation of treatment, dose 
reduction/delay, additional assessments (excluding follow-up labs), or concomitant therapy. In 
addition, any medically important laboratory abnormality may be reported as an adverse event 
at the discretion of the investigator. This includes laboratory abnormalities for which there is 
no intervention but the abnormal value(s) suggests a disease or organ toxicity. If clinical 
sequelae are associated with a laboratory abnormality, the diagnosis or medical condition will 
be reported (eg, renal failure, hematuria) not the laboratory abnormality (eg, elevated 
creatinine, urine red blood cells increased). 
8.4 
Other Events Requiring Rapid Reporting 
Protocol Specified Events are additional events [toxicities] specifically identified in this 
protocol that must be reported to Human Genome Sciences or designee in an expedited 
manner. Protocol Specified Events may or may not be SAEs as defined in this protocol. They 
are SAEs if they meet one or more of the criteria for an SAE (see Section 8.1). Protocol 
Specified Events are recorded on SAE Worksheets and sent to Human Genome Sciences 
within 24 hours of site personnel becoming aware of the event. 
The Protocol Specified Events for the study: 
• Grade 4 neutropenia for > 7 consecutive days or febrile neutropenia. 
• Grade 4 thrombocytopenia. 
• Grade 3 or greater non-hematologic AEs except transaminase, amylase and lipase 
abnormalities for which the following criteria apply: 
• Grade 4 elevations in transaminases. 
• Grade 4 elevations in lipase or amylase. 
• Grade 3 elevations in lipase or amylase associated with clinical/imaging findings of 
pancreatitis, resulting in chronic damage to the pancreas. 
• Any adverse event that results in discontinuation of treatment if that event is assessed as 
possibly, probably, or definitely related to mapatumumab or sorafenib. 
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8.5 
Reporting a Pregnancy 
Any pregnancy in a female participant or a female partner of a male participant must be 
reported to Human Genome Sciences Drug Safety as soon as the site becomes aware of the 
pregnancy. All pregnancies are reported up to 30 days following the last study agent 
treatment. Human Genome Sciences Drug Safety sends an acknowledgement memorandum to 
the principal investigator along with a Pregnancy Assessment Form. Additional Pregnancy 
Assessment Forms will be sent to the site every 3 months for reporting of follow-up 
information. Pregnancy assessment forms must be completed by the investigator until live 
birth, elective termination of the pregnancy, or miscarriage. The site is responsible for 
following the subject’s pregnancy to final outcome. 
Pregnancies are not considered adverse events. Complications or medical problems associated 
with a pregnancy are considered AEs and may be SAEs. Complications or medical problems 
are reported as AEs/SAEs according to the procedure described in Section 8.2. 
8.6 
Investigator Evaluation of Adverse Events 
The Investigator will evaluate all adverse events with respect to seriousness (criteria listed in 
Section 8.1 above), severity (intensity or grade) and causality (relationship to study agent) 
according to the following guidelines listed below. 
SEVERITY 
Severity will be graded using the NCI-CTCAE, Version 4.0. The NCI-CTCAE may 
be downloaded 
from 
the 
Cancer 
Treatment 
Evaluation 
Program 
website 
(http://ctep.info.nih.gov/reporting/ctc.html). In the event that an AE does not have an 
NCI-CTCAE code, the following severity classifications will be used: 
Mild  
causing no limitation of usual activities 
Moderate 
causing some limitation of usual activities 
Severe 
causing inability to carry out usual activities 
Life Threatening* potentially life threatening or disabling  
 
*Note – a severity assessment of life threatening is not necessarily the same as life threatening 
as a “Serious” criterion. The latter means that the event is an immediate threat to life as 
opposed to a potential threat to life. 
 
 


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CAUSALITY 
Definitely Related 
reasonable temporal relationship to study agent administration 
 
follows a known response pattern (eg, drug is known to cause this AE) 
 
there is no alternative etiology 
Probably Related 
reasonable temporal relationship 
 
follows a suspected response pattern (eg, based on similar drugs) 
 
no evidence for a more likely alternative etiology 
Possibly Related 
reasonable temporal relationship 
 
little evidence for a more likely alternative etiology 
Probably Not Related does not have a reasonable temporal relationship, OR 
 
good evidence for a more likely alternative etiology 
Not Related 
does not have a temporal relationship, OR 
 
definitely due to alternative etiology  
 
ICH guidelines (March, 1995) clarify “reasonable causal relationship” to mean “that there are 
facts [evidence] or arguments to suggest a causal relationship”. 
The causality assessment must be made by the investigator based on information available at 
the time that the SAE worksheet is completed. The initial causality assessment may be revised 
as new information becomes available. 
 *Note - If there is evidence that mapatumumab/placebo contributed to or exacerbated an 
event related to sorafenib; the event will be recorded as possibly, probably or definitely 
related to both sorafenib and mapatumumab. 
8.7 
Follow-up of Adverse Events 
Adverse events that occur during the course of the study are followed until final outcome is 
known or until the end of the safety follow-up period (30 days following the final dose of any 
study agent). Adverse events that have not resolved by the end of the safety follow-up period 
are recorded as ongoing. 
SAEs that have not resolved by the end of the follow-up period are followed until final 
outcome of recovered or recovered with sequelae is achieved. If it is not possible to obtain a 
final outcome for a SAE (eg, the subject is lost to follow up), the reason a final outcome could 
not be obtained will be documented by the investigator. 
8.8 
Serious Adverse Events Assessed During Long-Term Follow-up 
SAEs that occur after the safety follow-up period (30 days following the final dose of study 
agent) that are assessed by the investigator as possibly, probably, or definitely related to study 
agent must be reported to Human Genome Sciences on an SAE worksheet, as described in 
Section 8.2. Post-study SAEs will not be documented on the AE case report form. 


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8.9 
Reporting Serious Adverse Events to the Institutional Review 
Board/Ethics Committee 
All SAEs that are considered unexpected and related to the study agent will be reported by 
Human Genome Sciences or its designee as expedited (ie, 15-Day) reports to the appropriate 
regulatory authorities AND to all participating investigators. Each investigator must notify the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) responsible for 
reviewing the study at their site of all expedited reports. In addition, Human Genome Sciences 
or its designee will follow all applicable local and national regulatory requirements regarding 
safety reporting. Each investigator must also comply with the applicable regulatory 
requirements related to the reporting of SAEs to the IRB/IEC responsible for reviewing the 
study at their site, as well as the regulatory authority(ies) (if applicable). 
9 Endpoints and Statistical Analysis 
9.1 
General Statistical Considerations 
Analyses will be applied to a modified intention-to-treat population unless stated otherwise. 
This population is defined as the set of all randomized subjects who receive at least 1 dose of 
study treatment (mapatumumab/placebo and/or sorafenib) with subjects analyzed according to 
the groups they are randomized to, regardless of the treatment they subsequently receive. 
Additional analyses may be performed on the as-treated population, defined as the set of 
subjects receiving at least 1 dose of study medication analyzed according to the treatment that 
they actually receive. 
Analyses will be performed using the SAS System™, WinNonlin Enterprise Edition™, 
StatXact™, and the R statistical package. 
9.2 
Sample Size Rationale 
A total of approximately 100 subjects will be randomly assigned to 1 of 2 arms and treated 
with either sorafenib + placebo or the 2-agent combination of sorafenib and mapatumumab at 
30 mg/kg in a 1:1 ratio. A sample size of 50 subjects randomized and treated in each group is 
sufficient to estimate the median time to progression with a precision of approximately -1.9 M 
to +2.6 M relative to the observed median. In addition, a sample size of 50 patients per arm 
will provide 80% power to detect an improvement in TTP from 5.5 to 8.9 M with at a 
one-sided significance level of 0.10. 
9.3 
Efficacy 
9.3.1 
Primary Efficacy Endpoint 
The primary endpoint is time to progression (TTP) defined as the time from randomization to 
radiologic disease progression based on blinded independent review of imaging scans.  
9.3.2 
Primary Efficacy Analysis 
The primary analysis will be an estimate of median time to progression in each arm using 
Kaplan Meier methods, reported with 95% confidence intervals, along with testing the hazard 


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ratio for time to progression at a 1-sided significance level of 0.10 with a Cox proportional 
hazards model controlling for the factors stratifying the randomization as covariates. 
9.3.3 
Secondary Efficacy Endpoints 
Secondary endpoints include progression-free survival, overall response, disease control, 
overall survival, time to response, and duration of response (for responders) as defined below: 
• OS: time from randomization to death from any cause. 
• PFS: time from randomization to disease progression or death from any cause. 
• Objective response (CR+PR according to mRECIST for HCC). 
• Disease control (CR+PR+SD according to mRECIST for HCC). 
• Time to response: time from randomization to 1st PR or CR in responders only. 
• Duration of response: time from 1st PR or CR to disease progression; in responders only. 
 
All secondary endpoints will be based on blinded independent review of imaging scans. 
9.3.4 
Secondary Efficacy Analyses 
Secondary analyses include estimates, using Kaplan Meier methods, of median PFS and 
median OS along with associated logrank testing. In addition, estimates of overall response 
rate (CR+PR) and disease control rate (CR+PR+SD) will be reported with 95% confidence 
intervals and an estimate of the difference in response rates and disease control rates between 
groups will be reported and tested for significance with a Pearson chi-square test (or Fisher’s 
exact test).  
9.4 
Safety 
9.4.1 
Definition of Safety Variables  
The safety parameters assessed are given by the following: 
• Frequency, and severity of adverse events (AEs): 
- 
All AEs will be classified by System Organ Class and Preferred Term under the 
Medical Dictionary for Regulatory Activities (MedDRA) system of classification with 
a severity assigned according to the NCI-CTCAE (Version 4.0, 29 May 2009), or the 
rules specified in Section 8.6. 
- 
Laboratory parameters as presented in Appendix 7. 
- 
Laboratory toxicities will be graded based on the NCI-CTCAE (Version 4.0, 
29 May 2009). 
• Anti-mapatumumab antibody response. 
• Vital signs. 
• For frequency and severity of adverse events and laboratory toxicity grading, counts and 
rates will be presented. 
 
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9.4.2 
Human Genome Sciences Safety Review Committee 
The Human Genome Sciences Review Committeee (HGSRC) is comprised of the Department 
Heads of Biostatistics, Regulatory Affairs and Drug Development. The HGSRC will review 
safety data after: (1) 10 subjects have completed 1 cycle; and (2) 30 subjects have completed 
1 cycle. HGSRC reviews of safety data will be conducted approximately every 4 months 
thereafter, until 90% of subjects have reached radiologic progression. The HGSRC may 
conduct additional reviews at their own request and/or at the request of the Medical Monitor. 
The HGSRC may request the unblinding of treatment assignment for a subject and/or 
treatment groups. If treatment assignments are unblinded, the rationale for the unblinding will 
be documented. 
9.4.3 
Analysis of Safety Variables 
The safety analysis will consist of a presentation of rates of AEs observed. Specific AEs will 
be counted once for each subject for calculating rates, but will be presented in total in subject 
listings. In addition, if the same AE occurs multiple times within a particular subject, the 
highest severity and level of causality observed will be reported. If any associations of interest 
between AEs and baseline characteristics are observed, additional stratified results may be 
presented. All treatment-emergent AEs will be summarized overall, as well as categorized by 
the MedDRA system of classification. AEs will be presented overall, by severity, by relation 
to mapatumumab/placebo, and by relation to sorafenib. 
9.5 
Pharmacokinetics 
9.5.1 
Definition of Pharmacokinetic Evaluation 
Serum mapatumumab concentration data obtained from this study will be pooled with data 
obtained from other studies for use in a population PK analysis, which will be reported 
separately. 
9.5.2 
Analysis of Pharmacokinetics 
The serum mapatumumab concentration will be determined by enzyme-linked immunosorbent 
assay. Serum mapatumumab concentration results for this study will be presented using 
appropriate graphic and tabular summaries. 
9.6 
Pharmacodynamics 
Expression of biomarkers in tumor tissue and peripheral blood will be correlated with clinical 
outcomes and may be reported separately from the clinical study report.  
10 Study Administration 
10.1 Informed Consent 
A copy of the proposed informed consent document(s) must be submitted to the sponsor or 
designee for review and comment prior to submission to the reviewing IRB/IEC. The consent 
form must be approved by the IRB/IEC and contain all elements required by national, state, 
local, and institutional regulations or requirements. 


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It is the responsibility of the investigator to provide each subject with full and adequate verbal 
and written information using the IRB/IEC approved informed consent document(s), 
including the objective and procedures of the study and the possible risks involved before 
inclusion in the study. Each subject must voluntarily provide written informed consent 
(including consent for the use and disclosure of research-related health information). The 
consent must be obtained prior to performing any study-related procedures that are not part of 
normal patient care, including screening and changes in medications including any washout of 
medications. A copy of the signed informed consent must be given to the study subject. 
10.2 Institutional Review Board Review/Independent Ethics Committee 
Review and Approval 
The investigator or sponsor (as appropriate per national regulations) shall assure that an 
IRB/IEC, constituted in accordance with ICH Good Clinical Practices, will provide initial and 
continuing review of the study. 
Prior to shipment of the study agent and enrollment of study subjects, documented IRB/IEC 
approval of the protocol, informed consent form, and any advertisement for subject 
recruitment must be obtained and provided to the sponsor or designee. 
The IRB/IEC must also be informed of all protocol amendments prior to implementation. The 
investigator must provide reports of any change in research activity (ie, the completion, 
termination, or discontinuation of a study) to the IRB/IEC. 
10.3 Protocol Compliance 
Except for a change that is intended to eliminate an apparent immediate hazard to a study 
subject, the protocol shall be conducted as described. Any such change must be reported 
immediately to the sponsor and to the IRB/IEC. 
10.4 Protocol Revisions 
Protocol amendments will be prepared and approved by the sponsor. All protocol amendments 
will be signed by the investigator and submitted to the IRB/IEC for review prior to 
implementation. Documentation of IRB/IEC approval must be forwarded to the sponsor or 
designee. If an amendment significantly alters the study design, increases potential risk to the 
subject or otherwise affects statements in the informed consent form, the informed consent 
form must be revised accordingly and submitted to the IRB/IEC for review and approval. The 
approved consent form must be used to obtain informed consent from new subjects prior to 
enrollment and must be used to obtain informed consent from subjects already enrolled if they 
are affected by the amendment. 
10.5 Data Collection and Management 
Data collected for each study subject are recorded electronically on case report forms 
provided or approved by the sponsor.  


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The investigator is responsible for maintaining accurate, complete, and up-to-date records for 
each subject. The investigator is also responsible for maintaining any source documents 
related to the study, including any films, tracings, computer discs, or tapes. The investigator 
must promptly review the completed case report forms for each subject. As the person 
ultimately responsible for the accuracy of all data, the investigator must sign the Investigator's 
Statement in each subject's case report form. 
The anonymity of participating subjects must be maintained. Subjects are identified by an 
assigned subject number on case report forms and other documents submitted to the sponsor. 
Documents that identify the subject beyond subject number are not submitted to the sponsor 
(ie, the signed informed consent document) and must be maintained in strict confidence by the 
investigator, except to the extent necessary to allow auditing by the regulatory authorities, 
study monitor, or sponsor representatives. 
Sites enter subject data directly into the electronic data capture (EDC) system and the EDC 
system automatically generates queries resulting from computer checks embedded into the 
system, so as to ensure accuracy, quality, consistency, and completeness of the database. 
Manual queries resulting from review by monitors, medical coders, and other Data 
Management staff are also generated from within the EDC system, where they are tracked. 
Sites resolve the queries and correct the entered data when necessary. Every change to data is 
captured in the EDC system audit trail. At study end, each site is provided with a compact 
disk containing the electronic case report forms for each of their subjects. 
Upon completion of the study, or after reaching a pre-specified point in the study, Data 
Management locks the database and generates the SAS datasets necessary for data analysis 
and reporting. 
10.6 Study Monitoring 
The study sponsor, Human Genome Sciences, Inc., or designee, will monitor the study. Study 
monitors representing the sponsor will visit study sites routinely throughout the trial. The 
sponsor will review the paper subject diaries and electronic case report forms and compare 
them with source documents to verify accurate and complete collection of data and confirm 
that the study is being conducted according to the protocol. Auditors representing the sponsor 
may also similarly evaluate the study and its monitors. For these purposes, the investigator 
will make paper subject diaries and electronic case report forms and source documents 
available when requested. 
In addition, the study may be evaluated by representatives of the national regulatory 
authorities, who will also be allowed access to study documents. The investigators will 
promptly notify Human Genome Sciences of any audits they have scheduled with any 
regulatory authority. 
10.7 Drug Accountability 
Upon receipt, the designated unblinded pharmacy personnel at the study site are responsible 
for taking an inventory of the study agent, including any buffers or diluents. A record of this 


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inventory must be kept and usage must be documented on study agent inventory forms 
provided by the sponsor. 
Study agent inventory forms will be examined and reconciled by an unblinded Clinical 
Research Associate, or designee. At the end of the study, all used and unused study agent 
must be accounted for on a study agent accountability form provided to the investigator by 
Human Genome Sciences or its designee. 
10.8 Retention of Records 
The investigator shall retain all records and source documents pertaining to the study, 
including any films, tracings, computer discs, or tapes. They will be retained for the longer of 
the maximum period required by the country and institution in which the study is conducted, 
or the period specified by the sponsor at the time the study is completed, terminated, or 
discontinued. 
If the investigator leaves the institution, the records shall be transferred to an appropriate 
designee who accepts the responsibility for record retention. Notice of such transfer shall be 
documented in writing and provided to the sponsor. 
10.9 Financial Disclosure 
The investigator will provide Human Genome Sciences sufficient and accurate information on 
financial interests (proprietary or equity interests, payments exclusive of clinical trial costs) to 
allow complete disclosure to regulatory authorities. The investigator shall promptly update 
this information if any relevant changes occur during the course of the investigation and for a 
period of 1 year following study completion. 
10.10 Publication Policy 
This study is being conducted as part of a multi-center clinical study. Data from all sites 
participating in the multi-center clinical study will be pooled and analyzed. The investigator 
acknowledges that an independent, joint publication is anticipated to be authored by the 
investigators of the multi-center study and sponsor’s representatives. Neither institution nor 
principal investigator shall independently publish or present the results of the study prior to 
the publication of the multi-center study publication. The investigator agrees that the sponsor 
will be the coordinator and arbitrator of all multi-center study publications. For multi-center 
trials, no investigator will be authorized to publish study results from an individual center 
until the earlier of the multi-center trial results are published or 12 months after the end or 
termination of the multi-center trial at all sites. 
The investigator shall submit a copy of any proposed publication, manuscript, abstract, 
presentation or other document with respect to this study to the sponsor for review and 
comment at least 60 days prior to its submission for publication or presentation. No 
publication or presentation with respect to the study shall be made unless and until the entire 
sponsor’s comments on the proposed publication or presentation have been considered and 
any information determined by sponsor to be confidential information has been removed. 


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If requested in writing by the sponsor, the investigator shall withhold material from 
submission for publication or presentation for an additional 60 days to allow for the filing of a 
patent application or the taking of other measures to establish and preserve the sponsor’s 
proprietary rights. 
10.11 Study or Study Site Termination 
If Human Genome Sciences, the investigator, IRB/IEC, or a regulatory authority discovers 
conditions arising during the study that indicate that the study should be halted or that the 
study center should be terminated, this action may be taken after appropriate consultation 
between Human Genome Sciences and the investigator. Conditions that may warrant 
termination of the study include, but are not limited to, the following: 
• The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study. 
• A decision on the part of Human Genome Sciences to suspend or discontinue testing, 
evaluation, or development of the product. 
 
The study site may warrant termination under the following conditions: 
• Failure of the investigator to enroll subjects into the study at an acceptable rate. 
• Failure of the investigator to comply with pertinent regulatory authority regulations. 
• Submission of knowingly false information from the research facility to Human Genome 
Sciences, study monitor, or the regulatory authority. 
• Insufficient adherence to protocol requirements. 
 
 
 


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List of Appendices 
Appendix 1 
Child-Pugh Classification................................................................................. 59 
Appendix 2 
BCLC Staging and Treatment Strategy............................................................ 60 
Appendix 3 
Eastern Cooperative Oncology Group (ECOG) Performance Status............... 61 
Appendix 4 
New York Heart Association Classification for Congestive Heart Failure...... 62 
Appendix 5 
Modified Response Evaluation Criteria in Hepatocellular Carcinoma 
(mRECIST for HCC)........................................................................................ 63 
Appendix 6 
Exploratory Biomarker Sub-study.................................................................... 66 
Appendix 7 
Laboratory Tests............................................................................................... 69 
Appendix 8 
Treatment of Allergic/Hypersensitivity Reactions........................................... 70 
 
 
 
 
 


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Appendix 1 
Child-Pugh Classification 
(Zimmerman H and Reichen J, 2000) 
 
No. of Points 
Factor 
1 
2 
3 
Bilirubin (mg/dL) 
< 2 
2–3 
> 3 
Albumin (g/dL) 
> 3.5 
2.8–3.5 
< 2.8 
Prothrombin time (increased seconds) 
1–3 
4–6 
> 6 
Ascites 
None 
Slight 
Moderate 
Encephalopathy 
None 
Minimal 
Advanced 
 
Grade 
Score 
A 
5 – 6 
B 
7 – 9 
C 
10 – 15 
 
 


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Appendix 2 
BCLC Staging and Treatment Strategy 
 
 
 
Forner et al, 2010 
 
 
 


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Appendix 3 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
 
 
 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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Appendix 4 
New York Heart Association Classification for Congestive 
Heart Failure 
(The Criteria Committee of the New York Heart Association; Little, Brown & Co. 1994) 
Class 
New York Heart Association Classification for Congestive Heart Failure 
1 
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. 
2 
Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. 
3 
Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable 
at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. 
4 
Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. 
Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased. 
 
 
 
 


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Appendix 5 
Modified Response Evaluation Criteria in Hepatocellular 
Carcinoma (mRECIST for HCC) 
(Adapted from Lencioni and Llovet, 2010 for use in this study) 
Measurable disease: The presence of at least 1 target lesion, by contrast enhanced 
computerized tomography (CT) with use of multislice scanners, or contrast enhanced dynamic 
magnetic resonance imaging (MRI). 
Target lesion: Meets all the following criteria: 
- 
Located in the liver. 
- 
Can be accurately measured in at least 1 dimension. 
- 
Well-delineated area of viable, hypervascular (contrast enhancement in the arterial phase) 
tumor that is > 2 cm in the axial plane. 
- 
Suitable for repeat measurement. 
- 
Not previously treated with locoregional or systemic treatment unless the lesion shows a 
well-delineated area of viable (contrast enhancement in the arterial phase) tumor that is 
> 2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical 
enhancement as a result of the previous intervention, then it cannot be selected as a target 
lesion). 
 
A maximum of 5 target lesions may be selected. 
Nontarget lesion: Other lesions, including small lesions (≤ 2 cm in the axial plane). Note that 
malignant portal vein thrombosis should be considered a nonmeasurable, and therefore 
nontarget, lesion. Lymph nodes at the portal hepatic can be considered as malignant if the 
lymph node short axis is at least 2 cm. Selection of effusion, including ascities, as a nontarget 
lesion is prohibited. Similarly, bone lesions or any other lesion outside the CT or MRI of the 
abdomen or obtained by other modality, may not be selected as nontarget lesions. 
Measurement of lesions: Imaging studies will be by contrast enhanced CT, with use of 
multislice scanners, or contrast enhanced MRI. The same method must be used at baseline and 
during follow up. Note that the longest diameter of the viable tumor is not necessarily located 
in the same scan plane in which the baseline diameter was measured. The measurement of the 
viable tumor diameter should not include any major intervening areas of necrosis. (Please see 
the HGS1012-C1103 Radiographic Data Collection Manual). 
Evaluation of target lesions: 
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. 
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Stable Disease (SD): Any cases that do not qualify for CR, PR or PD. 
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. 
Evaluation of nontarget lesions: 
Complete Response (CR): Disappearance of intratumoral arterial enhancement. 
Incomplete Response/Stable Disease (IR/SD): Persistence of intratumoral arterial 
enhancement in 1 or more nontarget lesions. 
Progressive Disease (PD): Unequivocal progression of existing nontarget lesions.   
Evaluation of new lesions: A newly detected hepatic nodule will be classified as evidence of 
progression when its longest diameter is ≥ 1 cm and the nodule shows the 
hypervascularization in the arterial phase with washout in the portal venous or late venous 
phase.   
Liver lesions ≥ 1 cm that do not show a typical vascular pattern can be diagnosed as HCC by 
evidence of at least a 1 cm-interval growth in subsequent scans.  
An individual radiologic event will be adjudicated in retrospect as progression at the time it 
was 1st detected by imaging techniques, even if strict criteria were fulfilled only on subsequent 
radiologic testing. 
Images by another modality may be obtained, as clinically indicated post-baseline. Sites may 
conclude that post-baseline images based on another modality that indicate disease are 
evidence of radiologic progression if: (1) there was no imaging done at baseline; (2) if there 
was imaging done at baseline showing no disease present at that time; or (3) if there was 
imagine done at baseline indicating that the on-treatment assessment represents unequivocal 
worsening. In these cases the disease will be reported as ‘new lesions’. 
All images obtained on study will be provided the BICR for the independent efficacy read, or 
for confirmation of progression if required or requested. 
Evaluation of Overall Response: The overall response is determined at each assessment and 
is a result of the combined assessment of target lesions, nontarget lesions and new lesions. 


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Overall Response Assessment 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response* 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
*AFP is not included in assessment of overall response. 
 
Best Overall Response: 
The best overall response is the best response recorded from the start of treatment until 
disease progression. To be assigned a best overall response of CR or PR, changes in tumor 
measurements must be confirmed at the next scheduled disease assessment (no fewer than 
4 weeks after the initial documentation of PR or CR). 
 
 
 
 


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Appendix 6 
Exploratory Biomarker Sub-study 
1. Background 
Mapatumumab is a targeted therapy. Presently, the relationship between expression of the 
target, TRAIL-R1, and the anti-tumor activity of the antibody is incompletely understood. 
Studies conducted with cell lines derived from human tumors have suggested that the 
relationship between receptor expression and mapatumumab-induced tumor cell death may be 
complex. However, studies of human tumor cells in vitro and transplanted into animals may 
not accurately reflect the relationship between receptor expression and response to 
mapatumumab that may be observed in patients with cancer. One feature of this biomarker 
study is to compare TRAIL-R1 expression from available biopsy material. This could allow 
for a greater understanding of patterns of TRAIL-R1 expression in advanced hepatocellular 
carcinoma. 
It is also likely that other factors involved in TRAIL-R1 signaling could critically affect 
response to mapatumumab treatment. A 2nd goal of this biomarker study is to evaluate 
biomarkers that may be potential indicators or modifiers of response to mapatumumab. To 
identify factors that may indicate that a patient is responding to treatment, serum-based 
markers will be compared before and after treatment. To explore factors that are associated 
with the outcome of therapy and could be used prior to treatment to predict which patients 
will respond, somatic (inherited) differences that modify a patient’s drug response will be 
examined. 
The information generated from this sub-study will be used solely for research purposes to 
improve future treatment with mapatumumab. It will not be used to change diagnoses or alter 
therapy. Participation in this sub-study is optional. 
2. Study Objectives and Design 
2.1. 
Indicators of Response 
2.1.1. 
Serum-Based Markers of Response 
Induction of cell death in tumor cells can elicit the release of certain biomarkers into the 
serum. These markers can be quantified to evaluate treatment effect. To assess release of 
biomarkers associated with cell death, serum-based assays will be conducted, including, but 
not limited to, assessments of M30, a fragment of cytokeratin 18 that is generated by 
induction of programmed cell death in epithelial tissues. Other examples of markers of tumor 
cell death that will be examined include the cytokines TRAIL, TNFα, soluble Fas ligand, 
interferonα, interferonγ, interleukin-2, interleukin-6, interleukin-8, interleukin-10, and 
interleukin-12. The levels of these factors will be examined before and after treatment to see if 
they correlate with response to treatment. 
Serum will be isolated and the level of cytokines and other markers like M30 will be 
characterized. Collection, processing and handling of these samples are described in the 
laboratory manual. 


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Samples collected in this study will be stored for up to 15 years and may be analyzed with 
samples collected in other studies, but will only be used for mapatumumab-related research. 
2.2. 
Modifiers of Response 
2.2.1. 
Neoplastic Modifiers of Response 
Historically collected tumor biopsy material, if available, will be collected from subjects 
during Cycle 1. Samples will also be obtained from subjects who undergo a biopsy during the 
treatment period. Samples of resected tumor tissue that has been formalin-fixed and embedded 
in paraffin is acceptable; either tissue blocks or slides may be provided. Frozen samples of 
tumor tissue may also be provided. Biopsy material collected from fine needle aspirates may 
be provided; either cell pellets or cytological slides are acceptable. 
Levels of TRAIL receptors will be assessed in biopsy material using immunohistochemical 
techniques if samples are available as formalin-fixed/paraffin-embedded tissue blocks or 
slides. Historically obtained biopsy material or biopsy material obtained during the treatment 
period that is in the form of fresh frozen tissue or cell pellet samples will be utilized to isolate 
RNA for analysis of TRAIL receptor gene expression. 
Similar techniques will be used to evaluate other potential biomarkers and factors that may 
influence mapatumumab response. These may include but are not limited to caspase 8, AKT 
and Mcl-1. 
See the laboratory manual for collection, processing and handling of these samples. 
Samples collected in this study will be stored for up to 15 years and may be analyzed with 
samples collected in other studies, but will only be used for mapatumumab-related research. 
2.2.2. 
Somatic Modifiers of Response 
Inherited differences in the genes that code for drug targets or components of signaling 
pathways related to the target can dramatically influence the effect of pharmacotherapy. 
Variations in genes that could potentially impact mapatumumab’s activity, including 
polymorphic changes in the Fc gamma receptor and interleukin-6 promoter and K-Ras gene 
mutations, will be examined to see if they correlate with response to treatment. 
DNA will be isolated from the blood and polymorphisms and mutations in specific 
response-related genes will be characterized. Collection, processing and handling of these 
samples are described in the laboratory manual. 
Samples collected in this study will be stored for up to 15 years and may be analyzed with 
samples collected in other studies, but will only be used for mapatumumab-related research. 


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3. Statistical Analysis 
Associations will be assessed between candidate biomarkers and treatment outcomes captured 
in the clinical database. Statistical tests to be performed may include Pearson chi-square 
testing, Fisher’s exact test, ANOVA and ANCOVA. Results of the biomarker sub-study may 
be reported independent of the results of HGS1012-C1103. 
4. Subject Selection and Withdrawal 
Subjects enrolled in the HGS1012-C1103 research study are given the option to participate in 
the Biomarkers Sub-study. A subject may withdraw from the sub-study at any time by 
contacting their Study Investigator, who will contact the sponsor. The sponsor will destroy 
any remaining sample materials and will send a letter back to the Investigator confirming 
sample destruction. Any data or analysis generated from the sample prior to the request for 
destruction will not be destroyed. However, no new information will be generated from the 
sample and no new analysis will be performed. 
5. Confidentiality 
Information about sub-study subjects will be kept confidential and managed according to the 
requirements of local privacy regulations. Information obtained from samples will not be 
returned to subjects and will not be placed in the subject’s medical record. 
6. Ethical Considerations 
All subjects enrolled in the HGS1012-C1103 research study who agree to participate in the 
Biomarker Sub-study will be asked to sign a separate Biomarker Informed Consent. Choosing 
to not participate in this sub-study will not affect the subject’s ability to participate in the main 
clinical trial. The Biomarker Informed Consent will be submitted along with the main 
research study informed consent for review by the Institutional Review Board/Ethical 
Committee. 
7. Publication of Biomarker Results 
Any significant findings, based upon the analysis of aggregate data collected from this 
sub-study may be published by Human Genome Sciences. Personal identifiers will not be 
used in any publication resulting from this sub-study. 
 
 


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Appendix 7 
Laboratory Tests 
CBC with Differential 
Chemistry 
Total white blood cell (WBC) count differential: 
Electrolytes: 
 
Neutrophils 
 
Sodium 
 
Bands  
 
Potassium 
 
Lymphocytes  
 
Magnesium 
 
Monocytes 
 
Chloride 
 
Eosinophils 
 
Carbon dioxide/bicarbonate* 
 
Basophils 
 
Calcium 
        
 
 
 
Hemoglobin 
Enzymes: 
Hematocrit 
 
SGOT (AST) 
Red blood cell count 
 
SGPT (ALT) 
Platelet count 
 
Alkaline phosphatase 
Absolute Neutrophil Count 
 
Amylase 
Total white blood cell count 
 
Lipase 
 
 
Gamma glutamyl transferase (GGT) 
Prothrombin time (PT) 
 
Partial thromboplastin time (PTT) 
Other: 
International normalized ratio (INR) 
Creatinine 
 
Blood Urea Nitrogen 
Other: 
Total bilirubin 
Serum and Urine pregnancy 
Total protein 
Hepatitis B surface antigen 
Albumin 
Hepatitis C antibody 
 
B and T lymphocytes 
 
HCV RNA  
 
HBV DNA 
 
HBsAb 
 
*To be collected if included in routine automated serum chemistry panel. 
 
Refer to Section 6 (Study Procedures) for laboratory test collection schedule. 
 


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Appendix 8 
Treatment of Allergic/Hypersensitivity Reactions 
In the event of allergic/hypersensitivity reactions to mapatumumab/placebo, investigators will 
institute treatment measures according to best medical and nursing practice. The grading is 
based upon the NCI-CTCAE Version 4.0.0. 
The following treatment guidelines will be employed: 
• If chills and fever occur, the infusion will be interrupted. Subjects may be treated 
symptomatically and the infusion will be restarted at 50% of the original rate. 
 
Grade 1 allergic/hypersensitivity reaction (transient flushing or rash, drug fever < 38°C): 
• Decrease infusion rate by 50% and monitor for worsening condition. If the reaction 
worsens, stop the infusion. 
 
Grade 2 allergic/hypersensitivity reaction (rash, flushing, urticaria, dyspnea, drug fever 
< 38°C): 
• Stop the infusion. 
• Administer bronchodilators, oxygen, acetaminophen, etc as medically indicated. 
• Resume infusion at 50% of previous rate once reaction has decreased to ≤ Grade 1 in 
severity. Monitor closely for any worsening. If the reaction recurs, stop the infusion. 
 
Re-treatment following Grade 1 or Grade 2 allergic/hypersensitivity reactions: 
• Once the infusion rate has been decreased due to an allergic/hypersensitivity reaction, it 
will remain decreased for all subsequent infusions. 
• If the subject has a 2nd reaction at the lower infusion rate, the infusion will be stopped and 
the subject will receive no further treatment with mapatumumab/placebo. 
• If the subject experiences a Grade 3 or Grade 4 allergic/hypersensitivity reaction at any 
time, the subject will receive no further treatment with mapatumumab/placebo. 
• If there are questions concerning whether an observed reaction is an 
allergic/hypersensitivity of Grades 1-4, the medical monitor will be contacted immediately 
to assist with grading the reaction. 
 
Grade 3 or Grade 4 allergic/hypersensitivity reaction: 
• A Grade 3 hypersensitivity reaction consists of symptomatic bronchospasm requiring 
parenteral medications with or without urticaria, allergy-related edema/angioedema, or 
asymptomatic hypotension not requiring treatment. 
• A Grade 4 hypersensitivity reaction (ie, anaphylaxis) is a life-threatening event 
characterized by the same symptoms as in a Grade 3 reaction but also complicated by 
symptomatic hypotension or oxygen saturation of 90% or less. 
 


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Treatment of Grade 3 or Grade 4 allergic/hypersensitivity reaction: 
• Stop the infusion immediately and disconnect infusion tubing from the subject. 
• Administer epinephrine, bronchodilators, antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, etc, as medically indicated. 
 
Contact Human Genome Sciences to report an SAE and fax SAE worksheet. 
 
 
 
 
 
 


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Mapatumumab 
 
Protocol Amendment 02, 23 February 2011 
Protocol Number: HGS1012-C1103-02 
Protocol Title: 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 of Modifications and Rationale  
1. Subjects with a history of organ allograft will be excluded from participating as they were 
also not eligible in the registration trial for sorafenib. 
2. The prohibited medications section has been clarified to include any locoregional therapy 
including embolization, RFA or percutaneous ethanol injection.   
 
Associated Protocol Modifications:  
Title Page 
Formerly: 
Protocol Amendment 01 Date 21 December 2010 
Modified to:  
Protocol Amendment 02 Date 23 February 2011 
Study Synopsis Exclusion Criteria 
Section 4.2 
Exclusion Criteria 
Addition: 
3. History of organ allograft. 
 
Section 5.3.2    
Prohibited Medications 
Formerly: 
Subjects will not receive any investigational or noninvestigational cytotoxic chemotherapy, 
hormonal therapy, biological therapy (including monoclonal antibodies) or immunotherapy to 
treat hepatocellular carcinoma during the treatment period. Alternative anticancer therapies 
may be administered after radiologic disease progression has been documented, but will be 
avoided if possible during the 30 day safety follow up period after the last dose of study agent 
(mapatumumab/placebo and/or sorafenib) whichever is last. These medications are allowed in 
the long-term follow-up period after the 30 day safety follow-up period and documentation of 
radiologic disease progression. 


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Modified to: 
Subjects will not receive any investigational or noninvestigational cytotoxic chemotherapy, 
hormonal therapy, biological therapy (including monoclonal antibodies), immunotherapy or 
any locoregional therapy (such as embolization, RFA or percutaneous ethanol injection) to 
treat hepatocellular carcinoma during the treatment period. Alternative anticancer therapies 
may be administered after radiologic disease progression has been documented, but will be 
avoided if possible during the 30 day safety follow up period after the last dose of study agent 
(mapatumumab/placebo and/or sorafenib) whichever is last. These medications are allowed in 
the long-term follow-up period after the 30 day safety follow-up period and documentation of 
radiologic disease progression. 
AM02 
23Feb11 


 
 
 
CLINICAL PROTOCOL HGS1012-C1103 
Protocol Amendment: 01 
Date: 21 December 2010 
 
 
TITLE OF STUDY: 
 
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 
 
 
 
STUDY SPONSOR: 
Human Genome Sciences, Inc. 
 
14200 Shady Grove Road 
 
Rockville, Maryland 20850 
 
 
 
EudraCT Number: 
2010-020798-17 
 
 
 
 
 
Confidentiality 
This document contains proprietary and confidential information of Human Genome Sciences, Inc. Acceptance 
of this document constitutes agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without prior written approval from Human Genome Sciences, Inc., except that this 
document may be disclosed to study personnel under your supervision who need to know the contents for 
conducting the study and appropriate Institutional Review Boards and Independent Ethics Committee under the 
condition that they are requested to keep it confidential. The foregoing shall not apply to disclosure required by 
governmental regulations or laws however; Human Genome Sciences, Inc. must be promptly informed of any 
such disclosure. 
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Investigator Agreement 
I will provide copies of the protocol, any subsequent amendments and access to all 
information furnished by the sponsor to study personnel under my supervision. I will discuss 
this material with them to ensure that they are fully informed about the investigational study 
agent and the study protocol. I agree to conduct this clinical trial according to the protocol 
described herein, except when mutually agreed to in writing with the sponsor. I also agree to 
conduct this study in compliance with Good Clinical Practice standards as defined by the 
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice, all 
applicable national, state, and local regulations, as well as the requirements of the appropriate 
Institutional Review Board/Independent Ethics Committee and any other institutional 
requirements. 
 
 
Principal Investigator: 
 
 
 
Signature  
 
 
 
 
 
 
 
Date 
 
 
 
Name (please type or print) 
 
 
 
Institution 
 
 
 
Address 
 
 
 


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Study Synopsis 
Study Number: HGS1012-C1103 
Title of the Study: 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 
Clinical Development Phase: 2 
Objectives: 
Primary: 
• To evaluate the efficacy of mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma. 
 
Secondary: 
• To evaluate the safety of the mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma. 
• To determine serum mapatumumab concentrations. 
 
Diagnosis & Inclusion Criteria: 
Subjects enrolled in the study must meet the following inclusion criteria: 
1. Child-Pugh Class A (see Appendix 1). 
2. Barcelona Clinic Liver Cancer (BCLC) advanced stage (C) hepatocellular carcinoma, or 
BCLC intermediate stage (B) hepatocellular carcinoma if treatment with transarterial 
chemoembolization is not considered appropriate (see Appendix 2). 
3. Measurable disease demonstrating intratumoral arterial enhancement by contrast enhanced 
computerized tomography (CT), with use of multislice scanners, or contrast enhanced 
dynamic magnetic resonance imaging (MRI), with at least 1 tumor lesion that meets the 
following criteria: 
- 
Located in the liver. 
- 
Can be accurately measured in at least 1 dimension. 
- 
Well delineated area of viable, hypervascular (contrast enhancement in the arterial 
phase) tumor that is > 2 cm in the axial plane. 
- 
Suitable for repeat measurement. 
- 
Not previously treated with locoregional or systemic treatment unless the lesion shows 
a well-delineated area of viable (contrast enhancement in the arterial phase) tumor that 
is > 2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical 
enhancement as a result of the previous intervention, then it cannot be selected as a 
target lesion). 


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4. Radiologic eligibility (measurable disease) must be confirmed by the blinded, 
independent, central read (BICR) prior to randomization. 
5. Adequate bone marrow, renal and liver function: 
- 
Absolute neutrophil count ≥ 1.5 x 109 /L or ≥ 1500 /mm3. 
- 
Platelet count ≥ 50 x 109 /L or ≥ 50,000 /mm3. 
- 
Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L) without growth factor support or transfusional 
support. 
- 
Serum creatinine level ≤ 2.0 mg/dL or ≤ 176.8 µmol/L. 
- 
Total bilirubin < 3.0 mg/dL or < 51.3 µmol/L. 
- 
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5.0 x upper limit of 
normal. 
- 
Amylase and lipase ≤ 1.5 x upper limit of normal. 
- 
Serum albumin ≥ 2.8 g/dL or ≥ 28 g/L. 
- 
International normalized ratio ≤ 1.5. 
6. Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) 
Scale (see Appendix 3). 
7. Age 18 years or older. 
8. Have the ability to understand the requirements of the study, provide written informed 
consent (including consent for the use and disclosure of research-related health 
information), and comply with the study and follow-up procedures. 
 
Exclusion Criteria: 
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria: 
1. Any co-morbid condition that in the judgment of the investigator renders the subject at 
high risk of treatment complications or reduces the possibility of assessing clinical effect. 
2. Received prior investigational or non-investigational cytotoxic chemotherapy, hormonal 
therapy, biological therapy (including but not limited to monoclonal antibodies, small 
molecules or other immunotherapy) to treat hepatocellular carcinoma. 
3. Previously received mapatumumab and/or sorafenib. 
4. Underwent resection, radiofrequency ablation, radiation or chemoembolization within 
4 weeks before enrollment or not recovered from such treatments. 
5. Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy, 
immunotherapy, radiofrequency ablation) or other investigational agents during the study 
treatment period. 
6. Major surgery (ie, the opening of a major body cavity, requiring the use of general 
anesthesia) within 4 weeks before enrollment; minor surgery (except for insertion of 
vascular access device) within 2 weeks before enrollment; or not yet recovered from the 
effects of the surgery. 
7. Systemic steroids within 1 week before enrollment except steroids used as part of an 
antiemetic regimen or maintenance-dose steroids for non-cancerous disease. 
8. Hepatic encephalopathy, per the investigator’s evaluation. 
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9. History of clinically significant gastrointestinal bleeding requiring procedural intervention 
(eg, variceal banding, transjugular intrahepatic portosystemic shunt procedure, arterial 
embolization, topical coagulation therapy) within 4 weeks before enrollment. 
10. Gastrointestinal disease resulting in an inability to take oral medication or a requirement 
for intravenous hyperalimentation. 
11. History of any infection requiring hospitalization or intravenous antibiotics within 2 weeks 
before enrollment. 
12. Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) 
with no evidence of progression and neurologically stable off anticonvulsants and steroids. 
13. Known human immunodeficiency virus infection. 
14. Unstable angina, myocardial infarction, cerebrovascular accident, ≥ Class II congestive 
heart failure according to the New York Heart Association Classification for Congestive 
Heart Failure (see Appendix 4) within 6 months before enrollment. 
15. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. 
16. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure 
> 90 mmHg despite optimal medical management). 
17. Using and unable to discontinue use of concomitant strong CYP3A4 inducers 
(eg, including but not limited to St. John’s Wort, dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, phenobarbital). 
18. Pregnant female or nursing mother. All females with an intact uterus (unless amenorrheic 
for the 24 months before enrollment) must have a negative serum pregnancy test at 
screening. All non-sterile or non-postmenopausal females must practice a medically 
accepted method of contraception over the course of the study and for 60 days after the 
last dose of study agent. 
19. Males who do not agree to use effective contraception during the study and for a period of 
60 days following the final dose of study agent. 
20. Subject is currently enrolled in or has not yet completed at least 30 days since ending 
other investigational device or drug study(s) or subject is receiving other investigational 
agents. 
21. Acute or chronic severe renal insufficiency (glomoerular filtration rate 
< 30 mL/min/1.73 m2) or acute renal insufficiency of any severity due to 
the hepato-renal syndrome. 
22. Hepatitis B virus DNA levels > 2,000 IU/mL. 
 
Study Design and Schedule: 
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma. In addition to receiving sorafenib, subjects will be 
randomly assigned to 1 of 2 treatment groups in a 1:1 ratio to receive 30 mg/kg 
mapatumumab or placebo. 
Randomization will be stratified according to BCLC advanced stage C vs BCLC intermediate 
stage B and ECOG performance status (0 vs 1, 2).  
Approximately 100 advanced HCC subjects will be randomized/enrolled.   


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Study Treatment: 
Mapatumumab will be supplied in open label vials and third party unblinding will be 
employed. The study agent will be reconstituted by the unblinded site pharmacist or unblinded 
designee. The unblinded site pharmacist or unblinded designee will also be the person 
responsible for receiving and dispensing study agent but independent of all other study 
activities. All other study personnel, the subject, the Sponsor will remain blinded to the study 
agent received. Separate monitors will be responsible for the clinical (blinded monitor) and 
study agent (unblinded monitor) aspects of the study. 
Subjects will receive treatment every 21 days (ie, a cycle) as outlined below: 
Arm A:  
Sorafenib 400 mg orally twice daily continuously in each cycle + placebo 
intravenously on Day 1 of each cycle. 
Arm B: 
Sorafenib 400 mg orally twice daily continuously + mapatumumab (30 mg/kg) 
intravenously on Day 1 of each cycle. 
Subjects will continue to receive study treatment(s) until radiologic disease progression or 
unacceptable toxicity. Subjects unable to tolerate sorafenib may continue to receive 
mapatumumab/placebo every 21 days until radiographic progression. Subjects unable to 
tolerate mapatumumab/placebo may continue to receive sorafenib until radiographic 
progression. All subjects will have an end of treatment visit at least 30 days after the last dose 
of sorafenib and/or mapatumumab/placebo whichever is later. After discontinuation of 
treatment, subjects will continue to be followed for radiologic disease assessments every 
6 weeks, starting 6 weeks after the previous disease assessment while on treatment, until 
documented radiologic disease progression (if not previously documented) and then every 
3 months thereafter for survival until at least 90% of the subjects have met the survival 
endpoint. 
Disease Assessments: 
Radiologic disease assessments along with assessment of alpha fetoprotein will be performed 
at the end of every two 21-day cycles (ie, Cycles 2, 4, 6 and every 2 cycles thereafter). The 
disease assessment will be performed and documented no earlier than 5 days before the start 
of the next cycle. Clinical responses will be evaluated according to mRECIST for HCC (see 
Section 6.7 and Appendix 5). The same assessment method will be used throughout the study 
for each subject. If disease progression is based only on new lesions or is equivocal, images 
will be provided to the blinded, independent, central reader (BICR) for confirmation of 
disease progression. Partial response (PR) and complete response (CR) will be confirmed at 
the next scheduled disease assessment (no fewer than 4 weeks after the initial documentation 
of PR or CR). All imaging scans used for disease assessments will be made available for 
independent radiology review by the Sponsor or designee. 


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Safety Assessments: 
The safety of sorafenib and mapatumumab will be assessed by evaluation of the type, 
frequency, and severity of adverse events (ie, according to the NCI-CTCAE Version 4.0 
grading) and changes in clinical laboratory tests (hematology and clinical chemistry) and 
immunogenicity over time. In the event that an adverse event does not have an NCI-CTCAE 
Version 4.0 grading, the severity grades in Section 8.6 will be used. Adverse events (including 
serious adverse events) will be captured from the start of study agent administration (sorafenib 
and/or mapatumumab/placebo) through at least 30 days following the last dose of sorafenib 
and/or mapatumumab/placebo, whichever is later. Laboratory assessments will be performed 
at screening, and during each study visit outlined in the study calendar found in Section 6.3. 
The Human Genome Sciences Review Committeee (HGSRC) is comprised of the Department 
Heads of Biostatistics, Regulatory Affairs and Drug Development. The HGSRC will review 
safety data after: (1) 10 subjects have completed 1 cycle; and (2) 30 subjects have completed 
1 cycle. HGSRC reviews of safety data will be conducted approximately every 4 months 
thereafter, until 90% of subjects have reached radiologic progression. The HGSRC may 
conduct additional reviews at their own request and/or at the request of the Medical Monitor. 
The HGSRC may request the unblinding of treatment assignment for a subject and/or 
treatment groups. If treatment assignments are unblinded, the rationale for the unblinding will 
be documented. 
Immunogenicity: 
Blood samples for serum antibodies to mapatumumab will be obtained as outlined in  
Table 6-1. 
Dose Modification/Delay: 
Dose modifications will not be allowed for mapatumumab/placebo. Dose modifications of 
sorafenib for toxicity will be made according to the guidelines provided in the treatment 
section (Section 5.2.3) of the protocol. 
Details regarding pre-treatment and management of hypersensitivity reactions related to 
mapatumumab are provided in Section 5.1.5 and Appendix 8. 
Pharmacokinetics: 
Multiple blood specimens will be obtained from subjects for serum mapatumumab 
concentration determinations as outlined in Table 6-1. 
Pharmacodynamics: 
Subjects will be given the option to participate in a biomarker research sub-study. Consenting 
subjects will be asked to provide a historically obtained biopsy sample, if available, and 
several blood samples. In addition, samples will be requested from subjects who undergo a 
biopsy during the treatment period. 


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To examine biomarkers present peripherally, blood will be drawn during Cycles 1 and 2, from 
which DNA and serum proteins will be isolated. The biomarker sub-study is detailed in 
Appendix 6. 
Exploratory Assessments: 
Blood samples will be collected for quantification of B and T lymphocyte subsets on Day 1 
(prior to dosing) and Day 15 of Cycles 1 and 2. 
Study Endpoints: 
The following will be evaluated (these endpoints and the respective analyses are defined in 
Section 9): 
Primary: 
• Time to progression (TTP). 
 
Secondary: 
• Overall survival. 
• Progression-free survival. 
• Objective response (complete response [CR] + partial response [PR]). 
• Disease control (CR + PR + stable disease [SD]). 
• Response duration and time to response in responders. 
• Frequency and severity of treatment-emergent adverse events. 
• Laboratory parameters. 
• Serum mapatumumab concentrations for use in a population pharmacokinetic analysis. 
 
Statistical Methods: 
Sample Size: 
A total of approximately 100 subjects will be randomly assigned to 1 of 2 arms and treated 
with either sorafenib + placebo or the 2-agent combination of sorafenib and mapatumumab at 
30 mg/kg in a 1:1 ratio. A sample size of 50 subjects randomized and treated in each group is 
sufficient to estimate the median time to progression with a precision of approximately -1.9 M 
to +2.6 M relative to the observed median. In addition, a sample size of 50 patients per arm 
will provide 80% power to detect an improvement in TTP from 5.5 to 8.9 M with at a 
one-sided significance level of 0.10. 
Statistical Analysis: 
The primary analysis will be an estimate of median time to progression in each arm using 
Kaplan Meier methods, reported with 95% confidence intervals, along with testing the 
hazard ratio for time to progression at a 1-sided significance level of 0.10 with a Cox 
AM01 
21Dec10 


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proportional hazards model controlling for the factors stratifying the randomization as 
covariates. Secondary analyses include estimates, using Kaplan Meier methods, of median 
progression-free survival (PFS) and median overall survival (OS) along with associated 
logrank testing. In addition, estimates of overall response rate (CR+PR) and disease control 
rate (CR+PR+SD) will be reported with 95% confidence intervals and an estimate of the 
difference in response rates and disease control rates between groups will be reported and 
tested for significance with a Pearson chi-square test (or Fisher’s exact test). For frequency 
and severity of adverse events and laboratory toxicity grading, counts and rates will be 
presented. 
Study Calendar: 
The study calendar is located in Section 6.3 of the protocol. 
 
 


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Table of Contents 
Study Synopsis ........................................................................................................................... 3 
Table of Contents...................................................................................................................... 10 
List of Tables............................................................................................................................ 13 
List of Abbreviations................................................................................................................ 14 
1 Background......................................................................................................................... 16 
1.1 
Hepatocellular Carcinoma........................................................................................ 16 
1.2 
Treatment Options for Patients with Hepatocellular Carcinoma.............................. 16 
1.3 
The Role of the TRAIL Pathway in HCC ................................................................ 16 
1.3.1 TRAIL and TRAIL Receptors...................................................................... 16 
1.3.2 TRAIL and HBV/HCV Infection ................................................................. 17 
1.4 
Mapatumumab.......................................................................................................... 17 
1.4.1 Mapatumumab Pharmacology...................................................................... 17 
1.4.2 Non-Clinical Mapatumumab Safety Studies................................................ 18 
1.4.3 Clinical Experience with Mapatumumab ..................................................... 19 
1.5 
Rationale for the Evaluation of Mapatumumab in Combination with Sorafenib 
in Hepatocellular Carcinoma.................................................................................... 20 
1.6 
Rationale for Dose Selection.................................................................................... 21 
2 Study Objectives................................................................................................................. 22 
2.1 
Primary Objective..................................................................................................... 22 
2.2 
Secondary Objective................................................................................................. 22 
3 Study Design....................................................................................................................... 22 
3.1 
Basic Design Characteristics .................................................................................... 22 
4 Inclusion and Exclusion Criteria ........................................................................................ 23 
4.1 
Inclusion Criteria...................................................................................................... 23 
4.2 
Exclusion Criteria..................................................................................................... 24 
5 Study Treatment Regimen.................................................................................................. 26 
5.1 
Mapatumumab and Placebo...................................................................................... 26 
5.1.1 Formulation .................................................................................................. 26 
5.1.2 Packaging, Labeling, Preparation, and Storage............................................ 26 
5.1.3 Mapatumumab/Placebo Dose, Route of Administration and Schedule ....... 26 
5.1.4 Mapatumumab/Placebo Dose Toxicity/Delay.............................................. 27 
5.1.5 Management of Allergic/Hypersensitivity Reactions to 
Mapatumumab/Placebo ................................................................................ 28 
5.2 
Sorafenib................................................................................................................... 28 
5.2.1 Packaging, Labeling, Preparation, and Storage............................................ 28 
5.2.2 Anticipated Toxicities with Sorafenib.......................................................... 28 
5.2.3 Alteration of Sorafenib Dose/Schedule Due to Toxicity.............................. 29 


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5.3 
Concurrent Medications and Therapies.................................................................... 32 
5.3.1 Allowable Regimens..................................................................................... 32 
5.3.2 Prohibited Medications................................................................................. 32 
5.3.3 Prohibited Therapies..................................................................................... 32 
6 Study Procedures................................................................................................................ 32 
6.1 
Screening Procedures ............................................................................................... 32 
6.2 
Study Enrollment/Randomization Procedures.......................................................... 33 
6.3 
On-treatment Study Procedures................................................................................ 34 
6.4 
Follow-up Procedures............................................................................................... 37 
6.4.1 Safety Follow-up .......................................................................................... 37 
6.4.2 Long-term Follow-up ................................................................................... 37 
6.5 
Withdrawal of Subjects from Treatment .................................................................. 37 
6.6 
Withdrawal of Subjects from Study ......................................................................... 37 
6.7 
Disease Response Assessments................................................................................ 38 
7 Pharmacokinetic, Immunogenicity, Pharmacodynamic and Exploratory Assessments..... 39 
7.1 
Pharmacokinetic Assessments.................................................................................. 39 
7.2 
Immunogenicity........................................................................................................ 39 
7.3 
Pharmacodynamic Assessments............................................................................... 39 
7.4 
Exploratory Assessments (B and T Lymphocyte Subsets)....................................... 39 
7.4.1 Rationale for B and T Lymphocyte Analysis............................................... 39 
7.4.2 Collection of Samples for B and T Lymphocyte Analysis........................... 40 
8 Adverse Event Reporting.................................................................................................... 40 
8.1 
Definitions ................................................................................................................ 40 
8.2 
Reporting Adverse Events to the Sponsor or Designee............................................ 40 
8.3 
Laboratory Abnormalities as Adverse Events.......................................................... 41 
8.4 
Other Events Requiring Rapid Reporting................................................................. 41 
8.5 
Reporting a Pregnancy.............................................................................................. 42 
8.6 
Investigator Evaluation of Adverse Events .............................................................. 42 
8.7 
Follow-up of Adverse Events................................................................................... 43 
8.8 
Serious Adverse Events Assessed During Long-Term Follow-up........................... 43 
8.9 
Reporting Serious Adverse Events to the Institutional Review Board/Ethics 
Committee ................................................................................................................ 44 
9 Endpoints and Statistical Analysis ..................................................................................... 44 
9.1 
General Statistical Considerations............................................................................ 44 
9.2 
Sample Size Rationale.............................................................................................. 44 
9.3 
Efficacy..................................................................................................................... 44 
9.3.1 Primary Efficacy Endpoint........................................................................... 44 
9.3.2 Primary Efficacy Analysis............................................................................ 44 


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9.3.3 Secondary Efficacy Endpoints...................................................................... 45 
9.3.4 Secondary Efficacy Analyses....................................................................... 45 
9.4 
Safety........................................................................................................................ 45 
9.4.1 Definition of Safety Variables...................................................................... 45 
9.4.2 Human Genome Sciences Safety Review Committee.................................. 46 
9.4.3 Analysis of Safety Variables ........................................................................ 46 
9.5 
Pharmacokinetics...................................................................................................... 46 
9.5.1 Definition of Pharmacokinetic Evaluation ................................................... 46 
9.5.2 Analysis of Pharmacokinetics ...................................................................... 46 
9.6 
Pharmacodynamics................................................................................................... 46 
10 Study Administration.......................................................................................................... 46 
10.1 Informed Consent ..................................................................................................... 46 
10.2 Institutional Review Board Review/Independent Ethics Committee Review and 
Approval................................................................................................................... 47 
10.3 Protocol Compliance ................................................................................................ 47 
10.4 Protocol Revisions.................................................................................................... 47 
10.5 Data Collection and Management ............................................................................ 47 
10.6 Study Monitoring...................................................................................................... 48 
10.7 Drug Accountability ................................................................................................. 48 
10.8 Retention of Records ................................................................................................ 49 
10.9 Financial Disclosure ................................................................................................. 49 
10.10 Publication Policy..................................................................................................... 49 
10.11 Study or Study Site Termination .............................................................................. 50 
11 References .......................................................................................................................... 51 
List of Appendices.................................................................................................................... 58 
 
 


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List of Tables 
Table 5-1 
Sorafenib dose levels........................................................................................ 29 
Table 5-2 
Dose modifications of sorafenib for skin toxicity ............................................ 30 
Table 5-3 
Dose modifications of sorafenib for hypertension ........................................... 30 
Table 5-4 
Dose modifications of sorafenib for sorafenib-associated toxicity .................. 31 
Table 6-1 
Study calendar .................................................................................................. 34 
 
 
 


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List of Abbreviations 
AE 
adverse event 
AFP 
α - fetoprotein 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BCLC 
Barcelona Clinic Liver Cancer 
BICR 
blinded independent central read 
CR 
complete response 
CT 
computerized tomography 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
Fc 
heavy chain constant region or fragment of antibody 
GGT 
gamma-glutamyl transpeptidase 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HGS 
Human Genome Sciences 
HGSRC 
Human Genome Sciences Review Committee 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IR 
incomplete response 
IRB 
Institutional Review Board 
kg 
kilogram 
mg 
milligram 
mL 
milliliter 
mm 
millimeter 
mmHg 
millimeters of mercury 
mRECIST 
modified RECIST assessment for HCC 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
ng 
nanogram 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OS 
overall survival 
PD 
progressive disease 
PK 
pharmacokinetics 
PPT 
partial thromboplastin time 
PR 
partial response 
PS  
performance status 
PT 
prothrombin time 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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RNA 
ribonucleic acid 
SAE 
serious adverse event 
SD 
stable disease 
TNF 
tumor necrosis factor 
TRAIL 
tumor necrosis factor-related apoptosis-inducing ligand 
TRAIL-R1 
TRAIL receptor 1 
TRAIL-R2 
TRAIL receptor 2 
TTP 
time to progression 
 
 
 
 
 


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1 Background 
1.1 
Hepatocellular Carcinoma 
Hepatocellular carcinoma is the 5th most common cancer worldwide accounting for 2% of all 
malignancies. It is the 3rd leading cause of cancer-related death globally with 1 million new 
cases a year (WHO, 2007; IACR, 2002; Ferlay et al, 2004; Lopez et al, 2006). 
Hepatocellular carcinoma is more prevalent in males with a male:female ratio as high as 8:1. 
Depending on the endemic risk factors, hepatocellular carcinoma is diagnosed during the 
4th through 6th decades of life. The reported incidence of  hepatocellular carcinoma is 
increasing because of a better ability to diagnose the disease and because of the long-term 
consequences of hepatitis C virus (HCV) and hepatitis B virus (HBV) infection (Reis et al, 
2006). Worldwide the most common cause of hepatocellular carcinoma is chronic HBV 
infection (El-Serag et al, 2003). Endemic areas thus include China, South Asia and 
South Africa where the incidence of hepatocellular carcinoma can be as high as 120 cases 
per 100,000. In the United States, where HCV and alcohol are the main risk factors, 
the age-adjusted incidence rates have increased from 1.4 cases per 100,000 in 1980 to a 
current incidence of 4 cases per 100,000. This equates to about 8500-11,000 new cases 
diagnosed each year (IACR, 2002; Ferlay et al, 2004; Pawlik et al, 2004; Edwards, et al, 2005; 
Jemal et al, 2007; Bosch et al, 2004). 
1.2 
Treatment Options for Patients with Hepatocellular Carcinoma 
Surgery, including transplantation, is the only curative modality for hepatocellular carcinoma 
(Venook, 1994; Cha et al, 2003). The 5-year survival rate for patients with unresectable 
hepatocellular carcinoma is 11% in the US (ACS, 2007), < 8% in Europe (Capocaccia et al, 
2007), and < 10% in Asia (Teo and Fock, 2001). Symptomatic hepatocellular carcinoma has a 
very poor prognosis with a median survival of 1–8 months (Former et al, 2006; Llovet et al, 
1999a, b). 
Sorafenib, a multikinase inhibitor, is the 1st systemic therapy to significantly impact survival 
in patients with advanced hepatocellular carcinoma, as demonstrated in an international, 
multicenter Phase 3, placebo-controlled trial (Llovet et al, 2007). Sorafenib was approved in 
the United States and European Union for the 1st-line treatment of advanced hepatocellular 
carcinoma in late 2007 and the 2008 National Comprehensive Cancer Network guidelines 
have been updated with the addition of sorafenib as a treatment option for hepatocellular 
carcinoma patients. The updated Barcelona Clinic Liver Cancer (BCLC) guidelines 
recommend sorafenib for hepatocellular carcinoma patients with BCLC Advanced Stage (C) 
(Forner et al, 2010). 
1.3 
The Role of the TRAIL Pathway in HCC 
1.3.1 
TRAIL and TRAIL Receptors 
TRAIL is a member of the tumor necrosis factor (TNF) ligand superfamily, with homology 
to Fas/Apo1 ligand (Pitti et al, 1996; Wiley et al, 1995). TRAIL induces programmed 
cell death primarily in tumor cells through activation of TRAIL death receptors, TRAIL-R1 
(death receptor 4) or TRAIL-R2 (death receptor 5) (Ashkenazi et al, 1999; Evdokiou et al, 


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2002; Kothny-Wilkes et al, 1998; Lawrence et al, 2001; Pitti et al, 1996; Walczak et al, 1999; 
Wiley et al, 1995). 
TRAIL-R1, the target of mapatumumab, is detectable on tumor cells derived from colon, lung, 
liver, gastric, pancreas, uterus and esophagus and in tissue sections from various tumors of the 
colon, lung, pancreas, liver and stomach without significant expression in parallel normal 
tissues (Halpern et al, 2004; Roach et al, 2004). 
1.3.2 
TRAIL and HBV/HCV Infection 
Acutely infected tissues, including the liver, utilize the TRAIL pathway to eliminate virally 
and bacterially infected cells (Herr et al, 2007). In viral hepatitis, TRAIL and 1 of its 
receptors, TRAIL-R2, are upregulated and contribute to the elimination of infected 
hepatocytes associated with viral hepatitis (Bantel and Schulze-Osthoff, 2003; Lin et al, 2002; 
Matsuda et al, 2005). In addition to HBV and HCV infection, steatosis, exposure to bile acids 
and chronic alcohol exposure induce increased expression of TRAIL and TRAIL-R2, but not 
TRAIL-R1, in human hepatocytes (Dunn et al, 2007; Mundt et al, 2005). Cell surface 
expression of TRAIL-R2, but not TRAIL-R1, was altered and responsible for sensitization to 
TRAIL in hepatocytes exposed to bile acids (Higuchi et al, 2001; Malhi et al, 2007). These 
findings have been reproduced in preclinical models. Non-virally infected hepatocytes are 
refractory to TRAIL and TRAIL-R agonists but exposure of HCV-infected hepatocytes to 
TRAIL leads to a significant level of apoptosis (Volkmann et al, 2007). Inhibition of the 
TRAIL pathway may protect infected cells from apoptosis and allow for chronic infection 
(Mundt et al, 2003). Recent non-clinical observations demonstrated that natural killer cells 
expressing the ligand TRAIL, are enriched in the livers of patients with chronic HBV 
infection, and TRAIL is overexpressed in the livers of patients with HCV-associated steatosis 
(Mundt et al, 2005).  
In summary, preclinical data suggest that mapatumumab may promote apoptosis of cancer 
cells, including hepatocellular carcinoma cells. Whether viral infection, including HBV or 
HCV infection, will attenuate or modulate the effects of mapatumumab on hepatocytes is not 
yet known, but experience to date in a Phase 1b trial of mapatumumab in combination with 
sorafenib in subjects with advanced hepatocellular carcinoma who are positive for hepatitis B 
surface antigen or hepatitis C antibody indicates that the safety experience is consistent with 
underlying disease and known sorafenib toxicities (see Section 1.2). 
1.4 
Mapatumumab 
1.4.1 
Mapatumumab Pharmacology 
Mapatumumab is a fully human, agonist monoclonal antibody that activates the cell death 
pathway in tumor cells by specifically binding to TRAIL-R1 with high affinity. 
Mapatumumab efficiently induces apoptosis in human cancer cell lines expressing the 
TRAIL-R1 protein on the cell surface. Nonclinical studies have demonstrated that 
mapatumumab can induce cytotoxicity in multiple tumor cell lines representing both solid and 
hematological malignancies, including cancers of the biliary tract, colon, lung, breast, 
pancreas, esophagus, ovary, kidney, uterus, as well as lymphoma and various leukemias. 
Mapatumumab has also demonstrated anti-tumor activity as a single agent, preventing 


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tumor growth and in some cases causing regression of tumors in xenograft tumor models of 
multiple human malignancies, including lung, colon, kidney, and uterus (Camidge, 2007; 
Georgakis et al, 2005; Jin et al, 2007; Humphreys, 2004; Marini et al, 2006; Menoret et al, 
2006; Pukac et al, 2005). 
The relationship between receptor expression and response to therapy with mapatumumab 
remains unclear. In vitro studies of cell lines have shown that TRAIL-R1 expression level is 
not a consistent predictor of response to mapatumumab. Although both TRAIL-R1 expression 
and apoptosis in response to mapatumumab are increased in many tumor cell lines as 
compared with normal diploid cells, there are examples of mapatumumab cytotoxicity on cell 
lines with very low levels of detectable receptor, and conversely, mapatumumab resistant cell 
lines that have relatively high levels of TRAIL-R1 cell surface expression. 
Tumor cell cytotoxic activity can be enhanced when mapatumumab is administered in 
combination with chemotherapeutics or other anti-neoplastic agents. Enhanced apoptotic 
signaling, in vitro cell killing and in vivo anti-tumor activity have been observed when 
mapatumumab has been combined with various types of therapeutic agents and treatments 
including microtubule poisons, anti metabolites, topoisomerase inhibitors, proteosome 
inhibitors, platinum agents and radiation. Both the level and spectrum of activity of 
mapatumumab is enhanced in in vitro cytotoxicity and in vivo xenograft studies in 
combination with various chemotherapeutic and anti-neoplastic agents, including a xenograft 
model of hepatocellular carcinoma in combination with cisplatin and gemcitabine 
(Camidge, 2007; Pukac et al, 2005; Georgakis et al, 2005; Humphreys, 2004; Jin et al, 2007; 
Human Genome Sciences data on file). 
Please refer to the mapatumumab Investigator’s Brochure for detailed information regarding 
the nonclinical pharmacology, toxicology, and PK of mapatumumab. 
1.4.2 
Non-Clinical Mapatumumab Safety Studies 
To assess the nonclinical safety of mapatumumab, a 6-month toxicity study, with a 4-month 
recovery period, was conducted in chimpanzees. Mapatumumab was administered 
intravenously at up to 40 mg/kg every 10 days. No mapatumumab-specific toxicity was 
identified and no anti-mapatumumab antibodies were detected. 
To assess its off-target effects, mapatumumab was administered intravenously weekly to 
cynomolgus monkeys, whose TRAIL R1 homolog does not bind mapatumumab. 
Mapatumumab was well tolerated at doses of up to 50 mg/kg and was not highly 
immunogenic: of the 40 monkeys treated, 1 developed anti-mapatumumab antibodies. The 
positive response was observed in an animal in the high dose (50 mg/kg) group. 
In vitro, mapatumumab was found to decrease viability of normal human hepatocytes, 
although the observed effect was less than that observed with TRAIL. This effect was variable 
across donors and did not amplify with increasing concentrations of mapatumumab. It should 
be noted that in clinical studies, plasma mapatumumab concentrations have been achieved that 
are > 1100–fold greater than the minimum exposure resulting in reduced in vitro hepatocyte 
viability. Despite this, the clinical results do not reveal evidence of hepatotoxicity in those 


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studies. Hence it appears that the in vitro hepatocyte viability assay is not predictive of 
mapatumumab effects in vivo. 
1.4.3 
Clinical Experience with Mapatumumab 
Over 400 subjects have received mapatumumab in clinical trials to date. Preliminary clinical 
data are available from 218 subjects who received mapatumumab as a single agent at doses 
ranging from 0.01 to 20 mg/kg across 6 clinical trials. 
Based on available data, mapatumumab appears to be well tolerated and no significant safety 
issues have been observed. Adverse events have generally been mild to moderate in severity, 
manageable, and do not appear related to dose. The most frequently reported treatment-related 
adverse events occurring in > 10% of subjects were fatigue, hypotension, nausea and pyrexia. 
Severe events have been uncommon and generally judged not related to mapatumumab. 
Severe events judged at least possibly related to mapatumumab have been observed and a 
complete list can be found in the mapatumumab Investigator’s Brochure. Grade 3 or Grade 4 
hematologic, renal, or hepatic laboratory abnormalities also have been relatively uncommon 
with no significant trend or dose-response evident. Lymphopenia was the most commonly 
observed laboratory abnormality, but tended to be intermittent and reversible and was not 
associated with infectious events. 
In subjects with solid tumors, stable disease has been the best response observed with 
mapatumumab as a single-agent. However, 2 complete responses (CRs) and 1 partial response 
(PR) were observed in subjects with follicular lymphoma. 
In addition, preliminary clinical data are available from 234 subjects who received 
mapatumumab at doses ranging from 1 to 30 mg/kg every 21 days in combination with 
chemotherapy in 5 clinical trials (carboplatin/paclitaxel [N = 100], gemcitabine/cisplatin 
[N = 49], bortezomib [n = 69], or sorafenib [n = 16]. Mapatumumab has been generally well 
tolerated; adverse events and laboratory abnormalities have been consistent with those 
expected with underlying disease or chemotherapy. A listing of severe events considered at 
least possibly related to mapatumumab can be found in the mapatumumab Investigator’s 
Brochure. The most commonly occurring laboratory abnormalities have been hematologic 
(ie, anemia, neutropenia, thrombocytopenia, and leukopenia), as expected with chemotherapy. 
Grade 3/4 laboratory abnormalities have been relatively uncommon. Higher frequencies of 
Grade 3/4 neutropenia, leukopenia, lymphopenia, and thrombocytopenia have been observed. 
Data from randomized Phase 2 studies in combination with chemotherapy suggest that 
mapatumumab may increase rates of lymphopenia. 
One subject receiving mapatumumab in combination with carboplatin/paclitaxel has 
achieved a CR. Twenty-two subjects receiving mapatumumab in combination with 
paclitaxel/carboplatin and 12 subjects receiving mapatumumab in combination with 
gemcitabine/cisplatin have achieved PRs. Three subjects receiving mapatumumab in 
combination with bortezomib achieved CRs; 25 subjects receiving mapatumumab in 
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1.5 
Rationale for the Evaluation of Mapatumumab in Combination with 
Sorafenib in Hepatocellular Carcinoma 
Sorafenib is the standard of care for treatment of patients with advanced hepatocellular 
carcinoma. Sorafenib is a multikinase inhibitor that targets the Raf/mitogen-activated protein 
kinase/extracellular signal-regulated kinase signaling pathway, blocks tumor angiogenesis and 
induces apoptosis (Panka et al, 2006; Rahmani et al, 205; Yu et al, 2005; Wilhelm et al, 
2004). Sorafenib was approved by the European Medicines Agency and the Food and Drug 
Administration in 2007 for treatment of patients with hepatocellular carcinoma based on the 
demonstration of improved overall survival in the 602 patient randomized, placebo-controlled, 
Phase 3 “Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol” (SHARP) 
trial. Approximately half the 602 patients had either hepatitis C virus or hepatitis B virus as 
underlying etiology and 26% had alcohol-related cirrhosis. The median overall survival was 
10.7 months for patients in the sorafenib arm compared with 7.0 months for patients in the 
placebo arm (hazard ratio in the sorafenib group, 0.69 95% confidence interval, 0.55 to 0.87; 
p < 0.001). The median time to radiologic progression was 5.5 months in the sorafenib arm, 
compared with 2.8 months in the placebo arm (p < 0.0001) (Llovet et al, 2008). Seven patients 
in the sorafenib group (2%) and 2 patients in the placebo group (1%) had a PR; no patients 
had a CR. 
A 2nd randomized, placebo-controlled Phase 3 trial was conducted in the Asia-Pacific region 
(Cheng et al, 2009). The 226 patients randomly assigned to sorafenib or placebo in this trial 
appeared to have more advanced disease than those in the SHARP trial, with a higher 
frequency of extrahepatic spread, poorer ECOG PS, and higher levels of AFP, but still showed 
a benefit from treatment with sorafenib. The majority (73%) had hepatitis B virus as an 
underlying etiology. The median overall survival was 6.5 months for patients in the sorafenib 
arm, compared with 4.2 months in the placebo group (hazard ratio, 0.68, 95% confidence 
interval, 0.50-0.93; p = 0.014). The median time to progression was 2.8 months in the 
sorafenib group, compared with 1.4 months in the placebo group (hazard ratio, 0.57, 95% 
confidence interval 0.42-0.79; p = 0.0005). 
The mechanisms of sorafenib and mapatumumab action suggest that these agents could 
interact synergistically. Sorafenib sensitizes human cancer cell lines, including cell lines 
derived from hepatocellular carcinoma, to apoptotic stimuli by reducing expression of 
apoptotic regulatory proteins; Mcl-1, Bcl-xL, and FLIP (Kim et al,2008; Koehler et al, 2009; 
Rosato et al, 2007; Liu et al, 2006; Rahmani et al, 2005; Yu et al, 2005). Mcl-1, Bcl-xL 
and FLIP have also been shown to mediate sensitivity of a wide range of tumor cell lines 
to TRAIL receptor agonists (Meng et al, 2007; Rosato et al, 2007; Llobet et al 2010; 
Blechacz et al, 2009; Katz et al, 2009; Huang and Sincrope, 2010; and Menoret et al, 2006). 
Recent studies demonstrated the combination of sorafenib with TRAIL or TRAIL receptor 
antibodies has significant activity in hepatocellular carcinoma cell lines (Koehler et al, 2009) 
and colon tumor xenografts (Ricci et al, 2007) that were resistant to TRAIL and an antibody 
against TRAIL-R2. 
Mapatumumab activity has been evaluated preclinically in hepatocellular carcinoma cell lines 
by in vitro cytotoxicity assays both as a single agent and in combination with doxorubicin, 
cisplatin, gemcitabine or sorafenib. Single agent mapatumumab activity was observed in 4 of 


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10 hepatocellular carcinoma cell lines. Increased in vitro cytotoxicity, including examples of 
synergy, were observed in 8 of 10 cell lines when mapatumumab was combined with 
doxorubicin or cisplatin or the combination of cisplatin and gemcitabine (Humphreys et al, 
2008). Two of these hepatocellular carcinoma cell lines were evaluated for in vitro 
cytotoxicity of mapatumumab in combination with sorafenib. One displayed an increase in 
cytotoxicity from 30% to 60% when treated with a combination of sorafenib and 
mapatumumab. Importantly, treatment of a primary human hepatocyte cell line did not induce 
any apoptosis at doses of mapatumumab that were cytotoxic to hepatocellular carcinoma cell 
lines (
 and 
 [personal communication], 2008; Abdulghani et al, 2008). 
Therefore, collectively, the expression of TRAIL-R1 in hepatocellular carcinoma and 
preclinical activity observed with combinations of mapatumumab with chemotherapy or 
sorafenib supports the rationale that this combination may be able to effectively target 
hepatocellular carcinoma. 
1.6 
Rationale for Dose Selection 
As 
of 
June 
2010, 
mapatumumab 
has 
been 
administered 
with 
chemotherapy 
(ie, carboplatin/paclitaxel, gemcitabine/cisplatin, bortezomib, or sorafenib) to 234 subjects, 
including 61 subjects who received 20 mg/kg and 50 subjects who received 30 mg/kg 
mapatumumab. Based on available data, mapatumumab in combination with chemotherapy is 
generally well tolerated at dose levels up to and including 30 mg/kg, and no significant safety 
issues have been observed in the course of the clinical trials even at the higher doses.   
Preliminary PK data are available for subjects who received 1, 10, 20 or 30 mg/kg 
mapatumumab in combination with gemcitabine and cisplatin (n = 49), 10 or 30 mg/kg 
mapatumumab in combination with paclitaxel and carboplatin (n = 73), and 3, 10, or 
30 mg/kg mapatumumab in combination with sorafenib (n = 17). Serum or plasma 
mapatumumab concentrations are consistently within the range of expected concentrations 
predicted from Phase 1 study results in solid tumor patients administered mapatumumab as 
monotherapy. Mapatumumab PK is linear and not affected by the addition of therapeutic 
agents. As expected, the observed peak and trough levels of mapatumumab at 30 mg/kg are 
2 to 3 times higher than those observed at 10 mg/kg. Exposure appears to increase in 
proportion to dose and exposures for a given dose are similar across studies.  
A Phase 1b dose escalation study of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma who are positive for hepatitis B surface antigen or 
hepatitis C antibody is being conducted. Safety observations have been consistent with the 
underlying disease and known sorafenib toxicities. As of June 2010, 6 subjects have received 
3 mg/kg, 9 subjects have received 10 mg/kg, and 1 subject has received 30 mg/kg 
mapatumumab. The number of cycles completed ranges from 1 to 20; 4/16 (25.0%) of 
subjects have completed 11 or more cycles. Adverse events have generally been consistent 
with published reports of the toxicities associated with sorafenib and previous experience 
with mapatumumab, as well as underlying disease. The most frequently occurring 
treatment-emergent adverse events, regardless of severity or attribution of causality, 
include diarrhea (10/16, 62.5%), fatigue (9/16, 56.3%), nausea (9/16, 56.3%), and vomiting 
(7/16, 43.8%). Serious adverse events, regardless of attribution of causality, include 
hypertension, upper respiratory tract infection, atrial fibrillation, hyperbilirubinemia, 
PPD
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hypoglycemia, and hepatic pain. Severe adverse events considered at least possibly related to 
mapatumumab or its interaction with sorafenib include elevated lipase (3/16, 18.8%), hepatic 
pain (1/16, 6.3%), and thrombocytopenia (1/16, 6.3%). Laboratory abnormalities have 
generally been mild or moderate in severity, manageable, and/or consistent with those 
expected with chemotherapy or the underlying disease. The most frequent Grade 3 or Grade 4 
laboratory abnormalities include elevated total bilirubin (Grade 3, 4/16, 25.0%; Grade 4, 
1/16, 6.3%) and lymphopenia (Grade 3, 3/16, 18.8%; Grade 4, 2/16, 12.5%). Additional 
information on the safety experience can be found in the mapatumumab Investigators’ 
Brochure. 
Based on the information currently available, the safety profile continues to be favorable, 
supporting continued evaluation of mapatumumab in combination with chemotherapy, 
including sorafenib. The maximum tolerated dose has not been reached in any of the Phase 1 
or Phase 2 trials conducted to date. Thus, further evaluation of the 30 mg/kg dose is 
warranted. 
The dose of sorafenib for this study, 400 mg twice daily, is the approved dose for the 
treatment of unresectable hepatocellular carcinoma. 
2 Study Objectives 
2.1 
Primary Objective 
• To evaluate the efficacy of mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma. 
 
2.2 
Secondary Objective 
• To evaluate the safety of the mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma. 
• To determine serum mapatumumab concentrations. 
 
3 Study Design 
3.1 
Basic Design Characteristics 
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma.   
In addition to receiving sorafenib, subjects will be randomly assigned to 1 of 2 treatment 
groups in a 1:1 ratio: 30 mg/kg mapatumumab or placebo. 
Mapatumumab will be supplied in open label vials and 3rd party unblinding will be employed. 
The study agent will be reconstituted by the unblinded site pharmacist or unblinded designee. 
The unblinded site pharmacist or unblinded designee will also be the person responsible for 
receiving and dispensing study agent, but independent of all other study activities. All other 
study site personnel, the subject, and the Sponsor will remain blinded to the study agent 


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received. Separate monitors will be responsible for the clinical (blinded monitor) and study 
agent (unblinded monitor) aspects of the study. 
Number of Subjects: 
Approximately 100 subjects with advanced HCC will be randomized/enrolled. 
Treatment Groups: 
Subjects will receive treatment every 21 days (ie, a cycle) as outlined below: 
Arm A: 
Sorafenib 400 mg orally twice daily continuously in each cycle + placebo 
intravenously on Day 1 of each cycle 
Arm B:  
Sorafenib 400 mg orally twice daily continuously in each cycle + mapatumumab 
(30 mg/kg) intravenously on Day 1 of each cycle 
Randomization 
Randomization will be stratified according to BCLC advanced stage C vs BCLC intermediate 
stage B and ECOG performance status (0 vs 1, 2). 
Estimated Study Duration: 
The study is estimated to occur over approximately 24 months. Subjects will continue to 
receive sorafenib with or without mapatumumab/placebo until radiologic disease progression 
or unacceptable toxicity. Estimated median length of subject treatment is 6-8 months. All 
subjects will have an End of Treatment visit at least 30 days after the last dose of sorafenib 
and/or mapatumumab/placebo, whichever is later. After discontinuation of treatment, subjects 
will continue to be followed for radiologic disease assessments every 6 weeks (± 3 days), 
starting 6 weeks after the previous disease assessment while on treatment, until documented 
radiologic disease progression (if not previously documented). Thereafter, subjects will be 
followed every 3 months for survival until at least 90% of subjects have met the survival 
endpoint. 
4 Inclusion and Exclusion Criteria 
4.1 
Inclusion Criteria 
Subjects enrolled in the study must meet the following inclusion criteria: 
1. Child-Pugh Class A (see Appendix 1). 
2. Barcelona Clinic Liver Cancer (BCLC) advanced stage (C) hepatocellular carcinoma, or 
BCLC intermediate stage (B) hepatocellular carcinoma if treatment with transarterial 
chemoembolization is not considered appropriate (see Appendix 2). 
3. Measurable disease demonstrating intratumoral arterial enhancement by contrast enhanced 
computerized tomography (CT), with use of multislice scanners, or contrast enhanced 


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dynamic magnetic resonance imaging (MRI), with at least 1 tumor lesion that meets the 
following criteria: 
- 
Located in the liver. 
- 
Can be accurately measured in at least 1 dimension. 
- 
Well delineated area of viable, hypervascular (contrast enhancement in the arterial 
phase) tumor that is > 2 cm in the axial plane. 
- 
Suitable for repeat measurement. 
- 
Not previously treated with locoregional or systemic treatment unless the lesion shows 
a well-delineated area of viable (contrast enhancement in the arterial phase) tumor that 
is > 2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical 
enhancement as a result of the previous intervention, then it cannot be selected as a 
target lesion). 
4. Radiologic eligibility (measurable disease) must be must be confirmed by the BICR prior 
to randomization. 
5. Adequate bone marrow, renal and liver function: 
- 
Absolute neutrophil count ≥ 1.5 x 109 /L or ≥ 1500 /mm3. 
- 
Platelet count ≥ 50 x 109 /L or ≥ 50,000 /mm3. 
- 
Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L) without growth factor support or transfusional 
support. 
- 
Serum creatinine level ≤ 2.0 mg/dL or ≤ 176.8 µmol/L. 
- 
Total bilirubin < 3.0 mg/dL or < 51.3 µmol/L. 
- 
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5.0 x upper limit of 
normal. 
- 
Amylase and lipase ≤ 1.5 x upper limit of normal. 
- 
Serum albumin ≥ 2.8 g/dL or ≥ 28 g/L. 
- 
International normalized ratio ≤ 1.5. 
6. Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) 
Scale (see Appendix 3). 
7. Age 18 years or older. 
8. Have the ability to understand the requirements of the study, provide written informed 
consent (including consent for the use and disclosure of research-related health 
information), and comply with the study and follow-up procedures. 
 
4.2 
Exclusion Criteria 
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria: 
1. Any co-morbid condition that in the judgment of the investigator renders the subject at 
high risk of treatment complications or reduces the possibility of assessing clinical effect. 
2. Received prior investigational or non-investigational cytotoxic chemotherapy, hormonal 
therapy, biological therapy (including but not limited to monoclonal antibodies, small 
molecules or other immunotherapy) to treat hepatocellular carcinoma. 
3. Previously received mapatumumab or sorafenib. 
4. Underwent resection, radiofrequency ablation, radiation or chemoembolization within 
4 weeks before enrollment or not recovered from such treatments. 
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5. Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy, 
immunotherapy, radiofrequency ablation) or other investigational agents during the study 
treatment period. 
6. Major surgery (ie, the opening of a major body cavity, requiring the use of general 
anesthesia) within 4 weeks before enrollment; minor surgery (except for insertion of 
vascular access device) within 2 weeks before enrollment; or not yet recovered from the 
effects of the surgery. 
7. Systemic steroids within 1 week before enrollment except steroids used as part of an 
antiemetic regimen or maintenance-dose steroids for non-cancerous disease. 
8. Hepatic encephalopathy, per the investigator’s evaluation. 
9. History of clinically significant gastrointestinal bleeding requiring procedural intervention 
(eg, variceal banding, transjugular intrahepatic portosystemic shunt procedure, arterial 
embolization, topical coagulation therapy) within 4 weeks before enrollment. 
10. Gastrointestinal disease resulting in an inability to take oral medication or a requirement 
for intravenous hyperalimentation. 
11. History of any infection requiring hospitalization or intravenous antibiotics within 2 weeks 
before enrollment. 
12. Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) 
with no evidence of progression and neurologically stable off anticonvulsants and steroids. 
13. Known human immunodeficiency virus infection. 
14. Unstable angina, myocardial infarction, cerebrovascular accident, ≥ Class II congestive 
heart failure according to the New York Heart Association Classification for Congestive 
Heart Failure (see Appendix 4) within 6 months before enrollment. 
15. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. 
16. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure 
> 90 mmHg despite optimal medical management). 
17. Using and unable to discontinue use of concomitant strong CYP3A4 inducers 
(eg, including but not limited to St. John’s Wort, dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, phenobarbital). 
18. Pregnant female or nursing mother. All females with an intact uterus (unless amenorrheic 
for the 24 months before enrollment) must have a negative serum pregnancy test at 
screening. All non-sterile or non-postmenopausal females must practice a medically 
accepted method of contraception over the course of the study and for 60 days after the 
last dose of study agent. 
19. Males who do not agree to use effective contraception during the study and for a period of 
60 days following the final dose of study agent. 
20. Subject is currently enrolled in or has not yet completed at least 30 days since ending 
other investigational device or drug study(s) or subject is receiving other investigational 
agents. 
21. Acute or chronic severe renal insufficiency (glomoerular filtration rate 
< 30 mL/min/1.73 m2) or acute renal insufficiency of any severity due to 
the hepato-renal syndrome. 
22. Hepatitis B virus DNA levels > 2,000 IU/mL. 
 


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5 Study Treatment Regimen 
Sorafenib will be administered at a dose of 400 mg twice daily without food (at least 1 hour 
before or 2 hours after a meal). On days when both sorafenib and mapatumumab/placebo are 
administered together, the sorafenib should be taken at the same time as any other calendar 
day. 
5.1 
Mapatumumab and Placebo 
5.1.1 
Formulation 
Mapatumumab will be supplied as a lyophilized formulation in sterile, single-use 10 mL vials 
containing 100 mg mapatumumab. Upon reconstitution with 5.0 mL of sterile water for 
injection, each vial will contain 20 mg/mL mapatumumab in 0.13 mg/mL citric acid, 
2.8 mg/mL sodium citrate, 19 mg/mL glycine, 5 mg/mL sucrose, 0.2 mg/mL polysorbate 80, 
pH 6.5. 
Two hundred-fifty mL normal saline solution for intravenous infusion will be administered as 
placebo for mapatumumab. 
5.1.2 
Packaging, Labeling, Preparation, and Storage 
The Pharmacy Manual will provide instructions for preparation and storage of study agent. 
The product will be securely stored at 2-8ºC. 
The study agent label will contain, at a minimum, the following information: 
• Product name 
• Concentration 
• Lot number 
• Storage instructions 
• Investigational drug statement 
• Manufacturer’s name and address 
 
Study agent inventory/accountability forms will be examined and reconciled by the unblinded 
study monitor or designee. At the end of the study, all used and unused investigational study 
agent will be accounted for on a study agent accountability form provided to the investigator 
by the Sponsor or designee. Please refer to the HGS1012-C1103 Pharmacy Manual for more 
details regarding storage, handling and drug accountability. 
5.1.3 
Mapatumumab/Placebo Dose, Route of Administration and Schedule 
The dose of mapatumumab is 30 mg/kg. Mapatumumab dose calculations will be based upon 
the subject’s weight measured on Day 1 or within 3 days before Day 1 of each cycle. The 
planned duration of each treatment cycle will be 21 days. Mapatumumab/placebo will be 
administered on Day 1 of each cycle. 


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After reconstitution with sterile water for injection, the calculated mapatumumab dose to be 
administered to the subject will be further diluted in normal saline to a total volume of 
250 mL for intravenous infusion. After adding the reconstituted product, the bag will be 
gently inverted to mix the solution. Following reconstitution and/or dilution in normal saline, 
mapatumumab will be stored at 2-8ºC. The product will be administered to the subject within 
8 hours of reconstitution. Refer to the HGS1012-C1103 Pharmacy Manual for instructions on 
admixing and administering study agent.  
Two hundred-fifty mL normal saline solution for intravenous infusion will be administered as 
placebo for mapatumumab. 
Mapatumumab/placebo will be infused at a constant rate over 1 hour. 
Infusion and hypersensitivity reactions may occur. A suggested pre-medication regimen for 
mapatumumab/placebo consists of diphenhydramine and acetaminophen administered within 
1 hour prior to the start of the mapatumumab/placebo dose. Use of a pre-medication regimen 
and alternatives to this regimen are at the investigator’s discretion. 
Subjects will be monitored closely during and after infusion for any sign of acute adverse 
reaction. If an allergic reaction occurs, see Section 5.1.5 and Appendix 8 for suggested 
medical management. 
5.1.4 
Mapatumumab/Placebo Dose Toxicity/Delay 
Mapatumumab/placebo will be discontinued for Grade 4 transaminase elevations of any 
duration if they are considered related to mapatumumab. 
Mapatumumab/placebo may be delayed up to 2 weeks for toxicities considered related to 
mapatumumab as described below or if the investigator believes that a delay in dosing is 
warranted in the interest of subject safety. 
The National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE, Version 4.0) will be used to grade AEs. 
• Grade 4 neutropenia for > 7 consecutive days or febrile neutropenia. 
• Grade 4 thrombocytopenia. 
• Grade 3 or greater non-hematologic AEs except transient transaminase, amylase and 
lipase abnormalities for which the following criteria will apply: 
- 
Grade 3 or Grade 4 elevations in transaminases that do not resolve to baseline or 
Grade 1 before the next cycle. 
- 
Grade 3 elevations in lipase or amylase associated with clinical/imaging findings of 
pancreatitis, or resulting in chronic damage to the pancreas.  
- 
Any Grade 4 elevations in lipase or amylase for > 4 consecutive days. 
 
If mapatumumab/placebo is delayed for toxicity and the toxicity does not resolve (≤ Grade 1) 
or return to baseline within 2 weeks after the delayed dose was originally scheduled (based on 
a 21-day treatment cycle), the subject will be withdrawn from further treatment with 
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mapatumumab/placebo. If mapatumumab/placebo is delayed because the investigator believes 
a delay is warranted in the interest of subject safety and dosing of mapatumumab/placebo is 
not resumed within 2 weeks after the delayed dose was originally scheduled (based on a 
21-day treatment cycle), the subject will be withdrawn from future treatment with 
mapatumumab/placebo. Sorafenib dosing will continue while mapatumumab/placebo dosing 
is held. The subject will continue receiving sorafenib until radiologic progressive disease or 
an unacceptable toxicity occurs, at the discretion of the Investigator.  
Doses of mapatumumab may not be altered. 
5.1.5 
Management of Allergic/Hypersensitivity Reactions to 
Mapatumumab/Placebo 
The administration of any recombinant protein has the potential to induce local or system 
immunologic reactions; subjects could experience, for example, acute allergic reactions. To 
date, 2 such SAEs have been reported which were considered related to mapatumumab 
(hypersensitivity and angioedema/facial edema). In the event of allergic/hypersensitivity 
reactions, investigators will institute treatment measures according to best medical and 
nursing practice. Guidelines for treatment are provided in Appendix 8. 
For a NCI-CTCAE Version 4.0 Grade 3 or Grade 4 hypersensitivity reaction, treatment with 
mapatumumab/placebo will be discontinued. 
If mapatumumab/placebo is discontinued for Grade 3 or Grade 4 hypersensitivity reactions, 
the subject will continue to receive sorafenib, until radiologic progression or unacceptable 
toxicity. 
5.2 
Sorafenib 
5.2.1 
Packaging, Labeling, Preparation, and Storage 
Sorafenib is supplied as tablets, each containing 274 mg sorafenib tosylate, equivalent to 
200 mg of sorafenib. 
The recommended daily dose of sorafenib is 400 mg (2 x 200 mg tablets) taken orally twice 
daily without food (at least 1 hour before or 2 hours after a meal). 
Sorafenib will be stored at room temperature (15-30°C, 59-86°F) in a dry place. 
For country-specific formulation and packaging information, please refer to the instructions 
provided in the sorafenib product labeling. 
Supplier: Commercially available. 
5.2.2 
Anticipated Toxicities with Sorafenib 
Toxicities anticipated with the use of sorafenib include the following: 
• Cardiac: Cardiac ischemia and/or infarction, hypertension. 


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• Dermatologic: Hand-foot skin reaction, rash/desquamation. 
• Hemorrhagic: Increased risk of bleeding. 
• Gastrointestinal: Gastrointestinal perforation. 
• Other: Wound-healing complications, fatigue, weight-loss, alopecia, pruritis, dry skin, 
diarrhea, anorexia, nausea, vomiting, constipation, liver dysfunction and abdominal pain. 
 
Laboratory abnormalities observed in hepatocellular carcinoma patients treated with sorafenib 
include hypophosphatemia, lipase elevations, amylase elevations, hypoalbuminemia, 
international normalized ratio elevations, lymphopenia and thrombocytopenia. 
Refer to the product labeling accompanying the product for information approved in your 
country. 
5.2.3 
Alteration of Sorafenib Dose/Schedule Due to Toxicity 
Sorafenib may be reduced or delayed for toxicities considered related to sorafenib as 
described below, or if the investigator believes that a reduction in dose is warranted in the 
interest of subject safety. When a dose reduction is necessary, sorafenib dose may be 
reduced to 400 mg once daily. If an additional dose reduction is required, sorafenib may be 
reduced to a single 400 mg dose every other day (see Table 5-1). A maximum of 2 dose 
reductions of sorafenib will be allowed per subject. Additional dose reductions not mentioned 
in Table 5-1 will need to be discussed with the medical monitor. 
Table 5-1 
Sorafenib dose levels 
Dose Levels 
Sorafenib 
0 
400 mg twice daily 
-1 
400 mg once daily 
-2 
400 mg once every other day 
 
Skin toxicity and hypertension are associated with sorafenib. Guidelines for the management 
of these events are provided in Table 5-2 and Table 5-3, respectively. 
Skin Toxicity 
Hand-foot skin reaction and rash are common in subjects treated with sorafenib. Management 
may include topical therapies for symptomatic relief, temporary treatment interruption and/or 
dose modification, or in severe or persistent cases, permanent discontinuation. Skin toxicities 
will be managed according to Table 5-2. 
 
 


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Table 5-2 
Dose modifications of sorafenib for skin toxicity 
Skin Toxicity Grade 
Occurrence 
Suggested Dose Modification 
Grade 1:  
Numbness, dysesthesia, parethesia, 
tingling, painless swelling, erythema or 
discomfort of the hands or feet which does 
not disrupt the subject’s normal activities. 
Any occurrence 
Continue treatment with sorafenib 
and consider topical therapy for 
symptomatic relief. 
1st occurrence 
Continue treatment with sorafenib 
and consider topical therapy for 
symptomatic relief. If no improvement 
within 7 days, see below. 
No improvement within 
7 days or 2nd or 3rd 
occurrence 
Interrupt sorafenib treatment  
until toxicity resolves to Grade 0-1. 
When resuming treatment, decrease 
sorafenib dose by 1 dose level  
(400 mg daily or 400 mg every  
other day). 
Grade 2:  
Painful erythema and swelling of the hands 
or feet and/or discomfort affecting the 
subject’s normal activities. 
4th occurrence 
Discontinue sorafenib treatment. 
1st or 2nd occurrence 
Interrupt sorafenib treatment  
until toxicity resolves to Grade 0-1. 
When resuming treatment, decrease 
sorafenib dose by 1 dose level  
(400 mg daily or 400 mg every  
other day). 
Grade 3:  
Moist desquamation, ulceration, blistering 
or severe pain of the hands or feet, or 
severe discomfort that causes the subject 
to be unable to work or perform activities of 
daily living. 
3rd occurrence 
Discontinue sorafenib treatment. 
 
Hypertension 
Hypertension is a known and potentially serious adverse event associated with sorafenib 
treatment. Subjects will have their blood pressure monitored and recorded. If the subject’s 
blood pressure is elevated at any time (> 150/100 mmHg), even outside clinic visits, they will 
contact their study investigator. Guidelines for the management of hypertension are provided 
in Table 5-3. 
Table 5-3 
Dose modifications of sorafenib for hypertension 
Grade 
(CTCAE v3.0) 
Antihypertensive Therapy 
Blood Pressure  
Monitoring 
Sorafenib  
Dose 
Grade 1 
None 
Routine 
No change 
Grade 2 
(asymptomatic) 
Initiate monotherapy 
(suggest dihydropyridine 
calcium channel blocker) 
Increase frequency and monitor by 
a health professional every 2 days 
until stabilized. 
No change 
Grade 2 
(symptomatic/ 
persistent) 
OR 
diastolic BP  
> 110 mm Hg 
OR 
Grade 3 
Add agent(s): 
calcium channel blocker 
(if not already used), 
K+ channel opener 
(angiotensin blockers),  
beta-blocker, 
thiazide diuretic 
Increase frequency and monitor by 
health professional every 2 days 
until stabilized; continue monitoring 
every 2 days to stabilization after 
dosing restarted. 
Hold* sorafenib until 
symptoms resolve 
and 
diastolic BP  
< 100 mm/Hg 
 
Resume treatment 
at 1 dose level 
lower** 


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Table 5-3 
Dose modifications of sorafenib for hypertension 
Grade 
(CTCAE v3.0) 
Antihypertensive Therapy 
Blood Pressure  
Monitoring 
Sorafenib  
Dose 
Grade 4 
Discontinue sorafenib 
Discontinue sorafenib 
Discontinue 
sorafenib 
*Subjects requiring a delay of > 21 days will discontinue sorafenib, unless in the study investigator’s opinion, 
the subject may benefit from continued treatment. 
**Subjects requiring > 2 dose reductions will discontinue sorafenib. 
BP = Blood pressure. 
Refer to NCI-CTCAE v4.0 for grade definitions. 
(concluded) 
 
Guidelines 
for 
the 
management 
of 
other 
non-hematologic 
and 
hematologic 
sorafenib-associated toxicities are provided in Table 5-4. Those toxicities that are at least 
possibly related to an interaction with mapatumumab/placebo will have the mapatumumab 
toxicity guidelines in Section 5.1.4 applied. 
Table 5-4 
Dose modifications of sorafenib for sorafenib-associated toxicity 
Toxicity 
Grade 1 
Grade 2 
Grade 3* 
Grade 4* 
Non-
hematologic 
Continue at 
the same dose 
level 
Continue at 
the same dose 
level 
Withhold dose until toxicity is 
Grade ≤ 1, then resume 
treatment at the same dose 
level. If subject experiences 
a 2nd Grade 3 toxicity, 
withhold dose until toxicity is 
Grade ≤  1, then reduce 
dose to 400 mg orally daily 
and resume treatment. 
Withhold dose until toxicity 
is Grade ≤ 1, then reduce 
dose to 400 mg daily and 
resume treatment, or 
discontinue at the 
discretion of the principal 
investigator after 
discussion with study 
sponsor. 
Hematologic 
Continue at 
the same dose 
level 
Continue at 
the same dose 
level 
Withhold dose until toxicity is 
Grade ≤ 2, then resume 
treatment at the same dose 
level. If subject experiences 
a 2nd Grade 3 toxicity, 
withhold dose until toxicity is 
Grade ≤  2, then reduce 
dose to 400 mg orally daily 
and resume treatment. 
Withhold dose until toxicity 
is Grade ≤ 2, then reduce 
dose to 400 mg daily and 
resume treatment, or 
discontinue at the 
discretion of the principal 
investigator after 
discussion with study 
sponsor. 
See Table 5-2 and Table 5-3 for dose modifications due to skin toxicity and hypertension respectively. 
*Subjects who develop Grade 3 fever/chills, Grade 3 elevation of hepatic transaminases with ALT and AST 
< 10X upper limit of normal, Grade 3 hyperlipasemia or hyperamylasemia without clinical or other evidence of 
pancreatitis, Grade 3 leukopenia, or Grade 3/Grade 4 lymphopenia may continue sorafenib treatment without 
interruption at the discretion of the investigator. 
 
Sorafenib Discontinuation 
Temporary or permanent discontinuation of sorafenib will be considered in subjects who 
develop cardiac ischemia and/or infarction or severe or persistent hypertension despite 
institution of antihypertensive therapy. If a subject experiences a bleeding event that 
necessitates medical intervention or a gastrointestinal perforation, sorafenib will be 
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permanently discontinued. Subjects, who undergo a surgical procedure or intervention to 
decrease portal hypertension, including transjugular intrahepatic portosystemic shunt, will 
discontinue sorafenib. 
If the subject is withdrawn from further treatment with sorafenib, the subject may continue to 
receive mapatumumab/placebo alone every 21 days until radiologic progression or 
unacceptable toxicity. 
5.3 
Concurrent Medications and Therapies 
5.3.1 
Allowable Regimens 
Subjects may continue their baseline medication(s). The daily dose of each medication will be 
maintained throughout the study if possible. If for any reason deemed necessary by the 
investigator, a subject requires additional medication(s), the medication(s) route of 
administration and the indication for which it was given must be recorded in the source 
documents. All concomitant medications will be recorded on the appropriate case report form. 
Systemic, inhaled and topical steroids used as part of an antiemetic regimen or 
maintenance-dose for non-cancerous disease are permitted. 
5.3.2 
Prohibited Medications 
Subjects who require the use of strong CYP3A4 inducers (eg, including but not limited to 
St. John’s 
Wort, 
dexamethasone, 
phenytoin, 
carbamazepine, 
rifampin, 
rifabutin, 
phenobarbital) are not eligible for this study and use of these agents is prohibited as long as 
the subject is receiving sorafenib in this study. 
Subjects will not receive any investigational or noninvestigational cytotoxic chemotherapy, 
hormonal therapy, biological therapy (including monoclonal antibodies) or immunotherapy to 
treat hepatocellular carcinoma during the treatment period. Alternative anticancer therapies 
may be administered after radiologic disease progression has been documented, but will be 
avoided if possible during the 30 day safety follow up period after the last dose of study agent 
(mapatumumab/placebo and/or sorafenib) whichever is last. These medications are allowed in 
the long-term follow-up period after the 30 day safety follow-up period and documentation of 
radiologic disease progression. 
5.3.3 
Prohibited Therapies 
Subjects will not undergo major or elective surgery during the treatment period of the study; if 
surgery is required, the subject will be withdrawn from study treatment. 
6 Study Procedures 
6.1 
Screening Procedures 
The nature of this study and the potential risks and benefits associated with participation in the 
study will be explained to all potential study subjects. Written informed consent (including 
consent for the use and disclosure of research-related health information) must be obtained 
before any screening procedures are performed that are not considered standard of care. 
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All of the following assessments must be performed within 28 days prior to enrollment: 
• Obtain written informed consent for participation in the study. 
• Obtain informed consent for participation in the optional biomarker sub-study. 
- 
If consented, obtain tissue block/slides or cell pellet from diagnostic histologic/ 
cytologic sample. 
• Record demographics. 
• Obtain medical history, to include history of all treatments used to treat the current cancer 
and all prior cancer treatments. 
• Perform baseline complete physical examination including body weight and height. 
• Assess vital signs (blood pressure, heart rate, respiratory rate and temperature). 
• Evaluate performance status (ECOG scale; see Appendix 3). 
• Draw blood for laboratory tests (see Appendix 7): complete blood count with differential, 
chemistry, hepatitis B surface antigen, Hepatitis B virus DNA, hepatitis C antibody and 
testing for serum pregnancy (all females with an intact uterus [unless amenorrheic for the 
previous 24 months] regardless of age). 
• Obtain radiologic disease and AFP assessments. The method of disease assessment, as per 
mRECIST for HCC (see Appendix 5), will be consistent throughout the study.  
• Obtain electrocardiogram. 
• Record medications used within 28 days before enrollment. 
• Confirm that subject meets all inclusion/exclusion criteria. 
 
6.2 
Study Enrollment/Randomization Procedures 
Subjects that meet the eligibility criteria will be randomly assigned treatment by a 
central interactive voice response system in a 1:1 ratio to 1 of 2 treatment arms. The 
randomization will be stratified according to BCLC advanced stage C vs BCLC intermediate 
stage B and ECOG performance status (0 vs 1, 2). The 1st planned dose of sorafenib and 
mapatumumab/placebo will be administered no more than 3 days following randomization 
and not prior to randomization. All study site personnel (with the exception of the unblinded 
site pharmacist or unblinded designee), the subject, and the Sponsor will remain blinded to the 
study agent received. 
 


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6.3 
On-treatment Study Procedures 
Table 6-1 
Study calendar 
 
 
 
Cycle 1 
Cycle 2 
Additional 
Cycles
14 
Safety Follow-up Phase 
Long-
Term 
Follow-up 
Procedure 
Footnotes 
Screen
Phase 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 22 of 
last cycle on 
treatment 
≥ 30 days 
following 
last dose 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
 
 
CBC with differential; 
Coagulation 
parameters 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy 
2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis 
1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B and T lymphocyte 
subsets 
3 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
 
 
 
 
Immunogenicity  
4 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Pharmacokinetics 
5 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
Biomarkers 
6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Study Agent Admin 
 
 
Sorafenib 
7 
 
Twice daily 
 
 
 
Mapatumumab/ 
Placebo 
7 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Physical/Clinical 
 
 
Med Hx / Phys.Exam 
- 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
8 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
Body weight 
9 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Performance Status 
10 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 


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Table 6-1 
Study calendar 
 
 
 
Cycle 1 
Cycle 2 
Additional 
Cycles
14 
Safety Follow-up Phase 
Long-
Term 
Follow-up 
Procedure 
Footnotes 
Screen
Phase 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 22 of 
last cycle on 
treatment 
≥ 30 days 
following 
last dose 
 
Record AEs/ 
Conmeds 
11 
X 
<----------------Throughout the study----------------> 
 
Disease Assessments  
12 
X 
Performed at the end of every 2 cycles (ie, Cycles 2, 4, 6) and every 2 cycles thereafter until radiologic PD is documented. 
X 
α – Fetoprotein (AFP) 
12 
X 
Performed at the end of every 2 cycles (ie Cycles 2, 4, 6) and every 2 cycles thereafter until radiographic PD is 
documented. 
X 
ECG 
- 
X 
Repeat as clinically indicated 
 
Survival 
13 
 
 
X 
AE = adverse event; CBC = complete blood count; CT = computerized tomography; ECG -= electrocardiogram; PD = progressive disease. 
1 
Safety Labs: Day 1 (complete blood count with differential, coagulation parameters [INR, PT, PTT] and chemistry) must be performed within 3 days prior to dosing on Day 1 of each 
cycle.  See Appendix 7 for a detailed list of required laboratory assessments. 
2 
Pregnancy: Serum test at screening, urine test pre-dose Cycle 1 Day 1; must be negative to receive treatment. 
3 
B and T lymphocyte subsets: Blood samples for quantification of B and T lymphocytes will be obtained in Cycles 1 and 2 only. Samples will be obtained on Day 1 (prior to dosing) and 
Day 15 of Cycles 1 and 2. 
4 
Immunogenicity: Obtain prior to dosing on Day 1 of Cycles 1, 2, 4, 6, every 2 cycles thereafter and at the end of treatment visit (at least 30 days after the last dose). On days when 
immunogenicity and pharmacokinetic samples are collected they will be collected together. 
5 
Pharmacokinetics: Blood specimens will be collected for determination of serum mapatumumab concentrations from subjects as follows:  Cycle 1 (on Day 1 prior to the administration 
mapatumumab/placebo and at the completion of the mapatumumab/placebo infusion, and on Day 8), Cycles 2, 4 and 6 and thereafter on each even cycle (prior to dosing on Day 1), 
on the day of each disease assessment, and at the end of treatment visit (at least 30 days after the last dose). On days when immunogenicity and pharmacokinetic samples are 
collected they will be collected together.   
6 
Biomarkers: For subjects participating in the optional biomarker sub-study, historical biopsy samples will be collected, if available, and samples will be collected if obtained during the 
treatment period in Cycle 1 Days 1 (pre-dose mapatumumab), 2, 3, 8 and 15 and Cycle 2 Days 1 (pre-dose mapatumumab), 3, 8 and 15. In addition, blood samples will be obtained 
as follows: blood for isolation of DNA will be collected once, preferably in Cycle 1. Blood for isolation of serum will be collected in Cycles 1 and 2 (pre-dose on the day of 
mapatumumab/placebo dosing). Further details on the biomarker sub-study are outlined in Appendix 6. 
7 
Study Agent Administration:  Sorafenib will be administered at a dose of 400 mg twice daily without food (at least 1 hour before or 2 hours after a meal). On days when both sorafenib 
and mapatumumab/placebo are administered together, sorafenib should be taken at the same time as any other calendar day. 
8 
Vital Signs: Blood pressure will be monitored weekly for the first 6 weeks. Vital signs will be obtained within 30 minutes prior to administration of mapatumumab/placebo and at the end 
of infusion on Day 1 of each cycle. 
9 
Body Weight: To be obtained on the day of or within 3 days before dosing on Day 1 of each cycle. 


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Table 6-1 
Study calendar 
 
 
 
Cycle 1 
Cycle 2 
Additional 
Cycles
14 
Safety Follow-up Phase 
Long-
Term 
Follow-up 
Procedure 
Footnotes 
Screen
Phase 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 22 of 
last cycle on 
treatment 
≥ 30 days 
following 
last dose 
 
10 
Performance Status: Obtained prior to dosing on Day 1 of each cycle. 
11 
Adverse Events: AE collection begins with the start of 1
st study agent administration. Concurrent medications will be recorded within 28 days prior to Cycle 1 Day 1. 
12 
Disease and α – Fetoprotein (AFP) Assessments: Radiologic and AFP assessments will be performed at the end of every 2 cycles (ie, Cycles 2, 4, 6, etc). For subjects discontinuing 
treatment prior to documentation of radiologic disease progression, disease assessments will be performed every 6 weeks (± 3 days), starting 6 weeks after the previous disease 
assessment while on study, until radiologic disease progression is documented. If disease progression is based only on new lesions or is equivocal, images will be provided to the 
blinded, independent reader for confirmation of disease progression. All imaging scans used for disease assessments will be made available for independent radiology review by the 
Sponsor or designee. 
13 
Survival: Contact will be made with the subject every 3 months to document survival until at least 90% of subjects have met the survival endpoint. 
14 
Subjects who discontinue mapatumumab/placebo will complete the current cycle assessments per the study calendar.  Subsequently, subjects receiving sorafenib alone will return at 
least every 21 days and on additional days as clinically indicated for safety labs (CBC with differential, chemistry and coagulation parameters) for the duration of treatment. Disease 
assessments must be performed every 6 weeks until radiologic disease progression.  Adverse events and concomitant medications will be recorded throughout the study. 
(concluded) 
 


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6.4 
Follow-up Procedures 
6.4.1 
Safety Follow-up 
After discontinuation of study treatment, all subjects will return 1 day after cycle completion 
(approximately Day 22) and at least 30 days after the last dose of sorafenib and/or 
mapatumumab/placebo, for scheduled safety follow-up assessments as outlined in Table 6-1. 
6.4.2 
Long-term Follow-up 
For subjects discontinuing treatment prior to documentation of radiologic disease progression, 
and for subjects who experience stable disease or a response (PR, CR) but are no longer 
receiving treatment, radiologic disease assessments will be performed at 6 week intervals 
(± 3 days), starting 6 weeks after the previous radiologic disease assessment while on 
treatment, until radiologic disease progression is documented. Thereafter, subjects will be 
followed every 3 months for survival until at least 90% of subjects have met the survival 
endpoint. 
6.5 
Withdrawal of Subjects from Treatment 
Subjects will be free to withdraw from treatment at any time, for any reason, or they may be 
withdrawn/removed, if necessary, to protect their health (see reasons for withdrawal below). It 
is understood by all concerned that an excessive rate of withdrawals can render the study 
uninterpretable; therefore, unnecessary withdrawal of subjects will be avoided. 
Subjects may be withdrawn from treatment for any of the following reasons: 
• Radiologic disease progression. 
• Continued unacceptable toxicities despite optimal treatment or dose reduction. 
• Intercurrent illness, at the investigator’s discretion. 
• Withdrawal of consent. 
• Non-compliance/Lost to follow-up. 
• Pregnancy. 
• Termination of the study by the sponsor. 
 
Subjects who withdraw are to be followed for radiologic progression as outlined in 
Section 6.4.2. In addition, every effort will be made to collect safety information on each 
subject through 30 days following the last dose of study treatment, unless the subject 
withdraws consent and refuses to comply with the protocol stipulated safety follow-up and 
radiologic disease progression assessments, or share information obtained after the date of 
withdrawal of consent. 
6.6 
Withdrawal of Subjects from Study 
Subjects may be withdrawn from the study for any of the following reasons: 
• Withdrawal of consent. 


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• Non-compliance/Lost to follow-up. 
• Termination of the study by the sponsor. 
 
Every effort will be made to collect follow-up information on subjects in the long-term 
follow-up period of the study, unless the subject withdraws consent and refuses to share 
information obtained during the long-term follow-up period obtained after the date of 
withdrawal of consent. 
6.7 
Disease Response Assessments 
Imaging endpoints will be determined using the modified RECIST criteria for HCC proposed 
by Lencioni and Llovet (2010; mRECIST). mRECIST for HCC is a joint guideline of the 
American Association for the Study of Liver Diseases and the Journal of the National Cancer 
Institute.  
Lesions which manifest typical imaging characteristics for HCC demonstrate intratumoral 
arterial contrast on CT and MRI images. mRECIST accounts for newer therapies which may 
impact tumor vascularity and may not yield a typical cytotoxic decrease in tumor size by 
incorporating changes in vascularity into the criteria for target lesion response. Diligence in 
obtaining images during the hepatic arterial contrast enhancement phase is a requirement at 
baseline and all subsequent scans. The same imaging method must be used at baseline and 
during follow up. 
As in conventional RECIST, overall response is the result of the combined assessment of 
target, nontarget, and new lesions. There are also specifications for incorporating portal vein 
thrombosis, portal hepatic lymph nodes, and pleural effusions/ascites into the response 
assessment. As with conventional RECIST, the appearance of any new lesion overrides any 
existing lesion response, resulting in classification as progressive disease (PD). Key aspects of 
mRECIST as adapted for this study are summarized in Appendix 4. 
Baseline images will be provided to the BICR for confirmation of radiologic eligibility 
(measurable disease). Confirmation of radiologic eligibility for the study will be provided to 
the site by the BICR within 72 hours of receipt of images and will be required for 
randomization. 
Disease assessments and an assessment of α -fetoprotein will be performed at the end of every 
2 cycles (ie, Cycles 2, 4, 6 and every 2 cycles thereafter). The response assessment will be 
performed and documented no more than 5 days before the start of the next cycle. All images 
will be provided to the BICR following each disease assessment. 
If disease progression is based only on new lesions or is equivocal, images will be provided to 
the BICR for confirmation of radiologic disease progression prior to discontinuing study 
treatment. PR and CR will be confirmed at the next scheduled disease assessment (no fewer 
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7 Pharmacokinetic, Immunogenicity, Pharmacodynamic and 
Exploratory Assessments 
7.1 
Pharmacokinetic Assessments 
For determination of mapatumumab concentration, serum samples will be collected as 
outlined in Table 6-1. 
A manual will be provided regarding how to obtain blood samples, process samples, collect 
serum from the blood samples, and how to store and ship the serum samples. Bioanalysis will 
be carried out at Human Genome Sciences to determine mapatumumab concentration in each 
serum sample. 
7.2 
Immunogenicity 
Blood samples for serum antibodies to mapatumumab will be obtained as outlined in  
Table 6-1.  
7.3 
Pharmacodynamic Assessments 
Subjects will be given the option to participate in an exploratory biomarker research 
sub-study. Consenting subjects will be asked to provide a historically obtained biopsy sample, 
if available, and blood samples. In addition, samples will be requested from subjects who 
undergo a biopsy during the treatment period. 
To examine and quantify biomarkers present peripherally, blood will be drawn during 
Cycles 1 and 2, from which DNA and serum proteins will be isolated. The parameters 
evaluated may include, but may not be limited to, M30, TNFα, sTRAIL, soluble Fas ligand, 
interferon-α, 
interferon-γ, 
interleukin-2, 
interleukin-6, 
interleukin-8, 
interleukin-10, 
interleukin-12, and FC gamma receptor and interleukin-6 gene polymorphisms. The 
biomarker sub-study is detailed in Appendix 6.  
7.4 
Exploratory Assessments (B and T Lymphocyte Subsets) 
7.4.1 
Rationale for B and T Lymphocyte Analysis 
Over 400 subjects have received mapatumumab in doses ranging from 0.01 to 30 mg/kg 
across multiple Phase 1 and Phase 2 clinical trials in subjects with solid and hematologic 
malignancies. While there is no evidence to date that mapatumumab exacerbates adverse 
events associated with chemotherapy, the most commonly observed laboratory abnormality 
associated with mapatumumab has been lymphopenia. The lymphopenia has been intermittent 
and reversible and was not associated with infectious events. However, the lymphocyte 
subpopulation(s) affected have not been characterized. 
The evaluation of lymphocytes will include complete blood count/differential and lymphocyte 
subpopulation analysis (numbers and percentages of T and B cells) by flow cytometry at a 
central laboratory. Blood samples will be examined by flow cytometry for levels of T helper 
(CD4+), T cytotoxic (CD8+) and mature B cells (CD19+). 


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7.4.2 
Collection of Samples for B and T Lymphocyte Analysis 
Blood samples will be collected for quantification of B and T lymphocyte subsets on Day 1 
(prior to dosing) and Day 15 of Cycles 1 and 2 as outlined in Table 6-1. 
8 Adverse Event Reporting 
8.1 
Definitions 
ADVERSE EVENT (EXPERIENCE) - 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. This includes worsening (eg, increase in frequency or severity) of 
pre-existing conditions. 
SERIOUS ADVERSE EVENT – an adverse event resulting in any of the following outcomes: 
• death 
• is life threatening (ie, an immediate threat to life) 
• inpatient hospitalization 
• prolongation of an existing hospitalization 
• persistent or significant disability / incapacity 
• congenital anomaly / birth defect 
• is Medically Important* 
 
*Medical and scientific judgment will be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or result in hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other outcomes listed above. These should also 
usually be considered serious. (ICH guidelines, March 1995) 
Note: Hospitalizations not associated with an adverse event, for example, for administration 
of chemotherapy or hydration for chemotherapy administration, are not considered serious 
adverse events. 
UNEXPECTED ADVERSE EVENT - An adverse event, the nature or severity of which is 
not consistent with the applicable product information (eg, Investigator’s Brochure for an 
unapproved investigational product or package insert/summary of product characteristics for 
an approved product). Expected means that the event has previously been observed with the 
study agent and is identified and/or described in the applicable product information. It does 
not mean that the event is expected with the underlying disease(s) or concomitant 
medications. 
8.2 
Reporting Adverse Events to the Sponsor or Designee 
All adverse events (AEs) that are identified from the start of any study agent administration 
through the specified study follow-up period (through 30 days following administration of the 


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final study agent dose) will be recorded on the paper/electronic Adverse Event Case Report 
Form (AE case report form). All data fields on the AE case report form will be completed. 
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE Worksheet and sent to 
HGS within 24 hours of site personnel becoming aware of a SAE, regardless of expectedness. 
All pages of the SAE Worksheet will be completed, but the SAE worksheet will not be held 
until all information is available. Additional information and corrections will be provided on 
subsequent SAE Worksheets as described in the Study Procedure Manual. SAE Worksheets 
will be sent by facsimile to the Drug Safety Department at HGS using the fax number listed 
below. 
FAX #: 
 
8.3 
Laboratory Abnormalities as Adverse Events 
A laboratory abnormality will be reported as an adverse event if it is associated with an 
intervention. Intervention includes, but is not limited to, discontinuation of treatment, dose 
reduction/delay, additional assessments (excluding follow-up labs), or concomitant therapy. In 
addition, any medically important laboratory abnormality may be reported as an adverse event 
at the discretion of the investigator. This includes laboratory abnormalities for which there is 
no intervention but the abnormal value(s) suggests a disease or organ toxicity. If clinical 
sequelae are associated with a laboratory abnormality, the diagnosis or medical condition will 
be reported (eg, renal failure, hematuria) not the laboratory abnormality (eg, elevated 
creatinine, urine red blood cells increased). 
8.4 
Other Events Requiring Rapid Reporting 
Protocol Specified Events are additional events [toxicities] specifically identified in this 
protocol that must be reported to Human Genome Sciences or designee in an expedited 
manner. Protocol Specified Events may or may not be SAEs as defined in this protocol. They 
are SAEs if they meet one or more of the criteria for an SAE (see Section 8.1). Protocol 
Specified Events are recorded on SAE Worksheets and sent to Human Genome Sciences 
within 24 hours of site personnel becoming aware of the event. 
The Protocol Specified Events for the study: 
• Grade 4 neutropenia for > 7 consecutive days or febrile neutropenia. 
• Grade 4 thrombocytopenia. 
• Grade 3 or greater non-hematologic AEs except transaminase, amylase and lipase 
abnormalities for which the following criteria apply: 
• Grade 4 elevations in transaminases. 
• Grade 4 elevations in lipase or amylase. 
• Grade 3 elevations in lipase or amylase associated with clinical/imaging findings of 
pancreatitis, resulting in chronic damage to the pancreas. 
• Any adverse event that results in discontinuation of treatment if that event is assessed as 
possibly, probably, or definitely related to mapatumumab or sorafenib. 
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8.5 
Reporting a Pregnancy 
Any pregnancy in a female participant or a female partner of a male participant must be 
reported to Human Genome Sciences Drug Safety as soon as the site becomes aware of the 
pregnancy. All pregnancies are reported up to 30 days following the last study agent 
treatment. Human Genome Sciences Drug Safety sends an acknowledgement memorandum to 
the principal investigator along with a Pregnancy Assessment Form. Additional Pregnancy 
Assessment Forms will be sent to the site every 3 months for reporting of follow-up 
information. Pregnancy assessment forms must be completed by the investigator until live 
birth, elective termination of the pregnancy, or miscarriage. The site is responsible for 
following the subject’s pregnancy to final outcome. 
Pregnancies are not considered adverse events. Complications or medical problems associated 
with a pregnancy are considered AEs and may be SAEs. Complications or medical problems 
are reported as AEs/SAEs according to the procedure described in Section 8.2. 
8.6 
Investigator Evaluation of Adverse Events 
The Investigator will evaluate all adverse events with respect to seriousness (criteria listed in 
Section 8.1 above), severity (intensity or grade) and causality (relationship to study agent) 
according to the following guidelines listed below. 
SEVERITY 
Severity will be graded using the NCI-CTCAE, Version 4.0. The NCI-CTCAE may 
be downloaded 
from 
the 
Cancer 
Treatment 
Evaluation 
Program 
website 
(http://ctep.info.nih.gov/reporting/ctc.html). In the event that an AE does not have an 
NCI-CTCAE code, the following severity classifications will be used: 
Mild  
causing no limitation of usual activities 
Moderate 
causing some limitation of usual activities 
Severe 
causing inability to carry out usual activities 
Life Threatening* potentially life threatening or disabling  
 
*Note – a severity assessment of life threatening is not necessarily the same as life threatening 
as a “Serious” criterion. The latter means that the event is an immediate threat to life as 
opposed to a potential threat to life. 
 
 


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CAUSALITY 
Definitely Related 
reasonable temporal relationship to study agent administration 
 
follows a known response pattern (eg, drug is known to cause this AE) 
 
there is no alternative etiology 
Probably Related 
reasonable temporal relationship 
 
follows a suspected response pattern (eg, based on similar drugs) 
 
no evidence for a more likely alternative etiology 
Possibly Related 
reasonable temporal relationship 
 
little evidence for a more likely alternative etiology 
Probably Not Related does not have a reasonable temporal relationship, OR 
 
good evidence for a more likely alternative etiology 
Not Related 
does not have a temporal relationship, OR 
 
definitely due to alternative etiology  
 
ICH guidelines (March, 1995) clarify “reasonable causal relationship” to mean “that there are 
facts [evidence] or arguments to suggest a causal relationship”. 
The causality assessment must be made by the investigator based on information available at 
the time that the SAE worksheet is completed. The initial causality assessment may be revised 
as new information becomes available. 
 *Note - If there is evidence that mapatumumab/placebo contributed to or exacerbated an 
event related to sorafenib; the event will be recorded as possibly, probably or definitely 
related to both sorafenib and mapatumumab. 
8.7 
Follow-up of Adverse Events 
Adverse events that occur during the course of the study are followed until final outcome is 
known or until the end of the safety follow-up period (30 days following the final dose of any 
study agent). Adverse events that have not resolved by the end of the safety follow-up period 
are recorded as ongoing. 
SAEs that have not resolved by the end of the follow-up period are followed until final 
outcome of recovered or recovered with sequelae is achieved. If it is not possible to obtain a 
final outcome for a SAE (eg, the subject is lost to follow up), the reason a final outcome could 
not be obtained will be documented by the investigator. 
8.8 
Serious Adverse Events Assessed During Long-Term Follow-up 
SAEs that occur after the safety follow-up period (30 days following the final dose of study 
agent) that are assessed by the investigator as possibly, probably, or definitely related to study 
agent must be reported to Human Genome Sciences on an SAE worksheet, as described in 
Section 8.2. Post-study SAEs will not be documented on the AE case report form. 


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8.9 
Reporting Serious Adverse Events to the Institutional Review 
Board/Ethics Committee 
All SAEs that are considered unexpected and related to the study agent will be reported by 
Human Genome Sciences or its designee as expedited (ie, 15-Day) reports to the appropriate 
regulatory authorities AND to all participating investigators. Each investigator must notify the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) responsible for 
reviewing the study at their site of all expedited reports. In addition, Human Genome Sciences 
or its designee will follow all applicable local and national regulatory requirements regarding 
safety reporting. Each investigator must also comply with the applicable regulatory 
requirements related to the reporting of SAEs to the IRB/IEC responsible for reviewing the 
study at their site, as well as the regulatory authority(ies) (if applicable). 
9 Endpoints and Statistical Analysis 
9.1 
General Statistical Considerations 
Analyses will be applied to a modified intention-to-treat population unless stated otherwise. 
This population is defined as the set of all randomized subjects who receive at least 1 dose of 
study treatment (mapatumumab/placebo and/or sorafenib) with subjects analyzed according to 
the groups they are randomized to, regardless of the treatment they subsequently receive. 
Additional analyses may be performed on the as-treated population, defined as the set of 
subjects receiving at least 1 dose of study medication analyzed according to the treatment that 
they actually receive. 
Analyses will be performed using the SAS System™, WinNonlin Enterprise Edition™, 
StatXact™, and the R statistical package. 
9.2 
Sample Size Rationale 
A total of approximately 100 subjects will be randomly assigned to 1 of 2 arms and treated 
with either sorafenib + placebo or the 2-agent combination of sorafenib and mapatumumab at 
30 mg/kg in a 1:1 ratio. A sample size of 50 subjects randomized and treated in each group is 
sufficient to estimate the median time to progression with a precision of approximately -1.9 M 
to +2.6 M relative to the observed median. In addition, a sample size of 50 patients per arm 
will provide 80% power to detect an improvement in TTP from 5.5 to 8.9 M with at a 
one-sided significance level of 0.10. 
9.3 
Efficacy 
9.3.1 
Primary Efficacy Endpoint 
The primary endpoint is time to progression (TTP) defined as the time from randomization to 
radiologic disease progression based on blinded independent review of imaging scans.  
9.3.2 
Primary Efficacy Analysis 
The primary analysis will be an estimate of median time to progression in each arm using 
Kaplan Meier methods, reported with 95% confidence intervals, along with testing the hazard 


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ratio for time to progression at a 1-sided significance level of 0.10 with a Cox proportional 
hazards model controlling for the factors stratifying the randomization as covariates. 
9.3.3 
Secondary Efficacy Endpoints 
Secondary endpoints include progression-free survival, overall response, disease control, 
overall survival, time to response, and duration of response (for responders) as defined below: 
• OS: time from randomization to death from any cause. 
• PFS: time from randomization to disease progression or death from any cause. 
• Objective response (CR+PR according to mRECIST for HCC). 
• Disease control (CR+PR+SD according to mRECIST for HCC). 
• Time to response: time from randomization to 1st PR or CR in responders only. 
• Duration of response: time from 1st PR or CR to disease progression; in responders only. 
 
All secondary endpoints will be based on blinded independent review of imaging scans. 
9.3.4 
Secondary Efficacy Analyses 
Secondary analyses include estimates, using Kaplan Meier methods, of median PFS and 
median OS along with associated logrank testing. In addition, estimates of overall response 
rate (CR+PR) and disease control rate (CR+PR+SD) will be reported with 95% confidence 
intervals and an estimate of the difference in response rates and disease control rates between 
groups will be reported and tested for significance with a Pearson chi-square test (or Fisher’s 
exact test).  
9.4 
Safety 
9.4.1 
Definition of Safety Variables  
The safety parameters assessed are given by the following: 
• Frequency, and severity of adverse events (AEs): 
- 
All AEs will be classified by System Organ Class and Preferred Term under the 
Medical Dictionary for Regulatory Activities (MedDRA) system of classification with 
a severity assigned according to the NCI-CTCAE (Version 4.0, 29 May 2009), or the 
rules specified in Section 8.6. 
- 
Laboratory parameters as presented in Appendix 7. 
- 
Laboratory toxicities will be graded based on the NCI-CTCAE (Version 4.0, 
29 May 2009). 
• Anti-mapatumumab antibody response. 
• Vital signs. 
• For frequency and severity of adverse events and laboratory toxicity grading, counts and 
rates will be presented. 
 
AM01 
21Dec10 


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9.4.2 
Human Genome Sciences Safety Review Committee 
The Human Genome Sciences Review Committeee (HGSRC) is comprised of the Department 
Heads of Biostatistics, Regulatory Affairs and Drug Development. The HGSRC will review 
safety data after: (1) 10 subjects have completed 1 cycle; and (2) 30 subjects have completed 
1 cycle. HGSRC reviews of safety data will be conducted approximately every 4 months 
thereafter, until 90% of subjects have reached radiologic progression. The HGSRC may 
conduct additional reviews at their own request and/or at the request of the Medical Monitor. 
The HGSRC may request the unblinding of treatment assignment for a subject and/or 
treatment groups. If treatment assignments are unblinded, the rationale for the unblinding will 
be documented. 
9.4.3 
Analysis of Safety Variables 
The safety analysis will consist of a presentation of rates of AEs observed. Specific AEs will 
be counted once for each subject for calculating rates, but will be presented in total in subject 
listings. In addition, if the same AE occurs multiple times within a particular subject, the 
highest severity and level of causality observed will be reported. If any associations of interest 
between AEs and baseline characteristics are observed, additional stratified results may be 
presented. All treatment-emergent AEs will be summarized overall, as well as categorized by 
the MedDRA system of classification. AEs will be presented overall, by severity, by relation 
to mapatumumab/placebo, and by relation to sorafenib. 
9.5 
Pharmacokinetics 
9.5.1 
Definition of Pharmacokinetic Evaluation 
Serum mapatumumab concentration data obtained from this study will be pooled with data 
obtained from other studies for use in a population PK analysis, which will be reported 
separately. 
9.5.2 
Analysis of Pharmacokinetics 
The serum mapatumumab concentration will be determined by enzyme-linked immunosorbent 
assay. Serum mapatumumab concentration results for this study will be presented using 
appropriate graphic and tabular summaries. 
9.6 
Pharmacodynamics 
Expression of biomarkers in tumor tissue and peripheral blood will be correlated with clinical 
outcomes and may be reported separately from the clinical study report.  
10 Study Administration 
10.1 Informed Consent 
A copy of the proposed informed consent document(s) must be submitted to the sponsor or 
designee for review and comment prior to submission to the reviewing IRB/IEC. The consent 
form must be approved by the IRB/IEC and contain all elements required by national, state, 
local, and institutional regulations or requirements. 


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It is the responsibility of the investigator to provide each subject with full and adequate verbal 
and written information using the IRB/IEC approved informed consent document(s), 
including the objective and procedures of the study and the possible risks involved before 
inclusion in the study. Each subject must voluntarily provide written informed consent 
(including consent for the use and disclosure of research-related health information). The 
consent must be obtained prior to performing any study-related procedures that are not part of 
normal patient care, including screening and changes in medications including any washout of 
medications. A copy of the signed informed consent must be given to the study subject. 
10.2 Institutional Review Board Review/Independent Ethics Committee 
Review and Approval 
The investigator or sponsor (as appropriate per national regulations) shall assure that an 
IRB/IEC, constituted in accordance with ICH Good Clinical Practices, will provide initial and 
continuing review of the study. 
Prior to shipment of the study agent and enrollment of study subjects, documented IRB/IEC 
approval of the protocol, informed consent form, and any advertisement for subject 
recruitment must be obtained and provided to the sponsor or designee. 
The IRB/IEC must also be informed of all protocol amendments prior to implementation. The 
investigator must provide reports of any change in research activity (ie, the completion, 
termination, or discontinuation of a study) to the IRB/IEC. 
10.3 Protocol Compliance 
Except for a change that is intended to eliminate an apparent immediate hazard to a study 
subject, the protocol shall be conducted as described. Any such change must be reported 
immediately to the sponsor and to the IRB/IEC. 
10.4 Protocol Revisions 
Protocol amendments will be prepared and approved by the sponsor. All protocol amendments 
will be signed by the investigator and submitted to the IRB/IEC for review prior to 
implementation. Documentation of IRB/IEC approval must be forwarded to the sponsor or 
designee. If an amendment significantly alters the study design, increases potential risk to the 
subject or otherwise affects statements in the informed consent form, the informed consent 
form must be revised accordingly and submitted to the IRB/IEC for review and approval. The 
approved consent form must be used to obtain informed consent from new subjects prior to 
enrollment and must be used to obtain informed consent from subjects already enrolled if they 
are affected by the amendment. 
10.5 Data Collection and Management 
Data collected for each study subject are recorded electronically on case report forms 
provided or approved by the sponsor.  


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The investigator is responsible for maintaining accurate, complete, and up-to-date records for 
each subject. The investigator is also responsible for maintaining any source documents 
related to the study, including any films, tracings, computer discs, or tapes. The investigator 
must promptly review the completed case report forms for each subject. As the person 
ultimately responsible for the accuracy of all data, the investigator must sign the Investigator's 
Statement in each subject's case report form. 
The anonymity of participating subjects must be maintained. Subjects are identified by an 
assigned subject number on case report forms and other documents submitted to the sponsor. 
Documents that identify the subject beyond subject number are not submitted to the sponsor 
(ie, the signed informed consent document) and must be maintained in strict confidence by the 
investigator, except to the extent necessary to allow auditing by the regulatory authorities, 
study monitor, or sponsor representatives. 
Sites enter subject data directly into the electronic data capture (EDC) system and the EDC 
system automatically generates queries resulting from computer checks embedded into the 
system, so as to ensure accuracy, quality, consistency, and completeness of the database. 
Manual queries resulting from review by monitors, medical coders, and other Data 
Management staff are also generated from within the EDC system, where they are tracked. 
Sites resolve the queries and correct the entered data when necessary. Every change to data is 
captured in the EDC system audit trail. At study end, each site is provided with a compact 
disk containing the electronic case report forms for each of their subjects. 
Upon completion of the study, or after reaching a pre-specified point in the study, Data 
Management locks the database and generates the SAS datasets necessary for data analysis 
and reporting. 
10.6 Study Monitoring 
The study sponsor, Human Genome Sciences, Inc., or designee, will monitor the study. Study 
monitors representing the sponsor will visit study sites routinely throughout the trial. The 
sponsor will review the paper subject diaries and electronic case report forms and compare 
them with source documents to verify accurate and complete collection of data and confirm 
that the study is being conducted according to the protocol. Auditors representing the sponsor 
may also similarly evaluate the study and its monitors. For these purposes, the investigator 
will make paper subject diaries and electronic case report forms and source documents 
available when requested. 
In addition, the study may be evaluated by representatives of the national regulatory 
authorities, who will also be allowed access to study documents. The investigators will 
promptly notify Human Genome Sciences of any audits they have scheduled with any 
regulatory authority. 
10.7 Drug Accountability 
Upon receipt, the designated unblinded pharmacy personnel at the study site are responsible 
for taking an inventory of the study agent, including any buffers or diluents. A record of this 


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inventory must be kept and usage must be documented on study agent inventory forms 
provided by the sponsor. 
Study agent inventory forms will be examined and reconciled by an unblinded Clinical 
Research Associate, or designee. At the end of the study, all used and unused study agent 
must be accounted for on a study agent accountability form provided to the investigator by 
Human Genome Sciences or its designee. 
10.8 Retention of Records 
The investigator shall retain all records and source documents pertaining to the study, 
including any films, tracings, computer discs, or tapes. They will be retained for the longer of 
the maximum period required by the country and institution in which the study is conducted, 
or the period specified by the sponsor at the time the study is completed, terminated, or 
discontinued. 
If the investigator leaves the institution, the records shall be transferred to an appropriate 
designee who accepts the responsibility for record retention. Notice of such transfer shall be 
documented in writing and provided to the sponsor. 
10.9 Financial Disclosure 
The investigator will provide Human Genome Sciences sufficient and accurate information on 
financial interests (proprietary or equity interests, payments exclusive of clinical trial costs) to 
allow complete disclosure to regulatory authorities. The investigator shall promptly update 
this information if any relevant changes occur during the course of the investigation and for a 
period of 1 year following study completion. 
10.10 Publication Policy 
This study is being conducted as part of a multi-center clinical study. Data from all sites 
participating in the multi-center clinical study will be pooled and analyzed. The investigator 
acknowledges that an independent, joint publication is anticipated to be authored by the 
investigators of the multi-center study and sponsor’s representatives. Neither institution nor 
principal investigator shall independently publish or present the results of the study prior to 
the publication of the multi-center study publication. The investigator agrees that the sponsor 
will be the coordinator and arbitrator of all multi-center study publications. For multi-center 
trials, no investigator will be authorized to publish study results from an individual center 
until the earlier of the multi-center trial results are published or 12 months after the end or 
termination of the multi-center trial at all sites. 
The investigator shall submit a copy of any proposed publication, manuscript, abstract, 
presentation or other document with respect to this study to the sponsor for review and 
comment at least 60 days prior to its submission for publication or presentation. No 
publication or presentation with respect to the study shall be made unless and until the entire 
sponsor’s comments on the proposed publication or presentation have been considered and 
any information determined by sponsor to be confidential information has been removed. 


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If requested in writing by the sponsor, the investigator shall withhold material from 
submission for publication or presentation for an additional 60 days to allow for the filing of a 
patent application or the taking of other measures to establish and preserve the sponsor’s 
proprietary rights. 
10.11 Study or Study Site Termination 
If Human Genome Sciences, the investigator, IRB/IEC, or a regulatory authority discovers 
conditions arising during the study that indicate that the study should be halted or that the 
study center should be terminated, this action may be taken after appropriate consultation 
between Human Genome Sciences and the investigator. Conditions that may warrant 
termination of the study include, but are not limited to, the following: 
• The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study. 
• A decision on the part of Human Genome Sciences to suspend or discontinue testing, 
evaluation, or development of the product. 
 
The study site may warrant termination under the following conditions: 
• Failure of the investigator to enroll subjects into the study at an acceptable rate. 
• Failure of the investigator to comply with pertinent regulatory authority regulations. 
• Submission of knowingly false information from the research facility to Human Genome 
Sciences, study monitor, or the regulatory authority. 
• Insufficient adherence to protocol requirements. 
 
 
 


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activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in 
tumor progression and antiogenesis. Cancer Res 2004;64:7099-109. 
WHO. World Health Organization. Hepatitis B, 2002. 
Younes A, Kadin ME. Emerging applications for the tumor necrosis factor family of ligands 
and receptors in cancer therapy. J Clin Oncol 2003;21:3526-34. 
Yu C, Bruzek LM, Meng XW, et al. The role of Mcl-1down-regulation in the proapoptotic 
activity of the multikinase inhibitor BAY 43-9006. Oncogene 2005;24:6861-9. 
Zhu AX. Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be? 
Oncologist 2006;11(7):790-800. 
Zhu, AX. Development of sorafenib and other molecularly targeted agents in hepatocellular 
carcinoma. Cancer 2008;112:250-9. 
Zimmermann H, Reichen J. Assessment of liver function in the surgical patient. In: Blumgart 
LH, Fong Y, ed. Surgery of the Liver and Biliary Tract, London: WB Saunders; 35-64:2000. 
 
 
 


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List of Appendices 
Appendix 1 
Child-Pugh Classification................................................................................. 59 
Appendix 2 
BCLC Staging and Treatment Strategy............................................................ 60 
Appendix 3 
Eastern Cooperative Oncology Group (ECOG) Performance Status............... 61 
Appendix 4 
New York Heart Association Classification for Congestive Heart Failure...... 62 
Appendix 5 
Modified Response Evaluation Criteria in Hepatocellular Carcinoma 
(mRECIST for HCC)........................................................................................ 63 
Appendix 6 
Exploratory Biomarker Sub-study.................................................................... 66 
Appendix 7 
Laboratory Tests............................................................................................... 69 
Appendix 8 
Treatment of Allergic/Hypersensitivity Reactions........................................... 70 
 
 
 
 
 


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Appendix 1 
Child-Pugh Classification 
(Zimmerman H and Reichen J, 2000) 
 
No. of Points 
Factor 
1 
2 
3 
Bilirubin (mg/dL) 
< 2 
2–3 
> 3 
Albumin (g/dL) 
> 3.5 
2.8–3.5 
< 2.8 
Prothrombin time (increased seconds) 
1–3 
4–6 
> 6 
Ascites 
None 
Slight 
Moderate 
Encephalopathy 
None 
Minimal 
Advanced 
 
Grade 
Score 
A 
5 – 6 
B 
7 – 9 
C 
10 – 15 
 
 


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Appendix 2 
BCLC Staging and Treatment Strategy 
 
 
 
Forner et al, 2010 
 
 
 


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Appendix 3 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
 
 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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Appendix 4 
New York Heart Association Classification for Congestive 
Heart Failure 
(The Criteria Committee of the New York Heart Association; Little, Brown & Co. 1994) 
Class 
New York Heart Association Classification for Congestive Heart Failure 
1 
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. 
2 
Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. 
3 
Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable 
at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. 
4 
Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. 
Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased. 
 
 
 
 


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Appendix 5 
Modified Response Evaluation Criteria in Hepatocellular 
Carcinoma (mRECIST for HCC) 
(Adapted from Lencioni and Llovet, 2010 for use in this study) 
Measurable disease: The presence of at least 1 target lesion, by contrast enhanced 
computerized tomography (CT) with use of multislice scanners, or contrast enhanced dynamic 
magnetic resonance imaging (MRI). 
Target lesion: Meets all the following criteria: 
- 
Located in the liver. 
- 
Can be accurately measured in at least 1 dimension. 
- 
Well-delineated area of viable, hypervascular (contrast enhancement in the arterial phase) 
tumor that is > 2 cm in the axial plane. 
- 
Suitable for repeat measurement. 
- 
Not previously treated with locoregional or systemic treatment unless the lesion shows a 
well-delineated area of viable (contrast enhancement in the arterial phase) tumor that is 
> 2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical 
enhancement as a result of the previous intervention, then it cannot be selected as a target 
lesion). 
 
A maximum of 5 target lesions may be selected. 
Nontarget lesion: Other lesions, including small lesions (≤ 2 cm in the axial plane). Note that 
malignant portal vein thrombosis should be considered a nonmeasurable, and therefore 
nontarget, lesion. Lymph nodes at the portal hepatic can be considered as malignant if the 
lymph node short axis is at least 2 cm. Selection of effusion, including ascities, as a nontarget 
lesion is prohibited. Similarly, bone lesions or any other lesion outside the CT or MRI of the 
abdomen or obtained by other modality, may not be selected as nontarget lesions. 
Measurement of lesions: Imaging studies will be by contrast enhanced CT, with use of 
multislice scanners, or contrast enhanced MRI. The same method must be used at baseline and 
during follow up. Note that the longest diameter of the viable tumor is not necessarily located 
in the same scan plane in which the baseline diameter was measured. The measurement of the 
viable tumor diameter should not include any major intervening areas of necrosis. (Please see 
the HGS1012-C1103 Radiographic Data Collection Manual). 
Evaluation of target lesions: 
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. 
AM01 
21Dec10 


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Stable Disease (SD): Any cases that do not qualify for CR, PR or PD. 
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. 
Evaluation of nontarget lesions: 
Complete Response (CR): Disappearance of intratumoral arterial enhancement. 
Incomplete Response/Stable Disease (IR/SD): Persistence of intratumoral arterial 
enhancement in 1 or more nontarget lesions. 
Progressive Disease (PD): Unequivocal progression of existing nontarget lesions.   
Evaluation of new lesions: A newly detected hepatic nodule will be classified as evidence of 
progression when its longest diameter is ≥ 1 cm and the nodule shows the 
hypervascularization in the arterial phase with washout in the portal venous or late venous 
phase.   
Liver lesions ≥ 1 cm that do not show a typical vascular pattern can be diagnosed as HCC by 
evidence of at least a 1 cm-interval growth in subsequent scans.  
An individual radiologic event will be adjudicated in retrospect as progression at the time it 
was 1st detected by imaging techniques, even if strict criteria were fulfilled only on subsequent 
radiologic testing. 
Images by another modality may be obtained, as clinically indicated post-baseline. Sites may 
conclude that post-baseline images based on another modality that indicate disease are 
evidence of radiologic progression if: (1) there was no imaging done at baseline; (2) if there 
was imaging done at baseline showing no disease present at that time; or (3) if there was 
imagine done at baseline indicating that the on-treatment assessment represents unequivocal 
worsening. In these cases the disease will be reported as ‘new lesions’. 
All images obtained on study will be provided the BICR for the independent efficacy read, or 
for confirmation of progression if required or requested. 
Evaluation of Overall Response: The overall response is determined at each assessment and 
is a result of the combined assessment of target lesions, nontarget lesions and new lesions. 


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Overall Response Assessment 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response* 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
*AFP is not included in assessment of overall response. 
 
Best Overall Response: 
The best overall response is the best response recorded from the start of treatment until 
disease progression. To be assigned a best overall response of CR or PR, changes in tumor 
measurements must be confirmed at the next scheduled disease assessment (no fewer than 
4 weeks after the initial documentation of PR or CR). 
 
 
 
 


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Appendix 6 
Exploratory Biomarker Sub-study 
1. Background 
Mapatumumab is a targeted therapy. Presently, the relationship between expression of the 
target, TRAIL-R1, and the anti-tumor activity of the antibody is incompletely understood. 
Studies conducted with cell lines derived from human tumors have suggested that the 
relationship between receptor expression and mapatumumab-induced tumor cell death may be 
complex. However, studies of human tumor cells in vitro and transplanted into animals may 
not accurately reflect the relationship between receptor expression and response to 
mapatumumab that may be observed in patients with cancer. One feature of this biomarker 
study is to compare TRAIL-R1 expression from available biopsy material. This could allow 
for a greater understanding of patterns of TRAIL-R1 expression in advanced hepatocellular 
carcinoma. 
It is also likely that other factors involved in TRAIL-R1 signaling could critically affect 
response to mapatumumab treatment. A 2nd goal of this biomarker study is to evaluate 
biomarkers that may be potential indicators or modifiers of response to mapatumumab. To 
identify factors that may indicate that a patient is responding to treatment, serum-based 
markers will be compared before and after treatment. To explore factors that are associated 
with the outcome of therapy and could be used prior to treatment to predict which patients 
will respond, somatic (inherited) differences that modify a patient’s drug response will be 
examined. 
The information generated from this sub-study will be used solely for research purposes to 
improve future treatment with mapatumumab. It will not be used to change diagnoses or alter 
therapy. Participation in this sub-study is optional. 
2. Study Objectives and Design 
2.1. 
Indicators of Response 
2.1.1. 
Serum-Based Markers of Response 
Induction of cell death in tumor cells can elicit the release of certain biomarkers into the 
serum. These markers can be quantified to evaluate treatment effect. To assess release of 
biomarkers associated with cell death, serum-based assays will be conducted, including, but 
not limited to, assessments of M30, a fragment of cytokeratin 18 that is generated by 
induction of programmed cell death in epithelial tissues. Other examples of markers of tumor 
cell death that will be examined include the cytokines TRAIL, TNFα, soluble Fas ligand, 
interferonα, interferonγ, interleukin-2, interleukin-6, interleukin-8, interleukin-10, and 
interleukin-12. The levels of these factors will be examined before and after treatment to see if 
they correlate with response to treatment. 
Serum will be isolated and the level of cytokines and other markers like M30 will be 
characterized. Collection, processing and handling of these samples are described in the 
laboratory manual. 


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Samples collected in this study will be stored for up to 15 years and may be analyzed with 
samples collected in other studies, but will only be used for mapatumumab-related research. 
2.2. 
Modifiers of Response 
2.2.1. 
Neoplastic Modifiers of Response 
Historically collected tumor biopsy material, if available, will be collected from subjects 
during Cycle 1. Samples will also be obtained from subjects who undergo a biopsy during the 
treatment period. Samples of resected tumor tissue that has been formalin-fixed and embedded 
in paraffin is acceptable; either tissue blocks or slides may be provided. Frozen samples of 
tumor tissue may also be provided. Biopsy material collected from fine needle aspirates may 
be provided; either cell pellets or cytological slides are acceptable. 
Levels of TRAIL receptors will be assessed in biopsy material using immunohistochemical 
techniques if samples are available as formalin-fixed/paraffin-embedded tissue blocks or 
slides. Historically obtained biopsy material or biopsy material obtained during the treatment 
period that is in the form of fresh frozen tissue or cell pellet samples will be utilized to isolate 
RNA for analysis of TRAIL receptor gene expression. 
Similar techniques will be used to evaluate other potential biomarkers and factors that may 
influence mapatumumab response. These may include but are not limited to caspase 8, AKT 
and Mcl-1. 
See the laboratory manual for collection, processing and handling of these samples. 
Samples collected in this study will be stored for up to 15 years and may be analyzed with 
samples collected in other studies, but will only be used for mapatumumab-related research. 
2.2.2. 
Somatic Modifiers of Response 
Inherited differences in the genes that code for drug targets or components of signaling 
pathways related to the target can dramatically influence the effect of pharmacotherapy. 
Variations in genes that could potentially impact mapatumumab’s activity, including 
polymorphic changes in the Fc gamma receptor and interleukin-6 promoter and K-Ras gene 
mutations, will be examined to see if they correlate with response to treatment. 
DNA will be isolated from the blood and polymorphisms and mutations in specific 
response-related genes will be characterized. Collection, processing and handling of these 
samples are described in the laboratory manual. 
Samples collected in this study will be stored for up to 15 years and may be analyzed with 
samples collected in other studies, but will only be used for mapatumumab-related research. 


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3. Statistical Analysis 
Associations will be assessed between candidate biomarkers and treatment outcomes captured 
in the clinical database. Statistical tests to be performed may include Pearson chi-square 
testing, Fisher’s exact test, ANOVA and ANCOVA. Results of the biomarker sub-study may 
be reported independent of the results of HGS1012-C1103. 
4. Subject Selection and Withdrawal 
Subjects enrolled in the HGS1012-C1103 research study are given the option to participate in 
the Biomarkers Sub-study. A subject may withdraw from the sub-study at any time by 
contacting their Study Investigator, who will contact the sponsor. The sponsor will destroy 
any remaining sample materials and will send a letter back to the Investigator confirming 
sample destruction. Any data or analysis generated from the sample prior to the request for 
destruction will not be destroyed. However, no new information will be generated from the 
sample and no new analysis will be performed. 
5. Confidentiality 
Information about sub-study subjects will be kept confidential and managed according to the 
requirements of local privacy regulations. Information obtained from samples will not be 
returned to subjects and will not be placed in the subject’s medical record. 
6. Ethical Considerations 
All subjects enrolled in the HGS1012-C1103 research study who agree to participate in the 
Biomarker Sub-study will be asked to sign a separate Biomarker Informed Consent. Choosing 
to not participate in this sub-study will not affect the subject’s ability to participate in the main 
clinical trial. The Biomarker Informed Consent will be submitted along with the main 
research study informed consent for review by the Institutional Review Board/Ethical 
Committee. 
7. Publication of Biomarker Results 
Any significant findings, based upon the analysis of aggregate data collected from this 
sub-study may be published by Human Genome Sciences. Personal identifiers will not be 
used in any publication resulting from this sub-study. 
 
 


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Appendix 7 
Laboratory Tests 
CBC with Differential 
Chemistry 
Total white blood cell (WBC) count differential: 
Electrolytes: 
 
Neutrophils 
 
Sodium 
 
Bands  
 
Potassium 
 
Lymphocytes  
 
Magnesium 
 
Monocytes 
 
Chloride 
 
Eosinophils 
 
Carbon dioxide/bicarbonate* 
 
Basophils 
 
Calcium 
        
 
 
 
Hemoglobin 
Enzymes: 
Hematocrit 
 
SGOT (AST) 
Red blood cell count 
 
SGPT (ALT) 
Platelet count 
 
Alkaline phosphatase 
Absolute Neutrophil Count 
 
Amylase 
Total white blood cell count 
 
Lipase 
 
 
Gamma glutamyl transferase (GGT) 
Prothrombin time (PT) 
 
Partial thromboplastin time (PTT) 
Other: 
International normalized ratio (INR) 
Creatinine 
 
Blood Urea Nitrogen 
Other: 
Total bilirubin 
Serum and Urine pregnancy 
Total protein 
Hepatitis B surface antigen 
Albumin 
Hepatitis C antibody 
 
B and T lymphocytes 
 
HCV RNA  
 
HBV DNA 
 
HBsAb 
 
*To be collected if included in routine automated serum chemistry panel. 
 
Refer to Section 6 (Study Procedures) for laboratory test collection schedule. 
 


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Appendix 8 
Treatment of Allergic/Hypersensitivity Reactions 
In the event of allergic/hypersensitivity reactions to mapatumumab/placebo, investigators will 
institute treatment measures according to best medical and nursing practice. The grading is 
based upon the NCI-CTCAE Version 4.0.0. 
The following treatment guidelines will be employed: 
• If chills and fever occur, the infusion will be interrupted. Subjects may be treated 
symptomatically and the infusion will be restarted at 50% of the original rate. 
 
Grade 1 allergic/hypersensitivity reaction (transient flushing or rash, drug fever < 38°C): 
• Decrease infusion rate by 50% and monitor for worsening condition. If the reaction 
worsens, stop the infusion. 
 
Grade 2 allergic/hypersensitivity reaction (rash, flushing, urticaria, dyspnea, drug fever 
< 38°C): 
• Stop the infusion. 
• Administer bronchodilators, oxygen, acetaminophen, etc as medically indicated. 
• Resume infusion at 50% of previous rate once reaction has decreased to ≤ Grade 1 in 
severity. Monitor closely for any worsening. If the reaction recurs, stop the infusion. 
 
Re-treatment following Grade 1 or Grade 2 allergic/hypersensitivity reactions: 
• Once the infusion rate has been decreased due to an allergic/hypersensitivity reaction, it 
will remain decreased for all subsequent infusions. 
• If the subject has a 2nd reaction at the lower infusion rate, the infusion will be stopped and 
the subject will receive no further treatment with mapatumumab/placebo. 
• If the subject experiences a Grade 3 or Grade 4 allergic/hypersensitivity reaction at any 
time, the subject will receive no further treatment with mapatumumab/placebo. 
• If there are questions concerning whether an observed reaction is an 
allergic/hypersensitivity of Grades 1-4, the medical monitor will be contacted immediately 
to assist with grading the reaction. 
 
Grade 3 or Grade 4 allergic/hypersensitivity reaction: 
• A Grade 3 hypersensitivity reaction consists of symptomatic bronchospasm requiring 
parenteral medications with or without urticaria, allergy-related edema/angioedema, or 
asymptomatic hypotension not requiring treatment. 
• A Grade 4 hypersensitivity reaction (ie, anaphylaxis) is a life-threatening event 
characterized by the same symptoms as in a Grade 3 reaction but also complicated by 
symptomatic hypotension or oxygen saturation of 90% or less. 
 


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Treatment of Grade 3 or Grade 4 allergic/hypersensitivity reaction: 
• Stop the infusion immediately and disconnect infusion tubing from the subject. 
• Administer epinephrine, bronchodilators, antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, etc, as medically indicated. 
 
Contact Human Genome Sciences to report an SAE and fax SAE worksheet. 
 
 
 
 
 
 


PPD
PPD
PPD
PPD
PPD


 
 
 
CLINICAL PROTOCOL HGS1012-C1103 
Protocol Amendment: 00 
Date: 14 September 2010 
 
 
TITLE OF STUDY: 
 
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 
 
 
 
STUDY SPONSOR: 
Human Genome Sciences, Inc. 
 
14200 Shady Grove Road 
 
Rockville, Maryland 20850 
 
 
 
EudraCT Number: 
2010-020798-17 
 
 
 
 
 
 
Confidentiality 
This document contains proprietary and confidential information of Human Genome Sciences, 
Inc. Acceptance of this document constitutes agreement by the recipient that no unpublished 
information contained herein will be published or disclosed without prior written approval 
from Human Genome Sciences, Inc., except that this document may be disclosed to study 
personnel under your supervision who need to know the contents for conducting the study and 
appropriate Institutional Review Boards and Independent Ethics Committee under the 
condition that they are requested to keep it confidential. The foregoing shall not apply to 
disclosure required by governmental regulations or laws however; Human Genome Sciences, 
Inc. must be promptly informed of any such disclosure. 


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Investigator Agreement 
I will provide copies of the protocol, any subsequent amendments and access to all 
information furnished by the sponsor to study personnel under my supervision. I will discuss 
this material with them to ensure that they are fully informed about the investigational study 
agent and the study protocol. I agree to conduct this clinical trial according to the protocol 
described herein, except when mutually agreed to in writing with the sponsor. I also agree to 
conduct this study in compliance with Good Clinical Practice standards as defined by the 
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice, all 
applicable national, state, and local regulations, as well as the requirements of the appropriate 
Institutional Review Board/Independent Ethics Committee and any other institutional 
requirements. 
 
 
Principal Investigator: 
 
 
 
Signature  
 
 
 
 
 
 
 
Date 
 
 
 
Name (please type or print) 
 
 
 
Institution 
 
 
 
Address 
 
 
 


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Study Synopsis 
Study Number: HGS1012-C1103 
Title of the Study: 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 
Clinical Development Phase: 2 
Objectives: 
Primary: 
• To evaluate the efficacy of mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma. 
 
Secondary: 
• To evaluate the safety of the mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma. 
• To determine serum mapatumumab concentrations. 
 
Diagnosis & Inclusion Criteria: 
Subjects enrolled in the study must meet the following inclusion criteria: 
1. Child-Pugh Class A (see Appendix 1). 
2. Barcelona Clinic Liver Cancer (BCLC) advanced stage (C) hepatocellular carcinoma, or 
BCLC intermediate stage (B) hepatocellular carcinoma if treatment with transarterial 
chemoembolization is not considered appropriate (see Appendix 2). 
3. Measurable disease demonstrating intratumoral arterial enhancement by contrast enhanced 
computerized tomography (CT), with use of multislice scanners, or contrast enhanced 
dynamic magnetic resonance imaging (MRI), with at least 1 tumor lesion that meets the 
following criteria: 
- 
Located in the liver. 
- 
Can be accurately measured in at least 1 dimension. 
- 
Well delineated area of viable, hypervascular (contrast enhancement in the arterial 
phase) tumor that is > 2 cm in the axial plane. 
- 
Suitable for repeat measurement. 
- 
Not previously treated with locoregional or systemic treatment unless the lesion shows 
a well-delineated area of viable (contrast enhancement in the arterial phase) tumor that 
is > 2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical 
enhancement as a result of the previous intervention, then it cannot be selected as a 
target lesion). 


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4. Radiologic eligibility (measurable disease) must be confirmed by the blinded, 
independent, central read (BICR) prior to randomization. 
5. Adequate bone marrow, renal and liver function: 
- 
Absolute neutrophil count ≥ 1.5 x 109 /L or ≥ 1500 /mm3. 
- 
Platelet count ≥ 50 x 109 /L or ≥ 50,000 /mm3. 
- 
Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L) without growth factor support or transfusional 
support. 
- 
Serum creatinine level ≤ 2.0 mg/dL or ≤ 176.8 µmol/L. 
- 
Total bilirubin < 3.0 mg/dL or < 51.3 µmol/L. 
- 
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5.0 x upper limit of 
normal. 
- 
Amylase and lipase ≤ 1.5 x upper limit of normal. 
- 
Serum albumin ≥ 2.5 g/dL or ≥ 25 g/L. 
- 
International normalized ratio ≤ 1.5. 
6. Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) 
Scale (see Appendix 3). 
7. Age 18 years or older. 
8. Have the ability to understand the requirements of the study, provide written informed 
consent (including consent for the use and disclosure of research-related health 
information), and comply with the study and follow-up procedures. 
 
Exclusion Criteria: 
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria: 
1. Any co-morbid condition that in the judgment of the investigator renders the subject at 
high risk of treatment complications or reduces the possibility of assessing clinical effect. 
2. Received prior investigational or non-investigational cytotoxic chemotherapy, hormonal 
therapy, biological therapy (including but not limited to monoclonal antibodies, small 
molecules or other immunotherapy) to treat hepatocellular carcinoma. 
3. Previously received mapatumumab and/or sorafenib. 
4. Underwent resection, radiofrequency ablation, radiation or chemoembolization within 
4 weeks before enrollment or not recovered from such treatments. 
5. Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy, 
immunotherapy, radiofrequency ablation) or other investigational agents during the study 
treatment period. 
6. Major surgery (ie, the opening of a major body cavity, requiring the use of general 
anesthesia) within 4 weeks before enrollment; minor surgery (except for insertion of 
vascular access device) within 2 weeks before enrollment; or not yet recovered from the 
effects of the surgery. 
7. Systemic steroids within 1 week before enrollment except steroids used as part of an 
antiemetic regimen or maintenance-dose steroids for non-cancerous disease. 
8. Hepatic encephalopathy, per the investigator’s evaluation. 


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9. History of clinically significant gastrointestinal bleeding requiring procedural intervention 
(eg, variceal banding, transjugular intrahepatic portosystemic shunt procedure, arterial 
embolization, topical coagulation therapy) within 4 weeks before enrollment. 
10. Gastrointestinal disease resulting in an inability to take oral medication or a requirement 
for intravenous hyperalimentation. 
11. History of any infection requiring hospitalization or intravenous antibiotics within 2 weeks 
before enrollment. 
12. Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) 
with no evidence of progression and neurologically stable off anticonvulsants and steroids. 
13. Known human immunodeficiency virus infection. 
14. Unstable angina, myocardial infarction, cerebrovascular accident, ≥ Class II congestive 
heart failure according to the New York Heart Association Classification for Congestive 
Heart Failure (see Appendix 4) within 6 months before enrollment. 
15. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. 
16. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure 
> 90 mmHg despite optimal medical management). 
17. Using and unable to discontinue use of concomitant strong CYP3A4 inducers 
(eg, including but not limited to St. John’s Wort, dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, phenobarbital). 
18. Pregnant female or nursing mother. All females with an intact uterus (unless amenorrheic 
for the 24 months before enrollment) must have a negative serum pregnancy test at 
screening. All non-sterile or non-postmenopausal females must practice a medically 
accepted method of contraception over the course of the study and for 60 days after the 
last dose of study agent. 
19. Males who do not agree to use effective contraception during the study and for a period of 
60 days following the final dose of study agent. 
20. Subject is currently enrolled in or has not yet completed at least 30 days since ending 
other investigational device or drug study(s) or subject is receiving other investigational 
agents. 
21. Acute or chronic severe renal insufficiency (glomoerular filtration rate 
< 30 mL/min/1.73 m2) or acute renal insufficiency of any severity due to 
the hepato-renal syndrome. 
22. Hepatitis B virus DNA levels > 2,000 IU/mL. 
 
Study Design and Schedule: 
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma. In addition to receiving sorafenib, subjects will be 
randomly assigned to 1 of 2 treatment groups in a 1:1 ratio to receive 30 mg/kg 
mapatumumab or placebo. 
Randomization will be stratified according to BCLC advanced stage C vs BCLC intermediate 
stage B and ECOG performance status (0 vs 1, 2).  
Approximately 100 advanced HCC subjects will be randomized/enrolled.   


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Study Treatment: 
Mapatumumab will be supplied in open label vials and third party unblinding will be 
employed. The study agent will be reconstituted by the unblinded site pharmacist or unblinded 
designee. The unblinded site pharmacist or unblinded designee will also be the person 
responsible for receiving and dispensing study agent but independent of all other study 
activities. All other study personnel, the subject, the Sponsor will remain blinded to the study 
agent received. Separate monitors will be responsible for the clinical (blinded monitor) and 
study agent (unblinded monitor) aspects of the study. 
Subjects will receive treatment every 21 days (ie, a cycle) as outlined below: 
Arm A:  
Sorafenib 400 mg orally twice daily continuously in each cycle + placebo 
intravenously on Day 1 of each cycle. 
Arm B: 
Sorafenib 400 mg orally twice daily continuously + mapatumumab (30 mg/kg) 
intravenously on Day 1 of each cycle. 
Subjects will continue to receive study treatment(s) until radiologic disease progression or 
unacceptable toxicity. Subjects unable to tolerate sorafenib may continue to receive 
mapatumumab/placebo every 21 days until radiographic progression. Subjects unable to 
tolerate mapatumumab/placebo may continue to receive sorafenib until radiographic 
progression. All subjects will have an end of treatment visit at least 30 days after the last dose 
of sorafenib and/or mapatumumab/placebo whichever is later. After discontinuation of 
treatment, subjects will continue to be followed for radiologic disease assessments every 
6 weeks, starting 6 weeks after the previous disease assessment while on treatment, until 
documented radiologic disease progression (if not previously documented) and then every 
3 months thereafter for survival until at least 90% of the subjects have met the survival 
endpoint. 
Disease Assessments: 
Radiologic disease assessments along with assessment of alpha fetoprotein will be performed 
at the end of every two 21-day cycles (ie, Cycles 2, 4, 6 and every 2 cycles thereafter). The 
disease assessment will be performed and documented no earlier than 5 days before the start 
of the next cycle. Clinical responses will be evaluated according to mRECIST for HCC (see 
Section 6.7 and Appendix 5). The same assessment method will be used throughout the study 
for each subject. If disease progression is based only on new lesions or is equivocal, images 
will be provided to the blinded, independent, central reader (BICR) for confirmation of 
disease progression. Partial response (PR) and complete response (CR) will be confirmed at 
the next scheduled disease assessment (no fewer than 4 weeks after the initial documentation 
of PR or CR). All imaging scans used for disease assessments will be made available for 
independent radiology review by the Sponsor or designee. 


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Safety Assessments: 
The safety of sorafenib and mapatumumab will be assessed by evaluation of the type, 
frequency, and severity of adverse events (ie, according to the NCI-CTCAE Version 4.0 
grading) and changes in clinical laboratory tests (hematology and clinical chemistry) and 
immunogenicity over time. In the event that an adverse event does not have an NCI-CTCAE 
Version 4.0 grading, the severity grades in Section 8.6 will be used. Adverse events (including 
serious adverse events) will be captured from the start of study agent administration (sorafenib 
and/or mapatumumab/placebo) through at least 30 days following the last dose of sorafenib 
and/or mapatumumab/placebo, whichever is later. Laboratory assessments will be performed 
at screening, and during each study visit outlined in the study calendar found in Section 6.3. 
The Human Genome Sciences Review Committeee (HGSRC) is comprised of the Department 
Heads of Biostatistics, Regulatory Affairs and Drug Development. The HGSRC will review 
safety data after: (1) 10 subjects have completed 1 cycle; and (2) 30 subjects have completed 
1 cycle. HGSRC reviews of safety data will be conducted approximately every 4 months 
thereafter, until 90% of subjects have reached radiologic progression. The HGSRC may 
conduct additional reviews at their own request and/or at the request of the Medical Monitor. 
The HGSRC may request the unblinding of treatment assignment for a subject and/or 
treatment groups. If treatment assignments are unblinded, the rationale for the unblinding will 
be documented. 
Immunogenicity: 
Blood samples for serum antibodies to mapatumumab will be obtained as outlined in  
Table 6-1. 
Dose Modification/Delay: 
Dose modifications will not be allowed for mapatumumab/placebo. Dose modifications of 
sorafenib for toxicity will be made according to the guidelines provided in the treatment 
section (Section 5.2.3) of the protocol. 
Details regarding pre-treatment and management of hypersensitivity reactions related to 
mapatumumab are provided in Section 5.1.5 and Appendix 8. 
Pharmacokinetics: 
Multiple blood specimens will be obtained from subjects for serum mapatumumab 
concentration determinations as outlined in Table 6-1. 
Pharmacodynamics: 
Subjects will be given the option to participate in a biomarker research sub-study. Consenting 
subjects will be asked to provide a historically obtained biopsy sample, if available, and 
several blood samples. In addition, samples will be requested from subjects who undergo a 
biopsy during the treatment period. 


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To examine biomarkers present peripherally, blood will be drawn during Cycles 1 and 2, from 
which DNA and serum proteins will be isolated. The biomarker sub-study is detailed in 
Appendix 6. 
Exploratory Assessments: 
Blood samples will be collected for quantification of B and T lymphocyte subsets on Day 1 
(prior to dosing) and Day 15 of Cycles 1 and 2. 
Study Endpoints: 
The following will be evaluated (these endpoints and the respective analyses are defined in 
Section 9): 
Primary: 
• Time to progression (TTP). 
 
Secondary: 
• Overall survival. 
• Progression-free survival. 
• Objective response (complete response [CR] + partial response [PR]). 
• Disease control (CR + PR + stable disease [SD]). 
• Response duration and time to response in responders. 
• Frequency and severity of treatment-emergent adverse events. 
• Laboratory parameters. 
• Serum mapatumumab concentrations for use in a population pharmacokinetic analysis. 
 
Statistical Methods: 
Sample Size: 
A total of approximately 100 subjects will be randomly assigned to 1 of 2 arms and treated 
with either sorafenib + placebo or the 2-agent combination of sorafenib and mapatumumab at 
30 mg/kg in a 1:1 ratio. A sample size of 50 subjects randomized and treated in each group is 
sufficient to estimate the median time to progression with a precision of approximately -1.9 M 
to +2.6 M relative to the observed median. In addition, a sample size of 50 patients per arm 
will provide 80% power to detect an improvement in TTP from 5.5 to 8.9 M with at a 
one-sided significance level of 0.10. 
Statistical Analysis: 
The primary analysis will be an estimate of median time to progression in each arm 
using Kaplan Meier methods, reported with 95% confidence intervals, along with logrank 
testing for a difference between treatment groups controlling for factors stratifying the 


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randomization. Secondary analyses include estimates, using Kaplan Meier methods, of 
median progression-free survival (PFS) and median overall survival (OS) along with 
associated logrank testing. In addition, estimates of overall response rate (CR+PR) and 
disease control rate (CR+PR+SD) will be reported with 95% confidence intervals and an 
estimate of the difference in response rates and disease control rates between groups will be 
reported and tested for significance with a Pearson chi-square test (or Fisher’s exact test). For 
frequency and severity of adverse events and laboratory toxicity grading, counts and rates will 
be presented. 
Study Calendar: 
The study calendar is located in Section 6.3 of the protocol. 
 
 


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Table of Contents 
Study Synopsis ........................................................................................................................... 3 
Table of Contents...................................................................................................................... 10 
List of Tables............................................................................................................................ 13 
List of Abbreviations................................................................................................................ 14 
1 Background......................................................................................................................... 16 
1.1 
Hepatocellular Carcinoma........................................................................................ 16 
1.2 
Treatment Options for Patients with Hepatocellular Carcinoma.............................. 16 
1.3 
The Role of the TRAIL Pathway in HCC ................................................................ 16 
1.3.1 TRAIL and TRAIL Receptors...................................................................... 16 
1.3.2 TRAIL and HBV/HCV Infection ................................................................. 17 
1.4 
Mapatumumab.......................................................................................................... 17 
1.4.1 Mapatumumab Pharmacology...................................................................... 17 
1.4.2 Non-Clinical Mapatumumab Safety Studies................................................ 18 
1.4.3 Clinical Experience with Mapatumumab ..................................................... 19 
1.5 
Rationale for the Evaluation of Mapatumumab in Combination with Sorafenib 
in Hepatocellular Carcinoma.................................................................................... 20 
1.6 
Rationale for Dose Selection.................................................................................... 21 
2 Study Objectives................................................................................................................. 22 
2.1 
Primary Objective..................................................................................................... 22 
2.2 
Secondary Objective................................................................................................. 22 
3 Study Design....................................................................................................................... 22 
3.1 
Basic Design Characteristics .................................................................................... 22 
4 Inclusion and Exclusion Criteria ........................................................................................ 23 
4.1 
Inclusion Criteria...................................................................................................... 23 
4.2 
Exclusion Criteria..................................................................................................... 24 
5 Study Treatment Regimen.................................................................................................. 26 
5.1 
Mapatumumab and Placebo...................................................................................... 26 
5.1.1 Formulation .................................................................................................. 26 
5.1.2 Packaging, Labeling, Preparation, and Storage............................................ 26 
5.1.3 Mapatumumab/Placebo Dose, Route of Administration and Schedule ....... 26 
5.1.4 Mapatumumab/Placebo Dose Toxicity/Delay.............................................. 27 
5.1.5 Management of Allergic/Hypersensitivity Reactions to 
Mapatumumab/Placebo ................................................................................ 28 
5.2 
Sorafenib................................................................................................................... 28 
5.2.1 Packaging, Labeling, Preparation, and Storage............................................ 28 
5.2.2 Anticipated Toxicities with Sorafenib.......................................................... 28 
5.2.3 Alteration of Sorafenib Dose/Schedule Due to Toxicity.............................. 29 


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5.3 
Concurrent Medications and Therapies.................................................................... 32 
5.3.1 Allowable Regimens..................................................................................... 32 
5.3.2 Prohibited Medications................................................................................. 32 
5.3.3 Prohibited Therapies..................................................................................... 32 
6 Study Procedures................................................................................................................ 32 
6.1 
Screening Procedures ............................................................................................... 32 
6.2 
Study Enrollment/Randomization Procedures.......................................................... 33 
6.3 
On-treatment Study Procedures................................................................................ 34 
6.4 
Follow-up Procedures............................................................................................... 37 
6.4.1 Safety Follow-up .......................................................................................... 37 
6.4.2 Long-term Follow-up ................................................................................... 37 
6.5 
Withdrawal of Subjects from Treatment .................................................................. 37 
6.6 
Withdrawal of Subjects from Study ......................................................................... 37 
6.7 
Disease Response Assessments................................................................................ 38 
7 Pharmacokinetic, Immunogenicity, Pharmacodynamic and Exploratory Assessments..... 39 
7.1 
Pharmacokinetic Assessments.................................................................................. 39 
7.2 
Immunogenicity........................................................................................................ 39 
7.3 
Pharmacodynamic Assessments............................................................................... 39 
7.4 
Exploratory Assessments (B and T Lymphocyte Subsets)....................................... 39 
7.4.1 Rationale for B and T Lymphocyte Analysis............................................... 39 
7.4.2 Collection of Samples for B and T Lymphocyte Analysis........................... 40 
8 Adverse Event Reporting.................................................................................................... 40 
8.1 
Definitions ................................................................................................................ 40 
8.2 
Reporting Adverse Events to the Sponsor or Designee............................................ 40 
8.3 
Laboratory Abnormalities as Adverse Events.......................................................... 41 
8.4 
Other Events Requiring Rapid Reporting................................................................. 41 
8.5 
Reporting a Pregnancy.............................................................................................. 42 
8.6 
Investigator Evaluation of Adverse Events .............................................................. 42 
8.7 
Follow-up of Adverse Events................................................................................... 43 
8.8 
Serious Adverse Events Assessed During Long-Term Follow-up........................... 43 
8.9 
Reporting Serious Adverse Events to the Institutional Review Board/Ethics 
Committee ................................................................................................................ 44 
9 Endpoints and Statistical Analysis ..................................................................................... 44 
9.1 
General Statistical Considerations............................................................................ 44 
9.2 
Sample Size Rationale.............................................................................................. 44 
9.3 
Efficacy..................................................................................................................... 44 
9.3.1 Primary Efficacy Endpoint........................................................................... 44 
9.3.2 Primary Efficacy Analysis............................................................................ 44 


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9.3.3 Secondary Efficacy Endpoints...................................................................... 45 
9.3.4 Secondary Efficacy Analyses....................................................................... 45 
9.4 
Safety........................................................................................................................ 45 
9.4.1 Definition of Safety Variables...................................................................... 45 
9.4.2 Human Genome Sciences Safety Review Committee.................................. 46 
9.4.3 Analysis of Safety Variables ........................................................................ 46 
9.5 
Pharmacokinetics...................................................................................................... 46 
9.5.1 Definition of Pharmacokinetic Evaluation ................................................... 46 
9.5.2 Analysis of Pharmacokinetics ...................................................................... 46 
9.6 
Pharmacodynamics................................................................................................... 46 
10 Study Administration.......................................................................................................... 46 
10.1 Informed Consent ..................................................................................................... 46 
10.2 Institutional Review Board Review/Independent Ethics Committee Review and 
Approval................................................................................................................... 47 
10.3 Protocol Compliance ................................................................................................ 47 
10.4 Protocol Revisions.................................................................................................... 47 
10.5 Data Collection and Management ............................................................................ 47 
10.6 Study Monitoring...................................................................................................... 48 
10.7 Drug Accountability ................................................................................................. 48 
10.8 Retention of Records ................................................................................................ 49 
10.9 Financial Disclosure ................................................................................................. 49 
10.10 Publication Policy..................................................................................................... 49 
10.11 Study or Study Site Termination .............................................................................. 50 
11 References .......................................................................................................................... 51 
List of Appendices.................................................................................................................... 58 
 
 


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List of Tables 
Table 5-1 
Sorafenib dose levels........................................................................................ 29 
Table 5-2 
Dose modifications of sorafenib for skin toxicity ............................................ 30 
Table 5-3 
Dose modifications of sorafenib for hypertension ........................................... 30 
Table 5-4 
Dose modifications of sorafenib for sorafenib-associated toxicity .................. 31 
Table 6-1 
Study calendar .................................................................................................. 34 
 
 
 


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List of Abbreviations 
AE 
adverse event 
AFP 
α - fetoprotein 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
BCLC 
Barcelona Clinic Liver Cancer 
BICR 
blinded independent central read 
CR 
complete response 
CT 
computerized tomography 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
Fc 
heavy chain constant region or fragment of antibody 
GGT 
gamma-glutamyl transpeptidase 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HGS 
Human Genome Sciences 
HGSRC 
Human Genome Sciences Review Committee 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IR 
incomplete response 
IRB 
Institutional Review Board 
kg 
kilogram 
mg 
milligram 
mL 
milliliter 
mm 
millimeter 
mmHg 
millimeters of mercury 
mRECIST 
modified RECIST assessment for HCC 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
ng 
nanogram 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
OS 
overall survival 
PD 
progressive disease 
PK 
pharmacokinetics 
PPT 
partial thromboplastin time 
PR 
partial response 
PS  
performance status 
PT 
prothrombin time 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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RNA 
ribonucleic acid 
SAE 
serious adverse event 
SD 
stable disease 
TNF 
tumor necrosis factor 
TRAIL 
tumor necrosis factor-related apoptosis-inducing ligand 
TRAIL-R1 
TRAIL receptor 1 
TRAIL-R2 
TRAIL receptor 2 
TTP 
time to progression 
 
 
 
 
 


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1 Background 
1.1 
Hepatocellular Carcinoma 
Hepatocellular carcinoma is the 5th most common cancer worldwide accounting for 2% of all 
malignancies. It is the 3rd leading cause of cancer-related death globally with 1 million new 
cases a year (WHO, 2007; IACR, 2002; Ferlay et al, 2004; Lopez et al, 2006). 
Hepatocellular carcinoma is more prevalent in males with a male:female ratio as high as 8:1. 
Depending on the endemic risk factors, hepatocellular carcinoma is diagnosed during the 
4th through 6th decades of life. The reported incidence of  hepatocellular carcinoma is 
increasing because of a better ability to diagnose the disease and because of the long-term 
consequences of hepatitis C virus (HCV) and hepatitis B virus (HBV) infection (Reis et al, 
2006). Worldwide the most common cause of hepatocellular carcinoma is chronic HBV 
infection (El-Serag et al, 2003). Endemic areas thus include China, South Asia and 
South Africa where the incidence of hepatocellular carcinoma can be as high as 120 cases 
per 100,000. In the United States, where HCV and alcohol are the main risk factors, 
the age-adjusted incidence rates have increased from 1.4 cases per 100,000 in 1980 to a 
current incidence of 4 cases per 100,000. This equates to about 8500-11,000 new cases 
diagnosed each year (IACR, 2002; Ferlay et al, 2004; Pawlik et al, 2004; Edwards, et al, 2005; 
Jemal et al, 2007; Bosch et al, 2004). 
1.2 
Treatment Options for Patients with Hepatocellular Carcinoma 
Surgery, including transplantation, is the only curative modality for hepatocellular carcinoma 
(Venook, 1994; Cha et al, 2003). The 5-year survival rate for patients with unresectable 
hepatocellular carcinoma is 11% in the US (ACS, 2007), < 8% in Europe (Capocaccia et al, 
2007), and < 10% in Asia (Teo and Fock, 2001). Symptomatic hepatocellular carcinoma has a 
very poor prognosis with a median survival of 1–8 months (Former et al, 2006; Llovet et al, 
1999a, b). 
Sorafenib, a multikinase inhibitor, is the 1st systemic therapy to significantly impact survival 
in patients with advanced hepatocellular carcinoma, as demonstrated in an international, 
multicenter Phase 3, placebo-controlled trial (Llovet et al, 2007). Sorafenib was approved in 
the United States and European Union for the 1st-line treatment of advanced hepatocellular 
carcinoma in late 2007 and the 2008 National Comprehensive Cancer Network guidelines 
have been updated with the addition of sorafenib as a treatment option for hepatocellular 
carcinoma patients. The updated Barcelona Clinic Liver Cancer (BCLC) guidelines 
recommend sorafenib for hepatocellular carcinoma patients with BCLC Advanced Stage (C) 
(Forner et al, 2010). 
1.3 
The Role of the TRAIL Pathway in HCC 
1.3.1 
TRAIL and TRAIL Receptors 
TRAIL is a member of the tumor necrosis factor (TNF) ligand superfamily, with homology 
to Fas/Apo1 ligand (Pitti et al, 1996; Wiley et al, 1995). TRAIL induces programmed 
cell death primarily in tumor cells through activation of TRAIL death receptors, TRAIL-R1 
(death receptor 4) or TRAIL-R2 (death receptor 5) (Ashkenazi et al, 1999; Evdokiou et al, 


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2002; Kothny-Wilkes et al, 1998; Lawrence et al, 2001; Pitti et al, 1996; Walczak et al, 1999; 
Wiley et al, 1995). 
TRAIL-R1, the target of mapatumumab, is detectable on tumor cells derived from colon, lung, 
liver, gastric, pancreas, uterus and esophagus and in tissue sections from various tumors of the 
colon, lung, pancreas, liver and stomach without significant expression in parallel normal 
tissues (Halpern et al, 2004; Roach et al, 2004). 
1.3.2 
TRAIL and HBV/HCV Infection 
Acutely infected tissues, including the liver, utilize the TRAIL pathway to eliminate virally 
and bacterially infected cells (Herr et al, 2007). In viral hepatitis, TRAIL and 1 of its 
receptors, TRAIL-R2, are upregulated and contribute to the elimination of infected 
hepatocytes associated with viral hepatitis (Bantel and Schulze-Osthoff, 2003; Lin et al, 2002; 
Matsuda et al, 2005). In addition to HBV and HCV infection, steatosis, exposure to bile acids 
and chronic alcohol exposure induce increased expression of TRAIL and TRAIL-R2, but not 
TRAIL-R1, in human hepatocytes (Dunn et al, 2007; Mundt et al, 2005). Cell surface 
expression of TRAIL-R2, but not TRAIL-R1, was altered and responsible for sensitization to 
TRAIL in hepatocytes exposed to bile acids (Higuchi et al, 2001; Malhi et al, 2007). These 
findings have been reproduced in preclinical models. Non-virally infected hepatocytes are 
refractory to TRAIL and TRAIL-R agonists but exposure of HCV-infected hepatocytes to 
TRAIL leads to a significant level of apoptosis (Volkmann et al, 2007). Inhibition of the 
TRAIL pathway may protect infected cells from apoptosis and allow for chronic infection 
(Mundt et al, 2003). Recent non-clinical observations demonstrated that natural killer cells 
expressing the ligand TRAIL, are enriched in the livers of patients with chronic HBV 
infection, and TRAIL is overexpressed in the livers of patients with HCV-associated steatosis 
(Mundt et al, 2005).  
In summary, preclinical data suggest that mapatumumab may promote apoptosis of cancer 
cells, including hepatocellular carcinoma cells. Whether viral infection, including HBV or 
HCV infection, will attenuate or modulate the effects of mapatumumab on hepatocytes is not 
yet known, but experience to date in a Phase 1b trial of mapatumumab in combination with 
sorafenib in subjects with advanced hepatocellular carcinoma who are positive for hepatitis B 
surface antigen or hepatitis C antibody indicates that the safety experience is consistent with 
underlying disease and known sorafenib toxicities (see Section 1.2). 
1.4 
Mapatumumab 
1.4.1 
Mapatumumab Pharmacology 
Mapatumumab is a fully human, agonist monoclonal antibody that activates the cell death 
pathway in tumor cells by specifically binding to TRAIL-R1 with high affinity. 
Mapatumumab efficiently induces apoptosis in human cancer cell lines expressing the 
TRAIL-R1 protein on the cell surface. Nonclinical studies have demonstrated that 
mapatumumab can induce cytotoxicity in multiple tumor cell lines representing both solid and 
hematological malignancies, including cancers of the biliary tract, colon, lung, breast, 
pancreas, esophagus, ovary, kidney, uterus, as well as lymphoma and various leukemias. 
Mapatumumab has also demonstrated anti-tumor activity as a single agent, preventing 


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tumor growth and in some cases causing regression of tumors in xenograft tumor models of 
multiple human malignancies, including lung, colon, kidney, and uterus (Camidge, 2007; 
Georgakis et al, 2005; Jin et al, 2007; Humphreys, 2004; Marini et al, 2006; Menoret et al, 
2006; Pukac et al, 2005). 
The relationship between receptor expression and response to therapy with mapatumumab 
remains unclear. In vitro studies of cell lines have shown that TRAIL-R1 expression level is 
not a consistent predictor of response to mapatumumab. Although both TRAIL-R1 expression 
and apoptosis in response to mapatumumab are increased in many tumor cell lines as 
compared with normal diploid cells, there are examples of mapatumumab cytotoxicity on cell 
lines with very low levels of detectable receptor, and conversely, mapatumumab resistant cell 
lines that have relatively high levels of TRAIL-R1 cell surface expression. 
Tumor cell cytotoxic activity can be enhanced when mapatumumab is administered in 
combination with chemotherapeutics or other anti-neoplastic agents. Enhanced apoptotic 
signaling, in vitro cell killing and in vivo anti-tumor activity have been observed when 
mapatumumab has been combined with various types of therapeutic agents and treatments 
including microtubule poisons, anti metabolites, topoisomerase inhibitors, proteosome 
inhibitors, platinum agents and radiation. Both the level and spectrum of activity of 
mapatumumab is enhanced in in vitro cytotoxicity and in vivo xenograft studies in 
combination with various chemotherapeutic and anti-neoplastic agents, including a xenograft 
model of hepatocellular carcinoma in combination with cisplatin and gemcitabine 
(Camidge, 2007; Pukac et al, 2005; Georgakis et al, 2005; Humphreys, 2004; Jin et al, 2007; 
Human Genome Sciences data on file). 
Please refer to the mapatumumab Investigator’s Brochure for detailed information regarding 
the nonclinical pharmacology, toxicology, and PK of mapatumumab. 
1.4.2 
Non-Clinical Mapatumumab Safety Studies 
To assess the nonclinical safety of mapatumumab, a 6-month toxicity study, with a 4-month 
recovery period, was conducted in chimpanzees. Mapatumumab was administered 
intravenously at up to 40 mg/kg every 10 days. No mapatumumab-specific toxicity was 
identified and no anti-mapatumumab antibodies were detected. 
To assess its off-target effects, mapatumumab was administered intravenously weekly to 
cynomolgus monkeys, whose TRAIL R1 homolog does not bind mapatumumab. 
Mapatumumab was well tolerated at doses of up to 50 mg/kg and was not highly 
immunogenic: of the 40 monkeys treated, 1 developed anti-mapatumumab antibodies. The 
positive response was observed in an animal in the high dose (50 mg/kg) group. 
In vitro, mapatumumab was found to decrease viability of normal human hepatocytes, 
although the observed effect was less than that observed with TRAIL. This effect was variable 
across donors and did not amplify with increasing concentrations of mapatumumab. It should 
be noted that in clinical studies, plasma mapatumumab concentrations have been achieved that 
are > 1100–fold greater than the minimum exposure resulting in reduced in vitro hepatocyte 
viability. Despite this, the clinical results do not reveal evidence of hepatotoxicity in those 


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studies. Hence it appears that the in vitro hepatocyte viability assay is not predictive of 
mapatumumab effects in vivo. 
1.4.3 
Clinical Experience with Mapatumumab 
Over 400 subjects have received mapatumumab in clinical trials to date. Preliminary clinical 
data are available from 218 subjects who received mapatumumab as a single agent at doses 
ranging from 0.01 to 20 mg/kg across 6 clinical trials. 
Based on available data, mapatumumab appears to be well tolerated and no significant safety 
issues have been observed. Adverse events have generally been mild to moderate in severity, 
manageable, and do not appear related to dose. The most frequently reported treatment-related 
adverse events occurring in > 10% of subjects were fatigue, hypotension, nausea and pyrexia. 
Severe events have been uncommon and generally judged not related to mapatumumab. 
Severe events judged at least possibly related to mapatumumab have been observed and a 
complete list can be found in the mapatumumab Investigator’s Brochure. Grade 3 or Grade 4 
hematologic, renal, or hepatic laboratory abnormalities also have been relatively uncommon 
with no significant trend or dose-response evident. Lymphopenia was the most commonly 
observed laboratory abnormality, but tended to be intermittent and reversible and was not 
associated with infectious events. 
In subjects with solid tumors, stable disease has been the best response observed with 
mapatumumab as a single-agent. However, 2 complete responses (CRs) and 1 partial response 
(PR) were observed in subjects with follicular lymphoma. 
In addition, preliminary clinical data are available from 234 subjects who received 
mapatumumab at doses ranging from 1 to 30 mg/kg every 21 days in combination with 
chemotherapy in 5 clinical trials (carboplatin/paclitaxel [N = 100], gemcitabine/cisplatin 
[N = 49], bortezomib [n = 69], or sorafenib [n = 16]. Mapatumumab has been generally well 
tolerated; adverse events and laboratory abnormalities have been consistent with those 
expected with underlying disease or chemotherapy. A listing of severe events considered at 
least possibly related to mapatumumab can be found in the mapatumumab Investigator’s 
Brochure. The most commonly occurring laboratory abnormalities have been hematologic 
(ie, anemia, neutropenia, thrombocytopenia, and leukopenia), as expected with chemotherapy. 
Grade 3/4 laboratory abnormalities have been relatively uncommon. Higher frequencies of 
Grade 3/4 neutropenia, leukopenia, lymphopenia, and thrombocytopenia have been observed. 
Data from randomized Phase 2 studies in combination with chemotherapy suggest that 
mapatumumab may increase rates of lymphopenia. 
One subject receiving mapatumumab in combination with carboplatin/paclitaxel has 
achieved a CR. Twenty-two subjects receiving mapatumumab in combination with 
paclitaxel/carboplatin and 12 subjects receiving mapatumumab in combination with 
gemcitabine/cisplatin have achieved PRs. Three subjects receiving mapatumumab in 
combination with bortezomib achieved CRs; 25 subjects receiving mapatumumab in 
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1.5 
Rationale for the Evaluation of Mapatumumab in Combination with 
Sorafenib in Hepatocellular Carcinoma 
Sorafenib is the standard of care for treatment of patients with advanced hepatocellular 
carcinoma. Sorafenib is a multikinase inhibitor that targets the Raf/mitogen-activated protein 
kinase/extracellular signal-regulated kinase signaling pathway, blocks tumor angiogenesis and 
induces apoptosis (Panka et al, 2006; Rahmani et al, 205; Yu et al, 2005; Wilhelm et al, 
2004). Sorafenib was approved by the European Medicines Agency and the Food and Drug 
Administration in 2007 for treatment of patients with hepatocellular carcinoma based on the 
demonstration of improved overall survival in the 602 patient randomized, placebo-controlled, 
Phase 3 “Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol” (SHARP) 
trial. Approximately half the 602 patients had either hepatitis C virus or hepatitis B virus as 
underlying etiology and 26% had alcohol-related cirrhosis. The median overall survival was 
10.7 months for patients in the sorafenib arm compared with 7.0 months for patients in the 
placebo arm (hazard ratio in the sorafenib group, 0.69 95% confidence interval, 0.55 to 0.87; 
p < 0.001). The median time to radiologic progression was 5.5 months in the sorafenib arm, 
compared with 2.8 months in the placebo arm (p < 0.0001) (Llovet et al, 2008). Seven patients 
in the sorafenib group (2%) and 2 patients in the placebo group (1%) had a PR; no patients 
had a CR. 
A 2nd randomized, placebo-controlled Phase 3 trial was conducted in the Asia-Pacific region 
(Cheng et al, 2009). The 226 patients randomly assigned to sorafenib or placebo in this trial 
appeared to have more advanced disease than those in the SHARP trial, with a higher 
frequency of extrahepatic spread, poorer ECOG PS, and higher levels of AFP, but still showed 
a benefit from treatment with sorafenib. The majority (73%) had hepatitis B virus as an 
underlying etiology. The median overall survival was 6.5 months for patients in the sorafenib 
arm, compared with 4.2 months in the placebo group (hazard ratio, 0.68, 95% confidence 
interval, 0.50-0.93; p = 0.014). The median time to progression was 2.8 months in the 
sorafenib group, compared with 1.4 months in the placebo group (hazard ratio, 0.57, 95% 
confidence interval 0.42-0.79; p = 0.0005). 
The mechanisms of sorafenib and mapatumumab action suggest that these agents could 
interact synergistically. Sorafenib sensitizes human cancer cell lines, including cell lines 
derived from hepatocellular carcinoma, to apoptotic stimuli by reducing expression of 
apoptotic regulatory proteins; Mcl-1, Bcl-xL, and FLIP (Kim et al,2008; Koehler et al, 2009; 
Rosato et al, 2007; Liu et al, 2006; Rahmani et al, 2005; Yu et al, 2005). Mcl-1, Bcl-xL 
and FLIP have also been shown to mediate sensitivity of a wide range of tumor cell lines 
to TRAIL receptor agonists (Meng et al, 2007; Rosato et al, 2007; Llobet et al 2010; 
Blechacz et al, 2009; Katz et al, 2009; Huang and Sincrope, 2010; and Menoret et al, 2006). 
Recent studies demonstrated the combination of sorafenib with TRAIL or TRAIL receptor 
antibodies has significant activity in hepatocellular carcinoma cell lines (Koehler et al, 2009) 
and colon tumor xenografts (Ricci et al, 2007) that were resistant to TRAIL and an antibody 
against TRAIL-R2. 
Mapatumumab activity has been evaluated preclinically in hepatocellular carcinoma cell lines 
by in vitro cytotoxicity assays both as a single agent and in combination with doxorubicin, 
cisplatin, gemcitabine or sorafenib. Single agent mapatumumab activity was observed in 4 of 


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10 hepatocellular carcinoma cell lines. Increased in vitro cytotoxicity, including examples of 
synergy, were observed in 8 of 10 cell lines when mapatumumab was combined with 
doxorubicin or cisplatin or the combination of cisplatin and gemcitabine (Humphreys et al, 
2008). Two of these hepatocellular carcinoma cell lines were evaluated for in vitro 
cytotoxicity of mapatumumab in combination with sorafenib. One displayed an increase in 
cytotoxicity from 30% to 60% when treated with a combination of sorafenib and 
mapatumumab. Importantly, treatment of a primary human hepatocyte cell line did not induce 
any apoptosis at doses of mapatumumab that were cytotoxic to hepatocellular carcinoma cell 
lines (
 and 
 [personal communication], 2008; Abdulghani et al, 2008). 
Therefore, collectively, the expression of TRAIL-R1 in hepatocellular carcinoma and 
preclinical activity observed with combinations of mapatumumab with chemotherapy or 
sorafenib supports the rationale that this combination may be able to effectively target 
hepatocellular carcinoma. 
1.6 
Rationale for Dose Selection 
As 
of 
June 
2010, 
mapatumumab 
has 
been 
administered 
with 
chemotherapy 
(ie, carboplatin/paclitaxel, gemcitabine/cisplatin, bortezomib, or sorafenib) to 234 subjects, 
including 61 subjects who received 20 mg/kg and 50 subjects who received 30 mg/kg 
mapatumumab. Based on available data, mapatumumab in combination with chemotherapy is 
generally well tolerated at dose levels up to and including 30 mg/kg, and no significant safety 
issues have been observed in the course of the clinical trials even at the higher doses.   
Preliminary PK data are available for subjects who received 1, 10, 20 or 30 mg/kg 
mapatumumab in combination with gemcitabine and cisplatin (n = 49), 10 or 30 mg/kg 
mapatumumab in combination with paclitaxel and carboplatin (n = 73), and 3, 10, or 
30 mg/kg mapatumumab in combination with sorafenib (n = 17). Serum or plasma 
mapatumumab concentrations are consistently within the range of expected concentrations 
predicted from Phase 1 study results in solid tumor patients administered mapatumumab as 
monotherapy. Mapatumumab PK is linear and not affected by the addition of therapeutic 
agents. As expected, the observed peak and trough levels of mapatumumab at 30 mg/kg are 
2 to 3 times higher than those observed at 10 mg/kg. Exposure appears to increase in 
proportion to dose and exposures for a given dose are similar across studies.  
A Phase 1b dose escalation study of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma who are positive for hepatitis B surface antigen or 
hepatitis C antibody is being conducted. Safety observations have been consistent with the 
underlying disease and known sorafenib toxicities. As of June 2010, 6 subjects have received 
3 mg/kg, 9 subjects have received 10 mg/kg, and 1 subject has received 30 mg/kg 
mapatumumab. The number of cycles completed ranges from 1 to 20; 4/16 (25.0%) of 
subjects have completed 11 or more cycles. Adverse events have generally been consistent 
with published reports of the toxicities associated with sorafenib and previous experience 
with mapatumumab, as well as underlying disease. The most frequently occurring 
treatment-emergent adverse events, regardless of severity or attribution of causality, 
include diarrhea (10/16, 62.5%), fatigue (9/16, 56.3%), nausea (9/16, 56.3%), and vomiting 
(7/16, 43.8%). Serious adverse events, regardless of attribution of causality, include 
hypertension, upper respiratory tract infection, atrial fibrillation, hyperbilirubinemia, 
PPD
PPD


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hypoglycemia, and hepatic pain. Severe adverse events considered at least possibly related to 
mapatumumab or its interaction with sorafenib include elevated lipase (3/16, 18.8%), hepatic 
pain (1/16, 6.3%), and thrombocytopenia (1/16, 6.3%). Laboratory abnormalities have 
generally been mild or moderate in severity, manageable, and/or consistent with those 
expected with chemotherapy or the underlying disease. The most frequent Grade 3 or Grade 4 
laboratory abnormalities include elevated total bilirubin (Grade 3, 4/16, 25.0%; Grade 4, 
1/16, 6.3%) and lymphopenia (Grade 3, 3/16, 18.8%; Grade 4, 2/16, 12.5%). Additional 
information on the safety experience can be found in the mapatumumab Investigators’ 
Brochure. 
Based on the information currently available, the safety profile continues to be favorable, 
supporting continued evaluation of mapatumumab in combination with chemotherapy, 
including sorafenib. The maximum tolerated dose has not been reached in any of the Phase 1 
or Phase 2 trials conducted to date. Thus, further evaluation of the 30 mg/kg dose is 
warranted. 
The dose of sorafenib for this study, 400 mg twice daily, is the approved dose for the 
treatment of unresectable hepatocellular carcinoma. 
2 Study Objectives 
2.1 
Primary Objective 
• To evaluate the efficacy of mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma. 
 
2.2 
Secondary Objective 
• To evaluate the safety of the mapatumumab in combination with sorafenib in subjects with 
advanced hepatocellular carcinoma. 
• To determine serum mapatumumab concentrations. 
 
3 Study Design 
3.1 
Basic Design Characteristics 
This is a Phase 2, multi-center, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma.   
In addition to receiving sorafenib, subjects will be randomly assigned to 1 of 2 treatment 
groups in a 1:1 ratio: 30 mg/kg mapatumumab or placebo. 
Mapatumumab will be supplied in open label vials and third party unblinding will be 
employed. The study agent will be reconstituted by the unblinded site pharmacist or unblinded 
designee. The unblinded site pharmacist or unblinded designee will also be the person 
responsible for receiving and dispensing study agent, but independent of all other study 
activities. All other study site personnel, the subject, and the Sponsor will remain blinded to 


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the study agent received. Separate monitors will be responsible for the clinical (blinded 
monitor) and study agent (unblinded monitor) aspects of the study. 
Number of Subjects: 
Approximately 100 subjects with advanced HCC will be randomized/enrolled. 
Treatment Groups: 
Subjects will receive treatment every 21 days (ie, a cycle) as outlined below: 
Arm A: 
Sorafenib 400 mg orally twice daily continuously in each cycle + placebo 
intravenously on Day 1 of each cycle 
Arm B:  
Sorafenib 400 mg orally twice daily continuously in each cycle + mapatumumab 
(30 mg/kg) intravenously on Day 1 of each cycle 
Randomization 
Randomization will be stratified according to BCLC advanced stage C vs BCLC intermediate 
stage B and ECOG performance status (0 vs 1, 2). 
Estimated Study Duration: 
The study is estimated to occur over approximately 24 months. Subjects will continue to 
receive sorafenib with or without mapatumumab/placebo until radiologic disease progression 
or unacceptable toxicity. Estimated median length of subject treatment is 6-8 months. All 
subjects will have an End of Treatment visit at least 30 days after the last dose of sorafenib 
and/or mapatumumab/placebo, whichever is later. After discontinuation of treatment, subjects 
will continue to be followed for radiologic disease assessments every 6 weeks (± 3 days), 
starting 6 weeks after the previous disease assessment while on treatment, until documented 
radiologic disease progression (if not previously documented). Thereafter, subjects will be 
followed every 3 months for survival until at least 90% of subjects have met the survival 
endpoint. 
4 Inclusion and Exclusion Criteria 
4.1 
Inclusion Criteria 
Subjects enrolled in the study must meet the following inclusion criteria: 
1. Child-Pugh Class A (see Appendix 1). 
2. Barcelona Clinic Liver Cancer (BCLC) advanced stage (C) hepatocellular carcinoma, or 
BCLC intermediate stage (B) hepatocellular carcinoma if treatment with transarterial 
chemoembolization is not considered appropriate (see Appendix 2). 
3. Measurable disease demonstrating intratumoral arterial enhancement by contrast enhanced 
computerized tomography (CT), with use of multislice scanners, or contrast enhanced 


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dynamic magnetic resonance imaging (MRI), with at least 1 tumor lesion that meets the 
following criteria: 
- 
Located in the liver. 
- 
Can be accurately measured in at least 1 dimension. 
- 
Well delineated area of viable, hypervascular (contrast enhancement in the arterial 
phase) tumor that is > 2 cm in the axial plane. 
- 
Suitable for repeat measurement. 
- 
Not previously treated with locoregional or systemic treatment unless the lesion shows 
a well-delineated area of viable (contrast enhancement in the arterial phase) tumor that 
is > 2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical 
enhancement as a result of the previous intervention, then it cannot be selected as a 
target lesion). 
4. Radiologic eligibility (measurable disease) must be must be confirmed by the BICR prior 
to randomization. 
5. Adequate bone marrow, renal and liver function: 
- 
Absolute neutrophil count ≥ 1.5 x 109 /L or ≥ 1500 /mm3. 
- 
Platelet count ≥ 50 x 109 /L or ≥ 50,000 /mm3. 
- 
Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L) without growth factor support or transfusional 
support. 
- 
Serum creatinine level ≤ 2.0 mg/dL or ≤ 176.8 µmol/L. 
- 
Total bilirubin < 3.0 mg/dL or < 51.3 µmol/L. 
- 
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5.0 x upper limit of 
normal. 
- 
Amylase and lipase ≤ 1.5 x upper limit of normal. 
- 
Serum albumin ≥ 2.5 g/dL or ≥ 25 g/L. 
- 
International normalized ratio ≤ 1.5. 
6. Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) 
Scale (see Appendix 3). 
7. Age 18 years or older. 
8. Have the ability to understand the requirements of the study, provide written informed 
consent (including consent for the use and disclosure of research-related health 
information), and comply with the study and follow-up procedures. 
 
4.2 
Exclusion Criteria 
Subjects will be excluded from participating in the study if they meet any of the following 
exclusion criteria: 
1. Any co-morbid condition that in the judgment of the investigator renders the subject at 
high risk of treatment complications or reduces the possibility of assessing clinical effect. 
2. Received prior investigational or non-investigational cytotoxic chemotherapy, hormonal 
therapy, biological therapy (including but not limited to monoclonal antibodies, small 
molecules or other immunotherapy) to treat hepatocellular carcinoma. 
3. Previously received mapatumumab or sorafenib. 
4. Underwent resection, radiofrequency ablation, radiation or chemoembolization within 
4 weeks before enrollment or not recovered from such treatments. 


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5. Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy, 
immunotherapy, radiofrequency ablation) or other investigational agents during the study 
treatment period. 
6. Major surgery (ie, the opening of a major body cavity, requiring the use of general 
anesthesia) within 4 weeks before enrollment; minor surgery (except for insertion of 
vascular access device) within 2 weeks before enrollment; or not yet recovered from the 
effects of the surgery. 
7. Systemic steroids within 1 week before enrollment except steroids used as part of an 
antiemetic regimen or maintenance-dose steroids for non-cancerous disease. 
8. Hepatic encephalopathy, per the investigator’s evaluation. 
9. History of clinically significant gastrointestinal bleeding requiring procedural intervention 
(eg, variceal banding, transjugular intrahepatic portosystemic shunt procedure, arterial 
embolization, topical coagulation therapy) within 4 weeks before enrollment. 
10. Gastrointestinal disease resulting in an inability to take oral medication or a requirement 
for intravenous hyperalimentation. 
11. History of any infection requiring hospitalization or intravenous antibiotics within 2 weeks 
before enrollment. 
12. Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) 
with no evidence of progression and neurologically stable off anticonvulsants and steroids. 
13. Known human immunodeficiency virus infection. 
14. Unstable angina, myocardial infarction, cerebrovascular accident, ≥ Class II congestive 
heart failure according to the New York Heart Association Classification for Congestive 
Heart Failure (see Appendix 4) within 6 months before enrollment. 
15. Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. 
16. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure 
> 90 mmHg despite optimal medical management). 
17. Using and unable to discontinue use of concomitant strong CYP3A4 inducers 
(eg, including but not limited to St. John’s Wort, dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, phenobarbital). 
18. Pregnant female or nursing mother. All females with an intact uterus (unless amenorrheic 
for the 24 months before enrollment) must have a negative serum pregnancy test at 
screening. All non-sterile or non-postmenopausal females must practice a medically 
accepted method of contraception over the course of the study and for 60 days after the 
last dose of study agent. 
19. Males who do not agree to use effective contraception during the study and for a period of 
60 days following the final dose of study agent. 
20. Subject is currently enrolled in or has not yet completed at least 30 days since ending 
other investigational device or drug study(s) or subject is receiving other investigational 
agents. 
21. Acute or chronic severe renal insufficiency (glomoerular filtration rate 
< 30 mL/min/1.73 m2) or acute renal insufficiency of any severity due to 
the hepato-renal syndrome. 
22. Hepatitis B virus DNA levels > 2,000 IU/mL. 
 


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5 Study Treatment Regimen 
Sorafenib will be administered at a dose of 400 mg twice daily without food (at least 1 hour 
before or 2 hours after a meal). On days when both sorafenib and mapatumumab/placebo are 
administered together, the sorafenib should be taken at the same time as any other calendar 
day. 
5.1 
Mapatumumab and Placebo 
5.1.1 
Formulation 
Mapatumumab will be supplied as a lyophilized formulation in sterile, single-use 10 mL vials 
containing 100 mg mapatumumab. Upon reconstitution with 5.0 mL of sterile water for 
injection, each vial will contain 20 mg/mL mapatumumab in 0.13 mg/mL citric acid, 
2.8 mg/mL sodium citrate, 19 mg/mL glycine, 5 mg/mL sucrose, 0.2 mg/mL polysorbate 80, 
pH 6.5. 
Two hundred-fifty mL normal saline solution for intravenous infusion will be administered as 
placebo for mapatumumab. 
5.1.2 
Packaging, Labeling, Preparation, and Storage 
The Pharmacy Manual will provide instructions for preparation and storage of study agent. 
The product will be securely stored at 2-8ºC. 
The study agent label will contain, at a minimum, the following information: 
• Product name 
• Concentration 
• Lot number 
• Storage instructions 
• Investigational drug statement 
• Manufacturer’s name and address 
 
Study agent inventory/accountability forms will be examined and reconciled by the unblinded 
study monitor or designee. At the end of the study, all used and unused investigational study 
agent will be accounted for on a study agent accountability form provided to the investigator 
by the Sponsor or designee. Please refer to the HGS1012-C1103 Pharmacy Manual for more 
details regarding storage, handling and drug accountability. 
5.1.3 
Mapatumumab/Placebo Dose, Route of Administration and Schedule 
The dose of mapatumumab is 30 mg/kg. Mapatumumab dose calculations will be based upon 
the subject’s weight measured on Day 1 or within 3 days before Day 1 of each cycle. The 
planned duration of each treatment cycle will be 21 days. Mapatumumab/placebo will be 
administered on Day 1 of each cycle. 


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After reconstitution with sterile water for injection, the calculated mapatumumab dose to be 
administered to the subject will be further diluted in normal saline to a total volume of 
250 mL for intravenous infusion. After adding the reconstituted product, the bag will be 
gently inverted to mix the solution. Following reconstitution and/or dilution in normal saline, 
mapatumumab will be stored at 2-8ºC. The product will be administered to the subject within 
8 hours of reconstitution. Refer to the HGS1012-C1103 Pharmacy Manual for instructions on 
admixing and administering study agent.  
Two hundred-fifty mL normal saline solution for intravenous infusion will be administered as 
placebo for mapatumumab. 
Mapatumumab/placebo will be infused at a constant rate over 1 hour. 
Infusion and hypersensitivity reactions may occur. A suggested pre-medication regimen for 
mapatumumab/placebo consists of diphenhydramine and acetaminophen administered within 
1 hour prior to the start of the mapatumumab/placebo dose. Use of a pre-medication regimen 
and alternatives to this regimen are at the investigator’s discretion. 
Subjects will be monitored closely during and after infusion for any sign of acute adverse 
reaction. If an allergic reaction occurs, see Section 5.1.5 and Appendix 8 for suggested 
medical management. 
5.1.4 
Mapatumumab/Placebo Dose Toxicity/Delay 
Mapatumumab/placebo may be delayed up to 2 weeks for toxicities considered related to 
mapatumumab as described below or if the investigator believes that a delay in dosing is 
warranted in the interest of subject safety. 
The National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE, Version 4.0) will be used to grade AEs. 
• Grade 4 neutropenia for > 7 consecutive days or febrile neutropenia. 
• Grade 4 thrombocytopenia. 
• Grade 3 or greater non-hematologic AEs except transient transaminase, amylase and 
lipase abnormalities for which the following criteria will apply: 
- 
Grade 3 or Grade 4 elevations in transaminases that do not resolve to baseline or 
Grade 1 before the next cycle. 
- 
Grade 4 elevations in lipase or amylase associated with clinical/imaging findings of 
pancreatitis, or resulting in chronic damage to the pancreas.  
- 
Any Grade 4 elevations in lipase or amylase for > 4 consecutive days. 
 
If mapatumumab/placebo is delayed for toxicity and the toxicity does not resolve (≤ Grade 1) 
or return to baseline within 2 weeks after the delayed dose was originally scheduled (based on 
a 21-day treatment cycle), the subject will be withdrawn from further treatment with 
mapatumumab/placebo. If mapatumumab/placebo is delayed because the investigator believes 
a delay is warranted in the interest of subject safety and dosing of mapatumumab/placebo is 
not resumed within 2 weeks after the delayed dose was originally scheduled (based on a 


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21-day treatment cycle), the subject will be withdrawn from future treatment with 
mapatumumab/placebo. Sorafenib dosing will continue while mapatumumab/placebo dosing 
is held. The subject will continue receiving sorafenib until radiologic progressive disease or 
an unacceptable toxicity occurs, at the discretion of the Investigator.  
Doses of mapatumumab may not be altered. 
5.1.5 
Management of Allergic/Hypersensitivity Reactions to 
Mapatumumab/Placebo 
The administration of any recombinant protein has the potential to induce local or system 
immunologic reactions; subjects could experience, for example, acute allergic reactions. To 
date, 2 such SAEs have been reported which were considered related to mapatumumab 
(hypersensitivity and angioedema/facial edema). In the event of allergic/hypersensitivity 
reactions, investigators will institute treatment measures according to best medical and 
nursing practice. Guidelines for treatment are provided in Appendix 8. 
For a NCI-CTCAE Version 4.0 Grade 3 or Grade 4 hypersensitivity reaction, treatment with 
mapatumumab/placebo will be discontinued. 
If mapatumumab/placebo is discontinued for Grade 3 or Grade 4 hypersensitivity reactions, 
the subject will continue to receive sorafenib, until radiologic progression or unacceptable 
toxicity. 
5.2 
Sorafenib 
5.2.1 
Packaging, Labeling, Preparation, and Storage 
Sorafenib is supplied as tablets, each containing 274 mg sorafenib tosylate, equivalent to 
200 mg of sorafenib. 
The recommended daily dose of sorafenib is 400 mg (2 x 200 mg tablets) taken orally twice 
daily without food (at least 1 hour before or 2 hours after a meal). 
Sorafenib will be stored at room temperature (15-30°C, 59-86°F) in a dry place. 
For country-specific formulation and packaging information, please refer to the instructions 
provided in the sorafenib product labeling. 
Supplier: Commercially available. 
5.2.2 
Anticipated Toxicities with Sorafenib 
Toxicities anticipated with the use of sorafenib include the following: 
• Cardiac: Cardiac ischemia and/or infarction, hypertension. 
• Dermatologic: Hand-foot skin reaction, rash/desquamation. 
• Hemorrhagic: Increased risk of bleeding. 
• Gastrointestinal: Gastrointestinal perforation. 


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• Other: Wound-healing complications, fatigue, weight-loss, alopecia, pruritis, dry skin, 
diarrhea, anorexia, nausea, vomiting, constipation, liver dysfunction and abdominal pain. 
 
Laboratory abnormalities observed in hepatocellular carcinoma patients treated with sorafenib 
include hypophosphatemia, lipase elevations, amylase elevations, hypoalbuminemia, 
international normalized ratio elevations, lymphopenia and thrombocytopenia. 
Refer to the product labeling accompanying the product for information approved in your 
country. 
5.2.3 
Alteration of Sorafenib Dose/Schedule Due to Toxicity 
Sorafenib may be reduced or delayed for toxicities considered related to sorafenib as 
described below, or if the investigator believes that a reduction in dose is warranted in the 
interest of subject safety. When a dose reduction is necessary, sorafenib dose may be 
reduced to 400 mg once daily. If an additional dose reduction is required, sorafenib may be 
reduced to a single 400 mg dose every other day (see Table 5-1). A maximum of 2 dose 
reductions of sorafenib will be allowed per subject. Additional dose reductions not mentioned 
in Table 5-1 will need to be discussed with the medical monitor. 
Table 5-1 
Sorafenib dose levels 
Dose Levels 
Sorafenib 
0 
400 mg twice daily 
-1 
400 mg once daily 
-2 
400 mg once every other day 
 
Skin toxicity and hypertension are associated with sorafenib. Guidelines for the management 
of these events are provided in Table 5-2 and Table 5-3, respectively. 
Skin Toxicity 
Hand-foot skin reaction and rash are common in subjects treated with sorafenib. Management 
may include topical therapies for symptomatic relief, temporary treatment interruption and/or 
dose modification, or in severe or persistent cases, permanent discontinuation. Skin toxicities 
will be managed according to Table 5-2. 
 
 


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Table 5-2 
Dose modifications of sorafenib for skin toxicity 
Skin Toxicity Grade 
Occurrence 
Suggested Dose Modification 
Grade 1:  
Numbness, dysesthesia, parethesia, 
tingling, painless swelling, erythema or 
discomfort of the hands or feet which does 
not disrupt the subject’s normal activities. 
Any occurrence 
Continue treatment with sorafenib 
and consider topical therapy for 
symptomatic relief. 
1st occurrence 
Continue treatment with sorafenib 
and consider topical therapy for 
symptomatic relief. If no improvement 
within 7 days, see below. 
No improvement within 
7 days or 2nd or 3rd 
occurrence 
Interrupt sorafenib treatment  
until toxicity resolves to Grade 0-1. 
When resuming treatment, decrease 
sorafenib dose by 1 dose level  
(400 mg daily or 400 mg every  
other day). 
Grade 2:  
Painful erythema and swelling of the hands 
or feet and/or discomfort affecting the 
subject’s normal activities. 
4th occurrence 
Discontinue sorafenib treatment. 
1st or 2nd occurrence 
Interrupt sorafenib treatment  
until toxicity resolves to Grade 0-1. 
When resuming treatment, decrease 
sorafenib dose by 1 dose level  
(400 mg daily or 400 mg every  
other day). 
Grade 3:  
Moist desquamation, ulceration, blistering 
or severe pain of the hands or feet, or 
severe discomfort that causes the subject 
to be unable to work or perform activities of 
daily living. 
3rd occurrence 
Discontinue sorafenib treatment. 
 
Hypertension 
Hypertension is a known and potentially serious adverse event associated with sorafenib 
treatment. Subjects will have their blood pressure monitored and recorded. If the subject’s 
blood pressure is elevated at any time (> 150/100 mmHg), even outside clinic visits, they will 
contact their study investigator. Guidelines for the management of hypertension are provided 
in Table 5-3. 
Table 5-3 
Dose modifications of sorafenib for hypertension 
Grade 
(CTCAE v3.0) 
Antihypertensive Therapy 
Blood Pressure  
Monitoring 
Sorafenib  
Dose 
Grade 1 
None 
Routine 
No change 
Grade 2 
(asymptomatic) 
Initiate monotherapy 
(suggest dihydropyridine 
calcium channel blocker) 
Increase frequency and monitor by 
a health professional every 2 days 
until stabilized. 
No change 
Grade 2 
(symptomatic/ 
persistent) 
OR 
diastolic BP  
> 110 mm Hg 
OR 
Grade 3 
Add agent(s): 
calcium channel blocker 
(if not already used), 
K+ channel opener 
(angiotensin blockers),  
beta-blocker, 
thiazide diuretic 
Increase frequency and monitor by 
health professional every 2 days 
until stabilized; continue monitoring 
every 2 days to stabilization after 
dosing restarted. 
Hold* sorafenib until 
symptoms resolve 
and 
diastolic BP  
< 100 mm/Hg 
 
Resume treatment 
at 1 dose level 
lower** 


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Table 5-3 
Dose modifications of sorafenib for hypertension 
Grade 
(CTCAE v3.0) 
Antihypertensive Therapy 
Blood Pressure  
Monitoring 
Sorafenib  
Dose 
Grade 4 
Discontinue sorafenib 
Discontinue sorafenib 
Discontinue 
sorafenib 
*Subjects requiring a delay of > 21 days will discontinue sorafenib, in the study investigator’s opinion, the 
subject may benefit from continued treatment. 
**Subjects requiring > 2 dose reductions will discontinue sorafenib. 
BP = Blood pressure. 
Refer to NCI-CTCAE v4.0 for grade definitions. 
(concluded) 
 
Guidelines 
for 
the 
management 
of 
other 
non-hematologic 
and 
hematologic 
sorafenib-associated toxicities are provided in Table 5-4. Those toxicities that are at least 
possibly related to an interaction with mapatumumab/placebo will have the mapatumumab 
toxicity guidelines in Section 5.1.4 applied. 
Table 5-4 
Dose modifications of sorafenib for sorafenib-associated toxicity 
Toxicity 
Grade 1 
Grade 2 
Grade 3* 
Grade 4* 
Non-
hematologic 
Continue at 
the same dose 
level 
Continue at 
the same dose 
level 
Withhold dose until toxicity 
is Grade ≤ 1, then resume 
treatment at the same dose 
level. If subject experiences 
a 2nd Grade 3 toxicity, 
withhold dose until toxicity 
is Grade ≤  1, then reduce 
dose to 400 mg orally daily 
and resume treatment. 
Withhold dose until 
toxicity is Grade ≤ 1, then 
reduce dose to 400 mg 
daily and resume 
treatment, or discontinue 
at the discretion of the 
principal investigator after 
discussion with study 
sponsor. 
Hematologic 
Continue at 
the same dose 
level 
Continue at 
the same dose 
level 
Withhold dose until toxicity 
is Grade ≤ 2, then resume 
treatment at the same dose 
level. If subject experiences 
a 2nd Grade 3 toxicity, 
withhold dose until toxicity 
is Grade ≤  2, then reduce 
dose to 400 mg orally daily 
and resume treatment. 
Withhold dose until 
toxicity is Grade ≤ 2, then 
reduce dose to 400 mg 
daily and resume 
treatment, or discontinue 
at the discretion of the 
principal investigator after 
discussion with study 
sponsor. 
See Table 5-2 and Table 5-3 for dose modifications due to skin toxicity and hypertension respectively. 
*Subjects who develop Grade 3 fever/chills, Grade 3 elevation of hepatic transaminases with ALT and AST 
< 10X upper limit of normal, Grade 3 hyperlipasemia or hyperamylasemia without clinical or other evidence of 
pancreatitis, Grade 3 leukopenia, or Grade 3/Grade 4 lymphopenia may continue sorafenib treatment without 
interruption at the discretion of the investigator. 
 
Sorafenib Discontinuation 
Temporary or permanent discontinuation of sorafenib will be considered in subjects who 
develop cardiac ischemia and/or infarction or severe or persistent hypertension despite 
institution of antihypertensive therapy. If a subject experiences a bleeding event that 
necessitates medical intervention or a gastrointestinal perforation, sorafenib will be 


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permanently discontinued. Subjects, who undergo a surgical procedure or intervention to 
decrease portal hypertension, including transjugular intrahepatic portosystemic shunt, will 
discontinue sorafenib. 
If the subject is withdrawn from further treatment with sorafenib, the subject may continue to 
receive mapatumumab/placebo alone every 21 days until radiologic progression or 
unacceptable toxicity. 
5.3 
Concurrent Medications and Therapies 
5.3.1 
Allowable Regimens 
Subjects may continue their baseline medication(s). The daily dose of each medication will be 
maintained throughout the study if possible. If for any reason deemed necessary by the 
investigator, a subject requires additional medication(s) or change of dose, the medication(s), 
dosage change, route of administration, and the indication for which it was given must be 
recorded in the source documents. All concomitant medications will be recorded on the 
appropriate case report form. 
Systemic, inhaled and topical steroids used as part of an antiemetic regimen or 
maintenance-dose for non-cancerous disease are permitted. 
5.3.2 
Prohibited Medications 
Subjects who require the use of strong CYP3A4 inducers (eg, including but not limited to 
St. John’s 
Wort, 
dexamethasone, 
phenytoin, 
carbamazepine, 
rifampin, 
rifabutin, 
phenobarbital) are not eligible for this study and use of these agents is prohibited as long as 
the subject is receiving sorafenib in this study. 
Subjects will not receive any investigational or noninvestigational cytotoxic chemotherapy, 
hormonal therapy, biological therapy (including monoclonal antibodies) or immunotherapy to 
treat hepatocellular carcinoma during the treatment period. Alternative anticancer therapies 
may be administered after radiologic disease progression has been documented, but will be 
avoided if possible during the 30 day safety follow up period after the last dose of study agent 
(mapatumumab/placebo and/or sorafenib) whichever is last. These medications are allowed in 
the long-term follow-up period after the 30 day safety follow-up period and documentation of 
radiologic disease progression. 
5.3.3 
Prohibited Therapies 
Subjects will not undergo major or elective surgery during the treatment period of the study; if 
surgery is required, the subject will be withdrawn from study treatment. 
6 Study Procedures 
6.1 
Screening Procedures 
The nature of this study and the potential risks and benefits associated with participation in the 
study will be explained to all potential study subjects. Written informed consent (including 


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consent for the use and disclosure of research-related health information) must be obtained 
before any screening procedures are performed that are not considered standard of care. 
All of the following assessments must be performed within 28 days prior to enrollment: 
• Obtain written informed consent for participation in the study. 
• Obtain informed consent for participation in the optional biomarker sub-study. 
- 
If consented, obtain tissue block/slides or cell pellet from diagnostic histologic/ 
cytologic sample. 
• Record demographics. 
• Obtain medical history, to include history of all treatments used to treat the current cancer 
and all prior cancer treatments. 
• Perform baseline complete physical examination including body weight and height. 
• Assess vital signs (blood pressure, heart rate, respiratory rate and temperature). 
• Evaluate performance status (ECOG scale; see Appendix 3). 
• Draw blood for laboratory tests (see Appendix 7): complete blood count with differential, 
chemistry, hepatitis B surface antigen, Hepatitis B virus DNA, hepatitis C antibody and 
testing for serum pregnancy (all females with an intact uterus [unless amenorrheic for the 
previous 24 months] regardless of age). 
• Obtain radiologic disease and AFP assessments. The method of disease assessment, as per 
mRECIST for HCC (see Appendix 5), will be consistent throughout the study.  
• Obtain electrocardiogram. 
• Record medications used within 28 days before enrollment. 
• Confirm that subject meets all inclusion/exclusion criteria. 
 
6.2 
Study Enrollment/Randomization Procedures 
Subjects that meet the eligibility criteria will be randomly assigned treatment by a 
central interactive voice response system in a 1:1 ratio to 1 of 2 treatment arms. The 
randomization will be stratified according to BCLC advanced stage C vs BCLC intermediate 
stage B and ECOG performance status (0 vs 1, 2). The 1st planned dose of sorafenib and 
mapatumumab/placebo will be administered no more than 3 days following randomization 
and not prior to randomization. All study site personnel (with the exception of the unblinded 
site pharmacist or unblinded designee), the subject, and the Sponsor will remain blinded to the 
study agent received. 
 


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6.3 
On-treatment Study Procedures 
Table 6-1 
Study calendar 
 
 
 
Cycle 1 
Cycle 2 
Additional 
Cycles
14 
Safety Follow-up Phase 
Long-
Term 
Follow-up 
Procedure 
Footnotes 
Screen
Phase 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 22 of 
last cycle on 
treatment 
≥ 30 days 
following 
last dose 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
 
 
CBC with differential; 
Coagulation 
parameters 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy 
2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis 
1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B and T lymphocyte 
subsets 
3 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
 
 
 
 
Immunogenicity  
4 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Pharmacokinetics 
5 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
Biomarkers 
6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Study Agent Admin 
 
 
Sorafenib 
7 
 
Twice daily 
 
 
 
Mapatumumab/ 
Placebo 
7 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Physical/Clinical 
 
 
Med Hx / Phys.Exam 
- 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
8 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
Body weight 
9 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Performance Status 
10 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 


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Table 6-1 
Study calendar 
 
 
 
Cycle 1 
Cycle 2 
Additional 
Cycles
14 
Safety Follow-up Phase 
Long-
Term 
Follow-up 
Procedure 
Footnotes 
Screen
Phase 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 22 of 
last cycle on 
treatment 
≥ 30 days 
following 
last dose 
 
Record AEs/ 
Conmeds 
11 
X 
<----------------Throughout the study----------------> 
 
Disease Assessments  
12 
X 
Performed at the end of every 2 cycles (ie, Cycles 2, 4, 6) and every 2 cycles thereafter until radiologic PD is documented. 
X 
α – Fetoprotein (AFP) 
12 
X 
Performed at the end of every 2 cycles (ie Cycles 2, 4, 6) and every 2 cycles thereafter until radiographic PD is 
documented. 
X 
ECG 
- 
X 
Repeat as clinically indicated 
 
Survival 
13 
 
 
X 
AE = adverse event; CBC = complete blood count; CT = computerized tomography; ECG -= electrocardiogram; PD = progressive disease. 
1 
Safety Labs: Day 1 (complete blood count with differential, coagulation parameters [INR, PT, PTT] and chemistry) must be performed within 3 days prior to dosing on Day 1 of each 
cycle.  See Appendix 7 for a detailed list of required laboratory assessments. 
2 
Pregnancy: Serum test at screening, urine test pre-dose Cycle 1 Day 1; must be negative to receive treatment. 
3 
B and T lymphocyte subsets: Blood samples for quantification of B and T lymphocytes will be obtained in Cycles 1 and 2 only. Samples will be obtained on Day 1 (prior to dosing) and 
Day 15 of Cycles 1 and 2. 
4 
Immunogenicity: Obtain prior to dosing on Day 1 of Cycles 1, 2, 4, 6, every 2 cycles thereafter and at the end of treatment visit (at least 30 days after the last dose). On days when 
immunogenicity and pharmacokinetic samples are collected they will be collected together. 
5 
Pharmacokinetics: Blood specimens will be collected for determination of serum mapatumumab concentrations from subjects as follows:  Cycle 1 (on Day 1 prior to the administration 
mapatumumab/placebo and at the completion of the mapatumumab/placebo infusion, and on Day 8), Cycles 2, 4 and 6 and thereafter on each even cycle (prior to dosing on Day 1), 
on the day of each disease assessment, and at the end of treatment visit (at least 30 days after the last dose). On days when immunogenicity and pharmacokinetic samples are 
collected they will be collected together.   
6 
Biomarkers: For subjects participating in the optional biomarker sub-study, historical biopsy samples will be collected, if available, and samples will be collected if obtained during the 
treatment period in Cycle 1 Days 1 (pre-dose mapatumumab), 2, 3, 8 and 15 and Cycle 2 Days 1 (pre-dose mapatumumab), 3, 8 and 15. In addition, blood samples will be obtained 
as follows: blood for isolation of DNA will be collected once, preferably in Cycle 1. Blood for isolation of serum will be collected in Cycles 1 and 2 (pre-dose on the day of 
mapatumumab/placebo dosing). Further details on the biomarker sub-study are outlined in Appendix 6. 
7 
Study Agent Administration:  Sorafenib will be administered at a dose of 400 mg twice daily without food (at least 1 hour before or 2 hours after a meal). On days when both sorafenib 
and mapatumumab/placebo are administered together, sorafenib should be taken at the same time as any other calendar day. 
8 
Vital Signs: Blood pressure will be monitored weekly for the first 6 weeks. Vital signs will be obtained within 30 minutes prior to administration of mapatumumab/placebo and at the 
end of infusion on Day 1 of each cycle. 
9 
Body Weight: To be obtained on the day of or within 3 days before dosing on Day 1 of each cycle. 


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Table 6-1 
Study calendar 
 
 
 
Cycle 1 
Cycle 2 
Additional 
Cycles
14 
Safety Follow-up Phase 
Long-
Term 
Follow-up 
Procedure 
Footnotes 
Screen
Phase 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
3 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 22 of 
last cycle on 
treatment 
≥ 30 days 
following 
last dose 
 
10 
Performance Status: Obtained prior to dosing on Day 1 of each cycle. 
11 
Adverse Events: AE collection begins with the start of 1
st study agent administration. Concurrent medications will be recorded within 28 days prior to Cycle 1 Day 1. 
12 
Disease and α – Fetoprotein (AFP) Assessments: Radiologic and AFP assessments will be performed at the end of every 2 cycles (ie, Cycles 2, 4, 6, etc). For subjects discontinuing 
treatment prior to documentation of radiologic disease progression, disease assessments will be performed every 6 weeks (± 3 days), starting 6 weeks after the previous disease 
assessment while on study, until radiologic disease progression is documented. If disease progression is based only on new lesions or is equivocal, images will be provided to the 
blinded, independent reader for confirmation of disease progression. All imaging scans used for disease assessments will be made available for independent radiology review by the 
Sponsor or designee. 
13 
Survival: Contact will be made with the subject every 3 months to document survival until at least 90% of subjects have met the survival endpoint. 
14 
Subjects who discontinue mapatumumab/placebo will complete the current cycle assessments per the study calendar.  Subsequently, subjects receiving sorafenib alone will return at 
least every 21 days and on additional days as clinically indicated for safety labs (CBC with differential, chemistry and coagulation parameters) for the duration of treatment. Disease 
assessments must be performed every 6 weeks until radiologic disease progression.  Adverse events and concomitant medications will be recorded throughout the study. 
(concluded) 
 


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6.4 
Follow-up Procedures 
6.4.1 
Safety Follow-up 
After discontinuation of study treatment, all subjects will return 1 day after cycle completion 
(approximately Day 22) and at least 30 days after the last dose of sorafenib and/or 
mapatumumab/placebo, for scheduled safety follow-up assessments as outlined in Table 6-1. 
6.4.2 
Long-term Follow-up 
For subjects discontinuing treatment prior to documentation of radiologic disease progression, 
and for subjects who experience stable disease or a response (PR, CR) but are no longer 
receiving treatment, radiologic disease assessments will be performed at 6 week intervals 
(± 3 days), starting 6 weeks after the previous radiologic disease assessment while on 
treatment, until radiologic disease progression is documented. Thereafter, subjects will be 
followed every 3 months for survival until at least 90% of subjects have met the survival 
endpoint. 
6.5 
Withdrawal of Subjects from Treatment 
Subjects will be free to withdraw from treatment at any time, for any reason, or they may be 
withdrawn/removed, if necessary, to protect their health (see reasons for withdrawal below). It 
is understood by all concerned that an excessive rate of withdrawals can render the study 
uninterpretable; therefore, unnecessary withdrawal of subjects will be avoided. 
Subjects may be withdrawn from treatment for any of the following reasons: 
• Radiologic disease progression. 
• Continued unacceptable toxicities despite optimal treatment or dose reduction. 
• Intercurrent illness, at the investigator’s discretion. 
• Withdrawal of consent. 
• Non-compliance/Lost to follow-up. 
• Pregnancy. 
• Termination of the study by the sponsor. 
 
Subjects who withdraw are to be followed for radiologic progression as outlined in 
Section 6.4.2. In addition, every effort will be made to collect safety information on each 
subject through 30 days following the last dose of study treatment, unless the subject 
withdraws consent and refuses to comply with the protocol stipulated safety follow-up and 
radiologic disease progression assessments, or share information obtained after the date of 
withdrawal of consent. 
6.6 
Withdrawal of Subjects from Study 
Subjects may be withdrawn from the study for any of the following reasons: 
• Withdrawal of consent. 


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• Non-compliance/Lost to follow-up. 
• Termination of the study by the sponsor. 
 
Every effort will be made to collect follow-up information on subjects in the long-term 
follow-up period of the study, unless the subject withdraws consent and refuses to share 
information obtained during the long-term follow-up period obtained after the date of 
withdrawal of consent. 
6.7 
Disease Response Assessments 
Imaging endpoints will be determined using the modified RECIST criteria for HCC proposed 
by Lencioni and Llovet (2010; mRECIST). mRECIST for HCC is a joint guideline of the 
American Association for the Study of Liver Diseases and the Journal of the National Cancer 
Institute.  
Lesions which manifest typical imaging characteristics for HCC demonstrate intratumoral 
arterial contrast on CT and MRI images. mRECIST accounts for newer therapies which may 
impact tumor vascularity and may not yield a typical cytotoxic decrease in tumor size by 
incorporating changes in vascularity into the criteria for target lesion response. Diligence in 
obtaining images during the hepatic arterial contrast enhancement phase is a requirement at 
baseline and all subsequent scans. The same imaging method must be used at baseline and 
during follow up. 
As in conventional RECIST, overall response is the result of the combined assessment of 
target, nontarget, and new lesions. There are also specifications for incorporating portal vein 
thrombosis, portal hepatic lymph nodes, and pleural effusions/ascites into the response 
assessment. As with conventional RECIST, the appearance of any new lesion overrides any 
existing lesion response, resulting in classification as progressive disease (PD). Key aspects of 
mRECIST as adapted for this study are summarized in Appendix 4. 
Baseline images will be provided to the BICR for confirmation of radiologic eligibility 
(measurable disease). Confirmation of radiologic eligibility for the study will be provided to 
the site by the BICR within 72 hours of receipt of images and will be required for 
randomization. 
Disease assessments and an assessment of α -fetoprotein will be performed at the end of every 
2 cycles (ie, Cycles 2, 4, 6 and every 2 cycles thereafter). The response assessment will be 
performed and documented no more than 5 days before the start of the next cycle. All images 
will be provided to the BICR following each disease assessment. 
If disease progression is based only on new lesions or is equivocal, images will be provided to 
the BICR for confirmation of radiologic disease progression prior to discontinuing study 
treatment. PR and CR will be confirmed at the next scheduled disease assessment (no fewer 
than 4 weeks after the initial documentation of PR or CR). 


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7 Pharmacokinetic, Immunogenicity, Pharmacodynamic and 
Exploratory Assessments 
7.1 
Pharmacokinetic Assessments 
For determination of mapatumumab concentration, serum samples will be collected as 
outlined in Table 6-1. 
A manual will be provided regarding how to obtain blood samples, process samples, collect 
serum from the blood samples, and how to store and ship the serum samples. Bioanalysis will 
be carried out at Human Genome Sciences to determine mapatumumab concentration in each 
serum sample. 
7.2 
Immunogenicity 
Blood samples for serum antibodies to mapatumumab will be obtained as outlined in  
Table 6-1.  
7.3 
Pharmacodynamic Assessments 
Subjects will be given the option to participate in an exploratory biomarker research 
sub-study. Consenting subjects will be asked to provide a historically obtained biopsy sample, 
if available, and blood samples. In addition, samples will be requested from subjects who 
undergo a biopsy during the treatment period. 
To examine and quantify biomarkers present peripherally, blood will be drawn during 
Cycles 1 and 2, from which DNA and serum proteins will be isolated. The parameters 
evaluated may include, but may not be limited to, M30, TNFα, sTRAIL, soluble Fas ligand, 
interferon-α, 
interferon-γ, 
interleukin-2, 
interleukin-6, 
interleukin-8, 
interleukin-10, 
interleukin-12, and FC gamma receptor and interleukin-6 gene polymorphisms. The 
biomarker sub-study is detailed in Appendix 6.  
7.4 
Exploratory Assessments (B and T Lymphocyte Subsets) 
7.4.1 
Rationale for B and T Lymphocyte Analysis 
Over 400 subjects have received mapatumumab in doses ranging from 0.01 to 30 mg/kg 
across multiple Phase 1 and Phase 2 clinical trials in subjects with solid and hematologic 
malignancies. While there is no evidence to date that mapatumumab exacerbates adverse 
events associated with chemotherapy, the most commonly observed laboratory abnormality 
associated with mapatumumab has been lymphopenia. The lymphopenia has been intermittent 
and reversible and was not associated with infectious events. However, the lymphocyte 
subpopulation(s) affected have not been characterized. 
The evaluation of lymphocytes will include complete blood count/differential and lymphocyte 
subpopulation analysis (numbers and percentages of T and B cells) by flow cytometry at a 
central laboratory. Blood samples will be examined by flow cytometry for levels of T helper 
(CD4+), T cytotoxic (CD8+) and mature B cells (CD19+). 


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7.4.2 
Collection of Samples for B and T Lymphocyte Analysis 
Blood samples will be collected for quantification of B and T lymphocyte subsets on Day 1 
(prior to dosing) and Day 15 of Cycles 1 and 2 as outlined in Table 6-1. 
8 Adverse Event Reporting 
8.1 
Definitions 
ADVERSE EVENT (EXPERIENCE) - 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. This includes worsening (eg, increase in frequency or severity) of 
pre-existing conditions. 
SERIOUS ADVERSE EVENT – an adverse event resulting in any of the following outcomes: 
• death 
• is life threatening (ie, an immediate threat to life) 
• inpatient hospitalization 
• prolongation of an existing hospitalization 
• persistent or significant disability / incapacity 
• congenital anomaly / birth defect 
• is Medically Important* 
 
*Medical and scientific judgment will be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life threatening or result in death or result in hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other outcomes listed above. These should also 
usually be considered serious. (ICH guidelines, March 1995) 
Note: Hospitalizations not associated with an adverse event, for example, for administration 
of chemotherapy or hydration for chemotherapy administration, are not considered serious 
adverse events. 
UNEXPECTED ADVERSE EVENT - An adverse event, the nature or severity of which is 
not consistent with the applicable product information (eg, Investigator’s Brochure for an 
unapproved investigational product or package insert/summary of product characteristics for 
an approved product). Expected means that the event has previously been observed with the 
study agent and is identified and/or described in the applicable product information. It does 
not mean that the event is expected with the underlying disease(s) or concomitant 
medications. 
8.2 
Reporting Adverse Events to the Sponsor or Designee 
All adverse events (AEs) that are identified from the start of any study agent administration 
through the specified study follow-up period (through 30 days following administration of the 


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final study agent dose) will be recorded on the paper/electronic Adverse Event Case Report 
Form (AE case report form). All data fields on the AE case report form will be completed. 
Serious Adverse Events (SAEs) must ALSO be recorded on the SAE Worksheet and sent to 
HGS within 24 hours of site personnel becoming aware of a SAE, regardless of expectedness. 
All pages of the SAE Worksheet will be completed, but the SAE worksheet will not be held 
until all information is available. Additional information and corrections will be provided on 
subsequent SAE Worksheets as described in the Study Procedure Manual. SAE Worksheets 
will be sent by facsimile to the Drug Safety Department at HGS using the fax number listed 
below. 
FAX #: 
 
8.3 
Laboratory Abnormalities as Adverse Events 
A laboratory abnormality will be reported as an adverse event if it is associated with an 
intervention. Intervention includes, but is not limited to, discontinuation of treatment, dose 
reduction/delay, additional assessments (excluding follow-up labs), or concomitant therapy. In 
addition, any medically important laboratory abnormality may be reported as an adverse event 
at the discretion of the investigator. This includes laboratory abnormalities for which there is 
no intervention but the abnormal value(s) suggests a disease or organ toxicity. If clinical 
sequelae are associated with a laboratory abnormality, the diagnosis or medical condition will 
be reported (eg, renal failure, hematuria) not the laboratory abnormality (eg, elevated 
creatinine, urine red blood cells increased). 
8.4 
Other Events Requiring Rapid Reporting 
Protocol Specified Events are additional events [toxicities] specifically identified in this 
protocol that must be reported to Human Genome Sciences or designee in an expedited 
manner. Protocol Specified Events may or may not be SAEs as defined in this protocol. They 
are SAEs if they meet one or more of the criteria for an SAE (see Section 8.1). Protocol 
Specified Events are recorded on SAE Worksheets and sent to Human Genome Sciences 
within 24 hours of site personnel becoming aware of the event. 
The Protocol Specified Events for the study: 
• Grade 4 neutropenia for > 7 consecutive days or febrile neutropenia. 
• Grade 4 thrombocytopenia. 
• Grade 3 or greater non-hematologic AEs except transient transaminase, amylase and 
lipase abnormalities for which the following criteria apply: 
• Grade 3 or Grade 4 elevations in transaminases that do not resolve to baseline or Grade 1 
before the next cycle 
• Grade 4 elevations in lipase or amylase associated with clinical/imaging findings of 
pancreatitis, or resulting in chronic damage to the pancreas. 
• Any Grade 4 elevations in lipase or amylase for > 4 consecutive days. 
• Grade 3/4 elevations in liver function tests regardless of causality. 
PPD


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• Any adverse event that results in discontinuation of treatment if that event is assessed as 
possibly, probably, or definitely related to mapatumumab or sorafenib. 
 
8.5 
Reporting a Pregnancy 
Any pregnancy in a female participant or a female partner of a male participant must be 
reported to Human Genome Sciences Drug Safety as soon as the site becomes aware of the 
pregnancy. All pregnancies are reported up to 30 days following the last study agent 
treatment. Human Genome Sciences Drug Safety sends an acknowledgement memorandum to 
the principal investigator along with a Pregnancy Assessment Form. Additional Pregnancy 
Assessment Forms will be sent to the site every 3 months for reporting of follow-up 
information. Pregnancy assessment forms must be completed by the investigator until live 
birth, elective termination of the pregnancy, or miscarriage. The site is responsible for 
following the subject’s pregnancy to final outcome. 
Pregnancies are not considered adverse events. Complications or medical problems associated 
with a pregnancy are considered AEs and may be SAEs. Complications or medical problems 
are reported as AEs/SAEs according to the procedure described in Section 8.2. 
8.6 
Investigator Evaluation of Adverse Events 
The Investigator will evaluate all adverse events with respect to seriousness (criteria listed in 
Section 8.1 above), severity (intensity or grade) and causality (relationship to study agent) 
according to the following guidelines listed below. 
SEVERITY 
Severity will be graded using the NCI-CTCAE, Version 4.0. The NCI-CTCAE may 
be downloaded 
from 
the 
Cancer 
Treatment 
Evaluation 
Program 
website 
(http://ctep.info.nih.gov/reporting/ctc.html). In the event that an AE does not have an 
NCI-CTCAE code, the following severity classifications will be used: 
Mild  
causing no limitation of usual activities 
Moderate 
causing some limitation of usual activities 
Severe 
causing inability to carry out usual activities 
Life Threatening* potentially life threatening or disabling  
 
*Note – a severity assessment of life threatening is not necessarily the same as life threatening 
as a “Serious” criterion. The latter means that the event is an immediate threat to life as 
opposed to a potential threat to life. 
 
 


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CAUSALITY 
Definitely Related 
reasonable temporal relationship to study agent administration 
 
follows a known response pattern (eg, drug is known to cause this AE) 
 
there is no alternative etiology 
Probably Related 
reasonable temporal relationship 
 
follows a suspected response pattern (eg, based on similar drugs) 
 
no evidence for a more likely alternative etiology 
Possibly Related 
reasonable temporal relationship 
 
little evidence for a more likely alternative etiology 
Probably Not Related does not have a reasonable temporal relationship, OR 
 
good evidence for a more likely alternative etiology 
Not Related 
does not have a temporal relationship, OR 
 
definitely due to alternative etiology  
 
ICH guidelines (March, 1995) clarify “reasonable causal relationship” to mean “that there are 
facts [evidence] or arguments to suggest a causal relationship”. 
The causality assessment must be made by the investigator based on information available at 
the time that the SAE worksheet is completed. The initial causality assessment may be revised 
as new information becomes available. 
 *Note - If there is evidence that mapatumumab/placebo contributed to or exacerbated an 
event related to sorafenib; the event will be recorded as possibly, probably or definitely 
related to both sorafenib and mapatumumab. 
8.7 
Follow-up of Adverse Events 
Adverse events that occur during the course of the study are followed until final outcome is 
known or until the end of the safety follow-up period (30 days following the final dose of any 
study agent). Adverse events that have not resolved by the end of the safety follow-up period 
are recorded as ongoing. 
SAEs that have not resolved by the end of the follow-up period are followed until final 
outcome of recovered or recovered with sequelae is achieved. If it is not possible to obtain a 
final outcome for a SAE (eg, the subject is lost to follow up), the reason a final outcome could 
not be obtained will be documented by the investigator. 
8.8 
Serious Adverse Events Assessed During Long-Term Follow-up 
SAEs that occur after the safety follow-up period (30 days following the final dose of study 
agent) that are assessed by the investigator as possibly, probably, or definitely related to study 
agent must be reported to Human Genome Sciences on an SAE worksheet, as described in 
Section 8.2. Post-study SAEs will not be documented on the AE case report form. 


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8.9 
Reporting Serious Adverse Events to the Institutional Review 
Board/Ethics Committee 
All SAEs that are considered unexpected and related to the study agent will be reported by 
Human Genome Sciences or its designee as expedited (ie, 15-Day) reports to the appropriate 
regulatory authorities AND to all participating investigators. Each investigator must notify the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) responsible for 
reviewing the study at their site of all expedited reports. In addition, Human Genome Sciences 
or its designee will follow all applicable local and national regulatory requirements regarding 
safety reporting. Each investigator must also comply with the applicable regulatory 
requirements related to the reporting of SAEs to the IRB/IEC responsible for reviewing the 
study at their site, as well as the regulatory authority(ies) (if applicable). 
9 Endpoints and Statistical Analysis 
9.1 
General Statistical Considerations 
Analyses will be applied to a modified intention-to-treat population unless stated otherwise. 
This population is defined as the set of all randomized subjects who receive at least 1 dose of 
study treatment (mapatumumab/placebo and/or sorafenib) with subjects analyzed according to 
the groups they are randomized to, regardless of the treatment they subsequently receive. 
Additional analyses may be performed on the as-treated population, defined as the set of 
subjects receiving at least 1 dose of study medication analyzed according to the treatment that 
they actually receive. 
Analyses will be performed using the SAS System™, WinNonlin Enterprise Edition™, 
StatXact™, and the R statistical package. 
9.2 
Sample Size Rationale 
A total of approximately 100 subjects will be randomly assigned to 1 of 2 arms and treated 
with either sorafenib + placebo or the 2-agent combination of sorafenib and mapatumumab at 
30 mg/kg in a 1:1 ratio. A sample size of 50 subjects randomized and treated in each group is 
sufficient to estimate the median time to progression with a precision of approximately -1.9 M 
to +2.6 M relative to the observed median. In addition, a sample size of 50 patients per arm 
will provide 80% power to detect an improvement in TTP from 5.5 to 8.9 M with at a 
one-sided significance level of 0.10. 
9.3 
Efficacy 
9.3.1 
Primary Efficacy Endpoint 
The primary endpoint is time to progression (TTP) defined as the time from randomization to 
radiologic disease progression based on blinded independent review of imaging scans.  
9.3.2 
Primary Efficacy Analysis 
The primary analysis will be an estimate of median time to progression in each arm using 
Kaplan Meier methods, reported with 95% confidence intervals, along with logrank testing at 


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a 1-sided significance level of 0.10 for a difference between treatment groups controlling for 
factors stratifying the randomization. 
9.3.3 
Secondary Efficacy Endpoints 
Secondary endpoints include progression-free survival, overall response, disease control, 
overall survival, time to response, and duration of response (for responders) as defined below: 
• OS: time from randomization to death from any cause. 
• PFS: time from randomization to disease progression or death from any cause. 
• Objective response (CR+PR according to mRECIST for HCC). 
• Disease control (CR+PR+SD according to mRECIST for HCC). 
• Time to response: time from randomization to 1st PR or CR in responders only. 
• Duration of response: time from 1st PR or CR to disease progression; in responders only. 
 
All secondary endpoints will be based on blinded independent review of imaging scans. 
9.3.4 
Secondary Efficacy Analyses 
Secondary analyses include estimates, using Kaplan Meier methods, of median PFS and 
median OS along with associated logrank testing. In addition, estimates of overall response 
rate (CR+PR) and disease control rate (CR+PR+SD) will be reported with 95% confidence 
intervals and an estimate of the difference in response rates and disease control rates between 
groups will be reported and tested for significance with a Pearson chi-square test (or Fisher’s 
exact test).  
9.4 
Safety 
9.4.1 
Definition of Safety Variables  
The safety parameters assessed are given by the following: 
• Frequency, and severity of adverse events (AEs): 
- 
All AEs will be classified by System Organ Class and Preferred Term under the 
Medical Dictionary for Regulatory Activities (MedDRA) system of classification with 
a severity assigned according to the NCI-CTCAE (Version 4.0, 29 May 2009), or the 
rules specified in Section 8.6. 
- 
Laboratory parameters as presented in Appendix 7. 
- 
Laboratory toxicities will be graded based on the NCI-CTCAE (Version 4.0, 
29 May 2009). 
• Anti-mapatumumab antibody response. 
• Vital signs. 
• For frequency and severity of adverse events and laboratory toxicity grading, counts and 
rates will be presented. 
 


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9.4.2 
Human Genome Sciences Safety Review Committee 
The Human Genome Sciences Review Committeee (HGSRC) is comprised of the Department 
Heads of Biostatistics, Regulatory Affairs and Drug Development. The HGSRC will review 
safety data after: (1) 10 subjects have completed 1 cycle; and (2) 30 subjects have completed 
1 cycle. HGSRC reviews of safety data will be conducted approximately every 4 months 
thereafter, until 90% of subjects have reached radiologic progression. The HGSRC may 
conduct additional reviews at their own request and/or at the request of the Medical Monitor. 
The HGSRC may request the unblinding of treatment assignment for a subject and/or 
treatment groups. If treatment assignments are unblinded, the rationale for the unblinding will 
be documented. 
9.4.3 
Analysis of Safety Variables 
The safety analysis will consist of a presentation of rates of AEs observed. Specific AEs will 
be counted once for each subject for calculating rates, but will be presented in total in subject 
listings. In addition, if the same AE occurs multiple times within a particular subject, the 
highest severity and level of causality observed will be reported. If any associations of interest 
between AEs and baseline characteristics are observed, additional stratified results may be 
presented. All treatment-emergent AEs will be summarized overall, as well as categorized by 
the MedDRA system of classification. AEs will be presented overall, by severity, by relation 
to mapatumumab/placebo, and by relation to sorafenib. 
9.5 
Pharmacokinetics 
9.5.1 
Definition of Pharmacokinetic Evaluation 
Serum mapatumumab concentration data obtained from this study will be pooled with data 
obtained from other studies for use in a population PK analysis, which will be reported 
separately. 
9.5.2 
Analysis of Pharmacokinetics 
The serum mapatumumab concentration will be determined by enzyme-linked immunosorbent 
assay. Serum mapatumumab concentration results for this study will be presented using 
appropriate graphic and tabular summaries. 
9.6 
Pharmacodynamics 
Expression of biomarkers in tumor tissue and peripheral blood will be correlated with clinical 
outcomes and may be reported separately from the clinical study report.  
10 Study Administration 
10.1 Informed Consent 
A copy of the proposed informed consent document(s) must be submitted to the sponsor or 
designee for review and comment prior to submission to the reviewing IRB/IEC. The consent 
form must be approved by the IRB/IEC and contain all elements required by national, state, 
local, and institutional regulations or requirements. 


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It is the responsibility of the investigator to provide each subject with full and adequate verbal 
and written information using the IRB/IEC approved informed consent document(s), 
including the objective and procedures of the study and the possible risks involved before 
inclusion in the study. Each subject must voluntarily provide written informed consent 
(including consent for the use and disclosure of research-related health information). The 
consent must be obtained prior to performing any study-related procedures that are not part of 
normal patient care, including screening and changes in medications including any washout of 
medications. A copy of the signed informed consent must be given to the study subject. 
10.2 Institutional Review Board Review/Independent Ethics Committee 
Review and Approval 
The investigator or sponsor (as appropriate per national regulations) shall assure that an 
IRB/IEC, constituted in accordance with ICH Good Clinical Practices, will provide initial and 
continuing review of the study. 
Prior to shipment of the study agent and enrollment of study subjects, documented IRB/IEC 
approval of the protocol, informed consent form, and any advertisement for subject 
recruitment must be obtained and provided to the sponsor or designee. 
The IRB/IEC must also be informed of all protocol amendments prior to implementation. The 
investigator must provide reports of any change in research activity (ie, the completion, 
termination, or discontinuation of a study) to the IRB/IEC. 
10.3 Protocol Compliance 
Except for a change that is intended to eliminate an apparent immediate hazard to a study 
subject, the protocol shall be conducted as described. Any such change must be reported 
immediately to the sponsor and to the IRB/IEC. 
10.4 Protocol Revisions 
Protocol amendments will be prepared and approved by the sponsor. All protocol amendments 
will be signed by the investigator and submitted to the IRB/IEC for review prior to 
implementation. Documentation of IRB/IEC approval must be forwarded to the sponsor or 
designee. If an amendment significantly alters the study design, increases potential risk to the 
subject or otherwise affects statements in the informed consent form, the informed consent 
form must be revised accordingly and submitted to the IRB/IEC for review and approval. The 
approved consent form must be used to obtain informed consent from new subjects prior to 
enrollment and must be used to obtain informed consent from subjects already enrolled if they 
are affected by the amendment. 
10.5 Data Collection and Management 
Data collected for each study subject are recorded electronically on case report forms 
provided or approved by the sponsor.  


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The investigator is responsible for maintaining accurate, complete, and up-to-date records for 
each subject. The investigator is also responsible for maintaining any source documents 
related to the study, including any films, tracings, computer discs, or tapes. The investigator 
must promptly review the completed case report forms for each subject. As the person 
ultimately responsible for the accuracy of all data, the investigator must sign the Investigator's 
Statement in each subject's case report form. 
The anonymity of participating subjects must be maintained. Subjects are identified by an 
assigned subject number on case report forms and other documents submitted to the sponsor. 
Documents that identify the subject beyond subject number are not submitted to the sponsor 
(ie, the signed informed consent document) and must be maintained in strict confidence by the 
investigator, except to the extent necessary to allow auditing by the regulatory authorities, 
study monitor, or sponsor representatives. 
Sites enter subject data directly into the electronic data capture (EDC) system and the EDC 
system automatically generates queries resulting from computer checks embedded into the 
system, so as to ensure accuracy, quality, consistency, and completeness of the database. 
Manual queries resulting from review by monitors, medical coders, and other Data 
Management staff are also generated from within the EDC system, where they are tracked. 
Sites resolve the queries and correct the entered data when necessary. Every change to data is 
captured in the EDC system audit trail. At study end, each site is provided with a compact 
disk containing the electronic case report forms for each of their subjects. 
Upon completion of the study, or after reaching a pre-specified point in the study, Data 
Management locks the database and generates the SAS datasets necessary for data analysis 
and reporting. 
10.6 Study Monitoring 
The study sponsor, Human Genome Sciences, Inc., or designee, will monitor the study. Study 
monitors representing the sponsor will visit study sites routinely throughout the trial. The 
sponsor will review the paper subject diaries and electronic case report forms and compare 
them with source documents to verify accurate and complete collection of data and confirm 
that the study is being conducted according to the protocol. Auditors representing the sponsor 
may also similarly evaluate the study and its monitors. For these purposes, the investigator 
will make paper subject diaries and electronic case report forms and source documents 
available when requested. 
In addition, the study may be evaluated by representatives of the national regulatory 
authorities, who will also be allowed access to study documents. The investigators will 
promptly notify Human Genome Sciences of any audits they have scheduled with any 
regulatory authority. 
10.7 Drug Accountability 
Upon receipt, the designated unblinded pharmacy personnel at the study site are responsible 
for taking an inventory of the study agent, including any buffers or diluents. A record of this 


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inventory must be kept and usage must be documented on study agent inventory forms 
provided by the sponsor. 
Study agent inventory forms will be examined and reconciled by an unblinded Clinical 
Research Associate, or designee. At the end of the study, all used and unused study agent 
must be accounted for on a study agent accountability form provided to the investigator by 
Human Genome Sciences or its designee. 
10.8 Retention of Records 
The investigator shall retain all records and source documents pertaining to the study, 
including any films, tracings, computer discs, or tapes. They will be retained for the longer of 
the maximum period required by the country and institution in which the study is conducted, 
or the period specified by the sponsor at the time the study is completed, terminated, or 
discontinued. 
If the investigator leaves the institution, the records shall be transferred to an appropriate 
designee who accepts the responsibility for record retention. Notice of such transfer shall be 
documented in writing and provided to the sponsor. 
10.9 Financial Disclosure 
The investigator will provide Human Genome Sciences sufficient and accurate information on 
financial interests (proprietary or equity interests, payments exclusive of clinical trial costs) to 
allow complete disclosure to regulatory authorities. The investigator shall promptly update 
this information if any relevant changes occur during the course of the investigation and for a 
period of 1 year following study completion. 
10.10 Publication Policy 
This study is being conducted as part of a multi-center clinical study. Data from all sites 
participating in the multi-center clinical study will be pooled and analyzed. The investigator 
acknowledges that an independent, joint publication is anticipated to be authored by the 
investigators of the multi-center study and sponsor’s representatives. Neither institution nor 
principal investigator shall independently publish or present the results of the study prior to 
the publication of the multi-center study publication. The investigator agrees that the sponsor 
will be the coordinator and arbitrator of all multi-center study publications. For multi-center 
trials, no investigator will be authorized to publish study results from an individual center 
until the earlier of the multi-center trial results are published or 12 months after the end or 
termination of the multi-center trial at all sites. 
The investigator shall submit a copy of any proposed publication, manuscript, abstract, 
presentation or other document with respect to this study to the sponsor for review and 
comment at least 60 days prior to its submission for publication or presentation. No 
publication or presentation with respect to the study shall be made unless and until the entire 
sponsor’s comments on the proposed publication or presentation have been considered and 
any information determined by sponsor to be confidential information has been removed. 


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If requested in writing by the sponsor, the investigator shall withhold material from 
submission for publication or presentation for an additional 60 days to allow for the filing of a 
patent application or the taking of other measures to establish and preserve the sponsor’s 
proprietary rights. 
10.11 Study or Study Site Termination 
If Human Genome Sciences, the investigator, IRB/IEC, or a regulatory authority discovers 
conditions arising during the study that indicate that the study should be halted or that the 
study center should be terminated, this action may be taken after appropriate consultation 
between Human Genome Sciences and the investigator. Conditions that may warrant 
termination of the study include, but are not limited to, the following: 
• The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study. 
• A decision on the part of Human Genome Sciences to suspend or discontinue testing, 
evaluation, or development of the product. 
 
The study site may warrant termination under the following conditions: 
• Failure of the investigator to enroll subjects into the study at an acceptable rate. 
• Failure of the investigator to comply with pertinent regulatory authority regulations. 
• Submission of knowingly false information from the research facility to Human Genome 
Sciences, study monitor, or the regulatory authority. 
• Insufficient adherence to protocol requirements. 
 
 
 


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2007;12:66-80. 
Ries LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2004, 
National Cancer Institute. Bethesda, MD, 2006. 
Roach C, Sharifi A, Askaa J, et al. Development of sensitivity and specific 
immunohistochemical assays for pro-apoptotic TRAIL-receptors. Proceeding of the AACR 
2004, A4957. 
Rosato RR, Almenara JA, Coe S, et al. The multikinase inhibitor sorafenib potentiates TRAIL 
lethality in human leukemia cells in association with Mcl-1 and cFLIPL down-regulation. 
Cancer Res. 2007 Oct 1;67(19):9490-500. 
Siu L, Awada A, Takimoto C, et al. Phase I Trial of Sorafenib and Gemcitabine in Advanced 
Solid Tumors with an Expanded Cohort in Advanced Pancreatic Cancer. Clin Cancer Res 
2006:144-51 
Sorafenib (nexavar) [US package insert]. Wayne, NJ, US: Bayer HealthCare Pharmaceuticals, 
February, 2009. 
Spangenberg HC, Thimme R, Blum HE. Serum markers of hepatocellular carcinoma. Semin 
Liver Dis 2006;26(4):385-90. 
Teo, TK and Fock, KM. Hepatocellular carcinoma: an Asian perspective. Dig Dis 
2001;19:263-8. 
The Criteria Committee of the New York Heart Association. Nomenclature and criteria for 
diagnosis of disease of the heart and great vessels. 9th ed. Boston, Mass; Little, Brown & Co; 
1994; 253-6. 
Therasse P, Arbuck SG, Elizabeth A, et al. New guidelines to evaluate the response to 
treatment in solid tumors. JNCL 2000;92:205-16. 


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UNOS resources page. United Network for Organ Sharing web site [cited 6 Feb 2008]. 
Available from: URL: http://www.unos.org/resources/MeldPeldCalculator.asp?index=98 
Venook AP: Treatment of hepatocellular carcinoma: too many options? J Clin Oncol 
1994;12:1323-34. 
Volkmann X, Fischer U, Bahr M, et al. Increased hepatotoxicity of tumor necrosis 
factor-related 
apoptosis-inducing 
ligand 
in 
diseased 
human 
liver. 
Hepatology 
2007;45:1498-508. 
Walczak H, Miller RE, Ariail K, et al. Tumoricidal activity of tumor necrosis factor-related 
apoptosis-inducing ligand in vivo. Nat Med 1999;5(2):157-63. 
Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member 
of the TNF family that induces apoptosis. Immunity 1995;3(6):673-82. 
Wilhelm SM, Carter C, Tang L, et al. Bay 43-9006 exhibits broad spectrum oral antitumor 
activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in 
tumor progression and antiogenesis. Cancer Res. 2004; 64:7099-109. 
WHO. World Health Organization. Hepatitis B, 2002. 
Younes A, Kadin ME. Emerging applications for the tumor necrosis factor family of ligands 
and receptors in cancer therapy. J Clin Oncol 2003;21:3526-34. 
Yu C, Bruzek LM, Meng XW, et al. The role of Mcl-1down-regulation in the proapoptotic 
activity of the multikinase inhibitor BAY 43-9006. Oncogene 2005;24:6861-9. 
Zhu AX. Systemic therapy of advanced hepatocellular carcinoma: how hopeful should we be? 
Oncologist 2006;11(7):790-800. 
Zhu, AX. Development of sorafenib and other molecularly targeted agents in hepatocellular 
carcinoma. Cancer 2008;112:250-9. 
Zimmermann H, Reichen J. Assessment of liver function in the surgical patient. In: Blumgart 
LH, Fong Y, ed. Surgery of the Liver and Biliary Tract, London: WB Saunders; 35-64:2000. 
 
 
 


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List of Appendices 
Appendix 1 
Child-Pugh Classification................................................................................. 59 
Appendix 2 
BCLC Staging and Treatment Strategy............................................................ 60 
Appendix 3 
Eastern Cooperative Oncology Group (ECOG) Performance Status............... 61 
Appendix 4 
New York Heart Association Classification for Congestive Heart Failure...... 62 
Appendix 5 
Response Evaluation Criteria in Solid Tumors (mRECIST for HCC)............. 63 
Appendix 6 
Exploratory Biomarker Sub-study.................................................................... 66 
Appendix 7 
Laboratory Tests............................................................................................... 69 
Appendix 8 
Treatment of Allergic/Hypersensitivity Reactions........................................... 70 
 
 
 
 
 


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Appendix 1 
Child-Pugh Classification 
(Zimmerman H and Reichen J, 2000) 
 
No. of Points 
Factor 
1 
2 
3 
Bilirubin (mg/dL) 
< 2 
2–3 
> 3 
Albumin (g/dL) 
> 3.5 
2.8–3.5 
< 2.8 
Prothrombin time (increased seconds) 
1–3 
4–6 
> 6 
Ascites 
None 
Slight 
Moderate 
Encephalopathy 
None 
Minimal 
Advanced 
 
Grade 
Score 
A 
5 – 6 
B 
7 – 9 
C 
10 – 15 
 
 


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Appendix 2 
BCLC Staging and Treatment Strategy 
 
HCC
Stage O
PS 0. Child-Pugh A
Stage A –C
PS 0-2. Child-Pugh A-B
Stage D
PS >2. Child-Pugh C
HCC
Very early stage (O)
Single <2cm.
Early stage (A)
Single or 3 nodules <3cm. PS 0
Intermediate stage (B)
Multinodular, PS 0
Advanced stage (C)
Portal invasion. N1.M1.PS 1-2
Terminal
stage D
Single 
3 nodules <3cm
Portal pressure/bilirubin
Normal 
Increased
Associated diseases
No 
Yes
Resection
Liver Transplantation
(CLT/LDLT)
PEI/RF
Curative Treatments
Chemoembolization
Sorafenib
Non-curative treatments
Symptom 
Treatment
 
Forner et al, 2010 
 
 
 
 
 


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Appendix 3 
Eastern Cooperative Oncology Group (ECOG) 
Performance Status 
 
 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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Appendix 4 
New York Heart Association Classification for Congestive 
Heart Failure 
(The Criteria Committee of the New York Heart Association; Little, Brown & Co. 1994) 
Class 
New York Heart Association Classification for Congestive Heart Failure 
1 
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. 
2 
Patients with cardiac disease resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
3 
Patients with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, 
or anginal pain. 
4 
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. 
If any physical activity is undertaken, discomfort is increased. 
 
 
 
 


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Appendix 5 
Response Evaluation Criteria in Solid Tumors (mRECIST 
for HCC) 
(Adapted from Lencioni and Llovet, 2010 for use in this study) 
Measurable disease: The presence of at least 1 target lesion, by contrast enhanced 
computerized tomography (CT) with use of multislice scanners, or contrast enhanced dynamic 
magnetic resonance imaging (MRI). 
Target lesion: Meets all the following criteria: 
- 
Located in the liver. 
- 
Can be accurately measured in at least 1 dimension. 
- 
Well-delineated area of viable, hypervascular (contrast enhancement in the arterial phase) 
tumor that is ≥ 2 cm in the axial plane. 
- 
Suitable for repeat measurement. 
- 
Not previously treated with locoregional or systemic treatment unless the lesion shows a 
well-delineated area of viable (contrast enhancement in the arterial phase) tumor that is 
≥ 2 cm in the axial plane. (If the lesion is poorly demarcated or exhibits atypical 
enhancement as a result of the previous intervention, then it cannot be selected as a target 
lesion). 
 
A maximum of 5 target lesions may be selected. 
Nontarget lesion: Other lesions, including small lesions (< 2 cm in the axial plane). Note 
thatmalignant portal vein thrombosis should be considered a nonmeasurable, and therefore 
nontarget, lesion. Lymph nodes at the portal hepatic can be considered as malignant if the 
lymph node short axis is at least 2 cm. Inclusion of effusion, notably ascities, as a nontarget 
lesion is discouraged. If effusion is selected as a nontarget lesion, it must be confirmed by 
cytopathologic confirmation. In addition, cytopathologic confirmation of any effusion that 
appears or worsens is required when the target lesion(s) have met criteria for response or 
stable disease. 
Measurement of lesions: Imaging studies will be by contrast enhanced CT, with use of 
multislice scanners, or contrast enhanced MRI. The same method must be used at baseline and 
during follow up. Note that the longest diameter of the viable tumor is not necessarily located 
in the same scan plane in which the baseline diameter was measured. The measurement of the 
viable tumor diameter should not include any major intervening areas of necrosis. (Please see 
the HGS1012-C1103 Radiographic Data Collection Manual). 
Evaluation of target lesions: 
Complete Response (CR): Disappearance of intratumoral arterial enhancement in all target 
lesions. 


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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. 
Stable Disease (SD): Any cases that do not qualify for CR, PR or SD. 
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. 
Evaluation of nontarget lesions: 
Complete Response (CR): Disappearance of intratumoral arterial enhancement. 
Incomplete Response/Stable Disease (IR/SD): Persistence of intratumoral arterial 
enhancement in 1 or more nontarget lesions. 
Progressive Disease (PD): Unequivocal progression of existing nontarget lesions.   
Evaluation of new lesions: A newly detected hepatic nodule will be classified as evidence of 
progression when its longest diameter is ≥ 1 cm and the nodule shows the 
hypervascularization in the arterial phase with washout in the portal venous or late venous 
phase.   
Liver lesions ≥ 1 cm that do not show a typical vascular pattern can be diagnosed as HCC by 
evidence of at least a 1 cm-interval growth in subsequent scans.  
An individual radiologic event will be adjudicated in retrospect as progression at the time it 
was 1st detected by imaging techniques, even if strict criteria were fulfilled only on subsequent 
radiologic testing. 
Evaluation of Overall Response: The overall response is determined at each assessment and 
is a result of the combined assessment of target lesions, nontarget lesions and new lesions. 
Overall Response Assessment 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response* 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
*AFP is not included in assessment of overall response. 
 


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Best Overall Response: 
The best overall response is the best response recorded from the start of treatment until 
disease progression. To be assigned a best overall response of CR or PR, changes in tumor 
measurements must be confirmed at the next scheduled disease assessment (no fewer than 
4 weeks after the initial documentation of PR or CR). 
 
 
 
 


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Appendix 6 
Exploratory Biomarker Sub-study 
1. Background 
Mapatumumab is a targeted therapy. Presently, the relationship between expression of the 
target, TRAIL-R1, and the anti-tumor activity of the antibody is incompletely understood. 
Studies conducted with cell lines derived from human tumors have suggested that the 
relationship between receptor expression and mapatumumab-induced tumor cell death may be 
complex. However, studies of human tumor cells in vitro and transplanted into animals may 
not accurately reflect the relationship between receptor expression and response to 
mapatumumab that may be observed in patients with cancer. One feature of this biomarker 
study is to compare TRAIL-R1 expression from available biopsy material. This could allow 
for a greater understanding of patterns of TRAIL-R1 expression in advanced hepatocellular 
carcinoma. 
It is also likely that other factors involved in TRAIL-R1 signaling could critically affect 
response to mapatumumab treatment. A 2nd goal of this biomarker study is to evaluate 
biomarkers that may be potential indicators or modifiers of response to mapatumumab. To 
identify factors that may indicate that a patient is responding to treatment, serum-based 
markers will be compared before and after treatment. To explore factors that are associated 
with the outcome of therapy and could be used prior to treatment to predict which patients 
will respond, somatic (inherited) differences that modify a patient’s drug response will be 
examined. 
The information generated from this sub-study will be used solely for research purposes to 
improve future treatment with mapatumumab. It will not be used to change diagnoses or alter 
therapy. Participation in this sub-study is optional. 
2. Study Objectives and Design 
2.1. 
Indicators of Response 
2.1.1. 
Serum-Based Markers of Response 
Induction of cell death in tumor cells can elicit the release of certain biomarkers into the 
serum. These markers can be quantified to evaluate treatment effect. To assess release of 
biomarkers associated with cell death, serum-based assays will be conducted, including, but 
not limited to, assessments of M30, a fragment of cytokeratin 18 that is generated by 
induction of programmed cell death in epithelial tissues. Other examples of markers of tumor 
cell death that will be examined include the cytokines TRAIL, TNFα, soluble Fas ligand, 
interferonα, interferonγ, interleukin-2, interleukin-6, interleukin-8, interleukin-10, and 
interleukin-12. The levels of these factors will be examined before and after treatment to see if 
they correlate with response to treatment. 
Serum will be isolated and the level of cytokines and other markers like M30 will be 
characterized. Collection, processing and handling of these samples are described in the 
laboratory manual. 


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Samples collected in this study will be stored for up to 15 years and may be analyzed with 
samples collected in other studies, but will only be used for mapatumumab-related research. 
2.2. 
Modifiers of Response 
2.2.1. 
Neoplastic Modifiers of Response 
Historically collected tumor biopsy material, if available, will be collected from subjects 
during Cycle 1. Samples will also be obtained from subjects who undergo a biopsy during the 
treatment period. Samples of resected tumor tissue that has been formalin-fixed and embedded 
in paraffin is acceptable; either tissue blocks or slides may be provided. Frozen samples of 
tumor tissue may also be provided. Biopsy material collected from fine needle aspirates may 
be provided; either cell pellets or cytological slides are acceptable. 
Levels of TRAIL receptors will be assessed in biopsy material using immunohistochemical 
techniques if samples are available as formalin-fixed/paraffin-embedded tissue blocks or 
slides. Historically obtained biopsy material or biopsy material obtained during the treatment 
period that is in the form of fresh frozen tissue or cell pellet samples will be utilized to isolate 
RNA for analysis of TRAIL receptor gene expression. 
Similar techniques will be used to evaluate other potential biomarkers and factors that may 
influence mapatumumab response. These may include but are not limited to caspase 8, AKT 
and Mcl-1. 
See the laboratory manual for collection, processing and handling of these samples. 
Samples collected in this study will be stored for up to 15 years and may be analyzed with 
samples collected in other studies, but will only be used for mapatumumab-related research. 
2.2.2. 
Somatic Modifiers of Response 
Inherited differences in the genes that code for drug targets or components of signaling 
pathways related to the target can dramatically influence the effect of pharmacotherapy. 
Variations in genes that could potentially impact mapatumumab’s activity, including 
polymorphic changes in the Fc gamma receptor and interleukin-6 promoter and K-Ras gene 
mutations, will be examined to see if they correlate with response to treatment. 
DNA will be isolated from the blood and polymorphisms and mutations in specific response-
related genes will be characterized. Collection, processing and handling of these samples are 
described in the laboratory manual. 
Samples collected in this study will be stored for up to 15 years and may be analyzed with 
samples collected in other studies, but will only be used for mapatumumab-related research. 


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3. Statistical Analysis 
Associations will be assessed between candidate biomarkers and treatment outcomes captured 
in the clinical database. Statistical tests to be performed may include Pearson chi-square 
testing, Fisher’s exact test, ANOVA and ANCOVA. Results of the biomarker sub-study may 
be reported independent of the results of HGS1012-C1103. 
4. Subject Selection and Withdrawal 
Subjects enrolled in the HGS1012-C1103 research study are given the option to participate in 
the Biomarkers Sub-study. A subject may withdraw from the sub-study at any time by 
contacting their Study Investigator, who will contact the sponsor. The sponsor will destroy 
any remaining sample materials and will send a letter back to the Investigator confirming 
sample destruction. Any data or analysis generated from the sample prior to the request for 
destruction will not be destroyed. However, no new information will be generated from the 
sample and no new analysis will be performed. 
5. Confidentiality 
Information about sub-study subjects will be kept confidential and managed according to the 
requirements of local privacy regulations. Information obtained from samples will not be 
returned to subjects and will not be placed in the subject’s medical record. 
6. Ethical Considerations 
All subjects enrolled in the HGS1012-C1103 research study who agree to participate in the 
Biomarker Sub-study will be asked to sign a separate Biomarker Informed Consent. Choosing 
to not participate in this sub-study will not affect the subject’s ability to participate in the main 
clinical trial. The Biomarker Informed Consent will be submitted along with the main 
research study informed consent for review by the Institutional Review Board/Ethical 
Committee. 
7. Publication of Biomarker Results 
Any significant findings, based upon the analysis of aggregate data collected from this 
sub-study may be published by Human Genome Sciences. Personal identifiers will not be 
used in any publication resulting from this sub-study. 
 
 
 


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Appendix 7 
Laboratory Tests 
CBC with Differential 
Chemistry 
Total white blood cell (WBC) count differential: 
Electrolytes: 
 
Neutrophils 
 
Sodium 
 
Bands  
 
Potassium 
 
Lymphocytes  
 
Magnesium 
 
Monocytes 
 
Chloride 
 
Eosinophils 
 
Carbon dioxide/bicarbonate* 
 
Basophils 
 
Calcium 
        
 
 
 
Hemoglobin 
Enzymes: 
Hematocrit 
 
SGOT (AST) 
Red blood cell count 
 
SGPT (ALT) 
Platelet count 
 
Alkaline phosphatase 
Absolute Neutrophil Count 
 
Amylase 
Total white blood cell count 
 
Lipase 
 
 
Gamma glutamyl transferase (GGT) 
Prothrombin time (PT) 
 
Partial thromboplastin time (PTT) 
Other: 
International normalized ratio (INR) 
Creatinine 
 
Blood Urea Nitrogen 
Other: 
Total bilirubin 
Serum and Urine pregnancy 
Total protein 
Hepatitis B surface antigen 
Albumin 
Hepatitis C antibody 
 
B and T lymphocytes 
 
HCV RNA  
 
HBV DNA 
 
HBsAb 
 
*To be collected if included in routine automated serum chemistry panel. 
 
Refer to Section 6 (Study Procedures) for laboratory test collection schedule. 
 


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Appendix 8 
Treatment of Allergic/Hypersensitivity Reactions 
In the event of allergic/hypersensitivity reactions to mapatumumab/placebo, investigators will 
institute treatment measures according to best medical and nursing practice. The grading is 
based upon the NCI-CTCAE Version 4.0.0. 
The following treatment guidelines will be employed: 
• If chills and fever occur, the infusion will be interrupted. Subjects may be treated 
symptomatically and the infusion will be restarted at 50% of the original rate. 
 
Grade 1 allergic/hypersensitivity reaction (transient flushing or rash, drug fever < 38°C): 
• Decrease infusion rate by 50% and monitor for worsening condition. If the reaction 
worsens, stop the infusion. 
 
Grade 2 allergic/hypersensitivity reaction (rash, flushing, urticaria, dyspnea, drug fever 
< 38°C): 
• Stop the infusion. 
• Administer bronchodilators, oxygen, acetaminophen, etc as medically indicated. 
• Resume infusion at 50% of previous rate once reaction has decreased to ≤ Grade 1 in 
severity. Monitor closely for any worsening. If the reaction recurs, stop the infusion. 
 
Re-treatment following Grade 1 or Grade 2 allergic/hypersensitivity reactions: 
• Once the infusion rate has been decreased due to an allergic/hypersensitivity reaction, it 
will remain decreased for all subsequent infusions. 
• If the subject has a 2nd reaction at the lower infusion rate, the infusion will be stopped and 
the subject will receive no further treatment with mapatumumab/placebo. 
• If the subject experiences a Grade 3 or Grade 4 allergic/hypersensitivity reaction at any 
time, the subject will receive no further treatment with mapatumumab/placebo. 
• If there are questions concerning whether an observed reaction is an 
allergic/hypersensitivity of Grades 1-4, the medical monitor will be contacted immediately 
to assist with grading the reaction. 
 
Grade 3 or Grade 4 allergic/hypersensitivity reaction: 
• A Grade 3 hypersensitivity reaction consists of symptomatic bronchospasm requiring 
parenteral medications with or without urticaria, allergy-related edema/angioedema, or 
asymptomatic hypotension not requiring treatment. 
• A Grade 4 hypersensitivity reaction (ie, anaphylaxis) is a life-threatening event 
characterized by the same symptoms as in a Grade 3 reaction but also complicated by 
symptomatic hypotension or oxygen saturation of 90% or less. 
 


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Treatment of Grade 3 or Grade 4 allergic/hypersensitivity reaction: 
• Stop the infusion immediately and disconnect infusion tubing from the subject. 
• Administer epinephrine, bronchodilators, antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, etc, as medically indicated. 
 
Contact Human Genome Sciences to report an SAE and fax SAE worksheet. 
 
 
 
 
 
 


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SAP_001.pdf: 
CONFIDENTIAL
1
Human Genome Sciences, Inc.
Analytical Plan for Protocol HGS1012-C1103 (200149)
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
10 November 2011
Confidentiality
This document contains proprietary and confidential information of Human Genome Sciences, 
Inc. and may not be reproduced or disclosed in whole or part without prior written authorization 
from Human Genome Sciences, Inc.
 
2013N181891_00
200149


Human Genome Sciences, Inc.
CONFIDENTIAL
Analytical Plan for Protocol: 200149
Mapatumumab
2
TABLE OF CONTENTS
1
Introduction........................................................................................................................5
2
Study Objectives ................................................................................................................5
2.1
Primary Study Objectives ........................................................................................5
2.2
Secondary Study Objectives ....................................................................................5
3
Study Administrative Structure..........................................................................................5
4
Study Design......................................................................................................................6
4.1
Choice of Control Group .........................................................................................6
4.2
Study Population......................................................................................................7
4.3
Inclusion and Exclusion Criteria..............................................................................7
4.4
Treatment Assignment.............................................................................................7
4.5
Data Monitoring.......................................................................................................7
4.6
Interim Analysis.......................................................................................................7
5
General Statistical Considerations.....................................................................................7
5.1
Determination of Sample Size .................................................................................8
6
Study Subjects....................................................................................................................8
6.1
Subject Disposition..................................................................................................8
6.2
Extent of Exposure...................................................................................................8
6.3
Completion Status..................................................................................................11
6.4
Demographics and other Baseline Characteristics.................................................11
6.5
Concomitant Medications......................................................................................11
7
Efficacy Analyses ............................................................................................................12
7.1
Primary Efficacy Endpoint Analyses.....................................................................12
7.1.1
Primary Efficacy Endpoint(s) ......................................................................12
7.1.2
Primary Efficacy Analyses ..........................................................................12
7.1.3
Additional Analyses of Time to Progression...............................................12
7.1.4
Adjustment for Covariates...........................................................................13
7.1.5
Subgroup Analyses ......................................................................................13
7.2
Major Secondary Efficacy Endpoint Analyses......................................................13
7.2.1
Major Secondary Efficacy Endpoints ..........................................................13
7.2.2
Major Secondary Efficacy Analyses............................................................14
7.2.3
Adjustment for Covariates...........................................................................14
7.2.4
Subgroup Analyses ......................................................................................14
7.3
Handling of Dropouts and Missing Data ...............................................................14
7.3.1
Handling of Missing Data............................................................................15
7.3.2
Other Censoring Rules.................................................................................15
7.4
Protocol Prohibited Therapies and Medications....................................................16
7.4.1
Protocol Prohibited Locoregional Therapy..................................................16
7.4.2
Protocol Prohibited Medications..................................................................16
 
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Analytical Plan for Protocol: 200149
Mapatumumab
3
7.5
Assignment of Dates of Disease Progression or Disease Response ......................16
7.6
Other Efficacy Analyses ........................................................................................17
7.6.1
Exploratory Alpha Fetoprotein Analysis .....................................................17
7.6.2
Time to Disease Assessments Analysis .......................................................17
8
Safety Analysis ................................................................................................................18
8.1
Definition of Safety Variables ...............................................................................18
8.2
Analysis of Adverse Events...................................................................................18
8.3
Serious Adverse Events .........................................................................................18
8.4
Deaths and Discontinuations due to Adverse Events ............................................18
8.5
Clinical Laboratory Evaluation..............................................................................19
8.5.1
Exploratory Assessments (B & T Lymphocyte Subsets) Analysis..............19
8.6
Vital Signs..............................................................................................................19
8.7
Immunogenicity.....................................................................................................19
8.8
Subgroup Analyses ................................................................................................20
9
Pharmacokinetic and Pharmacodynamic Analyses .........................................................20
10
Other Analytical Considerations......................................................................................21
11
References........................................................................................................................22
 
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Analytical Plan for Protocol: 200149
Mapatumumab
4
List of Abbreviations
AE
adverse event
AFP
α-fetoprotein
ATC
Anatomical Therapeutic Chemical 
BCLC
Barcelona Clinic Liver Cancer
BICR
blinded independent central review
CR
complete response
DNA
deoxyribonucleic acid
eCRF
electronic case report form
ECOG
Eastern Cooperative Oncology Group
HCC
hepatocellular carcinoma
HGS
Human Genome Sciences
IWRS
interactive web response system
kg
kilogram
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MITT
modified intention-to-treat
mRECIST
modified Response Evaluation Criteria in Solid Tumors assessment 
NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse 
Events
OS
overall survival
PD
progressive disease
PFS
progression free survival
PR
partial response
PT
preferred term
RFA
radiofrequency ablation
SAE
serious adverse event
SD
stable disease
SLD
sum of longest diameters
SOC
system organ class
TRAIL-R1
tumor necrosis factor-related apoptosis inducing ligand receptor 1
TTP
time to progression
WHO
World Health Organization
 
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Human Genome Sciences, Inc.
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Analytical Plan for Protocol: 200149
Mapatumumab
5
1
Introduction
HGS1012-C1103 is a Phase 2, multi-center, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of mapatumumab in combination with 
sorafenib in subjects with advanced hepatocellular carcinoma.
2
Study Objectives
2.1
Primary Study Objectives
The primary objective of this study is to evaluate the efficacy of mapatumumab in 
combination with sorafenib in subjects with advanced hepatocellular carcinoma.
2.2
Secondary Study Objectives
The secondary objectives of this study are:

To evaluate the safety of mapatumumab in combination with sorafenib in subjects 
with advanced hepatocellular carcinoma.

To determine serum mapatumumab concentrations.
3
Study Administrative Structure
Human Genome Sciences (HGS) is the sponsor of this study. Data collected for this study 
will be recorded electronically on case report forms (eCRFs) provided or approved by the 
sponsor.
Sites will enter subject data directly into the eCRF system which will automatically 
generate queries resulting from computer checks embedded into the system, so as to 
ensure accuracy, quality, consistency, and completeness of the database. Manual queries 
resulting from review by monitors, medical coders, and other Data Management staff are 
also generated from within the electronic data capture system, where they are tracked. 
Sites resolve the queries and correct the entered data when necessary. Every change to 
data is captured in the electronic data capture system audit trail. 
HGS will have discretion to lock the database when 90% of all randomized and treated 
subjects have been followed to radiologic disease progression, or when all subjects have 
been followed for at least 12 months at which point blinded review of the remaining data 
will facilitate a decision on whether to lock the database or wait for remaining events.
 
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4
Study Design
In addition to receiving sorafenib, subjects will be randomly assigned to 1 of 2 treatment 
groups in a 1:1 ratio: 30 mg/kg mapatumumab or placebo. Approximately 100 subjects 
with advanced hepatocellular carcinoma will be randomized. Randomization will be 
stratified according to Barcelona Clinic Liver Cancer (BCLC) advanced stage C vs.
BCLC intermediate stage B and Eastern Cooperative Oncology Group (ECOG) 
performance status (0 vs. 1, 2).
Radiologic eligibility must be confirmed by a blinded independent central review (BICR) 
prior to randomization. Subjects will receive treatment every 21 days (ie, a cycle) as 
outlined below:
Arm A:
Sorafenib 400 mg orally twice daily continuously in each cycle + placebo 
intravenously on Day 1 of each cycle
Arm B:
Sorafenib 400 mg orally twice daily continuously in each cycle + 
mapatumumab (30 mg/kg) intravenously on Day 1 of each cycle
The study is estimated to occur over approximately 24 months. Subjects will continue to 
receive sorafenib and/or mapatumumab/placebo until radiologic disease progression or 
unacceptable 
toxicity. 
Subjects 
may 
discontinue 
either 
sorafenib 
or 
mapatumumab/placebo separately and remain on treatment. After discontinuation of 
treatment, subjects will continue to be followed for radiologic disease assessments every 
6 weeks (± 3 days), starting 6 weeks after the previous disease assessment while on 
treatment, until documented radiologic disease progression (if not previously 
documented). Thereafter, subjects will be followed every 3 months for survival until at 
least 90% of subjects have met the survival endpoint.
If disease progression is based only on a new lesion(s) or is equivocal, images will be 
provided to the BICR for confirmation of radiologic disease progression prior to 
discontinuing study treatment. Decisions regarding subject treatment will remain the 
responsibility of the investigator. Additionally, all images obtained on study will be 
provided to the BICR for the independent efficacy read.
4.1
Choice of Control Group
The control group in this study is Arm A: sorafenib 400 mg orally twice daily 
continuously in each cycle + placebo intravenously on Day 1 of each cycle. The control 
group will be used for comparison purposes for both primary and secondary efficacy and 
safety analyses. It will also be used to provide a measure of internal validity to the 
interpretation of results from the sorafenib + mapatumumab 30 mg/kg study arm,
commensurate with consistency of observed outcomes in the sorafenib + placebo study 
arm to historical outcomes in this patient population.
 
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4.2
Study Population
The study population consists of subjects 18 years of age or older with advanced 
hepatocellular carcinoma who meet a Child-Pugh Classification of A and either BCLC 
advanced stage (C) hepatocellular carcinoma, or BCLC intermediate stage (B) 
hepatocellular carcinoma if treatment with transarterial chemoembolization is not 
considered appropriate. Subjects must also have a performance status of 0, 1 or 2 on the 
ECOG scale and meet the radiologic and laboratory eligibility criteria as defined in 
Section 4 of the protocol.
4.3
Inclusion and Exclusion Criteria
The inclusion and exclusion criteria are stated in Section 4 of the protocol.
4.4
Treatment Assignment
Subjects that meet the eligibility criteria will be randomly assigned treatment by a 
central interactive web response system (IWRS) in a 1:1 ratio to 1 of 2 treatment arms
(Arm A: sorafenib + placebo or Arm B: sorafenib + mapatumumab 30 mg/kg). The 
randomization will be stratified according to BCLC advanced stage C vs. BCLC 
intermediate stage B and ECOG performance status (0 vs. 1, 2) as defined in Appendices 
2 and 3 of the protocol, respectively. 
4.5
Data Monitoring
To assure appropriate study conduct and adherence to Good Clinical Practice, this study 
incorporates ongoing and continuous monitoring as specified in Section 10.6 of the 
protocol.
4.6
Interim Analysis
This study has no interim analysis planned.
5
General Statistical Considerations
Statistical analyses performed on the efficacy data will be applied to a modified 
intention-to-treat (MITT) population unless stated otherwise. This population is defined 
as the set of all randomized subjects who receive at least part of 1 dose of study agent
(mapatumumab/placebo and/or sorafenib) with subjects analyzed according to the groups 
to which they are randomized, regardless of the treatment they subsequently receive. 
Additional analyses may be performed on the as-treated population, defined as the set of 
subjects receiving at least part of 1 dose of study agent analyzed according to the 
treatment that they actually receive. All analyses performed on safety, subject disposition, 
exposure and completion status will be applied to the as-treated population. Analyses 
performed on demographics and concomitant medications data will be applied to the 
MITT population.
 
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Assessments will be referred to by day of cycle beginning with Cycle 1/Day 1. This will 
allow data from subjects with small fluctuations in cycle length, or dosing delays to be 
reported in a consistent fashion. Cycle 1/Day 1 (predose) will typically be the baseline 
assessment unless data are missing, in which case screening data closest to the Cycle 
1/Day 1 assessment will be used. In the instance a subject discontinues all treatment, or 
discontinues mapatumumab/placebo, but remains on sorafenib treatment, an off-treatment 
distinction will be made when referencing disease assessments.
Categorical data analyses using the Pearson chi-square test will substitute Fisher’s exact 
test if 20% of expected contingency table cell counts are 5.
Analyses will be performed using the SAS System™, WinNonlin Enterprise Edition™, 
StatXact™, and the R statistical package.
5.1
Determination of Sample Size
A total of approximately 100 subjects will be randomly assigned to 1 of 2 arms and 
treated with either sorafenib + placebo or the 2-agent combination of sorafenib +
mapatumumab 30 mg/kg in a 1:1 ratio. A sample size of 50 subjects randomized and 
treated in each group is sufficient to estimate the median time to progression (TTP) with 
a precision of approximately -1.9 months to +2.6 months relative to the observed median. 
In addition, a sample size of 50 patients per arm will provide 80% power to detect an 
improvement in TTP from 5.5 to 8.9 months with at a one-sided significance level of 
0.10.
6
Study Subjects
6.1
Subject Disposition
Subject eligibility, compliance, and study completion will be summarized. Reasons for 
failing screening, failing enrollment (randomized but never received treatment) or not 
completing the study (as defined in Section 6.3 below) will be identified. 
6.2
Extent of Exposure
The extent of exposure to mapatumumab/placebo and to sorafenib will be assessed by 
examining duration of exposure in both months and cycles (cycles only relevant while 
subject is administered mapatumumab/placebo), dose intensity, relative dose intensity, 
dose reductions, dose omissions and dose delays by treatment group. 
Duration of exposure for mapatumumab/placebo will be calculated as the date of dosing 
for the last cycle plus 21 days minus the date of 1st treatment. For subjects who die prior 
to Day 21 of the last cycle, duration of exposure will be calculated as the date of death 
 
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minus the date of 1st treatment plus 1 day. Duration of exposure for sorafenib will be 
calculated as the date of last dose minus the date of 1st treatment plus 1 day. 
Cumulative dose received for mapatumumab will be calculated as
Cumulative dose received = 

K
k 1 Dose received at each cycle (mg/kg)
where K = total number of treatment cycles received by the subject. In the case that body 
weight is unknown at a visit, the last non-missing measurement prior to the visit will be 
used.
Cumulative dose received for sorafenib will be calculated as
Cumulative dose received = 

M
m 1 Dose received each day (mg)
where M = total number of days the subject received sorafenib.
Dose intensity will be expressed as the cumulative dose for mapatumumab (mg/kg) and 
sorafenib (mg) received, respectively, divided by duration of treatment (weeks) for each 
treatment, respectively. 
Dose intensity = 
(weeks)
 treatment
of
Duration 
mg)
or 
(mg/kg
received
dose
Cumulative
such that the definition of duration of treatment is dependent on the order of treatment 
discontinuation. If both mapatumumab and sorafenib are discontinued on the same date 
the duration of treatment for mapatumumab is defined as the date of dosing of 
mapatumumab in the last cycle plus 21 days minus the date of 1st treatment and the 
duration of treatment for sorafenib is defined as the date of last dose of sorafenib minus 
the date of 1st treatment plus 1 day. If mapatumumab is discontinued prior to sorafenib 
the duration of treatment for mapatumumab is defined as either the date of dosing of 
mapatumumab for the last cycle plus 21 days minus the date of 1st treatment, or the date 
of last dose of sorafenib minus the date of 1st treatment plus 1 day, whichever is greater. 
Duration of treatment for sorafenib will not differ from when both mapatumumab and 
sorafenib are discontinued on the same date. If sorafenib is discontinued prior to 
mapatumumab the duration of treatment for sorafenib is defined as the date of dosing of 
mapatumumab in the last cycle minus the date of 1st treatment plus 1 day. Duration of 
 
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treatment for mapatumumab will not differ from when both mapatumumab and sorafenib 
are discontinued on the same date.
Relative dose intensity will be expressed as the ratio of dose intensity and planned dose 
intensity
Relative dose intensity = 
mg/weeks)
or 
ks
(mg/kg/wee
intensity 
dose
Planned
mg/weeks)
or 
ks
(mg/kg/wee
intensity 
Dose
such that planned dose intensity for mapatumumab is equal to the planned dose (mg/kg) 
divided by the number of weeks within a cycle and planned dose intensity for sorafenib is 
800 mg times the duration of exposure to sorafenib in days divided by the number of 
weeks on treatment.
Mapatumumab/placebo doses that are administered 2 or more days from the target date of 
dosing will be considered delayed. The target date of dosing for each cycle is the 
previous date of dosing plus 21 days. The length of delay for a delayed dose is calculated 
as the actual date of dosing minus the target date of dosing. Descriptive statistics will be 
provided by treatment group.
Dose reductions are not permitted for mapatumumab/placebo. However, any 
mapatumumab/placebo dosing interruptions that take place resulting in a reduction from 
the intended dose will be considered dose reductions. Sorafenib dose reductions will be 
summarized. A dose reduction will be defined as a physician decision to reduce the 
prescribed dose to a lower level relative to the previous prescribed dose while on 
treatment (including reductions to 0 mg which would constitute dose omission, also 
analyzed separately, see below). The number of subjects requiring at least 1 dose 
reduction will be summarized along with the maximum dose level reduction attained for 
each subject. In addition, rates of subjects requiring dose reductions due to adverse events 
(AEs) or laboratory abnormalities will be provided. Statistical analysis of dose reduction 
rates will include Pearson chi-square testing (or Fisher’s exact testing, as appropriate) for 
differences between groups. Dosing errors for either mapatumumab/placebo or sorafenib 
will not be identified as dose reductions in the analysis.
In addition, all sorafenib dose reductions observed (possibly multiple events per subject) 
will be summarized by treatment group and reason. The percent of dose reductions that 
resulted in an eventual return to the original dose level from which the subject was 
reduced will be calculated.
The number of subjects requiring sorafenib dose omissions will be summarized by 
treatment group. A subject will be determined to have a dose omission if the prescribed 
dose for a given time interval (while on sorafenib treatment) is 0 tablets per day. 
Statistical analysis of the rate of subjects requiring dose omission (overall, due to AEs, 
 
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and due to laboratory abnormalities) will include Pearson chi-square testing (or Fisher’s 
exact testing, as appropriate). In addition, all dose omissions (possibly multiple events 
per subject) will be summarized by treatment group and reason. 
6.3
Completion Status
Subjects will continue to receive study agent(s) until radiologic disease progression or 
unacceptable toxicity. Subjects unable to tolerate sorafenib may continue to receive 
mapatumumab/placebo every 21 days until radiologic disease progression. Subjects 
unable to tolerate mapatumumab/placebo may continue to receive sorafenib until 
radiologic disease progression. All subjects will have an End of Treatment visit at least 
30 days after the last dose of sorafenib and/or mapatumumab/placebo, whichever is later. 
After discontinuation of treatment, subjects will continue to be followed for radiologic 
disease assessments every 6 weeks, starting 6 weeks after the previous disease 
assessment while on treatment, until documented radiologic disease progression (if not 
previously documented) and then every 3 months thereafter for survival until at least 90% 
of the subjects have met the survival endpoint. After discontinuation of study treatment, 
all subjects will return 1 day after cycle completion (approximately Day 22) and at least 
30 days after the last dose of sorafenib and/or mapatumumab/placebo.
Completion will be summarized with respect to completion of the planned course of 
treatment, completion of required short-term follow-up and completion of required long-
term follow-up. Completion of the planned course of treatment will be satisfied by 
subjects who are treated until radiologic disease progression. Completion of short-term 
follow-up will be satisfied by subjects who are followed through at least 30 days after the 
final dose (of any study agent) for scheduled safety assessments (or a pending disease 
assessment visit to confirm disease response if required), regardless of the reason for 
treatment discontinuation. Completion of long-term follow-up will be satisfied by those 
subjects who are followed for overall survival (OS). Completion of the study is defined 
as completing study treatment, completing short-term follow-up and completing long-
term follow-up. Subjects still being followed at the time of any analysis will be counted 
as “ongoing”.
6.4
Demographics and other Baseline Characteristics
Summary information related to medical history, sex, age, race, baseline disease state, 
and previous therapies will be presented. In general, counts and percentages will be 
presented for categorical data and mean, median, standard deviation, minimum, and 
maximum will be presented for continuous data.
6.5
Concomitant Medications
Concomitant medications will be coded according to drug name as defined in the World 
Health Organization (WHO) Drug Dictionary, classified according to the Anatomical 
Therapeutic Chemical (ATC) classification system and presented in tables and listings. 
 
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7
Efficacy Analyses
Efficacy analyses will be based on the BICR assessment. Evaluation of efficacy 
endpoints based on investigator data will be provided by applying modified Response 
Evaluation Criteria in Solid Tumors for hepatocellular carcinoma (mRECIST for HCC) 
(Lencioni, 2010 and Llovet, 2008) to investigator assessed tumor measurements. In 
addition, investigator reported objective response and disease control rates will be 
summarized with the caveat that these may differ from the application of mRECIST for 
HCC to the investigator assessed tumor measurements. Investigator reported disease 
progression dates will be presented in listings but not analyzed using time to event 
analysis techniques. Instead these analyses will be performed on time to progression 
(TTP) and progression free survival (PFS) dates resulting from application of mRECIST 
for HCC to investigator assessed tumor measurements along with the censoring 
guidelines and missing data rules described in this Analytical Plan.
7.1
Primary Efficacy Endpoint Analyses
7.1.1 Primary Efficacy Endpoint(s)
The primary endpoint is TTP defined as the time from randomization to radiologic 
disease progression based on BICR assessments of imaging scans using mRECIST for 
HCC (Llovet, et al, 2008 and Thomas, et al, 2010). 
7.1.2 Primary Efficacy Analyses
The primary analysis will be an estimate of median TTP in each arm using Kaplan Meier 
methods, reported with 95% confidence intervals, along with testing the hazard ratio for 
TTP at a 1-sided significance level of 0.10 with a Cox proportional hazards model 
controlling for the factors stratifying the randomization as covariates.
7.1.3 Additional Analyses of Time to Progression
While the primary analysis of TTP is based on the BICR determination of radiologic 
disease progression, additional analysis will be performed.

An analysis of TTP as determined by the BICR censoring subjects at the date of 
the last complete disease assessment performed prior to any protocol prohibited 
medications/therapy as specified in Section 5.3 of the protocol (eg, cytotoxic 
chemotherapy, hormonal therapy, biological therapy, immunotherapy or 
locoregional therapy).

An analysis of TTP based on application of mRECIST for HCC to investigator 
assessed tumor measurements. In this analysis all subjects will be censored for 
TTP at the date of the last complete disease assessment performed prior to any 
protocol prohibited locoregional therapy.
 
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
An analysis of TTP based on application of mRECIST for HCC to investigator 
assessed tumor measurements censoring subjects at the date of the last complete 
disease 
assessment 
performed 
prior 
to 
any 
protocol 
prohibited 
medications/therapy (eg, cytotoxic chemotherapy, hormonal therapy, biological 
therapy, immunotherapy or locoregional therapy).
7.1.4 Adjustment for Covariates
Adjustment for covariates including the stratification factors BCLC advanced stage C vs. 
BCLC intermediate stage B and ECOG performance status (0 vs. 1, 2) is planned for the 
primary analysis as well as the analyses described in Section 7.1.3. 
7.1.5 Subgroup Analyses
Subgroup analyses may be performed on the stratification factors BCLC advanced stage 
C vs. BCLC intermediate stage B and ECOG performance status (0 vs. 1, 2). Subgroup 
analyses may also be performed on laboratory parameters testing for the hepatitis B 
surface antigen and the hepatitis C surface antibody (positive for the hepatitis B surface 
antigen vs. not, positive for the hepatitis C surface antibody vs. not). 
7.2
Major Secondary Efficacy Endpoint Analyses
7.2.1 Major Secondary Efficacy Endpoints
Secondary efficacy endpoints include overall survival, progression free survival, 
objective response, disease control, time to response (for responders), and duration of 
response (for responders) as defined below:

Overall survival (OS): time from randomization to death from any cause.

Progression free survival (PFS): time from randomization to radiologic disease 
progression or death from any cause.

Objective response: CR+PR according to mRECIST for HCC.

Disease control: CR+PR+SD according to mRECIST for HCC.

Time to response: time from randomization to 1st PR or CR in responders only.

Duration of response: time from 1st PR or CR to radiologic disease progression; in 
responders only.
such that CR is complete response, PR is partial response and SD is stable disease.
All secondary endpoints will be based on BICR assessments of imaging scans. Additional 
analyses based on application of mRECIST for HCC to investigator assessed tumor 
measurements, or investigator determination of disease response will be performed. For 
 
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the purposes of establishing SD based on BICR or application of mRECIST for HCC to 
investigator assessed tumor measurements, at least 6 weeks from the baseline 
measurement must elapse without progressive disease (PD) in order to assign a best 
overall response of SD. Confirmation of PR and CR will occur no fewer than 4 weeks 
after initial documentation of PR or CR. If PR or CR that is pending confirmation is 
designated at an assessment followed by 1 or more non-evaluable assessments or 
assessments of SD, response may be confirmed thereafter.
7.2.2 Major Secondary Efficacy Analyses
Secondary analyses include estimates, using Kaplan Meier methods, of median PFS and 
median OS along with associated logrank testing. The hazard ratio will also be estimated 
for PFS and OS using Cox proportional hazard modeling adjusting for factors stratifying 
the randomization as covariates. In addition, estimates of overall response rate (CR+PR) 
and disease control rate (CR+PR+SD) will be reported with 95% confidence intervals 
and an estimate of the difference in response rates and disease control rates between 
groups will be reported and tested for significance with a Pearson chi-square test (or 
Fisher’s exact test, as appropriate). The analysis of PFS as determined by the BICR 
described in this section will be repeated, but with PFS based on application of 
mRECIST for HCC to investigator assessed tumor measurements. Analyses of TTP as 
described in Section 7.1.3 will be repeated for PFS. In addition, the analyses of objective 
response, disease control, time to response and duration of response will be repeated with 
2 analyses: 1) with endpoints based on application of mRECIST for HCC to investigator 
assessed tumor measurements and 2) with endpoints as provided directly by the 
investigator.
7.2.3 Adjustment for Covariates
Adjustment for covariates including the stratification factors BCLC advanced stage C vs. 
BCLC intermediate stage B and ECOG performance status (0 vs. 1, 2) is planned for 
secondary endpoints PFS and OS in Cox proportional hazard modeling and logrank 
testing. 
7.2.4 Subgroup Analyses
Subgroup analyses may be performed on the stratification factors BCLC advanced stage
C vs. BCLC intermediate stage B and ECOG performance status (0 vs. 1, 2). Subgroup 
analyses may also be performed on laboratory parameters testing for the hepatitis B 
surface antigen and the hepatitis C surface antibody (positive for the hepatitis B surface 
antigen vs. not, positive for the hepatitis C surface antibody vs. not). 
7.3
Handling of Dropouts and Missing Data
These rules will apply uniformly to all efficacy analyses based on the BICR assessment 
as well as efficacy analyses resulting from application of mRECIST for HCC to 
investigator assessed tumor measurements. For investigator reported outcomes, analyses 
 
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will present outcomes reported by the investigator without consideration of missing data 
or censoring rules. In general, subjects not classifiable under the mRECIST for HCC 
response categories due to insufficient data or early death will be classified as non-
evaluable for objective response, but will be counted in the denominator of all response 
rate calculations.
7.3.1 Handling of Missing Data
7.3.1.1
Missing Data at Baseline
If a subject has missing target lesion measurements at baseline, the subject will be 
assigned PD if criteria for PD is exhibited at the first disease assessment. Otherwise, the 
subject will be classified as non-evaluable for objective response and censored at date of 
randomization for TTP. For PFS the subject will be censored at date of randomization
unless the subject dies within the first 6W post-baseline in which case this date will 
qualify as a PFS event.
7.3.1.2
Missing Data at a Disease Assessment
If a subject has missing tumor measurements at some assessment for 1 or more target 
lesions, the sum of the longest diameters (SLD) will be reported for the remaining target 
lesions.  These data will be used to indicate radiologic disease progression if the SLD for 
the observed lesions increases at least 20% from the nadir SLD of all lesions, in spite of 
the missing data (or if other criteria for PD are met). If a subject has missing tumor 
assessments at some assessment for 1 or more non-target lesions, radiologic disease 
progression will be determined if at least 1 of the remaining non-target lesions exhibits 
unequivocal progression (or if other criteria for PD are met). If a subject has missing 
tumor measurements at some assessment(s) for 1 or more target or missing recorded 
response at some assessment(s) for 1 or more non-target lesions and criteria for PD are 
not met, an overall response of non-evaluable will be assigned for the assessment(s). 
7.3.1.3
Missing Disease Assessment(s)
If a subject has a completely missed assessment(s) followed by an assessment showing 
radiologic disease progression, then PD will be assigned at the target date of the first 
missed assessment following an assessment showing no progression. This target date is
defined as 42 days after the previous disease assessment showing no progression. If a 
subject has a missed assessment(s) followed by an assessment showing no radiologic 
disease progression, then the assumption will be that the subject remained stable during 
the missed assessment(s).
7.3.2 Other Censoring Rules
Subjects who reach the survival endpoint due to any reason prior to experiencing a 
radiologic disease progression will be censored for TTP at the date of their last complete 
disease assessment. Subjects remaining on study without radiologic disease progression
or death at the time of analysis will be censored for TTP and PFS at the date of their last 
 
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complete disease assessment. Subjects lost to follow-up prior to experiencing a radiologic 
disease progression or death will be censored for TTP and PFS at the date of their last 
complete disease assessment.
7.4
Protocol Prohibited Therapies and Medications
As specified in Section 5.3 of the protocol, subjects should not receive any 
investigational or noninvestigational cytotoxic chemotherapy, hormonal therapy, 
biological therapy (including monoclonal antibodies), immunotherapy or any 
locoregional therapy (such as embolization, radiofrequency ablation (RFA), or 
percutaneous ethanol injection) to treat hepatocellular carcinoma during the treatment 
period. Alternative anticancer therapies may be administered after radiologic disease 
progression has been documented.
7.4.1 Protocol Prohibited Locoregional Therapy
These censoring rules apply to the primary analysis of TTP as well as PFS and disease 
response endpoints as determined by the BICR. Any locoregional therapy received while 
on study including embolization, RFA or percutaneous ethanol injection and the date 
performed will be reported to the BICR. If the BICR reviewer believes that one of the 
target lesions selected at baseline has been affected by such therapy, and that subsequent 
response or SD is attributable to locoregional therapy, the BICR reviewer will call that 
subject non-evaluable at all future disease assessments that occur on or after the date of 
locoregional therapy. Otherwise, the BICR reviewer will assess the subject ignoring the 
locoregional therapy. 
7.4.2 Protocol Prohibited Medications
The primary analysis of TTP as well as PFS and disease response endpoints as 
determined by the BICR will not be impacted by protocol prohibited medications. 
Instead, additional analyses as described in Section 7.1.3 will be performed.
7.5
Assignment of Dates of Disease Progression or Disease 
Response
For all analyses of endpoints as assessed by BICR or by application of mRECIST for 
HCC to investigator assessed tumor measurements, there may be cases in which disease
assessments span a series of dates. For establishing the start date of a subsequently 
confirmed response in which the disease assessment spans multiple days, the response 
date assigned will be the latest date of evaluations corresponding to the disease 
assessment. The date of latest assessment will also be assigned for a mid-study 
assessment showing SD as the date assigned to that SD for the purposes of censoring 
duration of SD. 
The date of PD will be the 1st date at which any objective diagnostic test provides data 
indicating PD. Specifically, the date of PD will be the earliest of the following 3 dates:
 
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
Date of PD as indicated by target lesions: if PD is triggered by a change in SLD 
of target lesions, and all evaluations occurred on the same day, assign that date. If 
the dates of evaluation of the target lesions vary for the same assessment, assign 
the first evaluation date among target lesions.

Date of PD as indicated by non-target lesions: the 1st date for which any non-
target lesion exhibits a response of PD.

Date of PD as indicated by new lesions: the 1st date for which any new lesion is 
detected.
7.6
Other Efficacy Analyses
7.6.1 Exploratory Alpha Fetoprotein Analysis
Alpha fetoprotein (AFP) assessments will be performed in conjunction with radiologic 
disease assessments. 
A positive AFP outcome will be defined for this exploratory analysis as at least a 20% 
decrease in AFP serum levels from baseline. Additional definitions of positive AFP 
outcomes may be explored further. Estimates of positive AFP outcome rate may be 
reported with 95% confidence intervals and an estimate of the difference in positive AFP 
outcome rates between groups may be reported and tested for significance with a Pearson 
chi-square test (or Fisher’s exact test, as appropriate). Subjects included in this analysis 
are those with AFP levels elevated to ≥400 µg/L at baseline. Additional criteria may be 
explored further.
AFP serum levels may be summarized by study visit and may include descriptive 
statistics such as mean, median, standard deviation, minimum, and maximum, and the 
changes from baseline. Additional analyses may be performed.
7.6.2 Time to Disease Assessments Analysis
Estimates of median time to disease assessments in each arm using Kaplan Meier 
methods, reported with 95% confidence intervals will be provided for the first four 
disease assessments on study along with associated logrank testing. Subjects lost to 
follow-up or that reach the survival endpoint will be censored at the date of their last 
disease assessment. For disease assessments that span multiple days, the disease 
assessment date assigned will be the date when the first imaging scan from the disease 
assessment was performed.
 
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8
Safety Analysis
8.1
Definition of Safety Variables
The safety parameters assessed are given by the following:

Frequency, and severity of AEs:
-
All AEs will be classified by System Organ Class (SOC) and Preferred Term (PT) 
under the Medical Dictionary for Regulatory Activities (MedDRA) system of 
classification with a severity assigned according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 4.0), 
or the rules specified in Section 8.6 of the protocol.
-
Laboratory parameters as presented in Appendix 7 of the protocol.
-
Laboratory toxicities will be graded based on the NCI-CTCAE (Version 4.0).

Vital signs.

Anti-mapatumumab antibody response.
All analyses performed on safety will be performed on the as-treated population.
8.2
Analysis of Adverse Events
The safety analysis will consist of a presentation of rates of AEs observed. Specific AEs 
will be counted once for each subject for calculating rates, but will be presented in total 
in subject listings. In addition, if the same AE occurs multiple times within a particular 
subject, the highest severity and level of causality observed will be reported. If any 
associations of interest between AEs and baseline characteristics are observed, additional 
stratified results may be presented. All treatment-emergent AEs will be summarized 
overall, as well as categorized by the MedDRA system of classification. AEs will be 
presented overall, by severity, by relation to mapatumumab/placebo, and by relation to 
sorafenib.
8.3
Serious Adverse Events
Serious adverse events (SAEs) will be summarized by relation to mapatumumab/placebo
and by relation to sorafenib.
8.4
Deaths and Discontinuations due to Adverse Events
A summary of all subjects who die due to any cause or who discontinue study agent 
(mapatumumab/placebo and/or sorafenib) due to AEs will be provided.
 
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8.5
Clinical Laboratory Evaluation
Laboratory parameters will be assessed at baseline and throughout the study. Frequencies 
of worst observed grade 0 to 4 toxicity as defined by the NCI-CTCAE (Version 4.0) will 
be presented for each laboratory parameter.
Also, laboratory parameters will be assessed by presenting tables containing information 
related to 2-grade (or greater) laboratory shifts from baseline. Specific laboratory tests are 
listed in Appendix 7 of the protocol. Some laboratory tests can be graded for toxicity for 
either an increase or a decrease (sodium, potassium, magnesium, calcium, and glucose). 
Because of this, they will be listed twice in each presentation, once to detect an increase 
and once to detect a decrease (eg, hypoglycemia and hyperglycemia). For presentation of 
shifts from baseline in these cases, a 0 at baseline will indicate an absence of toxicity in 
the direction being detected (eg, for shift tables for hyperglycemia, a 0 at baseline will 
indicate an absence of hyperglycemia). For laboratory tests not graded by the NCI-
CTCAE, tables summarizing shifts outside of the normal range will be presented. 
8.5.1 Exploratory Assessments (B & T Lymphocyte Subsets) Analysis
As part of an exploratory analysis, blood samples will also be collected for quantification 
of B and T lymphocyte subsets to assess the effect of treatment on lymphocyte 
subpopulations. The results of these assessments will be presented in tabular form, and 
the outcome of the exploratory analyses of these results may be reported separately.
8.6
Vital Signs
Vital signs will be assessed at baseline and throughout the study. Vital signs will be 
summarized by study visit and will include descriptive statistics such as mean, median, 
standard deviation, minimum, and maximum for the value of the parameters and the 
changes from baseline. 
8.7
Immunogenicity
Serum samples for antibodies to mapatumumab will be obtained at baseline (prior to 
dosing on Cycle 1/Day 1), prior to dosing on Day 1 of Cycles 1, 2, 4, 6, every 2 cycles
thereafter, and at the End of Treatment visit (at least 30 days after the last dose). Rates of 
antibody response (persistent positive, transient positive, and negative) will be tabulated, 
and all data will be summarized in listings. A persistent positive immune response is 
defined as a subject who has 2 or more positive samples or for whom the last sample is 
positive. A transient positive response is defined as a subject who has only 1 positive 
response (if it is not the last sample). In these definitions, all data are counted, including 
baseline. 
 
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8.8
Subgroup Analyses
Subgroup analyses for safety data will be performed on laboratory parameters testing for 
the hepatitis B surface antigen and the hepatitis C surface antibody (positive for the 
hepatitis B surface antigen, positive for the hepatitis C surface antibody vs. others). There 
are no additional preplanned subgroup analyses for this study for the safety analysis. 
9
Pharmacokinetic and Pharmacodynamic Analyses
Serum mapatumumab concentration data obtained from this study will be pooled with 
data obtained from other studies for use in a population pharmacokinetic analysis, which 
will be reported separately. For this study report, serum mapatumumab concentration 
results, determined by enzyme-linked immunosorbent assay, will be presented using 
appropriate graphic and tabular summaries.
An optional exploratory biomarker sub-study is being conducted in conjunction with this 
study. As described in Section 7.3 and Appendix 6 of the protocol, serum proteins and 
DNA will be isolated from consenting subjects for an exploratory analysis of response-
related proteins and genes. In addition, samples of historical and post-treatment biopsy 
samples will be collected, if available, to assess the expression of factors associated with 
tumor response. Analysis of biological markers of apoptosis and potential indicators of 
biological response will consist of descriptive statistical summaries. Associations will be 
assessed between candidate biomarkers and treatment outcomes captured in the clinical 
database. Statistical tests to be performed may include Pearson chi-square testing, 
Fisher’s exact test (as appropriate), ANOVA and ANCOVA. In addition, analysis may be 
stratified based on disease response in order to evaluate potential association between 
fluctuations in these markers and clinical outcome. Results from these analyses may be 
reported separately. 
 
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10
Other Analytical Considerations
There are no other analytical considerations.
 
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11
References
Lencioni R, Llovet, J. Modified RECIST (mRECIST) assessment for hepatocellular 
carcinoma. Semin Liver Dis 2010;30: 52-60.
Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in 
hepatocellular carcinoma. J Natl Cancer Inst 2008;100(10):698-711.
Thomas, M.B, Jaffe, D., Choti, M.M., et al.  Hepatocellular carcinoma: consensus 
recommendations of the National Cancer Institute clinical trials planning meeting. J Clin 
Oncol 2010;28:3994-4005.
 
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