Clinical trial NCT02562755
Conditions: Hepatocellular Carcinoma (HCC)
Keywords: Hepatocellular Carcinoma (HCC) Pexastimogene Devacirepvec (Pexa-Vec) Sorafenib GM-CSF therapy Thymidine Kinase-Deactivated Vaccinia Virus Oncology Recombinant Vaccinia Virus Oncolytic Virus Therapy Oncolytic virotherapy
Sponsor: SillaJen, Inc.
Start date: 2015-10-01; Completion date: 2020-07-01
Enrollment: 459 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized Phase 3 study to determine whether treatment with vaccinia virus based immunotherapy (Pexa-Vec) followed by sorafenib increases survival compared to treatment with sorafenib in patients with advanced hepatocellular carcinoma who have not received prior systemic therapy.

Detailed description:
This is a multi-center, randomized, open-label, Phase 3 study comparing Pexa Vec followed by sorafenib versus sorafenib in patients with advanced HCC without prior systemic therapy.

A total of 459 patients were randomly assigned to 2 treatment arms- 234 patients in the Pexa-Vec followed by sorafenib treatment group and 225 patients in the sorafenib only treatment group.

Arms: arm 1: Pexa-Vec (pexastimogene devacirepvec) will be administered as 3 bi-weekly intratumoral (IT) injections of 1e9 pfu at day 1 and weeks 2 and 4, followed by sorafenib at Week 6. arm 2: Sorafenib (400 mg twice daily) begins on Day 1.
Interventions: intervention 1: Pexastimogene Devacirepvec (Pexa Vec) intervention 2: Sorafenib
Intervention descriptions: intervention 1: Pexa-Vec is a vaccinia virus based oncolytic immunotherapy designed to stimulate the immune system following infection and replication within tumor cells. intervention 2: Sorafenib belongs to the pharmacotherapeutic group of antineoplastic agents, protein kinase inhibitors, ATC code: L01XE05.

Sorafenib is a multi-kinase inhibitor which has demonstrated both anti-proliferative and anti-angiogenic properties in vitro and in vivo.

Sorafenib is approved for the treatment of advanced HCC and is the Standard Of Care for this disease.

Protocol documents:
Prot_000.pdf: 
 
 
 
A Phase 3 Randomized, Open-Label Study Comparing Pexa-Vec (Vaccinia GM-CSF / 
Thymidine Kinase-Deactivated Virus) Followed by Sorafenib Versus Sorafenib in Patients 
with Advanced Hepatocellular Carcinoma (HCC) Without Prior Systemic Therapy 
 
STUDY PROTOCOL NUMBER: 
JX594-HEP024 
INVESTIGATIONAL PRODUCT: 
Pexastimogene Devacirepvec (Pexa-Vec)  
PHASE: 
3 
IND NUMBER: 
BB-IND 6486 
EudraCT NUMBER: 
2014-001985-86 
SPONSOR: 
SillaJen Inc. 
450 Sansome St, Suite 200 
San Francisco, CA 94111- USA 
EU LEGAL REPRESENTATIVE: 
Quality Regulatory Clinical Ireland Ltd 
(QRC Consultants Ltd) 
21 Priory Office Park, Stillorgan 
Dublin A94F660, Ireland 
Tel: +44 1480 309 349 
MEDICAL MONITOR: 
Kyoungsoo Ha 
Mobile: +82-10-7471-4145 
Fax: +82-2-783-7555 
Email: ksha@kr.sillajen.com 
PROTOCOL DATE: 
17 February 2015 
AMENDMENT 1: 
3 October 2017 
AMENDMENT 2: 
26 June 2019 
 
Confidentiality Statement 
This document contains confidential information.  It is intended solely for the use of the principal 
investigator, co-investigators, staff, appropriate institutional review boards or ethical committees, and other 
required regulatory bodies. 




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INVESTIGATOR SIGNATURE PAGE 
PROTOCOL TITLE: 
A Phase 3 Randomized, Open-Label Study 
Comparing Pexa-Vec (Vaccinia GM CSF / 
Thymidine Kinase-Deactivated Virus) Followed by 
Sorafenib Versus Sorafenib in Patients with 
Advanced 
Hepatocellular 
Carcinoma 
(HCC) 
Without Prior Systemic Therapy 
PROTOCOL NUMBER: 
JX594-HEP024 
INVESTIGATIONAL PRODUCT:  
Pexa-Vec 
SPONSOR: 
SillaJen Inc. 
450 Sansome St, Suite 200 
San Francisco, CA 94111- USA 
PROTOCOL DATE 
17 February 2015 
AMENDMENT 1: 
3 October 2017 
AMENDMENT 2: 
26 June 2019 
 
I have read and understand the protocol and I agree that it contains all the ethical, legal and 
scientific information necessary to conduct this study.  I will conduct this study as outlined herein 
and will make a reasonable effort to complete the study within the time designated.  I will work 
according to the principles of Good Clinical Practice (GCP) as described (for the US) in the Code 
of Federal Regulations (CFR) Section 21, Parts 11, 50, 54, 56, and 312, The Declaration of 
Helsinki (2008), and GCP as described in the International Conference on Harmonization (ICH) 
document “Guidance for Industry – E6 Good Clinical Practice: Consolidated Guidance” .  Further, 
I will conduct the study in keeping with local and regulatory requirements. 
I will provide copies of the protocol and access to all relevant information to study personnel under 
my supervision.  I will discuss this material with them to ensure that they are fully informed about 
the drug and the study. 
 
  
Principal Investigator Signature 
 Date 
 
  
Principal Investigator Name (Printed) 
  


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TABLE OF CONTENTS 
1 LIST OF ABBREVIATIONS ..................................................................................................11 
2 PROTOCOL SYNOPSIS ........................................................................................................15 
3 BACKGROUND .....................................................................................................................26 
3.A 
Hepatocellular Carcinoma (HCC)................................................................................26 
3.A.1 
Current Treatment for HCC ...........................................................................26 
3.B 
Oncolytic Immunotherapy ...........................................................................................28 
3.B.1 
Pexa-Vec: Selective Tumor Infection and Active Immunotherapy ...............29 
3.C 
Preclinical Experience with Pexa-Vec .........................................................................30 
3.C.1 
Efficacy of Pexa-Vec in Rabbit VX-2 Carcinoma Model and Rat 
Carcinogen-Induced Primary Liver Tumors ..................................................30 
3.C.2 
Efficacy of Repeated Doses of Pexa-Vec Followed by Sorafenib 
Therapy in a Human Tumor Xenograft Model of Hepatocellular 
Carcinoma ......................................................................................................31 
3.C.3 
Toxicity and Biodistribution of Single or Repeated IV Doses of 
Pexa-Vec in the Rabbit ..................................................................................31 
3.D 
Clinical Experience ......................................................................................................32 
3.D.1 
Overview of Clinical Experience with Pexa-Vec ..........................................32 
3.D.2 
Pexa-Vec Evaluation in Non-HCC Indications .............................................34 
3.D.3 
Treatment of Solid Tumors within the Liver with Pexa-Vec.........................35 
3.D.3.a 
Phase 1 Liver Tumor Trial .............................................................35 
3.D.3.b 
Phase 2 Liver Cancer (HCC) Trial (JX594-IT-HEP007) ..............35 
3.D.3.c 
Phase 2 Study of HCC Patients Treated IV and IT with 
Pexa-Vec Prior to Sorafenib (JX594-HEP016) .............................36 
3.D.3.d 
Phase 2b Randomized Trial of Pexa-Vec Plus Best 
Supportive Care Versus Best Supportive Care in Patients 
with Advanced Hepatocellular Carcinoma Who Have Failed 
Sorafenib Treatment (JX594-HEP018/TRAVERSE) ....................37 
3.E 
Rationale ......................................................................................................................38 
3.E.1 
Rationale for Study ........................................................................................38 
3.E.2 
Rationale for Pexa-Vec Dose and Schedule and Sequential Sorafenib 
Therapy ..........................................................................................................39 
3.E.2.a 
Pexa-Vec Dose, Route and Interval Rationale ...............................39 
3.E.2.b 
Rationale for Sequential Therapy with Sorafenib ..........................40 
4 OBJECTIVES ..........................................................................................................................41 
4.A 
Primary Objective ........................................................................................................41 


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4.B 
Secondary Objectives...................................................................................................41 
4.C 
Exploratory Objectives ................................................................................................41 
5 STUDY DESIGN.....................................................................................................................43 
5.A 
Study Overview ...........................................................................................................43 
5.B 
Study Endpoints ...........................................................................................................44 
5.B.1 
Primary Endpoint ...........................................................................................44 
5.B.2 
Secondary Endpoints .....................................................................................44 
5.B.3 
Exploratory Endpoints ...................................................................................45 
5.C 
Dose and Regimen .......................................................................................................45 
5.C.1 
Dose Modifications, Delays, and Cancellations ............................................46 
5.C.1.a 
Dose Modifications ........................................................................46 
5.C.1.b 
Dose Delays ...................................................................................46 
5.C.1.c 
Dose Cancellations.........................................................................46 
5.C.1.d 
Treatment Withdrawal ...................................................................47 
5.D 
Overall Study Duration ................................................................................................47 
5.D.1 
Active Study Participation Phase ...................................................................47 
5.D.2 
Survival Follow Up Phase..............................................................................48 
6 SELECTION OF PATIENTS ..................................................................................................49 
6.A 
Inclusion Criteria .........................................................................................................49 
6.B 
Exclusion Criteria ........................................................................................................50 
6.C 
Screening, Eligibility, Arm Assignment, Study Completion, and Study 
Discontinuation ............................................................................................................53 
6.C.1 
Screening ........................................................................................................53 
6.C.1.a 
Screen Failures ...............................................................................53 
6.C.2 
Eligibility .......................................................................................................53 
6.C.2.a 
Laboratory Eligibility.....................................................................54 
6.C.3 
Patient Allocation to Treatment Arms ...........................................................54 
6.C.4 
Premature Study Discontinuation ..................................................................55 
6.C.4.a 
Data Collection for Premature Discontinued Patients ...................55 
7 STUDY PROCEDURES AND TREATMENT ......................................................................57 
7.A 
Screening......................................................................................................................57 
7.B 
Initial Treatment Phase (Baseline and Day 1 Until Week 6) .......................................58 
7.B.1 
Randomization (Upon Investigator Confirmation of Eligibility) ..................58 
7.B.2 
Arm A and Arm B:  Baseline Visit ................................................................59 


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7.B.3 
Arm A and Arm B:  Visit 1 (“Day 1”) ...........................................................60 
7.B.3.a 
Arm A:  Pexa-Vec Treatment #1 (Day 1) ......................................60 
7.B.3.b 
Arm B:  Sorafenib Treatment Start (Day 1)...................................61 
7.B.4 
Arm A:  Visit 2 (Pre-Day 15 or Pre-Week 2); Arm B: Visit 2 (Day 15 
or Week 2) ......................................................................................................62 
7.B.4.a 
Arm A:  Visit 2/ Pre-Day 15 or Pre-Week 2 ..................................62 
7.B.4.b 
Arm B:  Visit 2/ Day 15 (Week 2) .................................................63 
7.B.5 
Arm A:  Visit 3 / Pexa-Vec Treatment #2 (Day 15/Week 2) .........................63 
7.B.6 
Arm A:  Visit 4 (Pre-Day 29/Pre-Week 4); Arm B:  Visit 3 
(Day 29/Week 4) ............................................................................................64 
7.B.6.a 
Arm A:  Visit 4/ Pre-Day 29 (Pre-Week 4) ...................................64 
7.B.6.b 
Arm B:  Visit 3 / Day 29 (Week 4) ................................................65 
7.B.7 
Arm A:  Visit 5 / Pexa-Vec Treatment #3 (Day 29 / Week 4) .......................65 
7.B.8 
Arm A:  Visit 6 (Day 43/Week 6)/ Arm B: Visit 4 (“Day 43/Week 6”) .......66 
7.B.8.a 
Arm A:  Visit 6/Day 43 (Week 6) ..................................................66 
7.B.8.b 
Arm B:  Visit 4/Day 43 (Week 6) ..................................................67 
7.C 
Follow-up Phase...........................................................................................................68 
7.C.1 
Long-Term Follow-Up Visits and Monitoring (Arm A and Arm B) .............68 
7.C.1.a 
Every 3 Weeks ±4 Days:  Clinical Status Visits ............................68 
7.C.1.b 
Every 6 Weeks ±7 Days:  Symptomatic, QoL, and 
Radiographic Status Visits .............................................................68 
7.D 
End of Treatment Visit (ARM A and Arm B) .............................................................69 
7.E 
Safety Follow-Up .........................................................................................................70 
7.F 
Follow-Up Visits for Progression Free SURVIVAL ...................................................70 
7.G 
Survival Follow-up Phase ............................................................................................71 
8 PATIENT MANAGEMENT ...................................................................................................72 
8.A 
Treatments....................................................................................................................72 
8.A.1 
Expected Toxicities of Pexa-Vec Treatment .................................................72 
8.A.2 
Notable Safety Findings .................................................................................74 
8.A.3 
Risks Linked to IT Injection Procedure .........................................................76 
8.A.4 
Concomitant Authorized and Contraindicated Treatments ............................76 
8.A.4.a 
Definitions and Reporting of Concomitant Medication and 
Non-Drug Therapy .........................................................................76 
8.A.4.b 
Concomitant Authorized & Contraindicated Treatments ..............77 
8.A.5 
Potential Mechanisms of Pexa-Vec Shedding to the Environment, 
Biodissemination and Prevention of Transmission ........................................80 


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8.A.5.a 
Superficial Skin Pustules ...............................................................80 
8.A.5.b 
Urine, Feces, Blood, Throat and/or Saliva .....................................81 
8.A.6 
Expected Toxicities of Sorafenib Treatment .................................................81 
8.B 
Safety, Clinical, Demography, and Diagnosis Assessments........................................81 
8.C 
Efficacy Assessments...................................................................................................82 
8.C.1 
Biomarker/Immune Assessments ...................................................................82 
8.C.2 
Imaging Data Acquisition and Evaluations ...................................................82 
8.C.2.a 
Imaging Data Acquisition ..............................................................82 
8.C.2.b 
Imaging Data Evaluations ..............................................................84 
8.D 
Symptomatic and Quality of Life Assessments ...........................................................89 
8.E 
Pharmacoeconomic Assessments.................................................................................89 
9 MANAGEMENT OF NON-PATIENT EXPOSURE TO PEXA-VEC ..................................91 
9.A 
Exposure to Pexa-Vec ..................................................................................................91 
9.B 
Contacts Exhibiting Symptoms of Viral Infection.......................................................91 
10 INVESTIGATIONAL PRODUCTS (IP) ................................................................................92 
10.A Pexa-Vec (JX-594).......................................................................................................92 
10.A.1 Nomenclature of Pexa-Vec ............................................................................92 
10.A.2 Pharmaceutical Form of Pexa-Vec ................................................................92 
10.A.3 Packaging and Labeling of Pexa-Vec ............................................................92 
10.A.4 Biosafety/Containment Level Classification of Pexa-Vec ............................93 
10.A.5 Transport of Pexa-Vec ...................................................................................93 
10.A.5.a Interstate and International Transport ............................................93 
10.A.5.b Drug Receipt and Approval of Shipment.......................................93 
10.A.5.c Transport within the Institution .....................................................93 
10.A.6 Storage of Pexa-Vec ......................................................................................94 
10.A.7 Dispensing of Pexa-Vec .................................................................................94 
10.A.8 Handling of Pexa-Vec ....................................................................................94 
10.A.8.a Preparation of Pexa-Vec ................................................................94 
10.A.8.b Administration of Pexa-Vec ..........................................................95 
10.A.8.c Cleaning / Disinfection and Disposal ............................................95 
10.A.8.d Spills or Environmental Contamination.........................................95 
10.A.8.e Unused Drug Return or Destruction ..............................................96 
10.A.9 Drug Accountability .......................................................................................96 
10.B 
Sorafenib ......................................................................................................................96 
10.B.1 Nomenclature .................................................................................................96 


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10.B.2 Pharmaceutical Form of Sorafenib ................................................................97 
10.B.3 Packaging and Labeling of Sorafenib ............................................................97 
10.B.4 Transport of Sorafenib ...................................................................................97 
10.B.4.a Transport Conditions .....................................................................97 
10.B.4.b Drug Receipt and Approval of Shipment.......................................97 
10.B.4.c Transport within the Institution .....................................................97 
10.B.5 Storage of Sorafenib ......................................................................................97 
10.B.6 Drug Dispensing of Sorafenib........................................................................97 
10.B.7 Handling of Sorafenib ....................................................................................98 
10.B.7.a Posology .........................................................................................98 
10.B.7.b Method of Administration..............................................................98 
10.B.7.c Disposal..........................................................................................98 
10.B.7.d Unused Drug Return or Destruction ..............................................98 
10.B.8 Drug Accountability .......................................................................................99 
11 SAFETY REPORTING .........................................................................................................100 
11.A Definitions..................................................................................................................100 
11.B 
Intensity, Relationship and Outcome Evaluation.......................................................103 
11.B.1 Intensity ........................................................................................................103 
11.B.2 Relationship to the IP ...................................................................................103 
11.B.3 Outcome .......................................................................................................104 
11.C 
Time Period for Collection ........................................................................................104 
11.D Adverse Event Management ......................................................................................105 
11.D.1 Reporting ......................................................................................................105 
11.D.2 Follow-up .....................................................................................................106 
11.D.3 Documentation .............................................................................................106 
11.E 
Serious Adverse Event Management .........................................................................106 
11.E.1 Reporting ......................................................................................................106 
11.E.2 Follow-Up ....................................................................................................106 
11.E.3 Notifications .................................................................................................107 
11.F 
Special Situations .......................................................................................................107 
11.F.1 Post-Study SAE ...........................................................................................107 
11.F.2 Pregnancy .....................................................................................................107 
11.F.3 Overdose ......................................................................................................108 
11.F.4 Death ............................................................................................................108 


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12 STATISTICAL CONSIDERATIONS...................................................................................109 
12.A Overview ....................................................................................................................109 
12.B 
Sample Size Determination........................................................................................109 
12.C 
Analysis Populations ..................................................................................................110 
12.D Methods of Analysis ..................................................................................................111 
12.D.1 General Considerations ................................................................................111 
12.D.2 Disposition of Patients .................................................................................111 
12.D.3 Demographic and Baseline Characteristics .................................................112 
12.D.4 Treatments (Study Treatment, Concomitant Therapies) ..............................112 
12.D.4.a Study Treatments (Pexa-Vec and Sorafenib) ...............................113 
12.D.4.b Concomitant Medications ............................................................113 
12.D.5 Efficacy ........................................................................................................113 
12.D.5.a Primary Efficacy Analysis:  Overall Survival .............................113 
12.D.5.b Secondary Efficacy Analyses ......................................................114 
12.D.5.c Exploratory Efficacy Analysis .....................................................118 
12.D.6 Safety ...........................................................................................................120 
12.D.7 Quality of Life (QoL) ...................................................................................121 
12.D.8 Pharmacoeconomic Methods .......................................................................122 
13 ETHICAL REQUIREMENTS...............................................................................................125 
13.A Patient Privacy ...........................................................................................................125 
13.B 
IRB/IEC/REB ............................................................................................................126 
13.C 
Institutional Biosafety Committee (IBC) ...................................................................126 
13.D Informed Consent.......................................................................................................126 
13.E 
Review Committee.....................................................................................................127 
13.E.1 Data Monitoring Committee (DMC) ...........................................................127 
13.E.2 Steering Committee .....................................................................................127 
14 STUDY ADMINISTRATION...............................................................................................128 
14.A Documents .................................................................................................................128 
14.A.1 Investigator’s Brochure ................................................................................128 
14.A.2 Protocol Amendments ..................................................................................128 
14.A.3 Case Report Forms .......................................................................................128 
14.B 
Quality Control and Quality Assurance .....................................................................128 
14.B.1 Study Monitoring .........................................................................................128 
14.B.2 Audit and Inspection ....................................................................................129 


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14.C 
Record Retention .......................................................................................................129 
14.D Study Termination .....................................................................................................129 
14.E 
Publication and Presentation Policy...........................................................................130 
14.F 
Archiving ...................................................................................................................131 
14.F.1 Investigator Site File ....................................................................................131 
14.F.2 Trial Master File ..........................................................................................131 
15 REFERENCES ......................................................................................................................132 
APPENDIX A: SCHEDULE OF ACTIVITIES ..........................................................................140 


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1 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AASLD 
American Association for the Study of Liver Diseases 
ACE 
Angiotensin Converting Enzyme 
ADR 
Adverse Drug Reaction 
AE(s) 
Adverse Event(s) 
AFP 
Alfa-Fetoprotein 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Transaminase 
BCLC 
Barcelona Clinic Liver Cancer 
BID 
Twice daily (bis in die) 
BSC 
Best Supportive Care 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CDC 
Centers for Disease Control and Prevention (United States) 
CFR 
Code of Federal Regulations (United States) 
CI(s) 
Confident Interval(s) 
CLIP 
Cancer of the Liver Italian Program 
CR 
Complete Response 
CRO 
Contract Research Organization 
CSRI 
Client Service Receipt Inventory 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCE MRI 
Dynamic Contrast-Enhanced Magnetic Resonance Imaging 
DCR 
Disease Control Rate 
DLT(s) 
Dose Limiting Toxicity(ies) 
DMC 
Data Monitoring Committee 
DoR 
Duration of Response 
EASL 
European Association for the Study of the Liver  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 


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Abbreviation 
Definition 
EGF(EGFR) 
Epidermal Growth Factor (Receptor) 
EORTC 
European Organization for Research and Treatment of Cancer 
FACT-Hep 
Functional Assessment of Cancer Therapy – Hepatobiliary 
FDA 
Food and Drug Administration (United States) 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography  
FHSI-8 
Cancer Therapy–Hepatobiliary Symptom Index 8 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GLP 
Good Laboratory Practices 
GM-CSF 
Granulocyte-Macrophage Colony Stimulating Factor 
HCC 
Hepatocellular Carcinoma 
hGM-CSF 
Human Granulocyte-Macrophage Colony Stimulating Factor 
HIPAA 
Health Insurance Portability and Accountability Act 
HLA 
Human Leukocyte Antigen 
HR 
Hazard Ratio 
HRQoL 
Health-Related Quality of Life 
IB 
Investigators’ Brochure 
IBC 
Institutional Biosafety Committee 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
INN 
International Nonproprietary Name 
INR 
International Normalized Ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IT 
Intratumoral 
ITT 
Intent-To-Treat 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LD 
Longest Diameter 
LDH 
Lactate Dehydrogenase 
LMWH 
Low Molecular Weight Heparin 


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Abbreviation 
Definition 
mChoi 
Modified Choi 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFD 
Maximum Feasible Dose 
mRECIST 
Modified RECIST 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute (United States) 
NIH 
National Institutes of Health (United States) 
ORR 
Overall Response Rate 
PBS 
Phosphate Buffered Saline 
PD 
Progressive Disease 
PEG-IFN 
Pegylated Interferon 
PEIT 
Percutaneous Ethanol Injection Therapy 
PET 
Positron Emission Tomography 
PET-CT 
Positron Emission Tomography-Computerized Tomography 
Pexa-Vec 
Pexastimogene Devacirepvec, JX-594 
PFS 
Progression Free Survival 
pfu 
Plaque Forming Units 
PP 
Per Protocol 
PR 
Partial Response 
PROs 
Patient Reported Outcomes 
PT/INR 
Prothrombin Time/International Normalized Ratio 
PTT 
Partial Thromboplastin Time 
QoL 
Quality of Life 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFA 
Radiofrequency Ablation 
SAE(s) 
Serious Adverse Event(s) 
SAP 
Statistical Analysis Plan 
SCID 
Severe Combined Immunodeficiency 
SD 
Stable Disease 
SLD 
Sum of Longest Diameters 
SmPC 
Summary of Product Characteristics 


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Abbreviation 
Definition 
SOC 
Standard of Care 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUV 
Standardized Uptake Value 
TACE 
Transcatheter Arterial Chemoembolization 
TIR 
Time to Initial Response 
TK 
Thymidine Kinase 
TSP 
Time-to-Symptomatic Progression 
TTP 
Time To Progression 
UFH 
Unfractionated Heparin 
ULN 
Upper Limit of Normal 
US 
United States 
VEGFR 1, 2, 3 
Vascular Endothelial Growth Factor Receptor 1, 2, 3 
VIG 
Vaccinia Immune Globulin 
WBC 
White Blood Cell 
WNL 
Within Normal Limits 
 


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2 
PROTOCOL SYNOPSIS 
 
Title 
A Phase 3 Randomized, Open-Label Study Comparing Pexa-Vec (Vaccinia GM-CSF / 
Thymidine Kinase-Deactivated Virus) Followed by Sorafenib Versus Sorafenib in Patients 
with Advanced Hepatocellular Carcinoma (HCC) Without Prior Systemic Therapy 
Investigational 
Product 
The following products are considered as Investigational Product (IP): 
• 
Pexa-Vec 
• 
Sorafenib (standard of care [SOC]) 
Pexa-Vec 
Pexa-Vec (pexastimogene devacirepvec; investigational product code:  JX-594) is a 
replication-competent, transgene-expressing therapeutic vaccinia virus derived from the 
Wyeth vaccine strain (Dryvax®, Wyeth Laboratories).  Three genetic modifications are 
included:  
1. thymidine kinase (TK) gene deactivation,  
2. granulocyte macrophage colony stimulating factor (GM-CSF) gene insertion under control 
of the synthetic early-late promoter, and 
3. lac-Z gene insertion under control of the p7.5 promoter.  
Sorafenib 
Sorafenib belongs to the pharmacotherapeutic group of antineoplastic agents, protein kinase 
inhibitors, ATC code:  L01XE05. 
Sorafenib is a multi-kinase inhibitor which has demonstrated both anti-proliferative and anti-
angiogenic properties in vitro and in vivo. 
Sorafenib is approved for the treatment of advanced HCC and is the SOC of this disease. 
Phase 
3 
Objectives 
Primary Objective 
• 
To determine and compare the overall survival of patients with advanced HCC without 
prior systemic therapy, treated with Pexa-Vec followed by sorafenib (Arm A) versus 
sorafenib (Arm B) 
Secondary Objectives: 
• 
To determine and compare the 2 treatment arms response based on central assessments 
using modified Response Evaluation Criteria in Solid Tumors (mRECIST) for HCC for 
the following endpoints: 
 
Time-to-progression (TTP) 
 
Progression free survival (PFS) 
 
Overall response rate (ORR) 
 
Disease control rate (DCR) 
• 
To determine and compare the safety profiles of the 2 treatment arms 
• 
To determine and compare the time-to-symptomatic progression (TSP) of the  
2 treatment arms 


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• 
To determine and compare the Quality of Life (QoL) of the 2 treatment arms 
Exploratory Objectives: 
• 
To determine and compare the 2 treatment arms response based on both local and central 
assessments using RECIST 1.1 for the following endpoints: 
 
TTP 
 
PFS 
 
ORR 
 
DCR 
• 
To evaluate and compare the effect of treatment with Pexa-Vec followed by sorafenib 
(Arm A) versus sorafenib (Arm B) on the following endpoints, (based on local and 
central assessments for radiology endpoints): 
• 
Time to Initial Response (TIR) and Duration of overall Response (DoR) 
• 
Tumor size over time by reference to the sum of the longest diameters of the target 
lesions at screening 
• 
Efficacy (overall survival, PFS, TTP) in patient subgroups to be defined in the Statistical 
Analysis Plan (SAP) 
• 
Overall survival, PFS, TTP in patients subdivided according to the presence or not of an 
objective response (complete response [CR], partial response [PR] and/or at least 
3 months of stable disease) (if the number of patients is sufficient) 
• 
To determine and compare changes in clinical laboratory parameters in the 2 treatment 
arms including standard safety laboratory parameters, alpha-fetoprotein (AFP), and 
CD4/CD8 counts 
• 
To determine and compare the 2 treatment arms for overall survival by reference to the 
date of introduction of sorafenib 
• 
To describe the effects of Pexa-Vec on the immune response and identify biomarkers of 
response  
• 
To evaluate the comparative cost-effectiveness of Pexa-Vec followed by sorafenib 
versus sorafenib alone by collecting patient-level resource and service-use information 
Study Design 
This is a Phase 3 multi-center, randomized, open-label study of Pexa-Vec followed by 
sorafenib (Arm A) versus sorafenib (Arm B) in patients with advanced HCC without prior 
systemic therapy. 
A total of 600 patients will be randomized between one of 2 treatment arms in a 1:1 ratio 
 (300 in each arm) to reach at least 570 evaluable patients.  
Patients will be allocated to each arm via a dynamic stochastic minimization procedure 
performed independently for Asian and non-Asian patients.  The following criteria will be 
used: 
1. Center 
2. Main etiology: hepatitis C, hepatitis B, alcohol or other reasons (such as 
hemochromatosis, Wilson’s disease, type 2 diabetes, NASH) 
3. Presence of extrahepatic disease or not 
4. Vascular invasion or not 
5. Performance status 0 or 1 
6. AFP levels (<200, 200–400 or >400 ng/mL) 


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In experimental Arm A, Pexa-Vec will be administered as 3 bi-weekly intratumoral (IT) 
injections (Day 1, Week 2, Week 4).  A radiological assessment will be performed at 
Screening, Week 6 and repeated every 6 weeks.  Sorafenib will be started daily at Week 6 or 
2 weeks after the last IT injection but no earlier than Week 6. 
In Arm B, sorafenib will be started daily on Day 1.  Radiological assessments will be 
performed at Screening, on Week 6 and every 6 weeks.  
In both arms, if a patient discontinues the treatment phase prior to documented radiographic 
progression (e.g., permanently stops taking the study medication), the patient will perform 
PFS follow-up visits every 6 weeks for radiology evaluation until documented progression or 
until premature study discontinuation.  
Sorafenib is allowed and continued as long as the patient is clinically benefiting from the 
treatment and at least until progression or until unacceptable toxicity occurs.  
Beyond 12 months of treatment, the radiological evaluations will be performed every 
12 weeks until first occurrence of documented progression.  
When study treatments are permanently stopped (Pexa-Vec or sorafenib), patients will 
perform an End of Treatment Visit and a Safety Follow-Up Visit at least 28 days (and no 
more than 2 months) after last study treatment administration.  
For patients in both arms, a site reader will perform local tumor assessments based on 
RECIST 1.1 for patient management and radiological endpoints assessment.  An independent 
central review is also planned for blinded central assessment of all radiological endpoints, 
based on mRECIST for HCC and RECIST 1.1.  
Two interim analyses are planned; one futility analysis at 40% of the death events and one 
efficacy analysis at 80% of the events. 
A Data Monitoring Committee (DMC) will be in charge of reviewing safety and efficacy data 
regularly during the course of the study and at the time of the interim and final analyses.  The 
activities of the DMC are defined in the DMC Charter document.  The DMC’s main objective 
will be to ensure that the safety of the patients, to evaluate the benefit versus risk and the 
integrity of the data are respected at all times throughout the study and to give 
recommendations on its further conduct. 
No. of Patients 
A total of 600 patients will be enrolled to obtain 570 evaluable patients: 
• 
Arm A:  300 patients 
• 
Arm B:  300 patients 
Study Population 
Inclusion Criteria: 
1. 
Male or female patients, age ≥18 years old 
2. 
Histological/cytological diagnosis of primary HCC 
3.  
Advanced stage HCC (Barcelona Clinic Liver Cancer [BCLC] Stage C or B per 
American Association for the Study of Liver Disease [AASLD] guidelines) eligible for 
systemic 
therapy 
excluding 
cholangiocarcinoma, 
hepatocholangiocarcinoma, 
fibrolamellar carcinoma and hepatoblastoma  
4. 
Tumor status (as determined by radiology evaluation):  At least one measurable viable 
tumor in the liver, ≥1 cm longest diameter (LD), using a dynamic imaging technique 
(arterial phase of triphasic computerized tomography [CT] scan, or dynamic contrast-
enhanced magnetic resonance imaging [MRI]), and injectable under imaging-guidance 
(CT and/or ultrasound)  
5. 
At least one tumor that has not received prior local-regional treatment, or that has 
exhibited >25% increase in viable tumor size since prior local-regional treatment 


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6. 
Child-Pugh Class A.  NOTE:  paracentesis, albumin infusion or diuretic treatment 
cannot be used to downscore Child-Pugh score (e.g., to improve from severe to 
moderate/mild or from moderate to mild ascites) 
7. 
Performance status 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale 
8. 
Adequate hematological, hepatic, and renal function: 
a. 
Hemoglobin ≥9 g/dL  
b. Platelet count ≥75 x 109/L 
c. 
International normalized ratio (INR) ≤1.7 
d. White blood cell (WBC) count ≥2 x 109/L  
e. 
Absolute neutrophil count (ANC) ≥1 x 109/L 
f. 
Albumin 
≥2.8 g/dL, 
total 
bilirubin 
≤3.0 mg/dL 
(51.3 µmol/L); 
alanine 
aminotransferase (ALT), aspartate transaminase (AST) ≤5 times upper limit of 
normal (ULN) 
g. Serum chemistries sodium, potassium, and calcium within normal limits (WNL) or 
Grade 1  
h. Serum creatinine <2.0 mg/dL or creatinine clearance >60 mL/min according to 
Cockroft-Gault formula 
9. 
For patients who are sexually active: willing to use adequate barrier contraception 
method for at least 6 weeks after each treatment of Pexa-Vec, during sorafenib 
treatment, and for 2 weeks after sorafenib discontinuation 
10. Life expectancy of at least 3 months 
11. Written informed consent 
Exclusion Criteria: 
1. 
Major surgery within 4 weeks of study treatments (minor surgical procedures are 
allowed e.g., intravascular access line or Port-a-Cath®) 
2. 
Local-regional therapy of HCC within 4 weeks prior to randomization 
3. 
Histological 
diagnosis 
of 
cholangiocarcinoma, 
hepatocholangiocarcinoma, 
fibrolamellar carcinoma and hepatoblastoma 
4. 
History of moderate or severe ascites, bleeding esophageal varices, hepatic 
encephalopathy or pleural effusions related to liver insufficiency within 6 months of 
screening 
5.  
Bulky disease patients - tumors encompassing >50% of the liver volume and / or inferior 
vena cava invasion 
6.  
Known significant immunodeficiency due to underlying illness (e.g., HIV/AIDS) and/or 
immune-suppressive medication including high-dose corticosteroids (defined as 
≥20 mg/day prednisone or equivalent which is ongoing at the time of randomization 
and/or was taken for more than 4 weeks within the preceding 2 months of study 
treatment) 
7. 
Ongoing severe inflammatory skin condition (as determined by the Investigator) 
requiring medical treatment 
8. 
History of severe eczema (as determined by the Investigator) requiring medical 
treatment  


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9. 
Tumor(s) invading a major vascular structure (e.g., carotid artery) or other key 
anatomical structure (e.g., pulmonary airway) in the event of post-injection tumor 
swelling and/or necrosis (hepatic and portal vein involvement allowed) 
10. Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural 
effusions.  Mild ascites that does not preclude safe IT injection of Pexa-Vec is allowed 
at the discretion of the treating physician.  
11. Symptomatic cardiovascular disease, including but not limited to significant coronary 
artery disease (e.g., requiring angioplasty or stenting) or congestive heart failure within 
the preceding 12 months 
12. Current or past history of cardiovascular disease (e.g., past history of myocardial 
infarction, ischemic cardiomyopathy) unless cardiology consultation and clearance has 
been obtained for study participation 
13.  Medical conditions, per the investigator’s judgment, that predispose the patient to 
untoward medical risk in the event of volume loading (e.g., intravenous [IV] fluid bolus 
infusion), tachycardia, or hypotension during or following treatment with Pexa-Vec 
14. Viable central nervous system malignancy (history of completely resected or irradiated 
brain metastases allowed) 
15. Prior systemic therapy for HCC (NOTE:  Patients receiving 7 days or less exposure to 
systemic therapy are allowed) 
16. Known contraindications to sorafenib according to the drug prescribing information 
and/or severe hypersensitivity to sorafenib or any other component of sorafenib, or 
known intolerance to sorafenib 
17. Other medical condition or laboratory abnormality or active infection that in the 
judgment of the Principal Investigator may increase the risk associated with study 
participation or may interfere with interpretation of study results and/or otherwise make 
the patient inappropriate for entry into this study 
18. Hepatitis C virus therapy including interferon/pegylated interferon or ribavirin that 
cannot be discontinued within 14 days prior to any Pexa-Vec injection.  Medical 
Monitor should be consulted if the patient is taking any other antiviral medications to 
determine eligibility. 
19. Prior malignancies are not allowed except for the following:  adequately treated basal 
or squamous cell skin cancer, in situ cervical cancer, adequately treated cancer from 
which the patient has been disease-free for at least 3 years, unless Medical Monitor 
approval has been obtained for study participation. 
20. Significant bleeding event within the last 12 months that places the patient at risk for 
intrahepatic IT injection procedure based on Investigator assessment 
21. Anticoagulant or anti-platelet medication that cannot be interrupted prior to Pexa-Vec 
IT injections, including: 
• 
Aspirin that cannot be discontinued for 7 days prior to Pexa-Vec IT injections  
• 
Coumadin that cannot be discontinued for 7 days prior to Pexa-Vec IT injections  
• 
Low molecular weight heparin (LMWH) that cannot be discontinued >24 hours 
prior to Pexa-Vec IT injections 
• 
Unfractionated heparin (UFH) that cannot be discontinued >4 hours prior to 
Pexa-Vec IT injection  
• 
Oral direct thrombin inhibitor (dabigatran) or direct Factor Xa inhibitor 
(rivaroxaban, apixiban, and endoxaban) that cannot be discontinued for 4 days prior 
to Pexa-Vec IT injection 


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NOTE: LMWH or UFH may be used to transition patients on and off of the above anti-
coagulants (if deemed appropriate by the treating physician) prior to Pexa-Vec 
treatments as long as the last dose of LMWH is administered >24 hours prior to 
treatments and last dose of UFH is administered >4 hours prior to treatments. 
Please contact the Sponsor for questions regarding the management of other anticoagulant 
prior to treatments. 
22. Inability to suspend treatment with anti-hypertensive medication (including but not 
limited to:  diuretics, beta-blockers, angiotensin converting enzyme [ACE] inhibitors, 
aldosterone antagonists, etc.) for 48 hours prior to and 48 hours after each Pexa-Vec 
injection. 
23. Any prior or planned organ transplant (e.g., liver transplant) 
24. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation. Child-bearing potential 
patients with a positive hCG laboratory test (>10 mIU/mL) at screening and/or a urinary 
pregnancy test at Baseline will perform an ultrasound to confirm the pregnancy. 
25. Patients who experienced a severe systemic reaction or side-effect as a result of a 
previous vaccination with vaccinia 
26. Participation in a clinical study and treatment with an active IP within 4 weeks prior to 
randomization 
27. Patient unable or unwilling to comply with the protocol requirements  
28. Previous treatment with Pexa-Vec or other vaccinia vector based treatment 
29. Pulse oximetry O2 saturation <90% at rest on room air 
Drug Dosage 
Pexa-Vec:  1 × 109 plaque-forming units (pfu) (equivalent to 9.0 Log pfu) per treatment  
Sorafenib:  400 mg twice daily (BID), according to the package insert (including dose 
reductions) 
Treatment Plan 
Arm A 
Three IT injections (Day 1, Week 2, Week 4) of Pexa-Vec suspended in buffered saline will 
be made into 1 to 5 intrahepatic tumors by a qualified and trained Interventional Radiologist 
or other trained physician using imaging-guidance (ultrasound and/or CT).  As much as 
possible viable, safely injectable tumors ≥1 cm LD must be treated with a maximum of 
5 tumors treated on a given treatment day.  Different tumors may be treated on each treatment 
day.  The total prepared injection volume will be divided proportionally between 1 to  
5 tumors, relative to individual tumor volumes (specific instructions are described in IT 
Injection Manual and Worksheet). 
Patients will be observed in the clinic or hospital for a minimum of 8 hours after each IT 
injection.  Longer hospitalization is permitted based on Investigator decision. 
Patients will be eligible for each of the 3 Pexa-Vec injections if all of the following criteria 
are met prior to each treatment: 
• 
The patient continues to meet the following clinical and laboratory criteria: 
 
Adequate liver function (total bilirubin ≤3 mg/dL [51.3 µmol/L]; ALT and AST  
≤5 × ULN) 
 
Platelets ≥75 × 109/L (correction with transfusion or thrombopoietin based therapy 
allowed to meet re-treatment eligibility criteria) 


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 
Hemoglobin ≥9 g/dL (correction with transfusion or erythropoietin based therapy 
allowed to meet re-treatment eligibility criteria) 
 
INR ≤1.7 (correction with plasma protein support allowed to meet re-treatment 
eligibility criteria [e.g., fresh-frozen plasma]) 
 
Patient is still expected to have at least one viable, injectable intrahepatic tumor 
≥1 cm LD 
 
No clinically significant and/or rapidly accumulating ascites, pericardial and/or 
pleural effusions.  Minimal ascites that does not preclude safe IT injection of 
Pexa-Vec is allowed at the discretion of the treating physician 
Sorafenib will be started daily at Week 6, or 2 weeks after the last IT injection (whichever is 
later) and no earlier than Week 6.  Sorafenib is allowed as long as the patient is clinically 
benefiting from the treatment and at least until progression or until unacceptable toxicity 
occurs.  
Arm B 
Daily sorafenib will be initiated on Day 1 and continued as long as the patient is clinically 
benefiting from the treatment and at least until progression or until unacceptable toxicity 
occurs.  
Pre-Medications 
and Supportive 
Care 
The use of the following drugs will not be restricted during the course of the study:  
thrombopoietin, erythropoietin, G-CSF, antiemetics, antipyretics, antidepressants, steroids 
(NOTE:  oral or parenteral steroids are not allowed during the Pexa-Vec treatment period, 
and for 1 week prior to and 2 weeks after Pexa-Vec treatment), topical therapies for 
symptomatic relief of hand-foot skin reaction and rash related to sorafenib, biphosphonates, 
vitamin B12, and vitamin D. 
Antihypertensives (including diuretics) must be discontinued at least 48 hours prior to each 
Pexa-Vec injection and restarted no earlier than 48 hours after the injection.  
All patients in experimental Arm A should be pre-medicated with acetaminophen 
(paracetamol) or equivalent antipyretics (e.g., NSAIDs) at the discretion of the treating 
physician, (unless contraindicated) on each Pexa-Vec treatment day.  For acetaminophen, the 
following regimen may be used: 
• 
500–1000 mg at 2 hours pre-infusion/injection, 
• 
500–1000 mg at 4 hours post-procedure, 
• 
500–1000 mg every 6 hours thereafter, as needed (the total acetaminophen dose should 
be carefully assessed to avoid cumulative toxicity). 
Fevers may be associated with onset of rigors.  Meperidine or equivalent may be used for 
severe rigors. 
Patients should also be pre-hydrated with approximately 1 L of solute-containing fluids IV or 
orally within 12 hours of treatment initiation.  In addition, during the post-treatment 
observation period, patients should receive IV solute-containing fluids or other appropriate 
treatment as needed for blood pressure support. 
Protocol 
Assessments 
Safety and Clinical Laboratory Assessments: 
Clinical assessments include laboratory assessments (hematology, biochemistry, coagulation, 
AFP, CD4/CD8 counts), physical examination and vital signs.  Adverse events (AEs) and 
serious adverse events (SAEs) will be reported and graded according to National Cancer 
Institute’s Common Toxicity Criteria for Adverse Events (NCI CTCAE), version 4.03.  From 
signature of informed consent up to IP initiation, only SAEs caused by a protocol-required 


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procedure will be collected.  After IP initiation, all SAEs/AEs will be collected up to 28 days 
after last IP administration (Pexa-Vec or sorafenib).  
Hematology and biochemistry will be assessed every 2 weeks until Week 6, every 3 weeks 
during the Long Term Follow-Up phase, at the End of Treatment Visit and at the Safety 
Follow-Up Visit.  Coagulation will be assessed every 2 weeks until Week 6 and at the End of 
Treatment Visit. 
AFP levels will be assessed at Screening, at Week 6, every 6 weeks during the Long Term 
Follow-Up phase and at the End of Treatment Visit.  CD4/CD8 counts will be assessed at 
Screening, at Week 6 and at the End of Treatment Visit.  
All laboratory analyses will be performed in central laboratories except for the clinical 
investigational sites participating in China where laboratory testing will be completed by the 
local laboratory at each site. 
Radiographic Assessments: 
Patients will undergo imaging of the chest, abdomen and pelvis using helical/spiral contrast-
enhanced CT scanning (preferentially) or MRI with non-contrast CT of the chest at Screening, 
at Week 6 and every 6 weeks thereafter.  If study treatments are stopped before documented 
radiological progression, PFS visits (scan collected) will be performed for every 6 weeks to 
continue radiological assessment until documented progression.  Beyond 12 months of 
treatment, the evaluations will be performed every 12 weeks.  Radiographic assessments will 
be completed locally as per current practice according to RECIST 1.1.  All radiographic 
images will also be reviewed centrally in an independent and blinded manner according to 
mRECIST for HCC and RECIST 1.1 as defined in the imaging charter document. 
• 
CT Scan:  Tri-phasic contrast-enhanced imaging of the liver will include pre-contrast, 
arterial, and portal venous phases.  If additional delayed phase imaging is performed, 
these images should also be provided for independent evaluation.  
• 
MRI Scan:  on either a 1.5T or 3T MRI scanner using a body array coil.  Gadolinium 
should be administered as an IV bolus.  
Symptomatic Assessments: 
Symptomatic progression will be assessed through the disease-specific questionnaire FACT 
Hepatobiliary Symptom Index 8 (FHSI-8), a subset of the FACT-Hep questionnaire 
(Herdman 2011; Scalone 2012) and through the ECOG performance status. 
Questionnaires will be completed prior to any other visit procedures at Screening (for ECOG 
performance status only), at Baseline, at Week 6, and then every 6 weeks until symptomatic 
progression is determined.  These protocol-specified assessments must be performed 
regardless of whether a Pexa-Vec or sorafenib treatment is given or cancelled (missed) for 
any reason. 
After symptomatic progression is determined, active patients will continue to visit the 
hospital/clinic for scheduled protocol visits but symptomatic progression will no longer be 
assessed. 
 
Quality of Life: 
Generic and disease-specific measures are essential to provide a comprehensive picture of 
Health-Related Quality of Life (HRQoL) in HCC.  Patients will complete the FACT-Hep that 
is a 45-item questionnaire designed to measure HRQoL in patients with HCC.  The FACT-
Hep consists of 27-item FACT-General (FACT-G), which assesses generic HRQoL concerns 
using 5 subscales, and the 18-item hepatobiliary subscale, which assesses specific symptoms 
of hepatobiliary cancer and side effects of treatment. 


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Patient utility will be assessed with the EQ5D-3L questionnaire (Herdman 2011; 
Scalone 2012). 
All questionnaires will be completed by the patient prior to any other visit procedures at 
Baseline, at Week 6, and then every 6 weeks.  Beyond 12 months of treatment, the 
questionnaires should be completed every 12 weeks.  Questionnaires will also be completed 
at the End of Treatment Visit. 
Biomarker Analysis: 
Serum samples collected at Baseline, 8 hour post-IT (Arm A only), at Week 6 and at End of 
Treatment Visit, will be archived.  These samples will allow further assessments of immune 
response and identification of response biomarkers. 
Pharmacoeconomic Assessments: 
To determine a trial-based economic evaluation, patient-level resource and service-use will 
be collected to evaluate the comparative cost-effectiveness of Pexa-Vec followed by 
sorafenib versus sorafenib alone.  Detailed costs related data will be collected during the 
Phase 3 trial using data entered in electronic Case Report Forms (eCRF), hospital invoices, 
pharmacy worksheet and 2 other questionnaires: “health care resource utilization” and 
“patient accommodation and transport” derived from client service receipt inventory (CSRI) 
(Beecham 2001).  
The questionnaire “health care resource utilization” is designed to capture direct-medical 
costs related data non-documented neither in the CRF nor in hospital invoices.  The 
questionnaire will be completed by the patient prior to any other visit procedures at Baseline, 
Week 6, and then every 6 weeks until End of Treatment Visit.  Beyond 12 months of 
treatment, the questionnaires should be completed every 12 weeks until end of treatment visit. 
The “patient accommodation and transport” covers all expenses related to indirect-medical 
costs.  The questionnaire will be completed by the patient prior to any other visit procedures 
at Baseline, at Week 12, and at the End of Treatment Visit.  
Utility values collected throughout the EQ5D-3L, the QoL questionnaire will also be used to 
produce generic measure for economic appraisal.   
Endpoints: 
For secondary endpoints, central radiological assessments will be evaluated with mRECIST 
for HCC. 
For exploratory endpoints, local and central radiological assessments will be used and 
evaluated with RECIST 1.1. 
Primary Endpoint: 
• 
Overall Survival:  time from date of randomization to the date of death due to any cause.  
If a patient is not known to have died at the cut-off date for analysis, survival will be 
censored at the date of last contact. 
Secondary Endpoints: 
• 
Time to Progression (TTP):  time from randomization to the date of first documented 
radiographic tumor progression; TTP does not include deaths.  If a patient has not had a 
TTP event at the cut-off date for analysis, TTP will be censored at the date of last 
evaluable tumor assessment before the cut-off. 
• 
Progression Free Survival (PFS):  time from randomization to the date of first 
documented radiographic tumor progression or death due to any cause, whichever 
occurs first.  If a patient has not had a PFS event at the cut-off date for analysis, PFS 
will be censored at the date of last evaluable tumor assessment before the cut-off.  


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• 
Overall response rate (ORR):  proportion of patients whose best overall response during 
their participation in the study is either CR or PR.  The best overall response is the best 
response recorded from the randomization until disease progression. 
• 
Disease control rate (DCR):  proportion of patients whose best overall response during 
their participation in the study is either CR, PR, or stable disease (SD). 
• 
Safety:  assessed by the NCI CTCAE (version 4.03).  Incidence of AEs and SAEs will 
be reported. 
• 
Time to Symptomatic Progression (TSP): time from randomization until the first 
documented event of symptomatic progression defined as a decrease of 4 points or more 
from baseline in the FHSI-8 questionnaire (sub-part of the FACT-Hep questionnaire) or 
a decrease in performance status to 4, or death. 
• 
Changes in the QoL assessed by changes in the FACT-Hep and EQ5D-3L 
questionnaires. 
Exploratory Endpoints: 
• 
TTP, PFS, ORR, and DCR as described above will also be assessed centrally. 
• 
Duration of overall Response (DoR):  applies only to patients whose best overall 
response is CR or PR.  The start date is the date of first documented response (CR or 
PR) and the end date is the date of first documented disease progression or the date of 
death due to underlying cancer. 
• 
Time to Initial Response (TIR):  the start date is the date of randomization and the end 
date is the date of first documented response (CR or PR). 
• 
Relative change of tumor size over time.  Baseline tumor size is defined as the sum of 
the longest diameters for all target lesions as identified during screening. 
• 
Changes in clinical laboratory parameters will be described including standard safety 
assessments, AFP levels, CD4 and CD8 counts (all assessed centrally). 
• 
Additional immunology assays may be performed on archived samples to further assess 
the immune 
mechanisms involved and identify 
biomarkers of response.  
Pharmacoeconomy:  information obtained from questionnaires collecting patient-level 
resource and service-use (Health Care Resource Utilization, Patient accommodation and 
Transport and EQ5D-3L questionnaires) will be analyzed.  Detailed costs collected 
using data in eCRF, hospital invoices and pharmacy worksheet data will also be used as 
information for pharmacoeconomy analyses. 
Statistical 
Considerations 
This is a multicenter, randomized, open-label, Phase 3 study, comparing Pexa-Vec followed 
by sorafenib to sorafenib.  The primary efficacy population is defined as the Intent to Treat 
(ITT) population, which consists of all randomized patients.  All primary efficacy analyses 
will be performed based on data from this population.  Following the ITT principle, patients 
will be analyzed according to the treatment arm they were assigned to at randomization.  The 
Safety Population will consist of all patients who received at least one dose of the study 
treatment (Pexa-Vec or sorafenib).  For safety analyses, patients will be analyzed according 
to treatment actually received. 
The analyses of the primary and secondary efficacy endpoints will be performed on the ITT 
population and on a subset of the more significant endpoints repeated on the Per Protocol (PP) 
population which consists of patients without any major protocol deviations. 
It is assumed that Pexa-Vec does not reduce the hazard of death during the first 6 months of 
treatment (hazard ratio [HR] = 1.00 for the first 6 months), while it reduces the hazard by 
40% thereafter (HR = 0.6 after 6 months).  The median overall survival in the control arm is 
expected to be approximately 11 months. 
Based on the aforementioned assumptions, and assuming a 1:1 randomization a total of  
474 events of death should be observed to reject the null hypothesis of no Pexa-Vec effect 


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with a power of 86% (assuming that HR = 1 for the first 6 months and 0.6 thereafter) using a 
stratified log-rank test at a 1-sided cumulative 2.5% level of significance.  This corresponds 
to a HR smaller than or equal to 0.83 at the final analysis to declare a significant treatment 
benefit.  At the final analysis, the p-value of the re-randomization test (based on the stratified 
log-rank test) will be computed and compared to the threshold defined as 0.021 (if the analysis 
is performed at 474 events exactly) due to the alpha adjustment induced by the interim 
analysis for efficacy (as presented below).  If the p-value is lower than this boundary, the 
treatment will be considered as effective. 
A first interim analysis for futility will be performed when 190 deaths (40% of the required 
events for final analysis) are documented in the ITT population with a stopping boundary 
defined as HR = 1.1.  The p-value of the re-randomization test (based on the stratified log-
rank test) will be computed and compared to the threshold corresponding to HR = 1.1.  If 
exactly 190 events are considered in this analysis, the boundary for the p-value is defined as 
0.744.  If the p-value computed is higher than this threshold, the futility boundary will have 
been crossed.  
A second interim analysis for efficacy will be performed when 379 deaths (80% of the 
required events for final analysis) are documented in the ITT population.  An α-spending 
function due to Lan-DeMets with O’Brien-Fleming type stopping boundary (as implemented 
in EAST® 6.3) will be used for the interim efficacy analysis.  If the interim analysis is 
performed after exactly 379 events, the O’Brien-Fleming boundary for efficacy consists in 
using a significance level equal to 0.012, (corresponding to a HR equal to 0.79).  If the p-
value of the re-randomization test (based on the stratified log-rank test) is lower than this 
threshold, the efficacy boundary will have been crossed. 
The nominal p-values and critical values used to declare statistical significance at the time of 
interim analysis may be slightly different as based on the actual number of deaths that have 
been documented at the time of analysis. 
Assuming a non-uniform enrolment and about 5% loss to follow-up or withdrawal of consent 
rate, a total of 600 patients should be recruited in 19 months.  It is estimated that the required 
190 and 379 deaths for the interim analyses will be observed approximately 21 months and 
34 months respectively after starting the trial.  Likewise, it is estimated that the required  
474 events for final analysis will be observed approximately 29 months after the inclusion of 
the last patient. 
The primary analysis (overall survival) will be done using a stratified re-randomization test. 
For secondary endpoints, a hierarchical testing strategy will be adopted, TTP will be 
compared between the 2 treatment arms if the primary endpoint overall survival is statistically 
significant.  If TTP is statistically significant (i.e., p <0.025) then PFS will be compared 
between the treatment groups and finally ORR will be analyzed.  This approach ensures that 
the overall Type I error rate of the study is maintained at 2.5% (one-sided). 


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3 
BACKGROUND 
3.A 
HEPATOCELLULAR CARCINOMA (HCC) 
Hepatocellular carcinoma (HCC) is estimated to be the third most common cause of cancer-related 
deaths world-wide (Ferlay 2010; Hoos 2012), the 5th most common cancer diagnosis in men 
worldwide and the 7th most common cancer in women (El-Serag 2012).  Approximately  
750,000 people develop HCC world-wide each year with ~80% of cases reported in developing 
countries which have a high prevalence of hepatitis (El-Serag 2012).  However, HCC is one of the 
only cancers whose incidence is increasing in developed countries (Siegel 2014; El-Serag 2001; 
Goodgame 2003; Deuffic 1998).  Approximately 25,000 new cases of HCC are diagnosed annually 
in the United States (US) (Siegel 2014).  The incidence of HCC is 1,550 new cases in Canada 
(Canadian Cancer Society 2008) and approximately 50,000 in Europe (Ferlay 2013).  Most HCC 
cases (approximately 90%) develop in the context of liver disease, in particular hepatocellular 
cirrhosis (Simonetti 1991; Bosch 1999).  The most common causes of cirrhosis include chronic 
hepatitis B or C, and chemical substances such as excessive alcohol or aflatoxins (Chen 2003).  
Nonalcoholic steatohepatitis, a liver disease triggered by enhanced fat deposition in the liver, may 
also be a risk factor for the development of HCC (Hashimoto 2009; Mori 2004).  The risk of death 
from HCC is increased both in males and females with increasing body mass index class, linking 
obesity to development of HCC (Calle 2003).  Furthermore, diabetes has been shown to lead to 
increased risk of development of HCC in the presence of hepatitis B, hepatitis C, or alcoholic 
cirrhosis (El-Serag 2001).  Hemochromatosis, a disease which results from inappropriate iron 
absorption, leading to excessive iron deposition in liver (leading to liver cirrhosis) and other 
organs, is another risk factor for the development of HCC (Niederau 1985).  Patients with HCC 
generally present with advanced disease with a poor prognosis of 6 to 9 months median survival 
(Yoo 2003).  Therefore, development of effective methods for the prevention and early diagnosis 
of HCC methods are critical.  In addition, there exists a continued need for new therapies that will 
further improve survival of patients with HCC. 
 
3.A.1 
Current Treatment for HCC 
Surgical resection and liver transplant are the only curative treatments for HCC.  Small HCC 
tumor(s) (less than 3 cm in diameter) can be resected by hepatectomy, the most effective treatment.  
Surgery is associated with a reported 50–60% five-year survival rate, but unfortunately is feasible 
in only 10–15% of cases; most patients present with disease that is either too advanced or disease 
is accompanied by extensive cirrhosis that precludes surgery (Gondolesi 2004).  Resection in 
cirrhotic patients carries high morbidity and mortality. 


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For patients with unresectable HCC and who cannot receive liver transplantation, a large array of 
local-regional therapies are available including percutaneous ethanol injection therapy (PEIT), 
radiofrequency ablation (RFA), transarterial chemoembolization (TACE), Yttrium-90 and/or 
radio-embolization.  The choice of local-regional therapy depends on the size and location of the 
intrahepatic tumors and on the underlying liver function (Bruix 2005). 
Sorafenib is the only systemic therapy approved for the treatment of patients with advanced HCC.  
Sorafenib is a small molecule which inhibits growth signaling and pro-angiogenic pathways 
(Wilhelm 2004; Chang 2007) by targeting the serine/threonine kinases Raf-1 and B-Raf as well as 
receptor tyrosine kinases platelet-derived growth factor receptor β (PDGFR-β) and vascular 
endothelial growth factor receptors 1, 2, and 3 (VEGFR1, 2, 3) (Wilhelm 2004; Chang 2004).  
These sorafenib targets have been shown to be involved in the pathogenesis of HCC (Ito 1998; 
Villanueva 2007; Calvisi 2006; Semela 2004).  Results of a Phase 3 randomized trial with 
sorafenib conducted in 21 countries (n = 602; SHARP Trial) demonstrated a statistically significant 
survival advantage for sorafenib over placebo treatment (10.7 months versus 7.9 months, 
respectively; p <0.001).  Partial response by response evaluation criteria in solid tumors (RECIST) 
criteria was demonstrated in 2% of the sorafenib group and no patients had a complete response 
(Llovet 2008b).  A subsequent Phase 3 randomized trial with sorafenib was completed in sites in 
Asia (n = 226 patients; Asia-Pacific Trial).  Results demonstrated a statistically significant survival 
advantage for sorafenib (n = 150 patients) over placebo (n = 76 patients) (median 66.5 months 
versus 4.2 months, respectively; p = 0.014) (Cheng 2009).  The disease control rate (DCR) with 
sorafenib was 35% (confirmed at 12 weeks after treatment initiation); disease control was defined 
as an objective response (partial or complete) or stable disease (SD) that lasted at least 44 weeks  
The objective response rate (by RECIST criteria) was only 3% on sorafenib.  Sorafenib is now 
approved in multiple countries for patients with unresectable HCC.  
Nevertheless, despite a 2–3 month survival benefit in the front-line setting, sorafenib has 
significant toxicities and dose-reductions or treatment discontinuation is often required; this is 
currently being studied under non-protocol practice conditions on the GIDEON trial 
(Lencioni 2013; Lencioni 2012).  In addition, disease stabilization is transient and tumor 
progression occurs in all patients (Cheng 2009; Llovet 2008a).  
Several other systemic therapeutic agents have been tested in advanced HCC patients.  In the 1st 
line setting, 3 receptor tyrosine kinase inhibitors – sunitinib, brivanib, linifanib – have been 
compared directly against sorafenib (Cainap 2012; Cheng 2011; Johnson 2013).  In a fourth 1st 
line Phase 3 trial of a tyrosine kinase inhibitor (SEARCH), the combination of erlotinib plus 
sorafenib was compared to placebo plus sorafenib (Zhu 2014a).  In these trials sorafenib had a 


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consistent performance, demonstrating a median overall survival of 8.5–10 months.  None of the 
investigational therapies were however able to demonstrate superiority to sorafenib, or, in the case 
of brivanib and sunitinib, not even non-inferiority.  Most trials also showed a worse safety profile 
of experimental agents compared to sorafenib. 
 
3.B 
ONCOLYTIC IMMUNOTHERAPY  
Oncolytic immunotherapy employs viruses that are designed to preferentially replicate in and lyse 
cancer cells and in this process trigger anti-tumor immunity.  Following the first description of a 
virus engineered to replicate selectively in cancer cells over 20 years ago, the field of oncolytic 
immunotherapy has expanded dramatically.  Over 10 different viral species have entered clinical 
trials.  One oncolytic virus-based product (Onyx-015 adenovirus) entered a Phase 3 clinical trial 
in the US, and a similar virus, H101, was approved for use in combination with chemotherapy as 
a treatment for head and neck cancer by the Chinese State Food and Drug Administration in 
November 2005.  More recently, a Phase 3 pivotal trial of talimogene laherparepvec (T-VEC), an 
oncolytic herpes virus expressing granulocyte-macrophage colony stimulating factor (GM-CSF) 
in patients with advanced melanoma met its primary endpoint, demonstrating a significant 
improvement in durable response rate versus GM-CSF alone (16% vs 2%, p<0.0001) 
(Andtbacka 2013).  Furthermore, a Phase 3 trial of an oncolytic reovirus in combination with 
standard chemotherapy is currently underway in advanced head and neck cancer. 
Oncolytic immunotherapies kill cancer cells through a novel mechanism of action “oncolysis”, or 
virus replication-associated necrosis (Parato 2005; Kirn 2009) and can be targeted to cancer cells 
with activated genetic pathways and/or loss of tumor suppressor function (Heise 1997; 
Stojdl 2000; Martuza 1991).  Selective intratumoral (IT) replication of the virus leads to lysis of 
the infected cancer cell and spread to adjacent cancer cells.  In addition, these viruses can kill 
through other mechanisms, including induction or amplification of a tumor-specific cytotoxic 
T-lymphocyte response.  Oncolytic immunotherapies can also be armed for expression of 
therapeutic transgenes (Chase 1998; Todo 2001; Hermiston 2002; Hermiston 2005).  The latter 
can lead to bystander cell killing via enhanced immune response to the tumor (e.g., expression of 
cytokines such as GM-CSF).  Oncolytic immunotherapies expressing additional therapeutic 
transgenes have the potential to effectively treat cancers that have become refractory to currently-
approved treatments. 
 


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3.B.1 
Pexa-Vec: Selective Tumor Infection and Active Immunotherapy 
Pexa-Vec (Pexastimogene Devacirepvec, JX-594) is an oncolytic and immunotherapeutic vaccinia 
virus engineered to express GM-CSF.  Pexa-Vec mechanisms-of-actions include tumor cell 
infection and lysis (Breitbach 2011; Kim 2006; Park 2008), anti-tumor immune response 
induction (Heo 2013; Kim 2013) as well as acute vascular disruption (Breitbach 2013).  Pexa-Vec 
is derived from the commonly used Wyeth vaccine strain (Dryvax®, Wyeth laboratories).  
Three genetic modifications are included in Pexa-Vec:  
1. 
thymidine kinase (TK) gene deactivation,  
2. 
GM-CSF gene insertion under the control of the synthetic early-late promoter, and  
3. 
lac-Z gene insertion under control of the p7.5 promoter. 
Selective targeting of tumor cells by Pexa-Vec is attributed to both engineered mechanisms as well 
as to inherent vaccinia selectivity for cancers (Parato 2012).  TK gene inactivation renders viral 
replication dependent on the high cellular TK activity that is a hallmark of cancer cells 
(Hengstschlager 1998).  Vaccinia vaccine strains have been shown to be inherently tumor 
targeting (Thorne 2007; Yu 2004).  This may be attributable to the fact that many of the hallmarks 
of cancer (Hanahan 2000) (e.g., blocks in apoptotic pathways, dysregulation of cell cycle control 
and immune evasion) are also optimal cellular conditions for successful vaccinia virus replication.  
Furthermore, vaccinia replication and spread is dependent on epidermal growth factor receptor 
(EGFR) signaling (Katsafanas 2004), a pathway that is activated in most cancers (Hanahan 2000). 
GM-CSF is reportedly an effective cytokine for stimulating tumor-specific anti-tumoral immunity 
(Dranoff 1993).  Furthermore, the combination of vaccinia infection with GM-CSF production has 
been shown to result in enhanced efficacy in preclinical models, presumably due to additional 
immune stimulation due to GM-CSF expression within the tumor microenvironment 
(Thorne 2007).  GM-CSF is also expressed by other oncolytic viruses like T-Vec or Oncos-102.  
In addition, in melanoma patients GM-CSF when added to ipilimumab led to an improved outcome 
(Hodi 2013). 
Protective anti-tumor immunity has been demonstrated following vaccinia infection of murine 
tumors in vivo (Kirn 2007).  Pexa-Vec has also been shown to function as an immunotherapeutic 
in patients.  GM-CSF expression was associated with increased neutrophil, monocyte and 
eosinophil production in Pexa-Vec treated patients (Breitbach 2011; Park 2008).  Furthermore, 
inflammatory cell infiltration into tumors was also demonstrated with Pexa-Vec treatment 
(Hwang 2011; Mastrangelo 1999).  Finally, functional anti-tumor antibodies mediating 


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complement dependent cytotoxicity were induced after Pexa-Vec treatment of patients with liver 
tumors (Heo 2013; Kim 2013). 
 
3.C 
PRECLINICAL EXPERIENCE WITH PEXA-VEC 
3.C.1 
Efficacy of Pexa-Vec in Rabbit VX-2 Carcinoma Model and Rat Carcinogen-Induced 
Primary Liver Tumors 
Efficacy of Pexa-Vec as a single agent was studied in 2 liver cancer models.  The transgene product 
expressed by Pexa-Vec, hGM-CSF, is biologically active in rabbits, a species in which vaccinia 
virus replicates.  Accordingly, the virus was tested versus the transplantable orthotopic rabbit 
carcinoma VX-2 model in which cells are implanted under the liver capsule forming liver tumors 
and metastases in liver and lung (Kim 2006).  Tumor-bearing rabbits were treated with a single 
dose of 109 plaque forming units (pfu) of Pexa-Vec via IT or intravenous (IV) injection.  Seven 
weeks post therapy, mean tumor volume in both Pexa-Vec treated groups was significantly smaller 
when compared to the phosphate buffered saline (PBS) control group.  Furthermore, Pexa-Vec 
treatment prevented formation of metastases.  Median survival time of rabbits in the PBS control 
group was 50 days while median survival was not reached in either Pexa-Vec treated group at 
70 days (Kim 2006).  Rabbits treated with Pexa-Vec exhibited weight gain while control rabbits 
lost weight over the course of the study, presumably due to tumor progression.  The dose response 
of the effects of Pexa-Vec treatment was determined by comparing the efficacy of a single IV dose 
of 108 pfu used in a subsequent study with the results discussed above with application of 109 pfu.  
Whereas a dose of 109 pfu resulted in 88% inhibition of primary tumor growth and 100% inhibition 
of metastases at 7 weeks, the lower dose of 108 pfu inhibited primary growth by only 10%, while 
inhibiting the incidence of metastases by 48%. 
Pexa-Vec efficacy against primary liver tumors was investigated in an orthotopic primary liver 
tumor model.  Cirrhosis and liver cancers were induced in rats by chronic oral administration of 
N-nitrosodiethylamine and N-nitrosomorpholine (Kim 2006).  Tumor-bearing rats received 3 IV 
infusions of Pexa-Vec every 2 weeks.  Over 10 weeks, 5 of 6 animals treated with Pexa-Vec 
exhibited complete responses by ultrasound while tumors in all PBS control animals increased in 
size.  These preclinical studies provide rationale for the use of Pexa-Vec as a novel therapy for 
HCC (refer to the Investigator’s Brochure [IB] for further details). 
 


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3.C.2 
Efficacy of Repeated Doses of Pexa-Vec Followed by Sorafenib Therapy in a Human 
Tumor Xenograft Model of Hepatocellular Carcinoma 
Preclinical in vitro and in vivo data on the combination of Pexa-Vec and sorafenib were obtained.  
Sorafenib, when given concomitantly with Pexa-Vec, had a highly significant inhibitory effect on 
Pexa-Vec replication at clinically-relevant concentrations in cancer cell lines in vitro, including 
human HCC cell lines.  This effect was not unexpected since sorafenib inhibits the EGFR-ras 
signal transduction pathway by blocking raf kinase, and the dependence of vaccinia virus on 
activation of this pathway has been definitively demonstrated (Yang 2005).  Therefore, as with 
other inhibitors of this EGFR pathway, sorafenib can be utilized to block Pexa-Vec replication 
(Heo 2011).  
As a result, different Pexa-Vec and sorafenib treatment sequences were explored.  In vivo 
experiments were carried out with Pexa-Vec and sorafenib in a HepG2 (human HCC cancer cell 
line) xenograft tumor model in severe combined immunodeficiency (SCID) mice once tumors 
reached a size of approximately 900 mm3.  Two doses of Pexa-Vec administered prior to daily 
sorafenib therapy was superior to PBS control or daily sorafenib therapy alone in terms of tumor 
growth and time-to-tumor progression, and superior to Pexa-Vec alone in terms of time-to-tumor 
progression.  In addition, this sequence was superior to sorafenib followed by Pexa-Vec and to 
simultaneous treatment.  Of note, as predicted given the inhibitory effect of sorafenib on Pexa-Vec 
replication in vitro, simultaneous treatment resulted in efficacy that was equivalent to sorafenib 
alone (Heo 2011). 
 
3.C.3 
Toxicity and Biodistribution of Single or Repeated IV Doses of Pexa-Vec in the Rabbit 
An exploratory study in New Zealand White rabbits was conducted.  Animals in this study received 
one (n = 1M, 1F) or 3 (n = 3M, 3F) weekly IV doses of Pexa-Vec (1010 pfu/dose; approximately  
4 × 109 pfu/kg).  The treatments were well-tolerated: no overt clinical signs were observed 
throughout the 92 days of the study, with the following exception.  For the animals receiving 
multiple doses, following the first injection of Pexa-Vec on Day 1, the treated animals lost 
approximately 5% of their body weight by Day 6.  Thereafter, body weight rose intermittently 
until the end of measurements on Day 33.  Control animals gained weight steadily throughout the 
study (Kim 2006).  While the numbers of animals in this exploratory study are limited, histological 
and hematological findings are consistent with vaccinia virus infection.  Reversible lymphoid 
depletion in the thymus and lymphoid hyperplasia with red pulp expansion in the spleen were also 
considered physiopathological adaptations.  All of these findings appeared to be resolved by 


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Day 92 and none are considered to be of toxicological significance (refer to the IB for further 
details). 
A study entitled “Toxicity and Biodistribution of Recombinant Vaccinia Virus Pexa-Vec in the 
Rabbits” has been conducted in compliance with Good Laboratory Practices (GLP) guidelines.  
Nine groups of 5 rabbits/sex/group received IV administrations of a clinical lot (Lot No. C173-3) 
at doses of 3 × 106 and 3 × 107 pfu/kg (~0.2 and 2-fold the 109 pfu/patient dose on a pfu/kg basis).  
Rabbits were assigned to groups that received 3 weekly infusions of low dose or high dose 
Pexa-Vec or a single high dose Pexa-Vec.  Rabbits in a vehicle control group received 3 infusions.  
Pexa-Vec triggered treatment-related inappetence, and dose-related, reversible, early loss of body 
weight at both dose levels.  There were some mild, dose–related, reversible changes in hematology 
and clinical chemistry parameters.  Mild anemia was considered secondary to spleen enlargement.  
At the high dose only, abscesses were observed in the testes.  All of the observed changes appear 
to be reversible (refer to the IB for further details). 
 
3.D 
CLINICAL EXPERIENCE 
3.D.1 
Overview of Clinical Experience with Pexa-Vec 
Pexa-Vec has been evaluated in 21 completed and ongoing clinical trials to date.  Over 500 patients 
have been treated by IV infusion and/or IT injection with >900 IV infusions and >900 IT injections. 
 
Table 1:  
Pexa-Vec Clinical Development 
Study 
Indication / administration 
Phase 
Status 
No. of Patients 
 
Melanoma Mastrangelo, 
investigator initiated / IT 
1 
Completed 
7 
HEP001 
Liver metastases: dose escalation / 
up to 8 doses IT 
1 
Completed 
14 
IV011 
Solid tumors / 1 dose IV 
1 
Completed 
23 
MEL005 
Melanoma / 6 doses IT 
1/2 
Completed 
10 
P009 
Pediatric tumors / 1 dose IT 
1 
Stopped 
6 
HEP012 
CRC – neoadjuvant therapy /  
1 dose IT or IV 
2a 
Stopped 
2 


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Study 
Indication / administration 
Phase 
Status 
No. of Patients 
HEP007 
HCC primarily 1st line: 2 dose 
levels / 3 doses IT 
2a 
Completed 
30 
HEP016 
HCC 2nd line / 1 dose IV + 2 doses 
IT f/b Sorafenib 
2 
Enrolment 
completed; data 
analysis 
ongoing 
25 
HEP021 
HCC 1st line / 5 doses IV 
2 
Enrolment 
completed; data 
analysis 
ongoing 
16 
HEP018 
TRAVERSE (RCT):  1 dose IV + 5 
doses IT (randomized 2:1) 
Arm A:  JX594 + BSC 
Arm B:  BSC 
2b 
Completed 
129 
Arm A: 86 
CRC014 
CRC:  dose escalation / 4 doses IV 
1 
Completed 
15 
CRC019 
CRC:  single agent & combo 
(irinotecan) / 5 doses IV + 3 doses 
IT 
1/2a 
Enrolment 
completed; data 
analysis 
ongoing 
52 
REN022 
RCC / 5 doses IV 
1/2 
Enrolment 
completed; data 
analysis 
ongoing 
17 
HEP024 
PHOCUS (HCC): 3 doses IT vs 
Sorafenib 
3 
Ongoing 
186 
REN026 
RCC 
Part 1 = 4 IV infusions at  
2 dose levels  in combo with anti-
PD-1 
Part 2 = 3 doses IT or 4 IV 
injections in combo with anti-PD-1 
1b 
Ongoing 
6 
 
 
The most common adverse events (AEs) reported were acute, transient flu-like symptoms, 
including fever and chills.  Transient, hypotension responsive to fluid administration was also 
noted in a subset of patients within 24 hours of treatment.  Pexa-Vec related skin pustules were 
observed in less than 15% of patients receiving IT injections (1.6% of all IT treatments).  The 


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pustules were self-limited and resolved without sequela within 2–3 weeks of treatment, consistent 
with the timeline for pustule resolution utilizing wild-type vaccinia vaccine.  Evidence of anti-
tumor activity was observed in patients treated across all studies with Pexa-Vec, as will be 
discussed in the next sections.  
Radiographic signals of efficacy for Pexa-Vec were primarily assessed utilizing modified RECIST 
(mRECIST) or mChoi response criteria.  In HCC, conventional RECIST responses are uncommon 
following systemic treatment.  In the absence of decreased tumor size as measured by RECIST 
criteria, alternative methods for assessing anti-tumor response have been developed.  Modified 
RECIST criteria for HCC focuses on the contrast enhancing (or viable) portions of tumor with 
response defined as a ≥30% decrease in the sum of longest diameter (SLD) of the contrast 
enhancing areas of target tumors in the absence of non-target progression, progressive disease (PD) 
as ≥20% increase in the SLD of target tumors or the non-target progression, and SD as those not 
qualifying as PD (Llovet 2008b; Lencioni 2010).  Of note, Pexa-Vec replication in tumors may 
trigger an acute, local inflammatory response within tumors which may lead to transient tumor 
swelling (termed an “oncolytic flare response” or “pseudoprogression”).  In addition, the modified 
Choi (mChoi) criteria is a more qualitative radiographic assessment measures which incorporates 
the impact of anti-cancer treatment on tumor viability and necrosis.  The Choi response 
(Choi 2004; Choi 2007) is a measure of decreased tumor density and is defined as a decrease in 
10% or more of the longest diameter (LD) of the tumor and/or a decrease of 15% or more in the 
average tumor enhancement.  Despite potential transient tumor swelling due to edema and/or 
inflammation, Pexa-Vec has demonstrated anti-tumor activity based on mChoi or mRECIST for 
HCC criteria.  
 
3.D.2 
Pexa-Vec Evaluation in Non-HCC Indications 
Pexa-Vec was initially evaluated in patients with metastatic melanoma and was well-tolerated in 
a total of 17 patients treated by IT injection either weekly or twice weekly on 2 clinical trials 
(Mastrangelo 1999; Hwang 2011).  Evidence of tumor infection and anti-tumor activity was 
observed in both injected and non-injected tumors. 
An IV dose escalation study (JX594-IV-011) has been completed and results published 
(Breitbach 2011).  A total of 23 patients were treated and a maximum feasible dose (MFD) of  
3 × 107 pfu/kg was reached without definition of a maximum tolerable dose (MTD).  Pexa-Vec 
delivery to tumors following IV infusion of Pexa-Vec was demonstrated in tumor biopsies of 7 of 
8 evaluable patients treated at a dose of ≥1 × 109 pfu and in no patients treated at <1 × 109 pfu.  
Delayed reemergence of Pexa-Vec in blood was demonstrated in a subset of patients and was 


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associated with GM-CSF expression and white blood cell induction.  Furthermore, tumor response, 
disease control, and suppression of new tumor outgrowth were observed more frequently in higher 
dose cohorts than in patients receiving lower systemic doses of Pexa-Vec.  
Additional information on non-HCC studies can be found in the IB.  
 
3.D.3 
Treatment of Solid Tumors within the Liver with Pexa-Vec 
3.D.3.a 
Phase 1 Liver Tumor Trial  
A Phase 1 dose-escalation trial of Pexa-Vec in patients with primary or metastatic liver tumors 
(JX594-IT-HEP001) has been completed and the results published (Park 2008).  Pexa-Vec was 
administered by IT injection every 3 weeks in patients with refractory, injectable tumors within 
the liver at one of 4 dose levels (1 × 108 pfu to 3 × 109 pfu).  Patients were scheduled to receive  
2–4 treatments but could subsequently receive an additional 4 treatments if there was evidence 
response or clinical benefit.  Fourteen patients, including 3 HCC patients were enrolled and treated. 
Pexa-Vec was well-tolerated in study patients.  All patients treated with Pexa-Vec experienced 
mild-to-moderate flu-like symptoms, which included fever, chills, anorexia, aches/pain, fatigue, 
headache, and/or nausea.  No significant organ toxicity was reported.  Two patients were treated 
at the 3 × 109 pfu dose and both patients experienced dose limiting toxicities (DLTs) after a single 
treatment with Pexa-Vec.  The DLTs experienced by these study patients included asymptomatic 
Grade 3 hyperbilirubinemia (n = 2), and Grade 3 anorexia and right upper quadrant pain (n = 1).  
Hyperbilirubinemia was apparently due to tumor swelling post-treatment and occlusion of the 
adjacent bile duct.  The maximum-tolerated dose on the study was therefore defined as 1 × 109 pfu. 
Response and/or stable disease were observed in 9 out of the 10 evaluable patients.  Target tumor 
responses were demonstrated in 8 patients by RECIST criteria and/or Choi criteria.  Responding 
patients had various tumor types, including HCC.  In 3 cases positron-emission tomography – 
computed tomography (PET-CT) scans demonstrated a decrease in injected tumor metabolic 
activity (10–100% decrease standardized uptake value [SUV]).  Eight patients (57%) survived for 
at least 8 months, and up to 72+ months.  The median cancer-specific survival was 9 months. 
 
3.D.3.b 
Phase 2 Liver Cancer (HCC) Trial (JX594-IT-HEP007) 
A Phase 2 randomized dose-finding trial of Pexa-Vec in patients with liver cancer (HCC)  
(JX594-IT-HEP007) has been completed and the results published (Heo 2013).  Pexa-Vec was 
administered by IT injection every 2 weeks for 3 total doses in patients with injectable tumors 


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within the liver.  Study dose levels were 1 × 108 pfu (Arm A) and 1 × 109 pfu (Arm B).   
Thirty patients were treated (16 patients in Arm A, 14 patients in Arm B).  Twenty-nine patients 
received all 3 planned injections; one low-dose patient received 2 Pexa-Vec treatments.  IT 
injection was well-tolerated at both dose levels in this population of patients with HCC.  One 
treatment-related serious adverse event (SAE) was reported in the high-dose group (nausea and 
vomiting requiring prolonged hospitalization).  Flu-like symptoms (Grade 1–2) occurred in all 
patients over the first 12–24 hours after treatment, including fever, rigors, nausea or vomiting.  
Four patients responded to treatment based on mRECIST criteria (1 complete response; 3 partial 
responses).  Responses were observed in injected and non-injected tumors.  Further, overall 
survival was significantly longer in the high-dose arm compared with the low-dose arm (median 
14.1 months versus 6.7 months, hazard ratio [HR] 0.39; p-value 0.020, Gehan-Breslow-Wilcoxon 
test; 1-sided test for superiority of high-dose [Figure 1]).  The median overall survival was  
9.0 months for the entire population.  
 
Figure 1: 
Kaplan-Meier Plot of Overall Survival by Dose 
 
 
 
3.D.3.c 
Phase 2 Study of HCC Patients Treated IV and IT with Pexa-Vec Prior to Sorafenib 
(JX594-HEP016)  
Twenty-five patients were enrolled on this Phase 2 study investigating one IV dose of Pexa-Vec, 
followed by 2 IT injections (one week and 3 weeks after the IV infusion), prior to initiation of 
standard sorafenib therapy.  Twenty patients were resistant to sorafenib therapy before Pexa-Vec 
treatment.  Transient flu-like symptoms following Pexa-Vec treatments were the most common 


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AEs.  Subsequent therapy with sorafenib was well-tolerated.  The 2 agents were not used 
simultaneously, as sorafenib inhibits Pexa-Vec replication and can potentially impair its activity.  
Transient decreases in white blood cell (WBC) counts, in particular neutrophils and lymphocytes, 
may occur within the first 24 hours following each Pexa-Vec treatment dose.  Modified Choi 
responses and/or disease stabilization were observed following IV and IT Pexa-Vec therapy prior 
to and following standard sorafenib therapy.  One patient exhibited a partial response by RECIST 
criteria in addition to a response by Choi criteria. 
 
3.D.3.d 
Phase 2b Randomized Trial of Pexa-Vec Plus Best Supportive Care Versus Best 
Supportive Care in Patients with Advanced Hepatocellular Carcinoma Who Have 
Failed Sorafenib Treatment (JX594-HEP018/TRAVERSE)  
One hundred and twenty-nine patients having failed previous sorafenib therapy were enrolled on 
this Phase 2b study and randomized 2:1 to receive either Pexa-Vec plus best supportive care (BSC) 
or BSC alone.  Eighty-six patients were assigned to the Pexa-Vec arm and were to receive one IV 
dose followed by up to 5 IT injections (1, 3, 6, 12, and 18 weeks after the IV infusion), and 43 to 
BSC-only arm. 
The most common AEs related to Pexa-Vec experienced by patients in Arm A included: pyrexia 
(78.6%), chills (50.0%), pustular rash (28.6%), hypotension (26.2%), and nausea (25%).  These 
AEs were generally mild-to-moderate in severity and tolerable with the exception of hypotension, 
which was more severe than previously observed in other trials of Pexa-Vec. 
Grade 3 AEs possibly or probably related to Pexa-Vec included pyrexia (8.3%), hypotension 
(8.3%), blood bilirubin increased (4.8%), anemia (3.6%), blood aspartate transaminase (AST) 
increased (3.6%); fatigue, hepatic encephalopathy, hypertension, platelet count decreased, 
vomiting, (2.4% for each event); abdominal pain and blood alanine aminotransferase (ALT) 
increased (1.2% for each event).  Two Grade 4 or Grade 5 events were noted:  respiratory failure 
(Grade 4) and hepatic failure (Grade 5). 
Six patients presented with at least one Grade 3–4 AE possibly or probably related to IT injection 
procedure (7.1%):  these AEs included hypotension (2.4%), upper abdominal pain, acute 
respiratory failure, anemia, ascites, fluid overload, hepatic hemorrhage, pleural effusion, acute 
renal failure, staphylococcal sepsis, and troponin increase (1.2% for each event).  No procedure-
related AE resulted in the patient’s death. 


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The most frequent Pexa-Vec-related SAE, which occurred in 6 patients (8 SAEs) was severe 
hypotension defined as a systolic blood pressure <90 mmHg, lasting and requiring a medical 
treatment for at least 24 hours after Pexa-Vec administration.  Notably, anti-hypertensive 
medication was ongoing at the time of treatment with Pexa-Vec prior to the development of 
hypotension in the majority of these patients, thereby possibly exacerbating the potential for 
hypotension. 
Treatment with Pexa-Vec did not improve overall survival or other efficacy measures, compared 
with BSC, in patients with advanced HCC in this open-label study.  No significant improvement 
of overall survival was shown in Arm A compared to Arm B (p = 0.426, stratified log-rank test) 
for the Intent-to-Treat (ITT) population.  Median overall survival was 4.2 (95% confidence interval 
[CI]: 3.3 to 5.4 months) vs 4.4 months (95% CI:  3.2 to 6.0 months) for Arm A vs Arm B, 
respectively.  HR observed was 1.19 (95% CI:  0.78 to 1.80).  The overall disease control rate 
(proportion of patients with complete response [CR], partial response [PR], or SD) during the study 
was 13% (95% CI:  7% to 22%) vs 19% (95% CI:  8% to 33%) for Arm A vs Arm B, respectively.  
Notably, the majority of patients in TRAVERSE did not receive the complete protocol specified 
treatment regimen of JX-594.  In Arm A, 12 of 86 randomized patients (13.9%) received all 
6 planned treatments; and only half of the patients (51.2%) received at least 3 IT treatments (1 IV 
plus 3 IT) as administered in previous JX-594 HCC trials.   
The limited number of patients completing treatment on Arm A in conjunction with the 
significantly shorter median overall survival (~4.2 vs 4.4 months on Arms A and B, respectively) 
observed in this study versus studies of other agents for second line HCC (~7–9 months) suggests 
a relatively more advanced HCC patient population was included in TRAVERSE (Llovet 2013; 
Zhu 2014b). 
 
3.E 
RATIONALE 
3.E.1 
Rationale for Study 
Novel therapies are desperately needed for patients with advanced, unresectable HCC.  The only 
approved agent for advanced HCC, sorafenib, prolongs survival by only a few months, is not 
curative, and is generally cytostatic.  Furthermore, several agents with similar mechanisms-of-
action to sorafenib (including brivanib, sunitinib and linifanib) have failed to demonstrate 
improved outcome for advanced HCC patients when compared to sorafenib.  Pexa-Vec exhibits 
multiple different and complementary mechanisms-of-action to sorafenib.  By exploiting novel, 


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alternative mechanisms-of-action of Pexa-Vec relative to other investigational agents, Pexa-Vec 
administration prior to sorafenib may provide additional clinical benefit to sorafenib therapy alone. 
The rationale for Pexa-Vec treatment of HCC is based on: 
1. 
Exploiting novel, alternative mechanisms-of-action of Pexa-Vec relative to sorafenib as well 
as investigational agents in HCC. 
2. 
Preclinical liver cancer models that have demonstrated significant tumor responses with 
Pexa-Vec treatment (Section 3.C.1). 
3. 
Preclinical evidence that Pexa-Vec replication is driven by activated EGFR/Ras signaling 
(Section 3.B.1). 
4. 
Preclinical and clinical evidence suggest that anti-tumor activity of Pexa-Vec is dependent 
on targeting of the tumor endothelium and that Pexa-Vec spread within and between tumors 
is dependent upon the IT vasculature (Section 3.B.1).  High level tumor vascularity and 
angiogenesis is well established in HCC (Forner 2012). 
5. 
In Phase 1 and 2 clinical trials of Pexa-Vec for HCC, IT administration to hepatic tumors has 
been associated with both local and distant tumor responses (Section 3.D.3). 
6. 
Improved survival with high-dose IT injections of Pexa-Vec in advanced HCC patients 
(Section 3.D.3.b).  
7. 
Long survival of sorafenib naïve patients who have received Pexa-Vec prior to sorafenib 
initiation (Section 3.D.3.c). 
NOTE: The rationale for sorafenib therapy after completion of Pexa-Vec therapy is outlined 
below. 
Results from this pivotal trial will determine whether Pexa-Vec followed by sorafenib increases 
survival duration in advanced HCC patients compared to treatment with sorafenib alone, and 
whether sequential dosing with Pexa-Vec followed by sorafenib has a favorable safety profile. 
 
3.E.2 
Rationale for Pexa-Vec Dose and Schedule and Sequential Sorafenib Therapy 
3.E.2.a 
Pexa-Vec Dose, Route and Interval Rationale 
Due to the high rate of accessible tumors and clinical relevance of locoregional therapy in HCC, 
IT treatment is well established in all locoregional therapies.  IT injection of Pexa-Vec into liver 
tumors was well-tolerated at both the 1 × 108 pfu and the 1 × 109 pfu dose (equivalent to 9.0 Log 


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pfu) in HCC patients treated in the JX594-IT-HEP007 protocol regimen (3 IT injections, each 
2 weeks apart) (Section 3.D.3.b) (Heo 2013).  Of interest, overall survival was significantly longer 
in the high-dose arm compared with the low-dose arm (median 14.1 months versus 6.7 months, 
HR 0.39; p-value 0.020, Gehan-Breslow-Wilcoxon test; 1-sided test for superiority of high-dose).  
Therefore, the 1 × 109 pfu dose level administered 3 times every 2 weeks appears to have the 
highest likelihood of benefiting patients with advanced HCC while maintaining a tolerable safety 
profile of Pexa-Vec. 
 
3.E.2.b 
Rationale for Sequential Therapy with Sorafenib 
Pexa-Vec and sorafenib cannot be used simultaneously since sorafenib inhibits Pexa-Vec 
replication and can potentially impair its activity.  Therefore, sequential treatment appears as an 
appropriate option for therapeutic combination of the 2 agents.  
The sequential use of Pexa-Vec and sorafenib holds the potential for additive activity of these 
2 agents with unique mechanisms of action in HCC.  Preclinical and preliminary clinical data 
supports this hypothesis (Heo 2011).  Pexa-Vec acutely induces viral lytic effects and tumor 
vascular shutdown; in addition, Pexa-Vec is designed to induce a tumor-specific cytotoxic 
T lymphocyte response.  In contrast, sorafenib is generally cytostatic (<5% objective tumor 
response rate) with its main clinical impact elicited via inhibition of raf kinase signal transduction 
and angiogenesis (via inhibitory effects on the VEGF receptor in tumors).  The sequential 
combination of the two may lead to up-front Pexa-Vec mediated cell lysis and induction of 
systemic anti-tumor immunity followed by further sorafenib induced tumor control and prevention 
of regrowth. 
Sorafenib is currently the standard of care (SOC) and only approved systemic therapy for subjects 
with advanced HCC.  Based on the non-overlapping toxicity profile of the 2 agents, and the 
sequential design of the therapeutic regimen, the anticipated safety profile of the combination is 
expected to be tolerable.  This hypothesis is supported by data from a Phase 2 study of 25 HCC 
patients utilizing sequential Pexa-Vec followed by sorafenib which demonstrated no significant 
safety concerns (Section 3.D.3.c).  Pexa-Vec has not resulted in sorafenib-associated toxicities 
with the exception of nausea/reduction of appetite, and specifically has not been associated with 
the dose-limiting rash or diarrhea frequently associated with sorafenib dosing.  The most clinically 
important Pexa-Vec side effects (flu-like symptoms) occur within the first 24 hours post-dosing.  
Therefore, no additive toxicities are expected when in the timeframe sorafenib is initiated in this 
protocol. 
 


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4 
OBJECTIVES 
4.A 
PRIMARY OBJECTIVE 
• 
To determine and compare the overall survival of patients with advanced HCC without prior 
systemic therapy, treated with Pexa-Vec followed by sorafenib (Arm A) versus sorafenib 
(Arm B) 
 
4.B 
SECONDARY OBJECTIVES 
• 
To determine and compare the 2 treatment arms response based on central assessments using 
mRECIST for HCC for the following endpoints: 
 Time to Progression (TTP) 
 Progression Free Survival (PFS) 
 Overall Response Rate (ORR) 
 Disease Control Rate (DCR) 
• 
To determine and compare the safety profiles of the 2 treatment arms 
• 
To determine and compare the Time to Symptomatic Progression (TSP) of the 2 treatment 
arms 
• 
To determine and compare the Quality of Life (QoL) of the 2 treatment arms 
 
4.C 
EXPLORATORY OBJECTIVES 
• 
To determine and compare the 2 treatment arms response based on both local and central 
assessments using RECIST 1.1 for the following endpoints: 
 Time to Progression (TTP) 
 Progression Free Survival (PFS) 
 Overall Response Rate (ORR) 
 Disease Control Rate (DCR) 
• 
To evaluate and compare the effect of treatment with Pexa-Vec followed by sorafenib (Arm A) 
versus sorafenib (Arm B) on the following endpoints (based on local and central assessments 
for radiology endpoints): 


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 Time to Initial Response (TIR) and Duration of overall Response (DoR)  
 Tumor size over time by reference to the sum of the longest diameters of the target lesions 
at screening 
 Efficacy of Pexa-Vec (overall survival, PFS, TTP) in patient subgroups to be defined in 
the Statistical Analysis Plan (SAP) 
 Overall survival, PFS, TTP in patients subdivided according to the presence or not of an 
objective response (CR, PR and/or at least 3 months of SD [if the number of patients is 
sufficient]) 
• 
To determine and compare changes in clinical laboratory parameters in the 2 treatment arms 
including standard laboratory parameters, alpha-fetoprotein (AFP) and CD4/CD8 counts 
• 
To determine and compare the 2 treatment arms for overall survival by reference to the date of 
introduction of sorafenib 
• 
To describe the effects of Pexa-Vec on the immune response and identify biomarkers of 
response  
• 
To evaluate the comparative cost-effectiveness of Pexa-Vec followed by sorafenib versus 
sorafenib alone by collecting patient-level resource and service-use information 
 


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5 
STUDY DESIGN 
5.A 
STUDY OVERVIEW 
This is a multi-center, randomized, open-label, Phase 3 study comparing Pexa-Vec followed by 
sorafenib (Arm A) versus sorafenib (Arm B) in patients with advanced HCC without prior 
systemic therapy. 
A total of 600 patients will be randomized between the 2 treatment arms in a 1:1 ratio (300 in each 
arm) to reach at least 570 evaluable patients. 
This study is expected to start in Q3 2015 with recruitment to be completed by Q1 2020.  The 
study treatment phase is expected to be completed by Q1 2021. 
It is understood that this accrual rate is based on reasonable planning expectations.  The actual 
accrual rate should be compared to the expected rate on an ongoing basis.  If problems of 
recruitment are identified (by the Contract Research Organization [CRO] through monthly reports 
or by the Data Monitoring Committee [DMC]) this should be discussed between the Sponsor, the 
CRO and the Investigators as early as possible in order to define actions to meet the above 
timelines. 
Patients will be allocated to each arm via a dynamic stochastic minimization procedure performed 
independently for Asian and non-Asian patients.  The following criteria will be used: 
1. 
Center 
2. 
Main etiology: hepatitis C, hepatitis B, alcohol or other reasons (such as hemochromatosis, 
Wilson’s disease, type 2 diabetes, NASH) 
3. 
Presence of extrahepatic disease or not 
4. 
Vascular invasion or not 
5. 
Performance Status 0 or 1 on the ECOG scale. 
6. 
AFP levels (<200, 200–400, >400 ng/mL) 
Two interim analysis are planned; one futility analysis at 40% of the death events and one efficacy 
analysis at 80% of the events. 
 


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5.B 
STUDY ENDPOINTS 
5.B.1 
Primary Endpoint 
• 
Overall survival:  time from date of randomization to the date of death due to any cause.  If a 
patient is not known to have died at the cut-off date for analysis, survival will be censored at 
the date of last contact. 
 
5.B.2 
Secondary Endpoints 
• 
Central radiological assessments will be assessed with mRECIST for HCC: 
 Time to Progression (TTP): time from randomization to the date of first documented 
radiographic tumor progression; TTP does not include deaths.  If a patient has not had a 
TTP event at the cut-off date for analysis, TTP will be censored at the date of last evaluable 
tumor assessment before the cut-off. 
 Progression Free Survival (PFS): time from randomization to the date of first documented 
radiographic tumor progression or death due to any cause, whichever occurs first.  If a 
patient has not had a PFS event at the cut-off date for analysis, PFS will be censored at the 
date of last evaluable tumor assessment before the cut-off.  
 Overall response rate (ORR):  proportion of patients whose best overall response during 
their participation in the study is either CR or PR.  The best overall response is the best 
response recorded from the randomization until disease progression. 
 Disease control rate (DCR):  proportion of patients whose best overall response during 
their participation in the study is either CR, PR, or SD. 
• 
Safety will be assessed by the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE; version 4.03).  Incidence of AEs and SAEs will be reported. 
• 
Time to Symptomatic Progression (TSP) is the time from randomization until the first 
documented event of symptomatic progression defined as a decrease of 4 points or more from 
baseline in the FHSI-8 questionnaire (sub-part of the FACT-Hep questionnaire) or a decrease 
in Eastern Cooperative Oncology Group (ECOG) performance status to 4, or death. 
• 
Changes in QoL will be assessed by the changes in the FACT-Hep and EQ5D-3L 
questionnaires.  
 


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5.B.3 
Exploratory Endpoints 
Both central and local radiological assessments will be evaluated with RECIST 1.1. 
• 
TTP, PFS, ORR, and DCR as described above will also be assessed centrally. 
• 
Duration of overall Response (DoR):  applies only to patients whose best overall response is 
CR or PR.  The start date is the date of first documented response (CR or PR) and the end date 
is the date of first documented disease progression or the date of death due to underlying 
cancer. 
• 
Time to Initial Response (TIR):  the start date is the date of randomization and the end date is 
the date of first documented response (CR or PR). 
• 
Relative change of tumor size over time:  Tumor size is defined as the sum of the longest 
diameters for all target lesions as identified at screening. 
Changes in clinical laboratory parameters, including standard safety assessments, AFP levels, 
CD4/CD8 counts (all assessed centrally). 
Additional immunology assays may be performed on archived samples to further assess the 
immune mechanisms involved. 
Pharmacoeconomy analyses include all information obtained from questionnaires collecting 
patient-level resource and service-use (Health Care Resource Utilization questionnaire, patient 
accommodation and transport questionnaire derived from client service receipt inventory [CSRI] 
and EQ5D-3L questionnaire).  Detailed costs collected using data entered in electronic Case 
Report Form (eCRF), hospital invoices and pharmacy worksheet data will also be used as 
information for pharmacoeconomics analyses. 
 
5.C 
DOSE AND REGIMEN 
Refer to Section 10 for more information about study treatments. 
 
Arm A (Pexa-Vec followed by sorafenib): 
Pexa-Vec:  Three IT Pexa-Vec treatments are planned.  Each IT Pexa-Vec treatment will be 
administered at a dose of 1 × 109 pfu (equivalent to 9.0 Log pfu).  This dose will be suspended in 
sterile normal saline buffered in sodium bicarbonate.  Refer to Section 10.A.8 for additional 
details.  Pexa-Vec has to be administered within a specified treatment window of –1 and +7 days.  


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While the IT treatment can be performed anytime within the allowed window, it is preferred that 
it occurs in the beginning of the treatment window. 
Sorafenib:  sorafenib dosing of 400 mg (oral, twice daily [BID]) will be administered and managed 
according to the registered Summary of Product Characteristics (SmPC).  Treatment will be 
initiated at the visit Week 6, 2 weeks after the third Pexa-Vec IT (whichever is later).  If not all 
3 Pexa-Vec IT were performed, sorafenib should start no earlier than Week 6. 
 
Arm B (sorafenib): 
Sorafenib dosing of 400 mg (oral, BID) will be started on Day 1 and managed according to the 
registered SmPC. 
 
5.C.1 
Dose Modifications, Delays, and Cancellations 
5.C.1.a 
Dose Modifications 
Pexa-Vec:  No Pexa-Vec dose modifications are allowed. 
Sorafenib:  Dose modification will be allowed according to the registered SmPC. 
 
5.C.1.b 
Dose Delays 
Pexa-Vec:  Pexa-Vec must be administered within the specified treatment window  
(–1/+7 days) and there are no Pexa-Vec dose delays planned outside of this window.  
Sorafenib:  Sorafenib will be managed according to the registered SmPC. 
 
5.C.1.c 
Dose Cancellations 
Pexa-Vec:  If for any reason a Pexa-Vec IT treatment is not given within the allowed treatment 
window, it will be cancelled (i.e., missed for that time point), but then IT treatments should be 
resumed at the next scheduled treatment visit if re-treatment eligibility criteria are met as outlined 
in Section 6.C.2. 
Sorafenib:  Sorafenib will be taken by the patient at home.  Drug accountability will be recorded 
by designated site personnel.  The patient should be counseled on the importance of not missing 
doses unless instructed by the Investigator (e.g., due to toxicity).  
 


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5.C.1.d 
Treatment Withdrawal  
All patients should remain on study until progression or until unacceptable toxicity occurs. 
Sorafenib treatment is allowed as long as the patient is clinically benefiting according to the 
registered SmPC.  
If, however sorafenib and/or Pexa-Vec treatment is withdrawn (i.e., no further treatment will be 
administered at future visits), prior to Investigator determination of clinical benefit (e.g., patient 
withdrew consent, AE, concurrent prohibited medical condition, etc.) patients should complete an 
End of Treatment Visit.  Reason for treatment withdrawal should be recorded in the eCRF.  Patients 
should also return to the clinic for a safety follow-up visit at least 28 days after the last study 
treatment received.  
 
5.D 
OVERALL STUDY DURATION  
Overall study duration will consist of an active study participation phase (which includes: the 
Treatment Phase, the Long-Term Follow-Up Visits (Section 7.C.1), an End Of Treatment Visit 
(Section 7.D), a Safety Follow-Up (Section 7.E), and PFS visits (Section 7.F) if applicable) and a 
survival follow-up phase (consisting of patient and/or caregiver contact every 4 weeks). 
 
5.D.1 
Active Study Participation Phase 
The treatment phase is the first part of the active study participation phase:  will last from the first 
day of study administration until the last study treatment administration.  After this phase, i.e., at 
treatment discontinuation (Pexa-Vec and/or sorafenib), an End of Treatment visit will be 
performed, followed by a safety follow-up at least 28 days after the last study drug administration.  
• 
Patients in both Arm A and Arm B will remain in active study phase until they are no longer 
clinically benefiting from the treatment and at least until radiographic progression or 
unacceptable toxicity occurs.  In case a patient discontinues the treatment phase (e.g. 
permanently stops taking the study medication) prior to documented radiographic progression, 
the patient will perform PFS follow-up visit(s) every 6 weeks for radiology evaluation, until 
documented progression or until premature study discontinuation (refer to Section 6.C.4). 
 


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5.D.2 
Survival Follow Up Phase 
After the active study participation phase, patients in both Arm A and Arm B will enter survival 
follow-up.  During this phase, patients and/or their specified contacts will be contacted 
approximately every 4 weeks with the window of ±7 days for follow-up and collection of 
information on subsequent anti-cancer therapy received (e.g., type of therapy, start/stop date, or 
ongoing, etc.) until the patient dies, is lost to follow-up, or specifically withdraws consent for 
further survival contacts.   
 


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6 
SELECTION OF PATIENTS 
6.A 
INCLUSION CRITERIA 
Patients must meet the following inclusion criteria: 
1. 
Male or female patients, age ≥18 years old 
2. 
Histological/cytological diagnosis of primary HCC  
3. 
Advanced stage HCC (Barcelona Clinic Liver Cancer [BCLC] Stage C or B per American 
Association for the Study of Liver Disease [AASLD] guidelines) eligible for systemic 
therapy 
excluding 
cholangiocarcinoma, 
hepatocholangiocarcinomas, 
fibrolamellar 
carcinoma and hepatoblastoma.  
4. 
Tumor status (as determined by radiology evaluation):  At least one measurable viable tumor 
in the liver (≥1 cm LD and enhancing on arterial phase of triphasic CT scan or MRI), and 
injectable under imaging-guidance (CT and/or ultrasound)  
5. 
At least one tumor that has not received prior local-regional treatment, or that has exhibited 
>25% increase in viable tumor size since prior local-regional treatment 
6. 
Child-Pugh Class A.  NOTE:  paracentesis, albumin infusion or diuretic treatment cannot be 
used to downscore Child-Pugh score (e.g., to improve from severe to moderate/mild or from 
moderate-to-mild ascites) 
7. 
Performance status 0 or 1 on the ECOG scale 
8. 
Adequate hematological, hepatic, and renal function: 
a. 
Hemoglobin ≥9 g/dL  
b. 
Platelet count ≥75 × 109/L 
c. 
International normalized ratio (INR) ≤1.7 
d. 
WBC count ≥2 × 109/L  
e. 
Absolute neutrophil count (ANC) ≥1 × 109/L 
f. 
Albumin ≥2.8 g/dL, total bilirubin ≤3.0 mg/dL (51.3 µmol/L); ALT, AST ≤5 times 
upper limit of normal (ULN) 
g. 
Serum chemistries sodium, potassium, and calcium within normal limits (WNL) or 
Grade 1  


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h. 
Serum creatinine <2.0 mg/dL or creatinine clearance >60 mL/min according to 
Cockroft-Gault formula 
9. 
For patients who are sexually active:  willing to use adequate barrier contraception method 
for at least 6 weeks after each treatment of Pexa-Vec, during sorafenib treatment and for 
2 weeks after sorafenib discontinuation 
10. Life expectancy of at least 3 months 
11. Written informed consent 
 
6.B 
EXCLUSION CRITERIA 
Patients must not meet any of the following exclusion criteria: 
1. 
Major surgery within 4 weeks of study treatment (minor surgical procedures are allowed e.g., 
intravascular access line or Port-a-Cath®) 
2. 
Local-regional therapy of HCC within 4 weeks prior to Arm assignment 
3. 
Histological diagnosis of cholangiocarcinoma, hepatocholangiocarcinomas, fibrolamellar 
carcinoma and hepatoblastoma 
4. 
History of moderate or severe ascites, bleeding esophageal varices, hepatic encephalopathy 
or pleural effusions related to liver insufficiency within 6 months of Screening 
5. 
Bulky disease patients- tumors encompassing >50% of the liver volume and or inferior vena 
cava invasion. 
6. 
Known significant immunodeficiency due to underlying illness (e.g., HIV/AIDS) and/or 
immune-suppressive medication including high-dose corticosteroids (defined as ≥20 mg/day 
prednisone or equivalent which is ongoing at the time of randomization and/or was taken for 
more than 4 weeks within the preceding 2 months of study treatment) 
7. 
Ongoing severe inflammatory skin condition (as determined by the Investigator) requiring 
medical treatment  
8. 
History of severe eczema (as determined by the Investigator) requiring prior medical 
treatment  


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9. 
Tumor(s) invading a major vascular structure (e.g., carotid artery) or other key anatomical 
structure (e.g., pulmonary airway) in the event of post-injection tumor swelling and/or 
necrosis.  Hepatic and portal vein involvement allowed. 
10. Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural 
effusions.  Mild ascites that does not preclude safe IT injection of Pexa-Vec is allowed at the 
discretion of the treating physician.  
11. Symptomatic cardiovascular disease, including but not limited to significant coronary artery 
disease (e.g., requiring angioplasty or stenting) or congestive heart failure within the 
preceding 12 months  
12. Current or past history of cardiovascular disease (e.g., past history of myocardial infarction, 
ischemic cardiomyopathy) unless cardiology consultation and clearance has been obtained 
for study participation 
13. Medical conditions, per the investigator’s judgment, that predispose the patient to untoward 
medical risk in the event of volume loading (e.g., IV fluid bolus infusion), tachycardia, or 
hypotension during or following treatment with Pexa-Vec 
14. Viable central nervous system malignancy (history of completely resected or irradiated brain 
metastases allowed) 
15. Prior systemic therapy for HCC.  NOTE:  Patients receiving 7 days or less exposure to 
systemic therapy are allowed. 
16. Known contraindications to sorafenib according to the drug prescribing information and/or 
severe hypersensitivity to sorafenib or any other component of sorafenib, or known 
intolerance to sorafenib 
17. Other medical condition or laboratory abnormality or active infection that in the judgment 
of the Principal Investigator may increase the risk associated with study participation or may 
interfere with interpretation of study results and/or otherwise make the patient inappropriate 
for entry into this study 
18. Hepatitis C virus therapy including interferon/pegylated interferon or ribavirin that cannot 
be discontinued within 14 days prior to any Pexa-Vec injection.  Medical Monitor should be 
consulted if the patient is taking any other anti-viral medications to determine eligibility. 
19. Prior malignancies are not allowed except for the following:  adequately treated basal or 
squamous cell skin cancer, in situ cervical cancer, adequately treated cancer from which the 


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patient has been disease-free for at least 3 years, unless Medical Monitor approval has been 
obtained for study participation 
20. Significant bleeding event within the last 12 months that places the patient at risk for 
intrahepatic IT injection procedure based on Investigator assessment 
21. Anticoagulant or anti-platelet medication that cannot be interrupted prior to Pexa-Vec IT 
injections, including: 
a. 
Aspirin that cannot be discontinued for 7 days prior to Pexa-Vec IT injections  
b. 
Coumadin that cannot be discontinued for 7 days prior to Pexa-Vec IT injections 
c. 
Low molecular weight heparin (LMWH) that cannot be discontinued >24 hours prior 
to Pexa-Vec IT injections 
d. 
Unfractionated heparin (UFH) that cannot be discontinued >4 hours prior to Pexa-Vec 
IT injections 
e. 
Oral direct thrombin inhibitor (dabigatran) or direct Factor Xa inhibitor (rivaroxaban, 
apixiban, and endoxaban) that cannot be discontinued for 4 days prior to Pexa-Vec IT 
injection 
NOTE: LMWH or UFH may be used to transition patients on and off of the above 
anti-coagulants (if deemed appropriate by the treating physician) prior to 
Pexa-Vec treatments as long as the last dose of LMWH is administered 
>24 hours prior to treatments and last dose of UFH is administered >4 hours 
prior to treatments. 
Please contact the Sponsor for questions regarding the management of other anticoagulant 
prior to treatments. 
22. Inability to suspend treatment with anti-hypertensive medication (including but not limited 
to: diuretics, beta-blockers, angiotensin converting enzyme [ACE] inhibitors, aldosterone 
antagonists, etc.) for 48 hours prior to and 48 hours after each Pexa-Vec injection  
23. Any prior or planned organ transplant (e.g., liver transplant) 
24. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation.  Child-bearing potential patients with 
a positive hCG laboratory test (>10 mIU/mL) at Screening and/or a positive urinary test at 
Baseline will perform an ultrasound to assess the pregnancy. 


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25. Patients who experienced a severe systemic reaction or side-effect as a result of a previous 
vaccination with vaccinia  
26. Participation in a clinical study with an active investigational product within 4 weeks prior 
to randomization 
27. Patient unable or unwilling to comply with the protocol requirements 
28. Previous treatment with Pexa-Vec or other vaccinia vector based treatment 
29. Pulse oximetry O2 saturation <90% at rest on room air 
 
6.C 
 SCREENING, ELIGIBILITY, ARM ASSIGNMENT, STUDY COMPLETION, 
AND STUDY DISCONTINUATION 
6.C.1 
Screening  
Screening assessments will begin after the patient has signed the informed consent and a Patient 
Study Identification Number will be generated.  The Day 1 visit may occur within 21 days of the 
first screening procedure.  Screening window can be extended beyond 21 days with prior 
Sponsor’s approval. 
 
6.C.1.a 
Screen Failures 
The status and reason for failure will be reported in the eCRF.  Patients who do not meet all 
eligibility criteria during Screening should be screen-failed.  Any patients who are deemed “screen 
failures” cannot be re-screened for participation unless prior Sponsor’s approval was granted.  
 
6.C.2 
Eligibility 
The Principal Investigator is ultimately responsible for ensuring and endorsing that patient(s) meet 
all eligibility criteria (Inclusion/Exclusion Criteria) prior to randomization  
Patients will be eligible for each of the 3 Pexa-Vec IT injections if all of the following clinical and 
laboratory criteria are met prior to each Pexa-Vec IT treatment: 
• 
Adequate liver function (total bilirubin ≤3.0 mg/dL [51.3 µmol/L]; ALT and AST  
≤5 × ULN) 


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• 
Platelets ≥75 × 109/L (correction with transfusion or thrombopoietin based therapy allowed to 
meet re-treatment eligibility criteria) 
• 
Hemoglobin ≥9 g/dL (correction with transfusion or erythropoietin based therapy allowed to 
meet re-treatment eligibility criteria) 
• 
INR ≤1.7 (correction with plasma protein support allowed to meet re-treatment eligibility 
criteria [e.g., fresh-frozen plasma]) 
• 
Patient is still expected to have at least one viable, injectable intrahepatic tumor  
≥1 cm LD 
• 
No clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural 
effusions.  Minimal ascites that does not preclude safe IT injection of Pexa-Vec is allowed at 
the discretion of the treating physician and interventional radiologist. 
 
6.C.2.a 
Laboratory Eligibility 
Blood samples drawn at Screening to determine study eligibility must be sent to the central 
laboratory except for the clinical investigational sites participating in China where laboratory 
testing will be completed by local laboratory at each site.  Local laboratory results may be used to 
determine patient re-treatment eligibility before each Pexa-Vec IT injection (i.e., not for study 
eligibility); however, blood samples will need to be sent to the central laboratory in parallel which 
will prevail over the local laboratory results. 
During the screening period, hematology parameters can be re-tested after an authorized therapy. 
 
6.C.3 
Patient Allocation to Treatment Arms 
A total of 600 patients will be randomized between one of 2 treatment arms in a 1:1 ratio (300 in 
each arm).  Patients will be allocated to each arm via a dynamic stochastic minimization procedure 
performed independently for Asian and non-Asian patients.  The following criteria will be used:  
1. 
Center 
2. 
Main etiology:  hepatitis C, hepatitis B, alcohol or other reasons (such as hemochromatosis, 
Wilson’s disease, type 2 diabetes, NASH) 
3. 
Presence of extrahepatic disease or not 


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4. 
Vascular invasion or not 
5. 
Performance status 0 or 1 on the ECOG scale 
6. 
AFP levels (<200, 200–400 or ≥400 ng/mL) 
 
6.C.4 
Premature Study Discontinuation 
Premature discontinuation from active study participation may occur at any time due to any of the 
following reasons:  
1. 
Any situation where, in the opinion of the Investigator or the Medical Monitor, continued 
participation in the study would not be in the best interest of the patient. 
2. 
Patient initiates other anti-cancer therapy.  The anti-cancer therapy will be documented in 
the medical record and eCRF. 
3. 
An intercurrent illness develops that precludes objective clinical assessments. 
4. 
Prohibited concomitant medications are required or used. 
5. 
Patient is unable or unwilling to comply with study procedures. 
6. 
Consent for active study participation is withdrawn. 
7. 
Termination of the study by the Sponsor. 
8. 
Request by a Health Authority. 
 
6.C.4.a 
Data Collection for Premature Discontinued Patients 
The reason(s) for premature study discontinuation should be reported on eCRF and within the 
source documents.  AEs should be documented according to Section 11.  An End of Treatment 
Visit should be performed and will be followed by a Safety Visit at least 28 days after the last 
study drug administration (Pexa-Vec or sorafenib) to allow for collection and assessment of AEs 
and Concomitant Medications.  Refer to Section 7.C for details.  Patients who discontinue 
treatments will continue to be followed for survival follow-up (to allow for analysis of the primary 
trial endpoint), collection of other anti-cancer therapy data and EQ5D-3L questionnaire 
completion (if the patient is at a site where EQ5D-3L questionnaire is planned to be completed). 
In case a patient discontinues the treatment phase prior to documented radiographic progression 
(e.g., permanently stops taking the study medication), a PFS follow-up visit should be performed 


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every 6 weeks for radiology evaluation, until documented progression or until premature study 
discontinuation (Section 6.C.4).  
If a patient withdraws consent from active study participation (discontinues), the site should 
initiate protocol-specified survival contacts every 4 weeks with the window of ±7 days unless the 
patient explicitly withdraws consent for survival follow-up.  This consent withdrawal will be 
documented in the source documents and in the eCRF. 
Patients who discontinue the active study participation will not be replaced. 
 


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7 
STUDY PROCEDURES AND TREATMENT  
7.A 
SCREENING 
Screening assessments will begin after: 
• 
The signature of the informed consent form (ICF) 
• 
A patient study identification number is obtained (via Interactive Voice Response System 
[IVRS] / Interactive Web Response System [IWRS]).  The patient study identification number 
is unique and remains with the patient for the entirety of the trial. 
Patient eligibility for the study will be determined up to 21 days before Day 1 for Arm A or 
Baseline/Day 1 for Arm B.  Screening procedures may be completed in less than 21 days, which 
is preferred.  The 21-day screening window starts when the first protocol-required screening 
procedure is performed and does not include the ICF signature date.  Screening window can be 
extended beyond 21 days with prior Sponsor’s approval. 
Central laboratory results must be obtained prior to randomization and used for eligibility 
determination except for the clinical investigational sites participating in China where laboratory 
testing will be completed by local laboratory at each site.  These results are also used for Arm A 
patient eligibility to receive Day 1 IT injection.  Only central laboratory data can be used and will 
be entered into the clinical database. 
At the Screening visit, the following will occur:  
• 
Collection of detailed medical, surgical, and cancer history 
• 
Complete physical exam including weight, height, and vital signs (blood pressure, pulse, 
temperature including pulse oximetry for screening only) 
• 
CT (preferred) or MRI (if CT not possible) (refer to Section 8.C.2):  tumors are numbered with 
unique number and identified as Target or Non-Target tumors.  Tumors should be assigned the 
next available chronological number wherever possible.  
• 
Electrocardiogram (ECG) 
• 
BCLC and Cancer of the Liver Italian Program (CLIP) scoring (including Child-Pugh scoring). 
• 
Histological HCC diagnosis.  If no pathology report available, perform biopsy 
• 
European Association for the Study of the Liver (EASL) / European Organization for Research 
and Treatment of Cancer (EORTC) criteria  


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• 
Blood sample collection for central laboratory eligibility/safety assessment including: 
 Hematology, chemistry, and coagulation  
 CD4 and CD8 count 
 HIV, Hepatitis B and C testing 
 AFP 
 Pregnancy test for women of child-bearing potential (if positive, an ultrasound will be 
performed to confirm pregnancy) 
NOTE:  Definition of women of child-bearing potential = A sexually mature woman who 
has not undergone hysterectomy, or tubal ligation, vasectomy, or other means of permanent 
sterilization or who has not been naturally post-menopausal for at least 24 consecutive 
months for women ≤55 years or 12 consecutive months for women >55 years.  
• 
Standard urinalysis 
• 
ECOG performance status 
• 
Concomitant medications reporting 
• 
From the date of signature of the ICF and up to initiation of study treatments, only SAEs caused 
by a protocol-required procedure will be collected and reported to the Sponsor 
• 
Refer to Section 8.A.4.b for treatments to be stopped prior to Pexa-Vec treatment. 
 
7.B 
INITIAL TREATMENT PHASE (BASELINE AND DAY 1 UNTIL WEEK 6) 
7.B.1 
Randomization (Upon Investigator Confirmation of Eligibility) 
After patient eligibility has been confirmed by the Investigator (and by the Sponsor, as applicable), 
site personnel will access the IVRS/IWRS and provide relevant minimization information to obtain 
randomization assignment (to Arm A or Arm B).  The patient will keep the same number as the 
one given during the screening phase.   
If a patient is randomized to Arm A, a Pexa-Vec treatment kit number will be assigned for the 
Day 1 IT injection.  If the patient is randomized to Arm B, a sorafenib treatment kit number will 
be assigned for the first period.  Kits’ assignment to patients randomized in both Arms A and B 
are made through the IVRS/IWRS.  


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Randomization and Baseline procedures (Section 7.B.2) can be performed on the same day.  
 
7.B.2 
Arm A and Arm B:  Baseline Visit  
At the Baseline visit, up to 4 days before Day 1, the following will occur:  
• 
Baseline for symptomatic progression assessments, Health-Related Quality of Life (HRQoL) 
assessments, and pharmacoeconomic evaluations (all questionnaires should be completed prior 
to any Baseline Visit protocol assessments/exams): 
 ECOG performance status 
 Functional Assessment of Cancer Therapy - Hepatobiliary (FACT-Hep) questionnaire 
(FHSI-8 questions for scoring of symptomatic progression obtained as a subset of the 
FACT-Hep questionnaire)  
 EQ5D-3L questionnaire 
 Collection of pharmacoeconomic data through the Health Care Resource Utilization 
questionnaire and the Patient Accommodation and Transport questionnaire 
• 
Blood sample collection for the following testing: 
 Hematology, chemistry, and coagulation  
 Human leukocyte antigen (HLA) typing (selected sites only) 
 Urinary pregnancy test for women of child-bearing potential 
 Archival serum sample  
Refer to the Central Lab Manual for details on blood sample processing and shipping instructions. 
• 
Complete physical exam  
• 
Vital signs (e.g., blood pressure, temperature, and pulse) 
• 
Concomitant medications reporting 
• 
From the date of signature of the ICF and up to initiation of study treatments, only SAEs caused 
by a protocol-required procedure will be collected and reported to the Sponsor 
• 
An ultrasound may be optionally performed to assess suitability of IT injection within selected 
liver lesions and to select lesions for injection (Arm A); or to rule out pregnancy for patients 
with a positive hCG laboratory test (>10 mIU/mL). 


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• 
Pregnancy test (urine) for women of child-bearing potential (if positive, an ultrasound will be 
performed to confirm pregnancy) 
Patient Contact Log completion: include detailed contact information for the patient, 
family/caregivers, and preferred (to be updated periodically during study) in compliance with local 
regulations.  
 
7.B.3 
Arm A and Arm B:  Visit 1 (“Day 1”)  
All visit dates and visit windows will be counted from Day 1  
 
7.B.3.a 
Arm A:  Pexa-Vec Treatment #1 (Day 1) 
7.B.3.a.1 Identification of Liver Lesions for IT treatment 
Using the most recent CT/MRI scan (e.g., screening CT/MRI), a qualified and trained 
Interventional Radiologist will identify up to 5 intrahepatic tumors, each ≥1 cm LD, for injection.  
As noted at baseline visit above, a pre-treatment ultrasound may be performed if needed to confirm 
ability to inject tumors under imaging guidance.  
The Interventional Radiologist can select tumors for injection that were identified as target or non-
target tumors and numbered with a unique number at screening.  
The Interventional Radiologist will measure and document the LD of the tumors (with appropriate 
tumor numbers) selected for injection.  Tumor numbers and measurements will be documented by 
the Interventional Radiologist/physician performing the injection on the Pexa-Vec IT Injection 
Preparation Worksheet.  
The number(s) of the tumor(s) injected and the volume of solution injected into each tumor (among 
other data points) will be recorded in the eCRF. 
 
7.B.3.a.2 IT Injection Procedure 
The total Pexa-Vec dose for IT injection is 1 × 109 pfu (equivalent to 9.0 Log pfu) which is diluted 
in sterile buffered normal saline.  The volume of saline used for dilution will vary according to the 
number and size of tumors to be injected.  Each tumor will be injected with Pexa-Vec diluted in 
buffered normal saline solution in a volume that is approximately 25% of that tumor’s volume 
(percentage dependent on the size of the tumor) but will not exceed a specified upper limit.  After 
an appropriate pre-hydration (refer to Section 8.A.3), injections will be performed by the 


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Interventional Radiologist or other trained physician using imaging-guidance (ultrasound and/or 
CT).  All viable, safely injectable intrahepatic tumors ≥1 cm LD must be treated, with a maximum 
of 5 tumors treated on a given treatment day.  Different tumors may be treated on each treatment 
day, including new intrahepatic tumors that have developed since screening evaluation.  The total 
prepared injection volume will be divided proportionally between 1–5 intrahepatic tumors, relative 
to individual tumor volumes.  
Injection needles designed for percutaneous insertion into tissues will be used.  Depending on 
tumor size, either multi-pronged injection needles (provided by the Sponsor), or straight needles 
preferably with multiple side ports (not provided by the Sponsor), will be used.  
Refer to the “Pexa-Vec Intratumoral injection: Procedure Manual” and to the “Pexa-Vec 
Intratumoral (IT) Injection:  Preparation Worksheet” for more information about the specific 
calculation and preparation instructions and for the detailed injection procedure guidelines and 
needle use recommendations. 
 
7.B.3.a.3 Additional Procedures 
Patients will be observed in the clinic or hospital for a minimum of 8 hours after IT Pexa-Vec 
treatment.  The following evaluations will be performed:  
• 
Complete physical exam (before IT) 
• 
Medical, and surgical history update with any study procedure-related SAEs that would have 
occurred from the signature of the ICF (before IT) 
• 
Reporting of AEs (that occurred during or after IT) and concomitant medications 
• 
Vital signs (blood pressure, temperature, and pulse) within 60 minutes prior to injection to 
establish baseline, 15 minutes (±5 minutes) after injection completion and then every hour 
(±15 minutes) for at least 8 hours after treatment  
• 
Archival serum sample (8 hours with ±15 minutes after treatment) 
 
7.B.3.b 
Arm B:  Sorafenib Treatment Start (Day 1) 
For patients assigned to Arm B, sorafenib will be started at Day 1 at a dose of 400 mg BID.  Dosing 
reductions may be performed according to the registered SmPC. 
Arm B patients will complete the following procedures: 


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• 
Complete physical exam 
• 
Vital signs (blood pressure, temperature, and pulse) 
• 
Medical, and surgical history update with any study procedure-related SAEs that would have 
occurred from the signature of the ICF (before sorafenib initiation) 
• 
AE and concomitant medications reporting from the first dose of sorafenib intake 
• 
Sorafenib:  counsel patient on use and IVRS/IWRS first kit dispensation 
 
7.B.4 
Arm A:  Visit 2 (Pre-Day 15 or Pre-Week 2); Arm B: Visit 2 (Day 15 or Week 2) 
7.B.4.a 
Arm A:  Visit 2/ Pre-Day 15 or Pre-Week 2 
This visit will be performed up to 4 days before Visit 3/Day 15 (Week 2).  This visit must occur 
regardless of whether the Day 15 IT injection will be given.  
The Principal Investigator is ultimately responsible for ensuring and endorsing that patient(s) meet 
the required clinical and laboratory criteria prior to Pexa-Vec injection.  
Patients will be eligible for Treatment #2 if all of the following re-treatment criteria are met: 
1. 
Laboratory criteria: 
• 
Adequate liver function (total bilirubin ≤3 mg/dL [51.3 µmol/L]; ALT, and AST ≤5 × ULN) 
• 
Platelets ≥75 × 109/L (correction with transfusion or thrombopoietin based therapy allowed to 
meet re-treatment eligibility criteria) 
• 
Hemoglobin ≥9 g/dL (correction with transfusion or erythropoietin based therapy allowed to 
meet re-treatment eligibility criteria) 
• 
INR ≤1.7 (correction with plasma protein support allowed to meet re-treatment eligibility 
criteria [e.g., fresh-frozen plasma]) 
2. 
The patient is still expected to have at least one viable, injectable intrahepatic tumor ≥1 cm 
LD.  
3. 
No clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural 
effusions.  Minimal ascites that does not preclude safe IT injection of Pexa-Vec is allowed 
at the discretion of the treating physician. 


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Re-treatment eligibility assessments may be repeated until the patient becomes eligible for 
treatment within the specified window of –1/+7 days, but all eligibility criteria must be ultimately 
confirmed within 4 days prior to IT injection.  
Arm A patients will complete the following procedures: 
• 
Complete physical examination including weight and skin assessment  
• 
Vital signs (blood pressure, temperature, and pulse) 
• 
Blood sample collection for central laboratory assessment including: 
 Hematology, chemistry and coagulation (in the interest of time, local analysis may be 
obtained to confirm patient re-eligibility for treatment but samples should be sent to central 
laboratory in parallel)  
• 
AEs and concomitant medications reporting  
• 
If the patient meets eligibility criteria, contact the IVRS/IWRS to obtain Pexa-Vec kit number 
for Day 15 treatment. 
 
7.B.4.b 
Arm B:  Visit 2/ Day 15 (Week 2) 
This visit can occur Day 15 ± 3 days, but preferentially the closest as possible to Day 15. 
Arm B patients will complete the following procedures: 
• 
Complete physical examination including weight  
• 
Vital signs (blood pressure, temperature, and pulse) 
• 
Blood sample collection for central laboratory assessment including hematology, chemistry 
and coagulation parameters 
• 
AEs and concomitant medications reporting 
• 
Sorafenib:  collection of returned medication and IVRS/IWRS new kit dispensation 
• 
Update of the Patient Contact log as needed 
 
7.B.5 
Arm A:  Visit 3 / Pexa-Vec Treatment #2 (Day 15/Week 2)  
This visit can occur Day 15 –1/+7 days (Days 14–22) but preferentially the closest as possible to 
Day 15. 


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Pexa-Vec IT doses should be given at least 13 days apart.  
Clinical and laboratory eligibility criteria should have been confirmed at previous visit.  Refer to 
Section 6.C.2.  
All procedures are the same as Pexa-Vec Treatment #1 (Day 1).  Patients will be observed in the 
clinic or hospital for a minimum of 8 hours after IT Pexa-Vec treatment and following evaluations 
will be performed:  
• 
Complete physical exam (before IT) 
• 
Vital signs (blood pressure, temperature, and pulse) within 60 minutes prior to injection to 
establish baseline, 15 minutes (±5 minutes) after injection completion and then every hour 
(±15 minutes) for at least 8 hours after treatment  
• 
An ultrasound may be optionally performed to assess suitability of IT injection within selected 
liver lesions and to select lesions for injection 
• 
Reporting of AEs and concomitant medications 
• 
Update of the Patient Contact log as needed 
If an IT treatment is ultimately not administered within the protocol-specified window for any 
reason, this treatment must be cancelled (i.e., missed for this time point), but the patient should 
resume follow-up visits per the Schedule of Activities and IT treatments at the next scheduled 
treatment visit if there is still an IT administration planned and re-treatment eligibility criteria are 
met as outlined above.   
 
7.B.6 
Arm A:  Visit 4 (Pre-Day 29/Pre-Week 4); Arm B:  Visit 3 (Day 29/Week 4) 
7.B.6.a 
Arm A:  Visit 4/ Pre-Day 29 (Pre-Week 4) 
This visit will be performed up to 4 days before Visit 5/Day 29 (Week 4).  This visit must occur 
regardless of whether the Day 29 IT injection will be given.  
Arm A patients will complete the following procedures: 
• 
Complete physical examination including weight and skin assessment 
• 
Vital signs (blood pressure, temperature, and pulse) 
• 
Blood sample collection for central laboratory assessment including: 


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 Hematology, chemistry and coagulation (in the interest of time, local analysis may be 
obtained to confirm patient re-eligibility for treatment but samples should be sent to central 
laboratory in parallel)  
• 
AE and concomitant medications reporting 
• 
Refer to Section 6.C.2 for re-treatment eligibility criteria: If the patient meets eligibility 
criteria, contact the IVRS/IWRS to obtain Pexa-Vec kit number for Visit 4/Day 29 (Week 4) 
treatment. 
 
7.B.6.b 
Arm B:  Visit 3 / Day 29 (Week 4) 
This visit can occur Day 29 ± 3 days, but preferentially the closest to Day 29. 
Arm B patients will complete the following procedures: 
• 
Complete physical examination including weight  
• 
Vital signs (blood pressure, temperature, and pulse) 
• 
Blood sample collection for central laboratory assessment including: 
 Hematology, chemistry and coagulation 
• 
AEs and concomitant medications reporting 
• 
Sorafenib:  collection of returned medication and IVRS/IWRS new kit dispensation 
 
7.B.7 
Arm A:  Visit 5 / Pexa-Vec Treatment #3 (Day 29 / Week 4) 
This visit can occur Day 29 –1/+7 days (between Days 28–36), but preferentially the closest to 
Day 29. 
Pexa-Vec IT doses must be given at least 13 days apart. 
Clinical and laboratory eligibility criteria should have been confirmed at previous visit.  Refer to 
Section 6.C.2. 
All procedures are the same as Pexa-Vec Treatment #1 and #2 (Day 1 and Day 15), refer to 
Section 7.B.3.a and Section 7.B.5, respectively.  Patients will be observed in the clinic or hospital 
for a minimum of 8 hours after IT Pexa-Vec treatment and following evaluations will be 
performed:  


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• 
Complete physical exam (before IT) 
• 
Vital signs (blood pressure, temperature, and pulse) within 60 minutes prior to injection to 
establish baseline, 15 minutes (±5 minutes) after injection completion and then every hour 
(±15 minutes) for at least 8 hours after treatment  
• 
An ultrasound may be optionally performed to assess suitability of IT injection within selected 
liver lesions and to select lesions for injection 
• 
Reporting of AEs and concomitant medications 
If an IT treatment is ultimately not administered within the protocol-specified window for any 
reason, this treatment must be cancelled (i.e., missed for this time point), but the patient should 
resume follow-up visits per the Schedule of Activities. 
 
7.B.8 
Arm A:  Visit 6 (Day 43/Week 6)/ Arm B: Visit 4 (“Day 43/Week 6”) 
7.B.8.a 
Arm A:  Visit 6/Day 43 (Week 6) 
This visit should occur between Day 41 – Day 45.  
Sorafenib should be started 2 weeks (±2 days) after the last IT injection.  
Arm A patients will complete the following procedures: 
• 
Symptomatic progression assessments, HRQoL assessments, and pharmacoeconomic 
evaluations (all questionnaires should be completed by all patients prior to any Visit 6 protocol 
assessments/exams): 
 ECOG performance status 
 FACT-Hep questionnaire  
 EQ5D-3L questionnaire 
 Collection of pharmacoeconomic data through the Health Care Resource Utilization 
questionnaire  
• 
Complete physical examination including weight and skin assessment 
• 
Vital signs (blood pressure, temperature, and pulse) 
• 
Blood sample collection for central laboratory assessment including: 
 Hematology, chemistry and coagulation  


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 CD4 and CD8 count 
 AFP 
 Archival serum sample 
• 
AE and concomitant medication reporting 
• 
Update patient contact log 
• 
Sorafenib initiation:  patient counsel on use and IVRS/IWRS new kit dispensation 
• 
CT (preferred) or MRI (if CT not possible) (refer to Section 8.C.2).  
 
7.B.8.b 
Arm B:  Visit 4/Day 43 (Week 6) 
This visit will occur at Day 43 ±2 days (between Day 41 and Day 45).  Arm B patients will 
complete the following procedures: 
• 
Symptomatic progression assessments, HRQoL assessments, and pharmacoeconomic 
evaluations (all questionnaires should be completed by all patients prior to any 
assessments/exams): 
 ECOG performance status 
 FACT-Hep questionnaire  
 EQ5D-3L questionnaire 
 Collection of pharmacoeconomic data through the Health Care Resource Utilization 
questionnaire 
• 
Complete physical examination including weight  
• 
Vital signs (blood pressure, temperature, and pulse) 
• 
Blood sample collection for central laboratory assessment including: 
 Hematology, chemistry and coagulation 
 CD4 and CD8 count 
 AFP 
 Archival serum sample 


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• 
AE and concomitant medications reporting 
• 
Update patient contact log 
• 
Sorafenib: collection of returned medication and IVRS/IWRS new kit dispensation 
• 
CT (preferred) or MRI (if CT not possible) (refer to Section 8.C.2).  
 
7.C 
FOLLOW-UP PHASE 
7.C.1 
Long-Term Follow-Up Visits and Monitoring (Arm A and Arm B) 
7.C.1.a 
Every 3 Weeks ±4 Days:  Clinical Status Visits 
After Week 6, safety and clinical status will be assessed every 3 weeks ±4 days starting from the 
Week 6 visit date up to the End of Treatment visit.  The following procedures will be performed 
for both Arm A and Arm B patients: 
• 
Blood sample collection for central laboratory assessment including: 
 Hematology and chemistry 
• 
AEs and concomitant medications reporting 
• 
Update patient contact log 
• 
Sorafenib:  collection of returned medication and IVRS/IWRS new kit dispensation 
 
7.C.1.b 
Every 6 Weeks ±7 Days:  Symptomatic, QoL, and Radiographic Status Visits 
After Week 6, radiographic status will be evaluated every 6 weeks ±7 days starting from the 
Week 6 visit date up to the End of Treatment Visit.  
Beyond 12 months of treatment, the evaluation will be performed every 12 weeks.  
Both Arm A and B patients will complete the following procedures every 6 weeks (e.g., every 
other follow-up visit): 
• 
Symptomatic progression assessments, HRQoL assessments, and pharmacoeconomic 
evaluations (questionnaires should be completed by all patients prior to any protocol 
assessments/exams): 
 ECOG performance status 


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 FACT-Hep questionnaire  
 EQ5D-3L questionnaire 
 Collection of pharmacoeconomic data through the Health Care Resource Utilization 
questionnaire and the Patient Accommodation and Transport questionnaire (only at 
Week 12) 
• 
Blood sample collection for central laboratory assessment including: 
 Hematology and chemistry 
 AFP 
• 
Complete physical examination including weight and skin assessment for Arm A patients 
• 
CT (preferred) or MRI (if CT not possible) (refer to Section 8.C.2) 
• 
AE and concomitant medication reporting 
• 
Update patient contact log 
• 
Sorafenib:  collection of returned medication and new IVRS/IWRS dispensation 
 
7.D 
END OF TREATMENT VISIT (ARM A AND ARM B) 
This visit should be completed as soon as the last Pexa-Vec or sorafenib dose is administered.  The 
following evaluations will be performed:  
• 
Complete physical examination including weight (skin assessment in Arm A) 
• 
Vital signs (blood pressure, temperature, and pulse) 
• 
Symptomatic progression assessments, HRQoL assessments, and pharmacoeconomic 
evaluations: 
 ECOG performance status 
 FACT-Hep questionnaire  
 EQ5D-3L questionnaire 
 Collection of pharmacoeconomic data through the Health Care Resource Utilization 
questionnaire and the Patient Accommodation and Transport questionnaire 
• 
ECG 


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• 
Blood sample collection for central laboratory assessment including: 
 Hematology, chemistry and coagulation 
 CD4 and CD8 count 
 AFP 
 Archival serum sample 
• 
CT (preferred) or MRI (if CT not possible) (refer to Section 8.C.2).  
• 
AE and concomitant medications reporting 
• 
Update patient contact log 
 
7.E 
SAFETY FOLLOW-UP 
This visit should occur not less than 28 days and no more than 2 months after the last study drug 
administration (sorafenib or Pexa-Vec). 
The following evaluations will be performed: 
• 
Complete physical examination including weight (skin assessment in Arm A) 
• 
Vital signs (blood pressure, temperature, and pulse) 
• 
Reporting of AE having occurred within 28 days after the last study treatment administration 
• 
Reporting of concomitant medications (including potential anti-cancer therapies) and 
significant non-drug therapies within 28 days after the last study drug administration 
• 
Blood sample collection for central laboratory assessment including: 
 Hematology, chemistry  
 
7.F 
FOLLOW-UP VISITS FOR PROGRESSION FREE SURVIVAL 
For patients who complete the study treatment phase prior to documented radiographic 
progression, radiological evaluation should be obtained every 6 weeks until documented 
progression.  Beyond 12 months, the evaluations will be performed every 12 weeks until 
documented progression.   


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NOTE:  patients undergoing follow-up visits for PFS are still on the active study participation 
phase and may not receive other anti-cancer treatments.  
 
7.G 
SURVIVAL FOLLOW-UP PHASE 
After the Safety Follow-Up Visit, all patients will be monitored every month for: 
• 
Survival 
• 
Reporting of anti-cancer therapies 
Patient consent for survival follow-up contacts is implicit when patients consent to study 
participation.  If a patient withdraws consent from study procedures (discontinues), they will 
continue to be contacted for the protocol-specified survival follow-up unless the patient explicitly 
withdraws consent for survival follow-up.  
Due diligence should be used in contact efforts including: 
• 
At least 3 documented direct patient contact attempts and certified letter sent 
• 
If a patient cannot be directly contacted, utilize all contact information provided by the patient 
on the patient contact log 
• 
If all contact attempts are unsuccessful, death registries should be reviewed 
• 
These patient contact procedures should be followed for at least 3 months before the patient 
can be considered lost to follow-up.  Death registry data should be accessed for all patients 
until the study is completed. 
• 
If a patient explicitly withdraws consent for survival follow-up, or if the site is unable to contact 
the patient, other methods to determine survival may be used, including referencing death 
registries, clinic/hospital visit records, primary oncologist or physician records, and/or 
newspaper obituaries, in compliance with local regulations.  
 


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8 
PATIENT MANAGEMENT 
8.A 
TREATMENTS 
8.A.1 
Expected Toxicities of Pexa-Vec Treatment 
• 
Flu-Like Symptoms (mild-to-severe fever, rigors, anorexia, aches/pain, fatigue, 
headache, and/or nausea) 
These flu-like symptoms typically peak during the first 12 hours after Pexa-Vec treatment.  Acute, 
fever is expected within 4–12 hours post-treatment and has a typical duration of 18–24 hours, 
although these can last up to 72 hours. 
• 
Hypotension 
Across clinical trials and indications, mild-to-moderate transient hypotension can be observed 
within 24 hours following treatment with Pexa-Vec (21% of all patients as of October 2018).  
However, in the TRAVERSE trial (Study No. JX594-HEP018) for patients with advanced 2nd line 
HCC, 6 patients (8 total SAEs) have experienced severe hypotension following Pexa-Vec 
treatment, defined as a SBP <90 mmHg, lasting and/or requiring >24 hours of medical treatment, 
intensive care unit care, and vasopressor treatment.  Notably, anti-hypertensive medication was 
ongoing at the time of treatment with Pexa-Vec prior to the development of hypotension in the 
majority of these patients, thereby potentially exacerbating the potential for hypotension.  
A single event of severe hypotension has also been observed in JX594-HEP024, a study in 
sorafenib-naïve HCC.  The patient required IV fluid therapy and vasopressor treatment for 
36 hours.  The frequency of observation of this degree of hypotension on TRAVERSE compared 
to other studies of Pexa-Vec may possibly be due to the more advanced status of the TRAVERSE 
population with respect to co-morbid cirrhosis with associated intravascular volume depletion, 
third space fluid accumulation and diuretic therapy as well as confounding effects of concurrent 
anti-hypertensive medications administration. 
To mitigate risk of hypotension following Pexa-Vec treatment, the following are required: 
 Prehydration with 1 liter of solute-containing fluid (p.o. or IV) prior to each treatment 
 Suspension of anti-hypertensive medication (including diuretics, beta-blockers, ACE 
inhibitors, aldosterone antagonists, etc.) for 48 hours prior to and 48 hours after each 
Pexa-Vec injection 
 Observation of patients for at least 8 hours following each IT injection  


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 For patients with a history of cardiovascular disease, cardiology consultation and creatinine 
clearance must be obtained prior to enrollment.  NOTE:  Patients with active cardiac 
disease within 12 months of study entry are excluded from study participation. 
• 
Hematological Events 
Transient decreases in WBC counts (including neutrophils and lymphocytes), platelets and 
hematocrit can occur.  Transient thrombocytopenia (including reduced platelet count) occurred 
within days of treatment with Pexa-Vec and resolved within 1 week of treatment without medical 
intervention.  Transient leukopenia (including reduced neutrophil and lymphocyte counts), has 
been observed with resolution generally occurring within 7 days of treatment.  Leukopenia is a 
common finding associated with viral infection in general.  Conversely, transient leukocytosis 
(including neutrophil, eosinophil, and monocyte subsets) has also been observed.  An elevated 
WBC count is expected based on a GM-CSF mediated effect by Pexa-Vec and the infusion of an 
attenuated vaccinia virus. 
• 
Chemistry Changes 
Chemistry changes included hyponatremia and hyperglycemia; the relationship to Pexa-Vec 
treatment is not yet known.  Dose-related direct hyperbilirubinemia (due to tumor swelling and 
occlusion of biliary tract drainage) has been noted in patients treated with Pexa-Vec whose liver 
tumors were adjacent to or impeding the biliary tract at baseline.  In addition, acute respiratory 
distress secondary to airway obstruction was observed in one patient with HCC metastases to the 
lung following treatment.  Therefore, patients with liver tumors in a location that would potentially 
result in significant clinical adverse effects if post-treatment tumor swelling were to occur, 
including at the site of the common bile duct, should not be included as per Exclusion Criteria 8.  
Biliary tract drainage should be considered as clinically indicated if biliary occlusion does not 
resolve quickly enough clinically.  Acute post-treatment tumor swelling can result in 
hyperbilirubinemia within approximately one week following treatment; tumor swelling may 
resolve over time. 
• 
Rashes 
Rashes related to latent virus reactivation have been reported, both with Varicella-Zoster (i.e., 
“shingles”) and herpes simplex virus; whether these rashes are related to Pexa-Vec itself, or due 
to the fever induced, is unknown.  Small (<1 cm) superficial skin or oral mucous membrane 
pustules containing Pexa-Vec may develop after Pexa-Vec treatment.  If they develop, it is 
typically within 1 week after the first IV infusion only.  These pustules have rarely (<10%) been 
seen following IT injection.  These pustules generally resolve within approximately the following 


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2–3 weeks, a time course that is consistent with the usual course following intentional vaccination 
with wild-type [non-attenuated] vaccinia vaccine.  All pustules to date have been self-limited and 
resolved without complications or the need for specific anti-viral treatment.  
 
8.A.2 
Notable Safety Findings 
• 
Myocardial Infarction and/or Cardiac Ischemia  
On the PHOCUS trial (Study No. JX594-HEP024), one patient experienced a Grade 2 acute 
myocardial infarction (MI) [MCN #2017SLU000230] approximately 8 hours following their 
second Pexa-Vec injection.  The Investigator assessed the event possibly related to Pexa-Vec and 
injection procedure based on temporal association of the event with Pexa-Vec treatment and 
therefore, Pexa-Vec could not be ruled out as a potential cause of the event.  However, the 
Investigator acknowledged this patient had well-established pre-existing cardiovascular risk 
factors including hypertension, hyperlipidaemia, diabetes, and distant tobacco use, as potentially 
contributing alternative etiological factors.  Sponsor agreed with this assessment.  Subsequently, 
the patient developed a recurrent MI that occurred 6 days after Pexa-Vec treatment and appeared 
to be not immediately temporally related and unprovoked in a patient with significant underlying 
cardiovascular risk factors.  Approximately 2 weeks after initiation of sorafenib therapy, the 
patient experienced severe chest pain diagnosed as stable angina.  Following recovery from the 
angina episode and having re-initiated sorafenib, the patient developed unstable angina requiring 
re-hospitalization approximately 6 weeks after original sorafenib start date.  The Sponsor assessed 
the second episode of MI and subsequent stable angina event as unlikely related to both Pexa-Vec 
and sorafenib in the patient with significant CAD and previous MI.  Please refer to the IB for 
further details. 
A second patient who experienced an MI Grade 3 (MCN #2018SLU000115) was a 70-year old 
male with a history of hypertension, hyperlipidemia, type 2 diabetes mellitus, obesity, and a distant 
history of tobacco smoking.  Prior to enrollment in the study, the patient was seen for an abnormal 
CT finding of moderately prominent coronary artery calcification and had a pre-treatment cardiac 
work up including a 3-minute exercise test that revealed no acute ischemic ECG changes but was 
overall non-diagnostic.  No major cardiac dysfunction was revealed by echocardiogram or EKG.  
The patient was cleared for trial participation (understanding the risk of tachycardia and 
hypotension after treatment with Pexa-Vec).  The patient developed tachycardia following 
Pexa-Vec treatment and prior to the development of chest pain symptoms and subsequent finding 
of elevated troponin blood levels.  Angiogram revealed underlying CAD including significant 
narrowing of the ostium of one of the diagonal arteries.  These findings and clinical setting were 


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thought consistent with demand related MI secondary to tachycardia.  The patient was treated with 
medical therapy (atorvastatin and aspirin) for underlying CAD with discharge after an 
uncomplicated post-MI clinical course.  The Investigator assessed the causal relationship of 
deviated troponin level to investigational product Pexa-Vec as possibly related, and the Sponsor 
agreed with the Investigator’s assessment. 
The analysis of cardiac events demonstrated an incidence rate of under 1% of MI following 
treatment with Pexa-Vec across all indications which is relatively stable since the prior report of 
myocardial ischemia (MCN #2017SLU000230) 
Close monitoring of clinical trials for any cardiac toxicity including cardiac ischemia/MI will be 
continued.  Further, as outlined in Section 6.B, Exclusion Criteria, patients with significant current 
or past cardiovascular disease are excluded from the study unless cardiology consultation and 
clearance has been obtained for study participation.  Additionally, patients with symptomatic 
cardiovascular disease within the preceding 12 months, as well as patients with medical conditions 
that may predispose them to untoward medical risk in the event of volume load, tachycardia, and/or 
hypotension during or following Pexa-Vec treatment are excluded from the study.  To increase the 
rigor of cardiology evaluation prior to study entry, independent, central cardiology review will be 
required for patients who undergo local, pre-study cardiology screening prior to enrollment in 
studies of Pexa-Vec to ensure a consistent approach to evaluation of potential study candidates. 
In the case of a suspected myocardial ischemia, cardiology consultation should be arranged and 
cardiac work up including angiography, echocardiography, electrocardiogram, and cardiac 
enzymes (e.g., cardiac troponin) should be performed, as clinically indicated. 
• 
Portal Vein Thrombosis 
One patient has experienced acute portal vein thrombosis (PVT) in JX594-HEP024.  The patient 
experienced 
abdominal 
pain, 
abdominal 
distension, 
headache, 
and 
tonsillitis 
(MCN #2017SLU000212).  The patient had significant thrombosis of the portal vein at baseline 
and was diagnosed with acute PVT 5 days following the second Pexa-Vec injection.  The same 
patient has subsequently developed liver rupture, Grade 3 (PT: tumor rupture, MCN 
#2017SLU000235) after approximately a 3-week course of sorafenib treatment assessed as related 
to Pexa-Vec by the Investigator and deemed to be a rapid HCC progression by the Sponsor.  
Despite compelling alternative etiology, the Investigator concluded that the causal relationship of 
Pexa-Vec and acute PVT could not be completely ruled out and the Sponsor agreed with that 
assessment.  Notably, PVT is a common finding in patients with advanced HCC which is observed 


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in ~10−60% of HCC patients according the literature reported data (Catalano 2010; Quirk 2015; 
Chan 2016; etc.).   
 
8.A.3 
Risks Linked to IT Injection Procedure 
At the tumor or skin injection the following toxicities may be observed (refer to the IB for further 
details on patient management): 
• 
pain at the injection site, 
• 
general reactions (e.g., vasovagal reaction, hypotension, bradycardia, pyrexia, anxiety, nausea, 
vomiting, diarrhea), 
• 
anesthetic reactions, 
• 
prolonged bleeding from the injection site or internal bleeding (e.g., subcapsular liver 
hematoma, hemoperitoneum, hemothorax, hemobilia), 
• 
infection at the injection site that may cause sepsis and other infections (e.g., septicemia 
peritonitis, perihepatic abscess, pneumonia), 
• 
hepatic encephalopathy, 
• 
ascites, 
• 
puncture of other organs (e.g., pleural effusion, pneumothorax), 
• 
fluctuations of biological parameters: anemia, transient bilirubin and transaminases increases, 
creatinine increase. 
 
8.A.4 
Concomitant Authorized and Contraindicated Treatments 
8.A.4.a 
Definitions and Reporting of Concomitant Medication and Non-Drug Therapy 
Concomitant medications or significant non-drug therapies (therapeutic intervention [e.g., surgery, 
blood transfusion]) will be reported within the month before start of study treatment up to 28 days 
after the last dose of Pexa-Vec or sorafenib.  
All medications (International Nonproprietary Names [INN]), dosage, route of administration, 
frequency, duration of administration, and the indication will be recorded in the appropriate 
sections of the eCRF. 


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Concomitant medications or non-drug therapy used or performed to treat a SAE, an AE related to 
study treatments or any other significant AE as recommended by the Sponsor, should be recorded 
beyond the AE reporting period as described in Section 11. 
Each time a frequency, dosage, or an indication changes, a new entry must be made in the 
appropriate section of the eCRF. 
 
8.A.4.b 
Concomitant Authorized & Contraindicated Treatments 
8.A.4.b.1 Recommended Medications Related to Flu-like Symptoms (mild-to-severe fever, rigors, 
anorexia, aches/pain, fatigue, headache, and/or nausea) – Arm A 
Pre-Medication for Treatment Day 
Patients should receive approximately 1 liter of solute-containing fluids (e.g., normal saline) IV or 
orally within 12 hours of treatment initiation.  
All patients should be pre-medicated with acetaminophen (and/or equivalent, e.g., NSAIDs, unless 
contraindicated) on each treatment day.  For acetaminophen, the following regimen may be used: 
• 
500–1000 mg 2 hours pre-infusion 
• 
500–1000 mg at 4 hours post-procedure 
• 
500–1000 mg every 6 hours thereafter, as needed (the total acetaminophen dose should be 
carefully assessed to avoid cumulative toxicity) 
 
Acute Post-Treatment Symptom Management 
During the observation period post-treatment, patients should receive IV solute-containing fluid 
and other measures (e.g., vasopressor therapy) per SOC as needed for blood pressure support.  
Anti-rigor medication (e.g., meperidine) or support medications may be used as needed. 
Anti-emetics may be used at the Investigator’s discretion for treatment of nausea or vomiting; it is 
noted, however, that corticosteroids should not be used. 
Analgesics, anti-pyretics (e.g., prophylactic acetaminophen), antidepressants, bisphosphonates, 
EPO growth factors and other supportive care measures may be used at the Investigator’s 
discretion. 
 


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8.A.4.b.2 Management of Hypotension and Contraindicated Treatments - Arm A 
To mitigate risk of hypotension following Pexa-Vec treatment, the following are required: 
• 
Prehydration with 1 liter of solute-containing fluid (p.o. or IV) prior to each treatment 
• 
Suspension of anti-hypertensive medication for 48 hours prior to and 48 hours after all 
Pexa-Vec treatments 
• 
Anti-hypertensive medications include, but are not limited to, the following: 
 Diuretics 
 Beta-blockers 
 ACE inhibitors 
 Aldosterone agonists 
 
8.A.4.b.3 Agents with Potential Inhibitory Activity Against Vaccinia Viruses - Arm A 
In the extremely unlikely case of generalized vaccinia virus infection, encephalitis or another 
clinically-significant, progressive toxicity that, in the opinion of the Investigator could be related 
to Pexa-Vec replication, Investigators may consider the use of agents with vaccinia inhibitory 
activity, if available in their country for such clinical use.  Such agents may include anti-vaccinia 
immune globulin (VIG), cidofovir, and/or Arestvyr (USAN tecovirimat; ST-246).  In addition, 
based on limited preclinical data, interferon, ribavirin, and sorafenib may have anti-vaccinia 
activity.  For clarity, none of these agents have been used or approved for this purpose to date.  
Since these agents have not been used in Pexa-Vec treated patients to date, clinical judgment 
should be used when determining the optimal regimen and duration of treatment.  
The availability of these or similar antiviral products is country-dependent; options will be 
investigated and a plan for a response to infection-related toxicities will be documented and 
communicated to study staff prior to initiation of the clinical trial.  
 
8.A.4.b.4 Contraindicated Antiviral Therapy Shown to Inhibit Vaccinia Replication 
• 
Cidofovir (except to treat toxicities potentially related to uncontrolled Pexa-Vec replication) 
• 
Interferon/PEG-interferon, ribavirin (see also Exclusion Criteria 18) 
 


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8.A.4.b.5 Other Contraindicated Treatments 
• 
Anti-cancer therapy once a patient has been randomized 
• 
High dose systemic corticosteroids (defined as ≥20 mg/day prednisone or equivalent which is 
ongoing at the time of arm allocation and/or was taken for more than 4 weeks within the 
preceding 2 months of randomization) or other immunosuppressive medications (Arm A) 
• 
Anti-coagulation or anti-platelet medication that cannot be interrupted prior to IT injections 
(Arm A), including:  
 Aspirin that cannot be discontinued for 7 days prior to treatment 
 Coumadin that cannot be discontinued for 7 days prior to treatment 
 LMWH that cannot be discontinued >24 hours prior to treatment and UFH that cannot be 
discontinued >4 hours prior to treatment (LMWH or UFH may be used to transition 
patients on and off the above anti-coagulants, if deemed appropriate by the treating 
physician) prior to Pexa-Vec treatments as long as the last dose of LMWH is administered 
24 hours prior to treatments and the last dose of UFH is administered >4 hours prior to 
treatments) 
 Oral direct thrombin inhibitor (dabigatran) or direct Factor Xa inhibitor (rivaroxaban, 
apixiban, and endoxaban) that cannot be discontinued for 4 days prior to treatments 
 
8.A.4.b.6 Other Authorized Concomitant Treatments 
• 
thrombopoietin, erythropoietin, G-CSF 
• 
antidepressants 
• 
steroids (NOTE:  oral or parenteral steroids are not allowed during the Pexa-Vec treatment 
period, and for 1 week prior to and 2 weeks after Pexa-Vec treatment) 
• 
topical therapies for symptomatic relief of hand-foot skin reaction and rash related to sorafenib 
• 
biphosphonates, vitamin B12 and vitamin D  
• 
Hepatitis B antivirals are ALLOWED as DO NOT inhibit vaccinia virus replication: 
lamivudine, adefovir (and adefovir dipivoxil prodrug), telbivudine, tenofovir, emtricitabine, 
clevudine and entecavir.  The ability of combinations of these agents to inhibit vaccinia virus 


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replication has however not been evaluated.  Therefore, combination therapy with anti-viral 
agents should be avoided if at all possible. 
NOTES: 
• 
Please contact the Sponsor for any questions regarding management of immunosuppressive, 
anticoagulant, antihypertensive, or antiviral medications prior to treatments. 
• 
Sites will be notified as additional information regarding allowed and contraindicated antivirals 
becomes available 
 
8.A.5 
Potential Mechanisms of Pexa-Vec Shedding to the Environment, Biodissemination 
and Prevention of Transmission 
8.A.5.a 
Superficial Skin Pustules  
As mentioned in Section 8.A.1, small (<1 cm) superficial skin or oral mucous membrane pustules 
containing Pexa-Vec may develop after Pexa-Vec treatment.  If pustules develop, they do so 
typically within 1 week after the first administration.  These pustules generally resolve within 
approximately the following 2–3 weeks, a time course that is consistent with the usual course 
following intentional vaccination with wild-type (non-attenuated) vaccinia vaccine.  All pustules 
to date have been self-limited and resolved without complications or the need for specific anti-
viral treatment. 
Since these pustules contain Pexa-Vec they should be managed as per the “Recommendations for 
Pexa-Vec Handling and Patient Management” (Appendix B of the IB).  
The following steps should be carried out in the event of skin or oral mucosa pustule identification 
(patient or patient contact, which is unexpected): 
1. 
Record the AE (event term for Pexa-Vec related pustules must be recorded as 
“papularpustular rash”). 
2. 
Instruct the patient/contact to cover the pustule with non-occlusive dressing (or wear a mask 
when around other people if oral lesions are present).  Refer to the “Recommendations for 
Pexa-Vec Handling and Patient Management” (Appendix B of the IB) for further 
instructions. 
 


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8.A.5.b 
Urine, Feces, Blood, Throat and/or Saliva 
Testing for the presence of Pexa-Vec after patient treatment has been conducted in several clinical 
studies in throat swabs, urine, feces, and blood samples.  
Refer to the current Pexa-Vec IB for available data on shedding and to the “Pexa-Vec Guidelines” 
for recommendations on the care of Pexa-Vec treated patients.  No person-to-person transmission 
of Pexa-Vec has been reported. 
 
8.A.6 
Expected Toxicities of Sorafenib Treatment 
Per registered SmPC, the most common adverse reactions observed with sorafenib are diarrhea, 
rash, alopecia and hand-foot syndrome (corresponds to palmar plantar erythrodysaesthesia 
syndrome in Medical Dictionary for Regulatory Activities [MedDRA]). 
For further details on sorafenib toxicities, please refer to the registered SmPC.  
 
8.B 
SAFETY, CLINICAL, DEMOGRAPHY, AND DIAGNOSIS ASSESSMENTS  
The following parameters will be evaluated during the course of the study: 
• 
Inclusion/Exclusion criteria:  patient eligibility by the Investigator by confirming all 
inclusion/exclusion criteria.  Violation of any entry criterion excludes a patient from 
enrollment into the study.  If violation is discovered after enrollment, the patient may be 
discontinued. 
• 
Demography:  Date of birth (in countries where complete date of birth is not permitted, this 
will be de-identified as required), gender, race, ethnicity, childbearing potential status 
• 
History of studied disease including but not restricted to date of diagnosis and stage at 
diagnosis, histology and prior HCC therapy 
• 
BCLC and CLIP scoring 
• 
Pre-treatment biopsy if no histological diagnosis is present in medical file 
• 
Occurrence of AEs/SAEs (refer to Section 11) 
• 
Concomitant medications and significant non-drug therapies collection 
• 
Clinical laboratory evaluations:  


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 HIV and HCV serology; detection of antigen HBs at Baseline (approximately 15 mL of 
blood) 
 Standard serum chemistry panel: sodium, potassium, chloride, CO2 content, blood urea 
nitrogen (BUN), creatinine, random glucose, total bilirubin, ALT, AST, calcium, lactate 
dehydrogenase (LDH), total protein, albumin (approximately 5 mL of blood) 
 Hematology: complete blood count (CBC) with differential and platelet count 
(approximately 5 mL of blood) 
 Coagulation: partial thromboplastin time (PTT), prothrombin time/international 
normalized ratio (PT/INR) (approximately 5 mL of blood) 
 CD4 and CD8 counts (approximately 5 mL of blood) 
 AFP (approximately 5 mL of blood) 
 Blood pregnancy test at screening (approximately 5 mL of blood) and urinary pregnancy 
test at Baseline (for women of childbearing potential) 
 Standard urinalysis (Screening only) 
• 
Physical examinations of the major organ system including skin assessment in Arm A patients 
(after Pexa-Vec treatment has been initiated), weight and vital signs (blood pressure, pulse and 
temperature).  Height will be collected at Baseline. 
• 
Performance status on the ECOG scale 
 
8.C 
EFFICACY ASSESSMENTS 
8.C.1 
Biomarker/Immune Assessments 
Archival serum sample (10 mL of blood will be collected to prepare the serum sample): further 
immune analysis including analysis of soluble mediators, cell populations, immunophenotyping, 
enzyme-linked immunosorbent assay (ELISA), CDC assay may be performed. 
 
8.C.2 
Imaging Data Acquisition and Evaluations 
8.C.2.a 
Imaging Data Acquisition 
All patients (Arm A and Arm B) will undergo imaging of the chest, abdomen, and pelvis using 
helical/spiral contrast-enhanced CT scanning (preferentially) or MRI with non-contrast CT of the 


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chest at Screening.  Tumors will be numbered with a unique number and identified as Target or 
Non-Target tumors (refer to the next paragraph for definitions).  Tumors should be assigned the 
next available chronological number wherever possible.  
Collection of radiographic imaging scans will then occur at Week 6 (±2 day window) and continue 
thereafter every 6 weeks (±7 days) for as long as the patient remains on sorafenib therapy.  
Beyond 12 months of treatment, the evaluations will be performed every 12 weeks.  
If a patient discontinues the treatment phase prior to documented radiographic progression (e.g. 
permanently stops taking the study medication), PFS Follow-up Visits will be performed every 
6 weeks for radiology evaluation until documented radiographic progression or until premature 
study discontinuation.  
Imaging studies will continue after radiographic progression has been documented as long as the 
patient continues to receive sorafenib therapy on-study.  
Specific imaging acquisition instructions are provided in the Imaging Manual provided by the core 
imaging laboratory. 
Preferred Modality:  Triphasic helical/spiral CT of the abdomen (pre-contrast, arterial phase, and 
portal venous phase; delayed imaging of the abdomen is optional) and post-contrast helical/spiral 
CT of the chest and pelvis.  All follow-up scans must also be CT.  If a CT IV contrast allergy 
(toxicity) develops after the patient has been randomized, then a DCE MRI of the abdomen and 
pelvis with gadolinium contrast will be required along with a non-contrast CT of the chest. 
Alternative Modality:  While triphasic CT remains the preferred modality for the abdomen, if a 
patient is unable to undergo triphasic CT due to iodinated contrast allergy, then Dynamic Contrast 
Enhanced Magnetic Resonance Imaging (DCE MRI) of the abdomen and pelvis with gadolinium 
contrast will be required along with a non-contrast CT of the chest.  The abdominal MRI will be 
triphasic in nature, and the pelvic MRI will be performed following MRI of the abdomen.  If an 
MRI is performed at screening, all follow-up scans must also be DCE MRI of the abdomen and 
pelvis with gadolinium contrast with a non-contrast CT of the chest.  
The same method of assessment and the same technique should be used to assess each identified 
and reported lesion for the radiological baseline (screening CT/MRI) and each follow up scan 
collected during the study. 
 


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8.C.2.b 
Imaging Data Evaluations  
The management of patients is based on RECIST version 1.1 (Eisenhauer 2009).  If the site reader 
determines that radiographic PD has occurred, the patient will be considered to have progressed 
radiographically.  
In addition, independent central efficacy reads of the images will be performed in a blinded manner 
with both mRECIST for HCC and RECIST 1.1, by a group of expert radiologists:  2 primary 
readers and 1 reader who acts as the adjudicator of differences between the 2 primary readers (in 
the case of a disagreement about the date of progression or overall response).  
Modifications to the standard RECIST criteria were proposed for patients with HCC.  This is due 
to a poor correlation between RECIST responses (i.e., based solely on changes in tumor size), to 
molecularly targeted agents as well as locoregional therapy, and clinical benefit (Forner 2009; 
Llovet 2008a; Lencioni 2010).  Definitions and methodology indicated hereafter are based on 
RECIST 1.1.  For the central imaging process (exploratory objectives), mRECIST methodology 
will be described within the Imaging Charter. 
Regarding the study objectives, secondary endpoints will be based on central review according to 
central mRECIST for HCC and exploratory endpoints will be based on measurements according 
to both local and central RECIST 1.1. 
 
8.C.2.b.1 Measurability of Tumor 
All measurements should be recorded in metric notation (mm).  The radiological baseline will be 
defined according to the screening CT/MRI and tumor lesions/lymph nodes will be categorized as 
measurable (Target lesions) or non-measurable (Non-Target lesions).  Lymph nodes that have a 
short axis <10 mm at Baseline are considered non-pathological and should not be recorded or 
followed.  If no measurable lesions are identified at Baseline, the patient will not be allowed to 
enter the study. 
For tumor lesions:  the LD in the plane of measurement has to be recorded with a minimum size 
of 10 mm by CT scan when CT scan slice thickness is no greater than 5 mm. 
For nodal lesions:  at Baseline and in the follow-up, only the short axis of lymph node will be 
measured and followed.  To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed at Baseline. 
 


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8.C.2.b.2 Non-Measurable Lesions 
Non-measurable lesions are defined as all other lesions present at baseline, including small lesions 
(longest diameter <10 mm or pathological lymph node with ≥10 mm to <15 mm short axis) as well 
as truly non measurable lesions. 
 
8.C.2.b.3 Target / Non Target Tumors 
Each lesion reported must be uniquely and sequentially numbered on the eCRF, even if it resides 
in the same organ, from baseline and throughout the study.  For the evaluation of lesions at baseline 
and throughout the study, the lesions are classified as target and non-target lesions. 
Target Tumors:  Target tumors should be selected on the basis of their size (tumors with the LD 
which are able to be reproducibly measured across time points) and are preferred to be within the 
liver.  However, target tumors may be selected outside of the liver.  Up to a maximum of 5 tumors 
total, and a maximum of 2 tumors per organ (except for the liver where 5 tumors can be selected 
as non-target for the purpose of this trial), representative of all involved organs will be identified 
as target tumors and will be recorded and measured at baseline by the site reader. 
Selection of tumors outside the liver is subject to Sponsor’s approval. 
All post-baseline measurements must be performed using the same tumors and methods as the 
baseline assessment. 
Response assessments for target tumors are defined as: 
• 
Complete Response (CR):  Disappearance of all target tumors.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
• 
Partial Response (PR):  At least 30% decrease in the SLD of target tumors, taking as reference 
the baseline SLD of target tumors. 
• 
Progressive Disease (PD):  Radiographic tumor progression for target tumors requires an 
increases in the SLD of target tumors of at least 20% taking as reference the smallest sum of 
diameters of target tumors recorded since the treatment started (this includes the baseline sum 
if that is the smallest on study).  
• 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR, nor sufficient increase to 
qualify for PD, taking as reference the smallest SLD while on study (including Baseline).  
Contingent upon minimum duration of 6 weeks from enrollment. 


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• 
Non-Evaluable (NE):  Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a different method than baseline.  Rules 
for selecting non-evaluable include the following: 
1. 
All target tumors are not evaluable.  
2. 
Or, if at least 1 target tumor is not evaluable, the target tumor SLD is still calculated 
using the remaining evaluable/measurable target tumors.  The only acceptable 
assessment in this situation is progressive disease or non-evaluable.  If the SLD of 
target tumor has increased at least 20% from nadir (including Baseline if it is the nadir) 
then the response is PD.  Any other calculated result gives an assessment of non-
evaluable. 
NOTE: 
SLD = sum of the LDs of viable enhancing hepatic target tumors plus LDs of any non-
nodal extrahepatic target tumors plus the short axis diameters of any nodal target 
tumors will be calculated. 
 
Non-Target Tumors:  All other lesions, including pathological lymph nodes, are considered non-
target lesions.  Measurements of these lesions are not required and these lesions should be followed 
as “present”, “absent”, “worsening” or in rare cases “unequivocal progression” (as defined in the 
below note) throughout the study.  Multiple non-target lesions involving the same organ can be 
assessed as a group and recorded as a single item (i.e., multiple enlarged pelvic lymph nodes).  
Each non-target lesion identified at Baseline should be assessed at each subsequent evaluation and 
be recorded in the eCRF.  
Furthermore, for the purposes of this trial, special assessments are recommended for the following: 
• 
Malignant portal vein thrombosis should be considered a non-measurable tumor due to the 
difficulty of performing reliable repeat measurements of a malignant thrombus. 
• 
Porta hepatis lymph node can be considered as malignant if the lymph node short axis is at 
least 20 mm.  
• 
Ascites, pleural effusion, and pericardial effusion:  these may not be used to assess response 
as non-target tumors, nor may they be selected as evidence of new disease as radiographic 
progression.  They may not be used due to the incidence of therapeutic fluid removal and 
benign occurrence of these fluid collections which makes them unreliable as a marker of 
disease evolution. 


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Response assessments for non-target tumors are defined as: 
• 
Complete Response (CR):  Disappearance of all non-target tumors.  All lymph nodes must be 
non-pathological in size (<10 mm short axis). 
• 
Incomplete Response / Stable Disease (SD):  Neither CR nor PD 
• 
Progressive Disease (PD):  Unequivocal progression of existing non-target tumors  
• 
Non-Evaluable (NE):  Progression has not been documented and one or more non-target 
lesions have not been assessed or have been assessed using a different method than baseline 
not allowing a reliable comparison. 
Rules for selecting non-evaluable for non-target tumors include the following: 
1. 
All non-target tumors are not evaluable. 
2. 
Or, if at least 1 non-target tumor is not evaluable and no other non-target tumor 
demonstrates unequivocal progression, the assessment is “NE” 
3. 
If at least 1 non-target tumor is not evaluable and at least 1 other non-target tumor 
demonstrates unequivocal progression, the assessment is “unequivocal progression.” 
NOTE: 
To achieve “unequivocal progression” on the basis of the non-target disease, there must 
be an overall level of substantially worsening in non-target disease such that, even in 
the presence of CR, PR, or SD in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A “modest” increase in the size of one 
or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status.  The designation of progression solely on the basis of change in 
non-target disease in the face of CR, PR, or SD of target disease will therefore be 
extremely rare. 
 
8.C.2.b.4 New Tumors:  
The appearance of new lesion is always associated with PD.  A lesion identified on a follow-up 
assessment in an anatomical location that was not scanned at baseline is also considered a new 
lesion.  If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If at the next scheduled 
assessment, PD is confirmed, the date of progression would be the earlier date when PD was 
suspected. 


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New Tumor Progressive Disease (PD):  If a newly detected lesion is obviously a tumor, 
progression criteria is met at the current time point.  The evaluation of overall response at each 
assessment is a composite of the target lesions response, non-target lesions response and presence 
of new lesions as shown below. 
 
Table 2: 
Overall Response Assessment in RECIST 1.11 
Target Tumors 
Non-Target Tumors 
New 
Tumors 
Overall Response 
CR 
CR 
No 
CR2 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Non-PD or not all evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR2 
SD 
Non-PD or not all evaluated 
No 
SD2,3 
Not all evaluated 
Non-PD 
No 
NE1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1 
Responses for all possible combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions 
2 
this overall lesion response also applies when there are no non-target lesions identified at baseline. 
3 
once confirmed PR is achieved, all these assessments are considered PR. 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = non evaluable 
 
If no non-target lesions are identified at baseline, the non-target lesion response at each assessment 
will be considered “not applicable” (NA). 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate / biopsy) to confirm CR.  It may be sometimes 
reasonable to incorporate Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) 
scanning to complement CT in assessment of progression (especially in case of possible “new” 
lesion) or in case where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. 
For equivocal findings of PD (e.g., very small and uncertain new lesions, cystic changes or necrosis 
in existing lesions) treatment may continue until the next scheduled assessment. 


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8.D 
SYMPTOMATIC AND QUALITY OF LIFE ASSESSMENTS 
Patient-Reported Outcomes (PROs), defined as report of the status of patient's health condition 
that comes directly from the patient, will be recorded to assess HRQoL.  HRQoL will take into 
account the patient's subjective perception of the treatment (Pexa-Vec followed by Sorafenib 
versus Sorafenib) and the impact of HCC on their life.  Generic and disease-specific measures are 
essential to provide a comprehensive picture of HRQoL in HCC.  
The FACT-Hep is a 45-items questionnaire designed to measure HRQoL in patients with HCC.  
The FACT-Hep consists of 27-items FACT-General (FACT-G), which assesses generic HRQoL 
concerns using 5 sub-scales, and the 18-items hepatobiliary sub-scale, which assesses specific 
symptoms of hepatobiliary cancer and side effects of treatment.  The disease specific 
questionnaire, FACT Hepatobiliary Symptom Index 8 (FHSI-8), will be used to assess 
symptomatic progression.  A decrease of 4 points or more from Baseline FHSI-8 is considered as 
symptomatic progression.  ECOG performance status will also be assessed by the Investigator until 
symptomatic progression occurs; a decrease in ECOG performance status to 4 or death is 
considered symptomatic progression.  
The EQ-5D-3L, a generic, preference-based measure questionnaire will be used for PRO 
measurement to assess utility (Herdman 2011; Scalone 2013). 
All questionnaires (except ECOG performance status) should be completed by the patient.  Once 
done, a person (this person is often a nurse in outpatient or inpatient care, e.g., trial nurse or clinical 
researcher) will check all questions are answered.  Patients should not be shown their previous 
responses.  All questionnaires will be completed by the patient at Baseline, at Week 6 and then 
every 6 weeks until end of treatments.  Beyond 12 months of treatment, the questionnaires should 
be completed every 12 weeks. 
 
8.E 
PHARMACOECONOMIC ASSESSMENTS 
To determine a trial-based economic evaluation, patient-level resource and service-use will be 
collected to evaluate the comparative cost-effectiveness of Pexa-Vec followed by sorafenib versus 
sorafenib alone.  Detailed costs will be collected during the Phase 3 trial using data entered in 
eCRF, hospital invoices, pharmacy worksheet data and 2 other questionnaires:  “health care 
resource utilization” and “patient accommodation and transport” derived from CSRI 
(Beecham 2001).  


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The questionnaire “health care resource utilization” is designed to capture direct-medical costs 
non-documented neither in the CRF nor in hospital invoices.  The questionnaire will be completed 
by the patient prior to any other visit procedures at Baseline, Week 6, and then every 6 weeks until 
end of treatment visit.  Beyond 12 months of treatment, the questionnaires should be completed 
every 12 weeks until end of treatment visit. 
The “patient accommodation and transport” covers all expenses related to indirect-medical costs.  
The questionnaire will be completed by the patient prior to any other visit procedures at Baseline, 
at Week 12, and at the End of Treatment Visit.  
Utility values collected throughout the study with EQ5D-3L questionnaire will also be assessed to 
produce generic measures for economic appraisal.   


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9 
MANAGEMENT OF NON-PATIENT EXPOSURE TO PEXA-VEC 
Transmission to patient contact or caregivers has not been documented to date.  Nevertheless, the 
following guidelines should be considered as also noted in the current Pexa-Vec IB and Pexa-Vec 
Guidelines (Appendix B of the IB), to minimize the risk of potential transmission and to manage 
infected individuals should an unexpected transmission occur. 
 
9.A 
EXPOSURE TO PEXA-VEC 
If an accidental human exposure to Pexa-Vec occurs, no specific interventions other than local 
wound care, as needed, and close observation are indicated.  Specifically, the following is 
recommended: 
1. 
Implementation of local, institutional needle stick, or other exposure guidelines.  
2. 
Wash area thoroughly with soap and water. 
3. 
Cover area with non-occlusive dressing until complete resolution. 
4. 
Report the event to the Principal Investigator, the institution’s Biosafety Specialist, and/or 
physician knowledgeable in the care of individuals experienced with vaccinia infection.  
Record and report the event to the Sponsor by completing and submitting a Report of 
Exposure to Infectious Material form as indicated on the report form. 
 
9.B 
CONTACTS EXHIBITING SYMPTOMS OF VIRAL INFECTION 
If a contact of a patient treated with Pexa-Vec reports symptoms of a possible Pexa-Vec related 
toxicity: 
1. 
Immediately notify the institution’s Biosafety Specialist  
2. 
The individual should be referred to and medically monitored by a physician knowledgeable 
in the care and treatment of patients with vaccinia infections 
3. 
Report the event to the Sponsor by completing and submitting a Report of Possible Pexa-Vec 
Toxicity form.  Follow all instructions on the form regarding avoidance of excluded 
individuals, consideration (in conjunction with consultation with infectious diseases expert 
and the Sponsor) of antiviral treatment if warranted (refer to Section 8.A.3), obtaining 
clinical samples if applicable, monitoring the individual for response to treatment (if any), 
and resolution of symptoms. 


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10 
INVESTIGATIONAL PRODUCTS (IP) 
Pexa-Vec is in development for an advanced HCC patient population in sequential combination 
with sorafenib (SOC).  Therefore, in this study Pexa-Vec and sorafenib are considered as 
Investigational Product (IP).  
Pexa-Vec and sorafenib are provided free of charge by the Sponsor.  The Investigator/Pharmacist 
will not supply IP to any patient not randomized in the study, nor to any physicians or scientists 
who are not designated as sub-Investigators.  The Investigator must ensure that patients receive IP 
only from personnel who fully understand the procedures for dosing and administering the drugs. 
 
10.A 
PEXA-VEC (JX-594) 
10.A.1 
Nomenclature of Pexa-Vec 
• 
Sponsor code designation: Pexa-Vec; VACC-6.25.1 
• 
Synonyms:  
Recombinant Vaccinia/GM-CSF (VAC-6.25.1 [GM-CSF1]),  
VAC GM-CSF 
Vaccinia/GM-CSF (Pexa-Vec) 
• 
Generic Name:  Recombinant Vaccinia GM-CSF; RAC VAC GM-CSF (thymidine kinase-
deactivated plus GM-CSF) 
Pexa-Vec is provided with a technical sheet detailing its characteristics. 
 
10.A.2 
Pharmaceutical Form of Pexa-Vec 
Pexa-Vec is a viral suspension supplied in individual 4-mL glass vials.  Each vial contains 
Pexa-Vec diluted in 30 mM Tris 10% Sucrose buffer.  The recoverable volume of Pexa-Vec in 
each vial is 2 mL with an infectious titer of 1 × 109 pfu (9.0 Log pfu).  Each vial is intended for 
single use (i.e., 1 injection to 1 patient). 
 
10.A.3 
Packaging and Labeling of Pexa-Vec 
Each vial is packed in a cardboard box (secondary packaging) which constitutes a Pexa-Vec 
treatment kit (1-vial treatment kit). 


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The primary labels on the vials as well as the secondary labels on the cardboard boxes are in the 
language of countries where the study is to be performed.  Labels are compliant with local 
regulatory requirements and contain information including, but not limited to:  Sponsor name, 
product code, lot number, concentration, volume, storage conditions, route of administration and 
a cautionary statement in proper language.  
 
10.A.4 
Biosafety/Containment Level Classification of Pexa-Vec 
Depending on the country, Pexa-Vec is classified a Biosafety/Containment Level 1 or Level 2 
infectious substance.  All applicable infection control policies should be consulted and followed. 
Refer to the current Pexa-Vec IB and Pexa-Vec Guidelines (Appendix B of the IB) for 
recommendations on handling Pexa-Vec and for management of Arm A patients treated with 
Pexa-Vec, as well as for any Arm A patients who develop Pexa-Vec-related pustules. 
 
10.A.5 
Transport of Pexa-Vec 
10.A.5.a 
Interstate and International Transport 
Pexa-Vec is shipped on dry-ice with the official transport designation as a “Biological Substance, 
Category B” in compliance with International Air Transportation Association and Department of 
Transportation regulations and other local regulations for air and road transport of infectious 
substances (UN 3373 regulations). 
 
10.A.5.b Drug Receipt and Approval of Shipment 
The supply of Pexa-Vec is managed automatically using an IVRS/IWRS.  
Detailed information on drug receipt instructions and approval of shipment process are provided 
in the Product Handling Manual.  
 
10.A.5.c 
Transport within the Institution 
All transport of Pexa-Vec (in vial, IV bag or syringe containing the dose to be administered) within 
the institution must be done using a leak-proof container/bag clearly-marked with a biohazard 
symbol. 
 


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10.A.6 
Storage of Pexa-Vec 
Pexa-Vec must be stored at or below –60°C in an alarmed, temperature-monitored, secure freezer 
with restricted access.  Detailed information on drug storage requirements and temperature 
excursions management are provided in the Product Handling Manual.  
 
10.A.7 
Dispensing of Pexa-Vec 
On either the day of Pexa-Vec treatment or the day before, site personnel will access IVRS/IWRS 
to obtain kit number assignment for Pexa-Vec treatment.  
Pexa-Vec will be dispensed only with the written authorization of the Investigator or a sub-
Investigator to staff that have been specifically designated and trained for this study. 
Please refer to site user guide for IVRS/IWRS and the Product Handling Manual for detailed 
instructions. 
 
10.A.8 
Handling of Pexa-Vec 
All applicable institutional policies for preparation, transport, and disposal of viral vectors should 
be consulted and followed.  During all Pexa-Vec manipulations gloves, gown, surgical mask and 
goggles (or safety glasses with side shields) must be worn.  Headgear and overshoes are not 
mandatory. 
In addition, refer to the IB, Pexa-Vec Guidelines (Appendix B to the IB), and supplemental 
information (as available) for recommendations regarding proper handling during preparation, 
administration, and disposal of Pexa-Vec. 
 
10.A.8.a 
Preparation of Pexa-Vec 
Preparation of Pexa-Vec will be carried out in accordance with local regulatory requirements for 
Biosafety/Containment level (Level 1 or Level 2 depending on countries) in a pharmacy or 
laboratory, according to site’s standard operating procedures (SOPs) and all applicable laws and 
regulations.  
Pexa-Vec is suspended in sterile normal saline buffered with sodium bicarbonate.  Detailed 
information on drug preparation is provided in the Pexa-Vec IT Injection Preparation Worksheet.  
 


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10.A.8.b Administration of Pexa-Vec 
The injection volume (Pexa-Vec and sodium bicarbonate buffered sterile normal saline, when 
needed) will be approximately 25% of the size of the tumor to be injected (percentage dependent 
on the size [LD] of the tumor – refer to the IT injection of Pexa-Vec:  Procedure Manual for 
details), not to exceed a specified upper limit.  Tumor numbers and measurements will be 
documented at baseline and before each IT re-treatment and transmitted to the pharmacy for drug 
preparation purposes and to the study coordinator for eCRF completion.  Calculation and 
preparation instructions are provided in the Pexa-Vec IT Injection Preparation Worksheet. 
 
10.A.8.c 
Cleaning / Disinfection and Disposal 
Standard institutional policies should be followed for cleaning and decontamination while 
handling vaccinia virus-based products.  Hospital-grade chemical disinfectants containing:  bleach 
(with at least 0.6% of active chlorine), alcohols (≥60%), aldehydes, hydrogen peroxide (3%), 
iodophor (75 ppm), phenols or quaternary ammonium compounds are adequate for routine 
cleaning and disinfection of work areas after Pexa-Vec handling.  The manufacturer’s instructions 
should be followed to ensure adequate contact time and confirm the ability of the equipment to 
withstand the disinfectant used. 
All contaminated material (e.g., syringes, catheters, needles, tubing, gloves, used or unused vials, 
containers, bandages, etc.) should be disposed of in a clearly-marked biomedical waste container 
and discarded according to regular institution procedure for infectious waste i.e., autoclaving, 
incineration, or treatment with sodium hypochlorite solution.  Biomedical waste will not be left 
unattended in a public area; autoclaved medical waste must not be disposed of as regular trash. 
Textiles and fabrics can be laundered in hot water (71°C) with detergent and hot air drying.  
 
10.A.8.d Spills or Environmental Contamination 
In the event of a spill, people in the immediate area will be alerted and other institutional personnel 
will be notified as required by institutional policies.  Refer to the current Pexa-Vec IB and 
Pexa-Vec Guidelines (Appendix B of the IB) and the Technical Sheet, for detailed instructions.  
Spills and accidents that result in overt exposures to infectious material will be reported as required 
by institutional policies.  Refer to Section 9.A. 
 


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10.A.8.e 
Unused Drug Return or Destruction 
During the course of the study based on the Sponsor’s request and at termination of the study all 
unused Pexa-Vec patient kits will be destroyed locally or returned to the drug supply provider 
contracted by the Sponsor.  
For local destruction, the Investigator/Pharmacist or delegated person will ensure that destruction 
is performed according to written instructions available in the Pexa-Vec IB and the Technical 
Sheet and will not expose humans to any risks from Pexa-Vec.  A certificate of destruction will be 
completed and provided to the Sponsor (copy retained by the site).  The drug supply provider 
contracted by the Sponsor will coordinate the return of all unused Pexa-Vec patient kits.  A 
certificate of return will be completed and provided to the drug supply provider (copy retained by 
the site). 
Upon completion or termination of the study at a site, the monitor will verify that all used Pexa-Vec 
patient kits have been decontaminated (if applicable) and disposed, all unused Pexa-Vec patient 
kits have been returned or destroyed, and no IP remains on site.  
 
10.A.9 
Drug Accountability 
The Investigator/Pharmacist, or delegated person, will maintain a Pexa-Vec accountability log 
detailing the dates and quantities dispensed for each patient along with kit and vial numbers.  
Pexa-Vec accountability records will be verified by the monitor during site visits.  
All documentation related to Pexa-Vec shipment, receipt, authorization for use, dispensing, 
destruction, temperature monitoring, etc., must be filed in the Pharmacy Binder and must be 
available for inspection.  A copy of all drug accountability records will be returned to the Sponsor 
at the end of the study. 
 
10.B 
SORAFENIB 
10.B.1 
Nomenclature 
Sorafenib 200 mg film-coated tablets. 
Sorafenib is provided with its registered SmPC. 
 


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10.B.2 
Pharmaceutical Form of Sorafenib 
Sorafenib is provided as film-coated tablets for oral administration.  Each tablet contains 200 mg 
of sorafenib. 
 
10.B.3 
Packaging and Labeling of Sorafenib 
Sorafenib is supplied in a study-specific secondary packaging with a study-specific label for study 
identification and use.  The study-specific secondary packaging is a cardboard box that contains 1 
blister pack of 4 × 7 tablets (i.e., 28 tablets in total), that constitutes a sorafenib treatment kit. 
 
10.B.4 
Transport of Sorafenib 
10.B.4.a 
Transport Conditions 
Sorafenib is shipped per manufacturer instructions. 
 
10.B.4.b 
Drug Receipt and Approval of Shipment 
The supply of sorafenib is managed automatically using an IVRS/IWRS.  
Detailed information on drug receipt instructions and approval of shipment process are provided 
in the Product Handling Manual.  
 
10.B.4.c 
Transport within the Institution 
No specific instructions. 
 
10.B.5 
Storage of Sorafenib 
Sorafenib must be stored according to the manufacturer instructions (refer to the registered SmPC 
and Product Handling Manual). 
 
10.B.6 
Drug Dispensing of Sorafenib 
Site personnel will access IVRS/IWRS to obtain kit number assignment for sorafenib treatment.  


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Sorafenib will be dispensed only with the written authorization of the Investigator or a sub-
Investigator to staff that have been specifically designated and trained for this study. 
Please refer to site user guide for IVRS/IWRS and the Product Handling Manual for detailed 
instructions. 
 
10.B.7 
Handling of Sorafenib 
10.B.7.a 
Posology 
Per registered SmPC, the recommended dose of sorafenib in adults is 400 mg  
(2 tablets of 200 mg) twice daily (equivalent to a total daily dose of 800 mg).  
Sorafenib is allowed as long as the patient is clinically benefiting from the treatment and at least 
until progression or until unacceptable toxicity occurs.  
 
10.B.7.b 
Method of Administration 
Sorafenib has to be administered according manufacturer instructions (refer to the registered 
SmPC). 
For oral use, it is recommended that sorafenib is administered without food or with a low or 
moderate fat meal.  If the patient intends to have a high-fat meal, sorafenib tablets should be taken 
at least 1 hour before or 2 hours after the meal.  The tablets should be swallowed with a glass of 
water.  
 
10.B.7.c 
Disposal 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
10.B.7.d 
Unused Drug Return or Destruction 
During the course of the study based on the Sponsor’s request and at termination of the study all 
unused sorafenib will be destroyed locally or returned to the drug supply provider contracted by 
the Sponsor.  


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For local destruction, the Investigator/Pharmacist or delegated person will ensure that destruction 
is performed according to local requirements.  A certificate of destruction will be completed and 
provided to the Sponsor (copy retained by the site). 
The drug supply provider contracted by the Sponsor will coordinate the return of all unused 
sorafenib patient kits.  A certificate of return will be completed and provided to the drug supply 
provider (copy retained by the site). 
Upon completion or termination of the study at a site, the monitor will verify that all used sorafenib 
patient kits have been disposed, and all unused sorafenib patient kits have been returned or 
destroyed. 
 
10.B.8 
Drug Accountability 
The Investigator/Pharmacist or delegated person will maintain a sorafenib accountability log 
detailing the dates and quantities dispensed for each patient along with kit numbers.  Sorafenib 
accountability records will be verified by the monitor during site visits.  
All documentation related to sorafenib shipment, receipt, authorization for use, dispensing, 
destruction, temperature monitoring, etc., must be filed in the Pharmacy Binder and must be 
available for inspection.  A copy of all drug accountability records will be returned to the Sponsor 
at the end of the study. 
 


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11 
SAFETY REPORTING 
The condition of the patient will be monitored throughout the study. 
 
11.A 
DEFINITIONS 
Adverse Event (AE):  An AE for the purposes of this protocol is a medical occurrence or 
deterioration of a pre-existing medical condition occurring after first dosing with either study drug, 
and even if the event is not considered to be related to the study treatment(s).  Prior to first on-
study treatment, only SAEs caused by a protocol-required procedure (e.g., SAEs related to invasive 
procedures such as biopsies) will be collected and reported to the Sponsor as specified in 
Section 11.E. 
Examples of AEs include: 
1. 
Pre-existing conditions (any sign, symptom, physical examination finding or laboratory 
result) that worsens in nature, severity, or frequency compared to Day 1, before the first 
administration of the IP.  A pre-existing condition is one that is present prior to the first 
administration of the IP and is reported at Baseline or Day 1. 
2. 
Clinical laboratory abnormality, vital signs measurements, physical examinations or ECG 
findings should be reported as an AE only if it is considered clinically significant (i.e., with 
clinical manifestations or receiving treatment or clinical management) by the Investigator.  
3 
All Grade 3 and Grade 4 clinical laboratory results that represent an increase in severity from 
Baseline will be reported as AEs. 
4. 
Leukocytosis will not be reported as an AE; however, any clinical signs or symptoms 
resulting from leukocytosis will be recorded as an AE. 
5. 
All reactions from IP, including those occurring as a result of an overdose, abuse, withdrawal 
phenomena, sensitivity, or toxicity to the IP. 
6. 
Concurrent illness. 
7. 
Injury or accident. 
 
Adverse Drug Reaction (ADR):  All noxious and unintended responses to the IP related to any 
dose or to a study specific procedure as determined by the Investigator or the Sponsor. 
 


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Laboratory Abnormality:  A laboratory abnormality is reported as an AE if it is out of range and 
considered by the Investigator as clinically significant (i.e., with clinical manifestations or 
requiring treatment or clinical management). 
 
Other Significant AEs:  Any AE and any laboratory abnormality, other than those reported as 
SAEs, that are considered by the Investigator or the Sponsor to be of special interest because of 
clinical importance whether or not they lead to an intervention, including: 
• 
withdrawal, 
• 
modification of the schedule of administration of Pexa-Vec, 
• 
modification of the schedule of administration or the dose of sorafenib, 
• 
addition of significant concomitant therapy. 
 
Serious Adverse Event (SAE):  Any untoward medical occurrence that at any dose fulfills one or 
more of the following criteria: 
• 
Results in death; the death of a patient is not per se an AE but an outcome.  “Death” should be 
considered as a SAE only in case of “unexplained death" when no cause is identified.  The 
event that resulted in a fatal outcome should be determined and reported as a SAE. 
• 
Is life threatening; this term refers to an event in which the patient was at immediate risk of 
death at the time of the event; it does not refer to an event that hypothetically might have caused 
death if it was more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; the 
hospitalization is an action taken to treat the event.  It should not be reported as a SAE, but the 
AE leading to hospitalization. 
• 
Results in persistent or significant disability/incapacity; the disability is a substantial disruption 
of a person’s ability to conduct normal life functions. 
• 
Is a congenital anomaly/birth defect; a “congenital anomaly/birth defect” relates to events 
occurring to babies born after their mother and/or father have taken the IP at the time of 
pregnancy confirmation or during pregnancy. 


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• 
Is a medically significant defined as an event that may not be immediately life threatening or 
result in death or hospitalization but may jeopardize the patient or may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
NOTE: Medical and scientific judgment should be exercised in deciding whether some events 
should be considered as serious because their quick reporting to the Sponsor or its 
representative may be of interest for the overall conduct of the study. 
NOTE ABOUT HOSPITALIZATION: 
Planned hospitalization for the purpose of administering the study treatment and monitoring 
the patient per protocol will not be considered a SAE. 
It will not be considered an SAE if patients are hospitalized or their hospitalization is prolonged 
post-treatment for observation of Grade 1 or 2 flu-like symptoms, provided the hospitalization 
or prolongation of hospitalization does not last longer than 24 hours. 
Hospitalization planned before or during the study should not be considered as a SAE in case 
it occurs for: 
• 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition; 
• 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened in an unexpected way since signing informed 
consent; 
• 
Treatment on an emergency outpatient basis for an event not fulfilling any of the definitions 
of a SAE given above and not resulting in hospital admission; 
• 
Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition. 
 
Suspected Unexpected Serious Adverse Drug Reaction (SUSAR):  Any unexpected SAE 
considered as related to the IP or to a study specific procedure. 
Overdose:  An overdose is an administration of the IP at a higher dose than the highest dose already 
tested in clinical studies or higher than known therapeutic doses or higher than the dose planned 
according to the schedule of administration. 


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Overdose is not be considered an AE.  However, if the patient experiences an AE/SAE related to 
this overdose, it should be reported as such. 
 
11.B 
INTENSITY, RELATIONSHIP AND OUTCOME EVALUATION 
11.B.1 
Intensity 
The intensity of AEs/SAEs will be graded according to the NCI-CTCAE version 4.03 (dated 14 
June 2010). 
Should an event be missing in the CTCAE, the following 5-point scale is to be used: 
• 
Mild:  Discomfort noticed, but no disruption of normal daily activity 
• 
Moderate:  Discomfort sufficient to affect normal daily activity 
• 
Severe:  Inability to work or perform normal daily activity 
• 
Life-threatening:  Risk of death at the time of the event 
• 
Fatal:  The patient died 
 
The correspondence between the 2 scales is as follows: 
CTCAE 
5 point scale 
1 
Mild 
2 
Moderate 
3 
Severe 
4 
Life threatening 
5 
Death 
 
 
11.B.2 
Relationship to the IP 
The relationship to the IP of each AE/SAE will be evaluated by the Investigator with the “global 
introspection” method using the following levels: 


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• 
Not related:  The temporal relationship of the clinical event to the administration of the IP 
makes a causal relationship unlikely; and other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
• 
Related:  The temporal relationship of the clinical event to the administration of the IP makes 
a causal relationship possible; and other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event.  A clear-cut temporal 
association with improvement on cessation of the study drug or recurrence upon rechallenge 
may also be observed. 
 
11.B.3 
Outcome 
The outcome is rated as follows: 
• 
recovered, 
• 
not recovered, 
• 
recovered with sequelae, 
• 
fatal, 
• 
unknown. 
 
NOTE ON "FATAL": 
this outcome is to be used only for the event leading to death.  The 
outcome of all other events at the time of the death must be reported; if 
ongoing at the time of death, the outcome of those other events should 
be reported as "not recovered". 
 
11.C 
TIME PERIOD FOR COLLECTION 
From the date of signature of the informed consent form and up to prior to initiation of IP 
administration, only SAEs caused by a protocol-required procedure (e.g., SAEs related to invasive 
procedures such as biopsies) will be collected and reported to the Sponsor as specified in 
Section 11.E. 
After the initiation of IP and up to 28 days after the last dose of IP, all AEs and SAEs should be 
collected and recorded on the eCRFs as described in Section 11.D and SAE reported to the Sponsor 
as specified in Section 11.E. 


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Post-study SAEs (i.e., occurring more than 28 days after the last dose of IP), and evaluated by the 
Investigator as related to the IP should be collected and reported to the Sponsor indefinitely even 
after study closure as specified in Section 11.E.  These would however not be reported in the eCRF. 
 
11.D 
ADVERSE EVENT MANAGEMENT 
11.D.1 Reporting 
Any AE/SAE directly observed (physical examination, laboratory test, or other assessments), 
mentioned by the patient or reported by the patient upon non-directive questioning at each visit 
during the study, will be reported by the Investigator on the “Adverse Events” page of the eCRF 
as follows: 
• 
AE term (i.e., the nature of the event with self-explanatory and concise medical terminology 
[indicate a diagnosis or syndrome instead of symptoms]), 
• 
date of onset and date of end (i.e., actual dates when the event starts and is resolved rather than 
dates when the Investigator is informed), 
• 
outcome, 
• 
intensity, 
• 
relation to Pexa-Vec, sorafenib or study procedure (e.g., IT injection) 
• 
action taken regarding Pexa-Vec, sorafenib 
• 
action taken regarding the event, 
• 
evaluation of seriousness. 
 
AE requiring therapy must be treated with recognized standards of medical care to protect the 
health and wellbeing of the patient.  Any treatment given will be reported on the page 
"Concomitant medication" of the eCRF.  
The Sponsor or its representative reserves the right to ask for further information on any AE/SAE 
that may be considered of interest or when the event is not previously documented in the IB (new 
occurrence) and is thought to be related to Pexa-Vec, sorafenib, the combination or a study specific 
procedure. 
 


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11.D.2 Follow-up 
AE must be followed until resolution or the last visit planned by the protocol. 
The AE listed below must be followed until they are resolved or stable or returned to Baseline 
status, which may occur after the last visit planned by the protocol: 
• 
AE evaluated as related to Pexa-Vec and/or sorafenib or to a study specific procedure, 
• 
SAEs, 
• 
any other significant AE as recommended by the Sponsor. 
 
11.D.3 Documentation 
AE will be reported in the source document with at least the nature of the event, the start and end 
date, the relationship to the IP and the treatment (if applicable) of the event. 
 
11.E 
SERIOUS ADVERSE EVENT MANAGEMENT 
11.E.1 
Reporting 
SAE occurring during the course of a study, irrespective of the treatment received by the patient 
MUST be reported by the Investigator to the Sponsor or its representative within 24 hours of 
occurrence or knowledge of the event.  The Investigator will also complete the “SAE Form” to be 
provided to the Sponsor or its representative as specified in the SAE reporting guidelines located 
in the Investigator site file.  SAE related documentation, if any, must be kept at the study site in 
the Investigator site file. 
 
11.E.2 
Follow-Up 
Follow-up information (e.g., complications or progression of the initial SAE) must be notified as 
soon as possible to the Sponsor or its representative using a new SAE form with the box "follow-
up" ticked.  New information must be sent to the Sponsor or its representative within 24 hours of 
knowledge as specified in the Investigator site file.  The Sponsor or its representative may request 
further information as needed. 
All SAEs will be followed until the final outcome is known. 
 


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11.E.3 
Notifications  
The Sponsor or its representative will be responsible for reporting SUSARs and any follow-up 
information to Regulatory Authorities and to central Ethics Committees (ECs) as per local 
regulation.  In case of a SUSAR, the Sponsor or its representative will inform all Investigators 
involved in any study with Pexa-Vec that such an event occurred. 
The Sponsor or its representatives will provide copies of all safety reports submitted to regulatory 
authorities to the Investigator for inclusion in the Investigator site file. 
The Investigator is responsible for informing local Institutional Review Boards (IRBs) / 
Institutional Ethics Committee (IECs) / Research Ethics Boards (REBs), Institutional Biosafety 
Committees (IBCs), and other required institutional committees of SUSARs and any follow-up 
information as per local regulations. 
 
11.F 
SPECIAL SITUATIONS 
11.F.1 
Post-Study SAE 
Any SAE occurring more than 28 days after the last IP administration and that is considered by 
the Investigator to be related to the IP must be reported to the Sponsor or its representative, 
documented and followed-up as described in Section 11.E. 
 
11.F.2 
Pregnancy 
A patient’s treatment (Pexa-Vec or sorafenib) must be discontinued immediately if she becomes 
pregnant. 
If a patient or their partner becomes pregnant during the active study participation phase and up to 
6-weeks of last Pexa-Vec dose or sorafenib dose, the Investigator must report the pregnancy to the 
Sponsor or its representative, using a “Pregnancy form” within 24 hours of the site’s awareness of 
the pregnancy. 
NOTE: If a patient’s partner becomes pregnant, the Sponsor or its representatives will make 
every effort to obtain consent from the partner to collect data on the pregnancy. 
 
Pregnancies have to be followed by the Investigator up to the completion or termination of the 
pregnancy, collecting information about the pregnancy, the new-born medical status follow up on 
the status of the infant until 8–12 weeks of age. 


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Pregnancy itself is not considered as an AE.  However, any problem met during the pregnancy and 
its outcome should be reported as an AE or a SAE.  Spontaneous or induced abortions as well as 
ectopic pregnancy should be considered as serious.  Any problem concerning the newborn should 
also be reported as an AE or SAE. 
All pregnancies starting from the first IP administration and up to 6 weeks after the last IP 
administration must be reported. 
 
11.F.3 
Overdose 
Any overdose should be reported to the Sponsor’s representative and documented and followed-
up using an “Overdose form”.  In addition, any associated symptoms should be reported as an AE 
or SAE as per instructions in Section 11.D and Section 11.E, respectively. 
 
11.F.4 
Death 
Death of a study patient occurring during the active study participation phase must be reported to 
the Sponsor or its representative by phone and email or fax within 24 hours of the site’s awareness 
of the event as per the instructions in Section 11.E. 
Deaths that occur outside of this reporting period but that are the outcome of an unresolved AE or 
SAE will also be reported to the Sponsor or its representative on a dedicated eCRF page. 
In addition, if the patient’s death occurred within 28 days of the most recent dose of Pexa-Vec, or 
death was >28 days after the most recent dose of Pexa-Vec but was due to an unresolved potentially 
related AE or SAE, the Sponsor may also request formalin-fixed and flash frozen tissue specimens 
from normal organs examined as well as from as many tumor site(s) as possible to assess the 
biodistribution and safety of Pexa-Vec in humans.  Special histopathology stains for Pexa-Vec 
replication and gene expression, virus-induced cytopathic effects, and inflammatory infiltration 
(characterize immune cells in tissues) may be performed.  Tissue specimens may be retained by 
the Sponsor for up to 2 years after sampling for these purposes. 
A copy of the death certificate should be obtained.  
If an autopsy is performed, a copy of the autopsy report should be obtained by the site and provided 
to the Sponsor or its representative. 
 


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12 
STATISTICAL CONSIDERATIONS 
12.A 
OVERVIEW 
The primary objective of this study is to determine and compare overall survival (time to death) 
based on a stratified re-randomization test, for patients receiving Pexa-Vec followed by sorafenib 
(Arm A) versus those receiving sorafenib (Arm B) in patients with advanced HCC without prior 
systemic therapy. 
Secondary objectives are to determine and compare TTP, PFS, ORR, DCR, and to determine 
patient TSP, QoL, safety and tolerability of Pexa-Vec followed by sorafenib (Arm A) compared 
to sorafenib (Arm B).  
Other objectives include TIR, DoR and tumor size evolution over time.  In addition, overall 
survival, PFS and TTP will be analyzed in patients exhibiting tumor response or in subgroups of 
patients. 
Details of the statistical analyses will be specified prospectively in a SAP. 
 
12.B 
SAMPLE SIZE DETERMINATION 
Efficacy will be evaluated comparing the overall survival in the Pexa-Vec arm (Arm A, Pexa-Vec 
followed by sorafenib) with the sorafenib arm (Arm B). 
Unlike chemotherapy, cancer immunotherapies exert their effects on the immune system and 
demonstrate new kinetics that involve building a cellular immune response, followed by changes 
in tumor burden or patient survival.  Thus, a design anticipating a 6-month delayed separation of 
the Kaplan-Meier curves was applied.  The hazard ratios are described as a function of time 
recognizing differences before and after separation of curves. 
It is assumed that Pexa-Vec does not reduce the hazard of overall survival during the first 6 months 
of treatment (HR = 1.00 for the first 6 months), while it reduces the hazard by 40% thereafter (HR 
= 0.6 after 6 months).  The median overall survival in the control arm is expected to be 
approximately 11 months. 
Based on the aforementioned assumptions, and assuming a 1:1 randomization a total of 474 events 
of death should be observed to reject the null hypothesis of no Pexa-Vec effect with a power of 
86% (assuming that HR = 1 for the first 6 months and 0.6 thereafter) using a stratified log-rank 
test at a 1-sided cumulative 2.5% level of significance.  This corresponds to a HR smaller than or 
equal to 0.83 at the final analysis to declare a significant treatment benefit.  For this analysis, the 


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p-value of the re-randomization test (based on the stratified log-rank test) will be computed and 
compared to the threshold defined as 0.021 (if the analysis is performed at 474 events exactly) due 
to the alpha adjustment induced by the interim analysis for efficacy (using an α-spending function 
due to Lan-DeMets (Gordon 1983) with O’Brien-Fleming type (O’Brien 1979) stopping boundary 
as presented below).  If the p-value is lower than this boundary, the treatment will be considered 
as effective. 
A first interim analysis for futility will be performed when 190 deaths (40% of the required events 
for final analysis) are documented in the ITT population with a stopping boundary defined as HR 
= 1.1.  The p-value of the re-randomization test (based on the stratified log-rank test) will be 
computed and compared to the threshold corresponding to HR = 1.1.  If exactly 190 events are 
considered in this analysis, the boundary for the p-value is defined as 0.744.  If the p-value 
computed is higher than this threshold, the futility boundary will have been crossed.  
A second interim analysis for efficacy will be performed when 379 deaths (80% of the required 
events for final analysis) are documented in the ITT population.  An α-spending function due to 
Lan-DeMets with O’Brien-Fleming type stopping boundary (as implemented in EAST® 6.3) will 
be used for the interim efficacy analysis.  If the interim analysis is performed after exactly  
379 events, the O’Brien-Fleming boundary for efficacy consists in using a significance level equal 
to 0.012 (corresponding to a HR equal to 0.79).  If the p-value of the re-randomization test (based 
on the stratified log-rank test) is lower than this threshold, the efficacy boundary will have been 
crossed.   
The nominal p-values and critical values used to declare statistical significance at the time of 
interim and final analyses may be slightly different as based on the actual number of deaths that 
have been documented at the time of analysis.  
Assuming a non-uniform enrolment and about 5% lost to follow-up or withdrawal of consent rate, 
a total of 600 patients should be recruited in 19 months.  It is estimated that the required 190 deaths 
and 379 deaths for both interim analyses will be observed approximately 21 months and 34 months 
respectively after starting the trial.  Likewise, it is estimated that the required 474 events for final 
analysis will be observed approximately 29 months after the inclusion of the last patient. 
 
12.C 
ANALYSIS POPULATIONS 
The ITT population will comprise all randomized patients.  Following the intent-to-treat principle, 
patients will be analyzed according to the treatment and stratum that they were assigned to at 


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randomization.  The ITT population will be the primary population for efficacy analyses and for 
summaries of demographic and Baseline variables. 
The safety population will comprise all patients who receive at least one dose of any one 
component of the study treatment (Pexa-Vec or sorafenib).  The occurrence of death also 
constitutes a valid safety assessment.  Patients will be analyzed according to the treatment they 
actually received.  The safety population will be the population for safety and drug exposure 
analyses. 
Patients with no post-baseline assessments will be listed. 
The PP population will comprise all patients from the ITT population without any major protocol 
deviations who have completed a minimum exposure requirement.  In Arm A, the minimum 
exposure is at least one Pexa-Vec injection and in Arm B, the minimum exposure consists in at 
least 2 weeks of sorafenib.  However, if a patient progressed as per Investigator radiology data, 
discontinued for AE, or died before the minimum exposure requirement could be met, that patient 
will still be included in the PP population.  
 
12.D 
METHODS OF ANALYSIS 
12.D.1 General Considerations 
Statistical summaries will be produced using SAS software version 9.2 or higher. 
Continuous variables will be described using the number of observations (N), arithmetic mean 
(Mean), standard deviation, minimum (MIN), median (Median), and maximum (MAX).  
Categorical variables will be summarized by frequency (N) and percentage (%).  Proportions will 
be estimated with their exact (binomial) 95% CIs when appropriate. 
 
12.D.2 Disposition of Patients 
The number of screening failure patients and reasons for screening failure will be summarized.  A 
patient listing will be provided with the reason of screening failure. 
The disposition data will be presented by patient and treatment arm in data listings and the 
following items will be presented by treatment arm in a summary table on the ITT population: 
• 
The number of patients randomized 
• 
The number of patients included in each population 


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• 
The number of patients excluded from the populations and reasons for exclusion 
• 
The number of patients who are still on treatment (Pexa-Vec or sorafenib) 
• 
The number of patients who have completed: 
 The end of treatment visit 
 The safety follow-up visit 
• 
The number of patients who discontinued Pexa-Vec and reasons for discontinuation Pexa-Vec 
• 
The number of patients who discontinued sorafenib and reasons for discontinuation the 
sorafenib 
• 
The number of patients who discontinued sorafenib before or after progression 
• 
The number of patients who were followed for overall survival after end of study treatments  
• 
The number of patients who discontinued the study during the survival follow-up for overall 
survival and reasons for discontinuation during this follow-up (lost to follow-up, withdrawal 
of consent) 
 
12.D.3 Demographic and Baseline Characteristics 
Baseline demographics and disease characteristics data will be listed and summarized by treatment 
arm. 
Qualitative data (e.g., gender, ethnic origin, PS) will be summarized by means of contingency 
tables for each treatment arm, and quantitative data (e.g., age and body weight) will be summarized 
by appropriate descriptive statistics (mean, standard deviation, median, minimum, and maximum) 
for each treatment arm. 
The numbers and percentage of patients with relevant medical history/current medical conditions 
will be presented by treatment arm, system organ class and preferred term. 
 
12.D.4 Treatments (Study Treatment, Concomitant Therapies)  
The safety population will be used for all summaries and listings about treatments. 
 


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12.D.4.a 
Study Treatments (Pexa-Vec and Sorafenib) 
Exposure to Pexa-Vec will be provided by summarizing the dose received during each treatment 
session (in pfu, corrected if not complete) and the cumulative dose (sum of doses received during 
each injection).  In addition, number of Pexa-Vec doses received (partial doses will be counted as 
one dose) will be categorized (0, 1, 2 or 3) and summarized. 
Exposure of Sorafenib will be provided by summarizing the duration of exposure, the dose (in 
mg/day), and the information about dose reduction by treatment arm.  Number of patients who 
received the planned dose and who had a dose reduction during the study will be summarized. 
In addition, total duration of study treatment (including Pexa-Vec and Sorafenib) will be listed and 
summarized by treatment arm. 
Sorafenib compliance will be summarized for each treatment arm.  This will be based on the 
number of tablets dispensed and used as reported in the eCRF. 
 
12.D.4.b Concomitant Medications 
Medications and/or non-drug therapies will be collected as described in Section 8. 
The concomitant medications (i.e., ongoing at the start of study treatment or taken during the 
course of the study) will be coded using the WHO Drug Dictionary and will be listed and 
summarized by active ingredient and treatment arm by means of frequency counts and percentages.  
Any prior medications or significant non-drug therapies starting and ending within the month 
before start of study treatment will be listed. 
 
12.D.5 Efficacy 
12.D.5.a 
Primary Efficacy Analysis:  Overall Survival 
Overall survival is defined as the time from randomization until death from any cause.  For patients 
not known to have died at the time of the analysis, overall survival will be censored on the date 
they were last known to be alive.  If a patient withdraws early, overall survival will not be censored 
at the date of withdrawal unless this is the date they were last known to be alive.  Date of death 
will be obtained from the death certificate (preferable) or from a written statement from the 
primary care or attending physician, or from death registry data. 


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The primary analysis will be a comparison of overall survival between Arm A and Arm B using a 
stratified re-randomization test using stratified log rank test stratified by region at the one-sided 
2.5% level in the ITT population with etiology, extrahepatic disease, vascular invasion, 
performance status and AFP levels as covariates in the model. 
Overall survival will be presented descriptively for each treatment arm using Kaplan-Meier curves.  
Summary statistics from the Kaplan-Meier distribution will be determined, including median 
overall survival and 25% and 75% quartiles with corresponding 95% CIs.  The proportions of 
patients alive at 6, 12, 18, and 24 months, along with corresponding 95% CIs, will also be provided 
by treatment arm. 
 
12.D.5.a.1 Supportive Analysis 
Estimates of the HRs (Arm A over Arm B) with 95% CIs will be obtained from a proportional 
hazard (PH) model stratified by stratification factor (i.e., region) with etiology, extrahepatic 
disease, vascular invasion, performance status and AFP levels as covariates in the model.  In order 
to take the delayed effect into account, the model will allow for a time dependent treatment effect.  
In particular, it is expected that the Pexa-Vec effect can only be seen after about 6 months since 
the beginning of treatment.  An interaction test will be conducted to check the statistical 
significance of the interaction.  
 
Sensitivity Analysis 
• 
An unstratified re-randomization test will be performed to assess the robustness of the results. 
• 
In addition, a stratified and an unstratified log-rank test will be performed.  HR (together with 
associated 95% CI) resulting from an unstratified Cox model will also be presented. 
Following the ITT principle, patients will be analyzed according to the treatment arm and strata 
they were assigned to at randomization. 
The Kaplan-Meier curves, re-randomization test, log-rank test and the Cox model analyses will 
also be repeated on the PP set. 
 
12.D.5.b Secondary Efficacy Analyses 
A hierarchical testing strategy will be adopted, TTP will be compared between the 2 treatment 
arms if the primary endpoint overall survival is statistically significant.  If TTP is statistically 


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significant (i.e., p <0.025) then PFS will be compared between the treatment groups and finally 
ORR will be analyzed. 
The analyses of the secondary efficacy endpoints will be performed on the ITT population and a 
subset will be repeated on the PP population. 
 
12.D.5.b.1 Time to Tumor Progression (TTP)  
• 
Time to Tumor Progression (TTP) is defined as the time from randomization to the date of first 
documented radiographic tumor progression; TTP does not include deaths.  If a patient has not 
had a TTP event at the cut-off date for analysis, TTP will be censored at the date of last 
evaluable tumor assessment before the cut-off. 
If a progression is observed after 2 or more missing or non-evaluable tumor assessments, then the 
date of progression will be censored at the latest occurring evaluable tumor assessment before 
missing; for a progression observed after a single missing or non-evaluable tumor assessment, the 
actual date of disease progression will be used. 
A re-randomization test using stratified log rank test stratified for region will be performed at the 
one-sided 2.5% level to compare the 2 treatment arms.  HR (together with associated 95% CI) 
resulting from the stratified Cox model will also be presented.  
TTP will be presented descriptively for each treatment arm separately using Kaplan Meier curves.  
Summary statistics from the Kaplan Meier distributions will be determined, including median TTP 
and 25% and 75% quartiles with corresponding 95% CIs.  The proportions of patients remaining 
progression free at 3, 6, and 9 months, along with 95% CIs will also be provided by treatment arm.  
 
Sensitivity Analyses: 
• 
Analyses will be repeated in the same way except that unstratified re-randomization test will 
be used.  HR (together with associated 95% CI) resulting from an unstratified Cox model will 
also be presented.  In addition, a stratified and an unstratified log-rank test will be performed. 
• 
Analyses will be repeated in the same way except that TTP will not be censored if a progression 
is observed after 2 or more missing or non-evaluable tumor assessments. 
Analyses will be performed based on local assessments using mRECIST for HCC and will be 
repeated both locally and centrally using RECIST 1.1 criteria as exploratory analyses. 
 


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12.D.5.b.2 Progression Free Survival (PFS) 
Progression free survival (PFS) is defined as the time from randomization to the date of first 
documented radiographic tumor progression or death due to any cause, whichever occurs first.  If 
a patient has not had a PFS event at the cut-off date for analysis, PFS will be censored at the date 
of last evaluable tumor assessment before the cut-off. 
If a progression is observed after 2 or more missing or non-evaluable tumor assessments, then the 
date of progression will be censored at the latest occurring evaluable tumor assessment before 
missing; for a progression observed after a single missing or non-evaluable tumor assessment, the 
actual date of disease progression will be used. 
A re-randomization test using stratified log rank test stratified for region will be performed at the 
one-sided 2.5% level to compare the 2 treatment arms.  HR (together with associated 95% CI) 
resulting from the stratified Cox model will also be presented.  
PFS will be presented descriptively for each treatment arm separately using Kaplan-Meier curves.  
Summary statistics from the Kaplan-Meier distributions will be determined, including median PFS 
and 25% and 75% quartiles with corresponding 95% CIs.  The proportions of patients remaining 
progression-free at 3, 6, and 9 months, along with 95% CIs will also be provided by treatment arm. 
 
Sensitivity Analyses: 
• 
Analyses will be repeated in the same way except that unstratified re-randomization test will 
be used.  HR (together with associated 95% CI) resulting from an unstratified Cox model will 
also be presented.  In addition, a stratified and an unstratified log-rank test will be performed. 
 
• 
Analyses will be repeated in the same way except that TTP will not be censored if a progression 
is observed after 2 or more missing or non-evaluable tumor assessments. 
 
Secondary endpoint analyses will be performed based on central assessments using mRECIST for 
HCC and will be repeated both locally and centrally using RECIST 1.1 criteria as exploratory 
analyses. 
 


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12.D.5.b.3 Overall Response Rate (ORR) 
Overall response rate (ORR) is defined as the proportion of patients whose best overall response 
is either CR or PR.  The best overall response is the best response recorded from the randomization 
until disease progression.  
Proportions of patients with a best overall response of CR or PR will be presented by treatment 
arm along with exact 95% CIs.  The Chi-square test will be used to compare the 2 treatment arms 
with respect to the ORR at a 1-sided 2.5% level of significance.  As a sensitive analysis, a two-
sided 95% CI for the difference in proportion of patients whose best overall response is either CR 
or PR, stratified by stratification factor, will be computed by using the method of Yan and Su 
(Yan 2010). 
Secondary endpoint analyses will be performed based on central assessments using mRECIST for 
HCC and will be repeated both locally and centrally using RECIST 1.1 criteria as exploratory 
analyses. 
 
12.D.5.b.4 Disease Control Rate (DCR) 
Disease control rate (DCR) is defined as the proportion of patients whose best overall response is 
either CR, PR, or SD.  
Proportions of patients with a best overall response of CR, PR, or SD will be presented by 
treatment arm along with exact 95% CIs.  The Chi-square test will be used to compare the 
2 treatment arms with respect to the DCR at a 1-sided 2.5% level of significance.  As a sensitive 
analysis, a two-sided 95% CI for the difference in proportion of patients whose best overall 
response is either CR, PR or SD, stratified by stratification factor, will be computed by using the 
method of Yan and Su (Yan 2010). 
Secondary endpoint analyses will be performed based on central assessments using mRECIST for 
HCC and will be repeated both locally and centrally using RECIST 1.1 criteria as exploratory 
analyses. 
 
12.D.5.b.5 Time to Symptomatic Progression (TSP) 
Time to symptomatic progression (TSP) is defined as the time from randomization until the first 
documented event of symptomatic progression defined as a decrease of 4 points or more from 
baseline in the FHSI-8 questionnaire or a decrease in ECOG performance status to 4, or death.  If 


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a patient has not had a TSP event at the cut-off date for analysis, TSP will be censored at the date 
of last evaluable tumor assessment before the cut-off. 
If a progression is observed after 2 or more missing or non-evaluable FHSI-8 or ECOG 
assessments, then the date of progression will be censored at the latest occurring FHSI-8 or ECOG 
assessment before missing; for a progression observed after a single missing or non-evaluable 
FHSI-8 or ECOG assessment, the actual date of symptomatic progression will be used. 
A log-rank test stratified for region will be performed at the one-sided 2.5% level to compare the 
2 treatment arms.  HR (together with associated 95% CI) resulting from the stratified Cox model 
will also be presented.  
TSP will be presented descriptively for each treatment arm separately using Kaplan-Meier curves.  
Summary statistics from the Kaplan-Meier distributions will be determined, including median TSP 
and 25% and 75% quartiles with corresponding 95% CIs.  The proportions of patients remaining 
progression-free at 3, 6, and 9 months, along with 95% CIs will also be provided by treatment arm.  
 
Sensitivity Analyses: 
• 
Analyses will be repeated in the same way except that unstratified log-rank test will be used.  
HR (together with associated 95% CI) resulting from an unstratified Cox model will also be 
presented. 
 
12.D.5.c 
Exploratory Efficacy Analysis 
As mentioned in the secondary endpoints paragraph, TPP, PFS, ORR, and DCR will be assessed 
both locally and centrally using RECIST 1.1.  In addition, the following endpoints will be assessed: 
 
12.D.5.c.1  Time to Initial Response (TIR) 
The Time to Initial Response (TIR) is defined as the time from randomization until the first 
documented response (CR or PR).  Patients who did not achieve a response will be censored at last 
adequate tumor assessment date otherwise. 
A Kaplan-Meier curve will be constructed for each treatment arm.  Median TIR and 25% and 75% 
quartiles will be presented along with 95% CIs for each treatment arm.  In addition, the Kaplan-
Meier estimates with 95% CIs at 3, 6, and 9 months will be presented by treatment arm. 


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Analyses will be performed based on central assessments using mRECIST for HCC and will be 
repeated using both local and central RECIST 1.1 criteria.  
 
12.D.5.c.2 Duration of Response (DoR) 
Duration of response (DoR) applies only to patients whose best overall response is CR or PR.  The 
DoR is defined as the time from the first documented response (CR or PR) until the event defined 
as first documented disease progression.  If a patient has not had a DoR event at the cut-off date 
for analysis, DoR will be censored at the date of last evaluable tumor assessment before the cut-
off. 
If a progression is observed after 2 or more missing or non-evaluable tumor assessments, then the 
date of progression will be censored at the latest occurring evaluable tumor assessment before 
missing assessments; for a progression observed after a single missing or non-evaluable tumor 
assessment, the actual date of disease progression will be used. 
DoR will be summarized by treatment arm.  A Kaplan-Meier curve will be constructed for each 
treatment arm.  Median DoR and 25% and 75% quartiles will be presented along with 95% CIs for 
each treatment arm.  In addition, the Kaplan-Meier estimates with 95% CIs at 3, 6, and 9 months 
will be presented by treatment arm. 
Analyses will be performed based on central assessments using mRECIST for HCC and will be 
repeated using both local and central RECIST 1.1 criteria.  
 
12.D.5.c.3  Tumor Size Over Time 
The effect of Pexa-Vec on tumor size over time will be studied.  Tumor size is defined as the SLD 
for target lesions as identified during Screening for baseline determination when the same method 
of evaluation is used.  For each time point, tumor size will be calculated along with the relative 
change from Baseline.  A repeated measurements analysis model will be used to compare the 
2 treatment arms with respect to changes in the tumor size longitudinally over time. 
Analyses will be performed based on central assessments using mRECIST for HCC and will be 
repeated using both local and central RECIST 1.1 criteria.  
 


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12.D.5.c.4  Efficacy in Subgroups of Patients 
Efficacy of Pexa-Vec will be evaluated with respect to overall survival, PFS and TTP in subgroups 
of patients (if the number of patients is sufficient) according to minimization criteria and other 
criteria described in the SAP. 
Efficacy of Pexa-Vec will also be evaluated with respect to overall survival, PFS and TTP in 
patients subdivided according to the presence or not of an objective response (CR or PR), if the 
number of patients with CR or PR is sufficient.  These analyses will be interpreted with due 
caution. 
Analyses based on radiological endpoints will be performed based on central assessments using 
mRECIST for HCC and will be repeated using both local and central RECIST 1.1 criteria. 
 
12.D.5.c.5  Efficacy with the Date of Introduction of Sorafenib as a Reference 
Efficacy of Pexa-Vec will be evaluated with respect to overall survival by reference to the date of 
introduction of sorafenib (instead of the date of randomization). 
A Kaplan-Meier curve will be constructed for each treatment arm.  Median overall survival, PFS, 
or TTP and 25% and 75% quartiles will be presented along with 95% CIs for each treatment arm.  
In addition, the Kaplan-Meier estimates with 95% CIs at 3, 6, and 9 months will be presented by 
treatment arm. 
 
12.D.5.c.6  Biomarkers Evaluation 
Descriptive statistics will be used to summarize baseline clinical and immune parameters, as well 
as changes over time.  Exploratory analyses will be conducted to correlate baseline parameters 
with patient outcome and response to treatments.  
 
12.D.6 Safety 
Safety is a secondary endpoint of the study. 
Analyses will be based on the safety population.  The safety summary tables will include all safety 
assessments collected from the start of treatment with Pexa-Vec or sorafenib up to 28 days after 
the last treatment dose of Pexa-Vec or sorafenib.  All safety data will be listed and those collected 
before the first Pexa-Vec injection and later than 28 days after the last treatment dose will be 
flagged in the listings. 


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The assessment of safety will be based mainly on the frequency of AEs and on the number of 
laboratory values that fall outside of predetermined ranges.  Other safety data (e.g., ECG, vital 
signs) will be considered as well and reported as AEs. 
Overall incidence of AEs and SAEs will be evaluated for each arm of treatment and for the study 
as a whole. 
AEs will be coded and tabulated using the MedDRA classification scheme and based on NCI 
CTCAE v4.03: 14 June 2010.  All AEs, AEs leading to discontinuation, and SAEs recorded during 
the study will be listed and summarized by body system organ class and preferred terms, severity 
(grade), relationship to each study treatment component (Pexa-Vec and sorafenib) and treatment 
arm.  AEs related to study procedure will be also listed. 
AEs will be summarized by presenting the number and percentage of patients having at least one 
AE.  Data will be presented by system organ class, preferred term and maximum grade.  A patient 
with multiple occurrence of an AE will be counted only once in the AE category.  
 
Laboratory Abnormalities 
The summaries will include all laboratory assessments collected no later than 28 days after study 
treatment discontinuation.  All laboratory assessments will be listed and those collected during 
28 days after study treatment discontinuation will be flagged in the listings. 
All laboratory values will be converted into SI units and the severity grade calculated using 
appropriate common terminology criteria for AEs (NCI CTCAE, version 4.03).  A listing of 
laboratory values will be provided by laboratory parameter, patient, and treatment arm.  A separate 
listing will display notable laboratory abnormalities (i.e., newly occurring CTCAE Grade 3 or 
Grade 4 laboratory toxicities).  The frequency of laboratory abnormalities will be displayed by 
parameter and treatment arm. 
 
12.D.7 Quality of Life (QoL) 
Quality of life (QoL) will be measured with the validated cancer-specific patient reported 
outcomes instrument to evaluate the differences over time between the 2 treatment arms. 
The number of patients with QoL data and the number of patients missing or expected to have 
QoL assessments will be summarized by each treatment arm for scheduled assessment time points. 


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Descriptive statistics will be used to summarize the individual item and scored sub scale scores of 
QoL data at each scheduled assessment time point.  Patients will be included if they completed at 
least one questionnaire item at each scheduled assessment time point. 
Additionally, change from baseline in the domain scores at the time of each assessment will be 
summarized.  Patients with an evaluable baseline score and at least one evaluable post baseline 
score during the treatment period will be included in the change from baseline analyses 
(assessments after disease progression will be excluded).  A general linear model that includes 
treatment and the baseline stratification factor in the model will be used to compare the actual and 
change from baseline in the sub-scale scores at each scheduled time point of assessment.  
Additionally, a repeated measurements analysis model, (implemented via SAS PROC MIXED) 
that includes terms for treatment, baseline stratification factor, baseline value and time of visit by 
treatment group will be used to compare the 2 treatment groups with respect to changes in the QoL 
domain scores longitudinally over time. 
Time to definitive deterioration in the global health status / QoL scale, and in each of the secondary 
scales, will be compared between the 2 treatment arms in the ITT using the stratified log-rank test 
and at one-sided type I error rate as of 2.5%.  The distributions will be presented descriptively 
using Kaplan-Meier curves.  Summary statistics from the Kaplan-Meier distributions will be 
determined, including the median time to definitive 5% deterioration and the proportions of 
patients without definitive 5% deterioration at 3 and 6 months.  Both point estimates and 95% CIs 
will be presented. 
 
12.D.8 Pharmacoeconomic Methods 
Analysis of pharmacoeconomic data and production of a final pharmacoeconomic report will be 
handled separately from the final clinical report of this study.  Information obtained from the 
collection of medical care utilization data in this study may be combined with other data such as 
cost data or other clinical parameters in the production of a final report. 
Health Resources Utilization 
An appropriate approach for pharmacoeconomic analysis is to record Health Resources Utilization 
under alternative treatment strategies according a 2-stage process.  The first is to measure resource 
use in physical units as used by trials patients.  The second stage is to add costs to these resources 
using prices or unit costs.  Costs will be assessed according to countries specificity and from a 
societal perspective. 


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The collected data of Health Care Resource will be aggregated in a pharmacoeconomic model to 
perform cost-utility and cost-effectiveness analysis.  Thus, a Markov model will be built to 
evaluate the cost-effectiveness and cost-utility of Pexa-Vec plus sorafenib versus sorafenib alone.  
The course of the disease will be divided into distinct states and transition probabilities will be 
assigned for movement between them over a discrete time period.  Six health states will be chosen 
to represent the natural history of the disease: 
• 
First-line treatment with Pexa-Vec,  
• 
First-line treatment with sorafenib following Pexa-Vec, non-progressive advanced disease, 
• 
First-line treatment with sorafenib following Pexa-Vec, progressive advanced disease, 
• 
BSC, 
• 
Palliative Care, 
• 
Death. 
 
Sensitivity analysis to test the robustness of the model to changes in values for input variables will 
be performed.  Thus, in order to assess the overall impact of uncertainty on the model results, we 
will apply probabilistic sensitivity analysis.  The outcomes of probabilistic sensitivity analysis are 
going to be: 
• 
An acceptability curve to provide the probability of Pexa-Vec to be more cost efficient than 
Sorafenib for the possible range of “willingness-to-pay” values given the uncertainty of the 
input model parameters.  
• 
A cost-effectiveness plan 
The markov model will be able to adapt to any required sub-group analysis by changing the input 
parameters of the model (clinical parameters, utilities and costs adaptations).  Additionally, the 
model will support any desired country adaptation by performing input parameterization. 
Cost-effectiveness will be expressed as incremental cost-effectiveness ration per life-years gained.  
Cost-utility will be expressed in terms of the additional cost-effectiveness ration (ICER) per 
quality-adjusted life-year (QALY) gained.  Individual patient-level data will be used to quantify 
costs during the study and quality of life referred as utility will be assessed by the EuroQol-5D 
(EQ5D-3L) questionnaire.  The health outcome should be quality-adjusted life-year (QALY) based 
on EQ5D-3L but the results of specific HRQoL questionnaire (FACT-G) might be presented for 


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information as an additional study in case EQ5D-3L is not sensitive or specific enough.  A specific 
algorithm will be used to map FACT-G data into EQ5D-3L. 
The cost-effectiveness and cost-utility analysis will adopt a time-horizon over which the costs and 
benefits of alternative treatments may vary. 
 


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13 
ETHICAL REQUIREMENTS  
All parties involved with this clinical trial, including Sponsor, representatives of the Sponsor, and 
the Investigators, will conduct the study in compliance with the protocol and according to the 
International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practices (E6), 
the Declaration of Helsinki, and all regulatory and institutional requirements, including those for 
patient privacy, informed consent, IRB/IEC/REB review and approval, source documentation, and 
record retention and including any local regulation. 
 
13.A 
PATIENT PRIVACY 
Patient medical information obtained for the purposes of this trial will be considered confidential 
and will not be disclosed to anyone not directly concerned with the trial prior written permission.  
Upon the patient’s request and written permission, medical information may be given to his/her 
personal physician or other appropriate medical personnel responsible for the patient’s welfare. 
Patient confidentiality requirements of the region(s) where the trial is conducted will be met. 
However, data generated for this study, with full access, must be available for inspection upon 
request to representatives of the Food and Drug Administration (FDA) or other national or local 
health authorities; the Sponsor or its representatives; the associated IRB/IEC/REB and other 
institutional committees, as required; and/or as required by law. 
Patients will be identified only by unique patient’s number.  However, release of research results 
or data that reveal patient names or other identifiers, such as photographs, audio or videotapes, 
must be carried out in accordance with the Department of Health and Human Services proposed 
Standards for Privacy of Individual Health information, 45 CFR 164.508, and all applicable laws 
or other country-specific regulations.  Written authorization must be obtained from the patient and 
IRB/IEC/REB (or other institutional committee delegated to represent patient privacy 
considerations) prior to the release of such information.  Identifiable patient data may not be used 
for purposes of promoting the IP. 
In the US, a written Health Insurance Portability and Accountability Act (HIPAA) authorization 
must be signed by the study participant before participating in the study to permit the use and 
disclosure of his/her personal health information as stated in the written authorization.  Any other 
applicable laws and other country-specific regulations must also be followed. 
 


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13.B 
IRB/IEC/REB 
This study must have the approval of a properly-constituted IRB/IEC/REB.  Before the IP may be 
used to treat patients, the Investigator will provide the Sponsor or its representatives with a copy 
of the IRB/IEC/REB approval letter stating that the study protocol and ICF have been reviewed 
and approved.  A copy of the approved ICF and other documents, as requested, will be provided 
to the Sponsor or its representatives. 
 
13.C 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) 
In the US, this study must have the approval of an IBC, which has been created under the guidance 
of the National Institutes of Health (NIH) to ensure proper monitoring and conduct of gene transfer 
protocols.  In other countries, other requirements for biosafety or infection control may apply and 
will be followed, as applicable. 
 
13.D 
INFORMED CONSENT 
Written consent will be obtained from the patient before he/she can participate in the study.  The 
content and process of obtaining informed consent will be in accordance with all applicable 
regulatory requirements. 
Prior to the initiation of any procedures relating to the study, a patient’s consent shall be 
documented by the use of a consent form written in the patient’s native language that has been 
approved by the IRB/IEC/REB and that is signed and personally dated by the patient at the time 
of consent.  The person who conducted the informed consent discussion shall sign and personally 
date the consent form.  A copy of the signed and dated informed consent will be given to the 
patient.  The Investigator must keep each patient’s original, signed and dated consent form on file 
for inspection by a regulatory authority or authorized party at any time. 
Depending on national regulations, an authorized person other than the Investigator may inform 
the patient, sign and date the consent form. 
During the patient’s participation in the trial, whenever important new information becomes 
available that may be relevant to the patient's consent, the consent form will be updated 
accordingly for IRB/IEC/REB approval.  The patient should be informed in a timely manner if 
new information becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial.  The communication of this information should be documented.  The 
approved revised consent form will be signed and dated by the patient. 


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13.E 
REVIEW COMMITTEE 
13.E.1 
Data Monitoring Committee (DMC) 
The DMC will conduct periodic safety and efficacy reviews (every 4 months) and review the data 
from both interim analyses.  The role, process and constitution of the DMC will be specified in a 
separate DMC Charter.  Its main mission will be to evaluate the benefit versus risk, to ensure the 
integrity of the data are respected at all times throughout the study and to give recommendations 
on its further conduct.  
 
13.E.2 
Steering Committee 
A Steering Committee will be implemented to lead the design and the conduct of the study.  
Members of the Steering Committee will be experts in leading the conduct of clinical studies in 
HCC and will consist of Investigators involved in the study.  Meetings of the Steering Committee 
will be held approximately every 6 months and the Sponsor’s representatives will attend each 
meeting.  The Steering Committee will be responsible for ensuring the study is being conducted 
with the highest scientific and ethical standards and will provide input to the study protocol and 
potential modifications of the protocol.  The Steering Committee will review reports relevant to 
the conduct of the study and may attend the open session of the DMC meeting. 
 


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14 
STUDY ADMINISTRATION 
14.A 
DOCUMENTS  
14.A.1 
Investigator’s Brochure 
The Investigator will review the current version of the Pexa-Vec IB, including Appendix B: 
Pexa-Vec Guidelines, which contains detailed information regarding warnings, precautions, 
contraindications, AEs, recommendations for managing the potential for virus transmission to 
health care workers and patient contacts, and other significant data pertaining to the IP.  It is 
obligatory that the Investigator be familiar with all sections of this document, and ensures adequate 
training of relevant study personnel, prior to initiation of the study.  New information between 
Pexa-Vec IB updates will be communicated in the form of an IB Attachment or letter. 
 
14.A.2 
Protocol Amendments 
The Sponsor will initiate any significant changes to this protocol in writing as a protocol 
amendment.  The amendment must be submitted to National Health Authorities and the 
IRB/IEC/REB with a revised ICF, if necessary and as locally requested.  Written documentation 
of IRB/IEC/REB approval must be received before the amendment may take effect. 
 
14.A.3 
Case Report Forms 
Clinical data will be recorded on eCRFs provided by the Sponsor or its representatives.  All data 
recorded in the eCRFs must be substantiated by data contained within the patients’ original source 
documents.  The electronic system should allow all corrections to the eCRFs to be dated and 
traceable to the individual making the correction.  The Investigator will ensure that all eCRFs are 
completed accurately.  A copy (electronic or paper) of all eCRFs will be retained by the site as part 
of the study documents. 
  
14.B 
 QUALITY CONTROL AND QUALITY ASSURANCE 
14.B.1 
Study Monitoring 
The Sponsor or its representatives will monitor the site at appropriate intervals to ensure protocol 
and Good Clinical Practice (GCP) compliance and accurate data recording.  The frequency of 
monitoring may vary depending on enrollment rate and the quality of data collected.  The 
Investigator and staff are expected to cooperate and provide all relevant study documentation upon 


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request.  Each site will also be routinely monitored by phone or email to keep abreast of patient 
status and to answer questions. 
In addition to routine monitoring visits, direct access to all study-related records must also be 
granted at any time for inspection by FDA or other national or local health authorities, the Sponsor 
or its representatives, the associated IRB/IEC/REB and other institutional committees, as required, 
and/or as required by law. 
 
14.B.2 
Audit and Inspection 
After appropriate notification, the Investigator will make all study-related source data and 
documents available to a quality assurance auditor mandated by the Sponsor or legal 
representative, or to domestic or foreign regulatory inspectors.  The main purposes of an audit or 
inspection are to confirm that the rights and well-being of the patients have been adequately 
protected, and that all data relevant for the study have been processed and reported in compliance 
with GCP and applicable regulatory requirements. 
 
14.C 
RECORD RETENTION 
The Investigator must retain the following:  protocols; amendments; IRB/IEC/REB approvals; IBC 
approvals (if applicable); copies of the Form FDA 1572; completed, signed, dated consent forms; 
patient medical records and original source documents; eCRFs; drug accountability records; all 
study-related correspondence; and any other documents pertaining to the conduct of the study. 
According to ICH (E6), essential documents should be retained until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the Sponsor.  It is the responsibility of the Sponsor to inform 
the Investigator/Institution as to when these documents no longer need to be retained. 
 
14.D 
STUDY TERMINATION 
The Sponsor retains the right to terminate the study or terminate a study site and remove all the 
study materials from the study site at any time.  Specific instances that may precipitate such 
termination are as follows: 


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• 
Completion of the study at an investigational site 
• 
Unanticipated adverse medical experiences in this or other studies indicating a potential health 
hazard caused by the investigational drug 
• 
Significant protocol deviation and/or lack of compliance and cooperation on the part of the 
Investigator, including but not limited to: failure to obtain signed ICF prior to initiating study 
related procedures; unsatisfactory patient enrollment with regard to quality or quantity; 
deviation from protocol requirements without prior approval from the Sponsor; or inaccurate 
and/or incomplete data recording on a recurrent basis 
• 
Investigator withdrawal from participation in study 
• 
Lack of patient recruitment at an investigational site 
• 
Withdrawal of investigational drug from investigational use 
• 
Termination of this study by the Sponsor or Health Authority 
• 
In the event of premature termination of the study or a site, the Sponsor will work with the 
Investigator(s) to arrange safety follow-up for all patients exposed to Pexa-Vec.  The Follow-
Up plan will be communicated to the IRB/IEC/REB, IBC (as applicable), and Regulatory 
authorities. 
 
14.E 
PUBLICATION AND PRESENTATION POLICY 
The results of this study may be published or presented at scientific meetings.  If this is envisaged, 
the co-authors agree to submit all manuscripts or abstracts to the Sponsor prior to scientific meeting 
or journal submission allowing for reasonable time to review, consistent with SillaJen policy.  This 
allows the Sponsor to protect proprietary information and to provide medical/scientific review.  
For intellectual property protection purposes, SillaJen can request the coauthors to delay 
publication or presentation of results.  
Consistent with Good Publication Practices (Graf 2009), authorship is to follow the criteria 
outlined by the International Committee of Medical Journal Editors, and/or follow the policies 
outlined by the journal or scientific congress.  Financial support for medical writing assistance or 
travel provided to the authors is also to be acknowledged.  
In accordance with consistent editorial practice, the Sponsor supports the publication of primary 
study results from multicenter studies in their entirety prior to any secondary analyses.  Publication 
of individual center data unless ancillary study/data is discouraged.  A publication in which the 


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contribution of the Sponsor’s personnel exceeded that of conventional monitoring will be 
considered for co-authorship provided all other criteria of International Committee of Medical 
Journal Editors are met.  
 
14.F 
ARCHIVING 
14.F.1 
Investigator Site File 
In accordance with the ICH GCP standards, the Investigator is responsible for on-site storage and 
maintenance of all records pertaining to the study for the maximum period of time required by 
local requirements. 
No study site document may be destroyed without prior written agreement between the 
Investigator and the Sponsor.  The Sponsor must be notified if the Investigator assigns the study 
documentation to another party or moves it to another location. 
 
14.F.2 
Trial Master File 
The Sponsor, or representative will archive the trial master file in accordance with GCP and 
applicable regulatory requirements and will inform the Investigator when the archiving of the study 
documentation is no longer required. 
 


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15 
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APPENDIX A: 
SCHEDULE OF ACTIVITIES 


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SAP_001.pdf: 
 
Statistical Analysis Plan 
 
A Phase 3 Randomized, Open-Label Study Comparing Pexa-Vec (Vaccinia 
GM-CSF / Thymidine Kinase-Deactivated Virus) Followed by Sorafenib versus 
Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC) Without 
Prior Systemic Therapy 
 
STUDY PROTOCOL NUMBER: 
JX594-HEP024 
PHASE: 
3 
IND NUMBER: 
BB-IND 6486 
EudraCT NUMBER: 
2014-001985-86 
SPONSOR: 
SillaJen Inc. 
450 Sansome St, Suite 650 
San Francisco, CA 94111- USA 
 
 
COORDINATING INVESTIGATOR: 
Ghassan K. Abou-Alfa, MD 
DATE: 
15 January, 2020 
 
 
The confidential information contained in this document is the property of SillaJen, Inc.  It is provided to you in confidence, for review 
by you, your staff, regulatory authorities, and members of ethics committees or institutional review boards. It is understood that this 
information will not be disclosed to any other third party, in any form, without prior authorization from the Sponsor, except to the 
extent necessary to obtain the written informed consent from the persons to whom the Investigational Medicinal Product may be 
administered. 
 
 
 




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JX594-HEP024 Statistical Analysis Plan 
Final Version 
15 Jan 2020 
DOCUMENT HISTORY 
 
Version 
Date 
Description 
Author 
1.0 
10-Apr-2019 
Initial Release for Interim Analysis 
Shenghua Mao 
2.0 
15-Jan-2020 
Update for Final Analysis 
Shenghua Mao 
 
 


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Table of Contents 
1. UPSTREAM DOCUMENTATION .............................................................................. 9 
2. STUDY DESIGN ...................................................................................................... 10 
3. STUDY OBJECTIVES ............................................................................................. 12 
3.1 
OD Primary Objectives .................................................................................. 12 
3.2 
OD Secondary Objectives ............................................................................. 13 
3.3 
Exploratory Objectives .................................................................................. 13 
4. OVERALL STUDY DURATION................................................................................ 15 
5. TREATMENT PLAN ................................................................................................. 16 
5.1 
Randomization .............................................................................................. 16 
5.2 
Duration of Treatment ................................................................................... 16 
6. DEFINITION OF THE POPULATIONS TO BE ANALYZED .................................... 17 
6.1 
Intent-To-Treat (ITT) Population .................................................................... 17 
6.2 
Safety Population .......................................................................................... 17 
6.3 
Per Protocol (PP) Population ........................................................................ 17 
6.4 
Protocol Deviations ....................................................................................... 18 
7. STATISTICAL DESIGN ........................................................................................... 19 
7.1 
Sample Size Determination ........................................................................... 19 
7.2 
Coding Dictionaries ....................................................................................... 19 
7.3 
Missing Data ................................................................................................. 19 
7.4 
Definitions and Derived Variables ................................................................. 21 
7.4.1 
Definitions ......................................................................................... 21 
7.4.2 
Derived Variables ............................................................................. 26 
8. STATISTICAL METHODS ....................................................................................... 30 
8.1 
General Principles ......................................................................................... 30 
8.2 
Patient Enrollment and Disposition ............................................................... 30 
8.3 
Analysis of Demographic and Baseline Characteristics ................................ 32 
8.4 
Medical History and Current Medical Condition ............................................ 33 
8.5 
Minimization/Stratification Factors ................................................................. 33 
8.6 
Protocol Deviation Summaries ...................................................................... 33 
8.7 
Treatments .................................................................................................... 34 
8.7.1 
Prior and Concomitant Medications .................................................. 34 
8.7.2 
Further Anti-Cancer Therapies ......................................................... 34 


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8.7.3 
Study Treatment ............................................................................... 35 
8.8 
Analysis of Efficacy ....................................................................................... 35 
8.8.1 
OD Primary Efficacy Endpoint and Analysis ..................................... 36 
8.8.1.1 
Time To Progression (TTP) ................................................ 36 
8.8.1.2 
Overall Response Rate (ORR) ........................................... 37 
8.8.1.3 
Disease Control Rate (DCR) .............................................. 38 
8.8.1.4 
Time to Tumor Marker Elevation (TTME) ........................... 38 
8.8.2 
Secondary Efficacy Endpoints and Analyses .................................... 39 
8.8.2.1 
Overall Survival Analysis (OS) ........................................... 39 
8.8.2.2 
Progression Free Survival (PFS) ........................................ 40 
8.8.3 
Exploratory Efficacy Endpoints and Analyses ................................... 41 
8.8.3.1 
Time to Initial Response ..................................................... 41 
8.8.3.2 
Time to Symptomatic Progression (TSP) ........................... 42 
8.8.3.3 
Duration of Response (DoR) .............................................. 42 
8.8.3.4 
Tumor Size Over Time ....................................................... 43 
8.8.3.5 
Efficacy in Subgroups of Patients ....................................... 43 
8.8.3.6 
Efficacy with Other Date of Introduction as a Reference .... 45 
8.8.3.7 
Efficacy with Respect to Objective Response .................... 46 
8.8.3.8 
Clinical and Efficacy Laboratory Evaluations ...................... 46 
8.9 
Analysis of Safety .......................................................................................... 47 
8.9.1 
Adverse Events ................................................................................. 47 
8.9.2 
Deaths .............................................................................................. 48 
8.9.3 
Laboratory Abnormalities .................................................................. 49 
8.9.4 
Other Laboratory Data ...................................................................... 49 
8.10 
Analysis of Quality of Life .............................................................................. 50 
8.10.1 Questionnaires .................................................................................. 50 
8.10.2 Statistical Methods ............................................................................ 51 
9. CHANGE IN PLANNED ANALYSIS ......................................................................... 52 
10. REFERENCES ........................................................................................................ 53 
11. APPENDICES .......................................................................................................... 54 
11.1 
Tumor Response Evaluation by mRECIST ................................................... 54 
11.1.1 Target Tumors .................................................................................. 54 
11.1.2 Non-Target Tumors .......................................................................... 55 
11.1.3 New Tumors ..................................................................................... 56 
11.2 
Tumor Response Evaluation by RECIST 1.1 ................................................ 58 


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11.2.1 Measurability of Tumor ..................................................................... 58 
11.2.2 Target / Non Target Tumors ............................................................. 58 
11.2.3 Target Tumors: ................................................................................. 59 
11.2.4 Non-Target Tumors: ......................................................................... 60 
11.2.5 New Tumors ..................................................................................... 61 
11.3 
Re-randomization Algorithm .......................................................................... 63 
11.3.1 Introduction ....................................................................................... 63 
11.3.2 Dynamic Randomization Algorithm ................................................... 63 
11.3.3 Implement the Algorithm ................................................................... 64 
11.3.4 Output Result .................................................................................... 65 
 
 
 
 
 


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LIST OF ABBREVATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AFP 
Alfa-Fetoprotein 
BOR 
Best Overall Response 
BSA 
Body Surface Area 
CI 
Confidence Interval 
CMD 
Concomitant Medication 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DMC 
Data Monitoring Committee  
DoR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EQ5D-3L 
EuroQoL-5D 
FACT-G 
Functional Assessment of Cancer Therapy - General 
FACT-Hep 
Functional Assessment of Cancer Therapy - Hepatobiliary 
FHSI-8 
FACT Hepatobiliary Symptom Index-8  
HCC 
Hepatocellular Carcinoma 
HR 
Hazard Ratio 
ICER 
Incremental Cost-Effectiveness Ratio 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
INT 
Integer Part 
IT 
Intratumoral 
ITT 
Intent To Treat 
IVRS 
Interactive Voice Response System 
LFU 
Loss to Follow Up 
MAX 
Maximum 
MIN 
Minimum 
NCI 
National Cancer Institute (United States) 
NE 
Not Evaluable 
OD 
Orphan Drug 
ORR 
Overall Response Rate 
OS 
Overall Survival 


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Abbreviation 
Definition 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PP 
Per Protocol 
PR 
Partial Response 
PS 
Performance Status 
PSA 
Probabilistic Sensitivity Analysis 
PT 
Preferred Term 
QALY 
Quality-Adjusted Life-Year 
QoL 
Quality of Life 
(m)RECIST 
(modified) Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
sd 
Standard Deviation 
SD 
Stable Disease 
SI 
International System of units 
SLD 
Sum of Longest Diameters 
SOC 
System Organ Class 
TA 
Tumor Assessment 
TIR 
Time to Initial Response 
TSP 
Time to Symptomatic Progression 
TTME 
Time to Tumor Markers Elevation 
TTP 
Time To Progression 
UNK 
Unknown 
WHO 
World Health Organization 
 


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1. UPSTREAM DOCUMENTATION 
This Statistical Analysis Plan (SAP) is prepared based on the final protocol (JX594-
HEP024) dated 17 February 2015, amendment 1 dated 3 October 2017, and amendment 
2 dated 26 June 2019. 
 


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2. STUDY DESIGN 
This is a Phase 3 multi-center, randomized, open-label study of Pexa-Vec followed by 
sorafenib (Arm A) versus sorafenib (Arm B) in patients with advanced hepatocellar 
carcinoma (HCC) without prior systemic therapy. 
A total of 600 patients were to be randomized between one of two treatment arms in a 
1:1 ratio (300 in each arm) to reach at least 570 evaluable patients. The final efficacy 
analysis was planned when 474 events (deaths) had been observed or at study early 
termination after the interim analysis.  In addition to regular safety reviews, the interim 
analysis for futility was to be performed when approximately 40% (190/474) of the total 
planned number of deaths are documented and the details of the interim analysis for 
futility were provided in the separate SAP dated of 13 May, 2019. The Data Monitoring 
Committee (DMC) was in charge of reviewing safety data regularly during the course of 
the study, and safety and efficacy data at the time of interim and final analyses. The DMC 
reviewed unblinded data on enrollment, patient disposition, safety (e.g. mortality, adverse 
events, labs, vital signs, physical examination) and efficacy. Additional details are 
provided in the DMC Charter.  
After signing the informed consent and satisfying all inclusion and exclusion criteria, 
patients were randomized to receive either Pexa-Vec followed by sorafenib or sorafenib 
alone in a 1:1 ratio (refer to Section 5.1).  
In case of the discontinuation of the trial, as per the memorandum to file on interim 
analysis DMC meeting recommendation and study closure activities, the enrollment was 
supposed to be stopped at the date of discontinuation of the trial and no further treatment 
with Pexa-Vec to be administered. Patients randomized to Arm A and scheduled for their 
first treatment or awaiting re-treatment were able to initiate Sorafenib at the discretion of 
the principal investigator/designee provided the criteria are met. Sorafenib supply was 
provided until 31 Oct 2019. 
In experimental Arm A, Pexa-Vec was administered as 3 bi-weekly intratumoral (IT) 
injections (Day 1, Week 2, Week 4). Radiological assessments were performed at 
screening, Week 6 and then repeated every 6 weeks until end of study treatment.  At the 
discontinuation of study, radiographic imaging was required only for patients who 
transitioned onto Sorafenib prior to week 6 visit. Sorafenib was started daily at Week 6, 
or 2 weeks after the last IT injection, whichever is later.  
In Arm B, daily sorafenib was started on Day 1, and was allowed as long as the patient 


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was clinically benefiting from the treatment and at least until progression or until 
unacceptable toxicity occurs.  Radiological assessments were to be performed at 
Screening, on Week 6 and every 6 weeks until end of study treatment administration. 
In both arms, in case study treatments are discontinued prior to the occurrence of 
progression, Progression Free Survival (PFS) Visits were to be performed on every 
6 weeks radiological assessment.  
Beyond 12 months of treatment, the radiological evaluations were to be performed every 
12 weeks until first occurrence of documented progression (or study treatment 
discontinuation whichever is later).  
When study treatments were permanently discontinued (Pexa-Vec or sorafenib), patients 
were to perform an End of Treatment Visit and a Safety Follow-Up Visit at least 28 days 
after last study treatment administration (and no more than 2 months).  
For imaging data evaluations for efficacy analyses, site readers were to perform tumor 
assessments based on RECIST 1.1 (Eisenhauer 2009). In addition, independent central 
efficacy reads of the images were to be performed in a blinded manner with both 
mRECIST (modified for the purposes of the trial, as specified in the Imaging Charter) for 
HCC and RECIST 1.1, by a group of expert radiologists: 2 primary readers and 1 reader 
who acts as the adjudicator of differences between the 2 primary readers (in the case of 
a disagreement about the date of progression or overall response). 
Up to a maximum of 5 tumors total, and a maximum of 2 tumors per organ (except for the 
liver where 5 tumors can be selected as non-target for this trial), representative of all 
involved organs will be identified as target tumors and were to be recorded and measured 
at baseline by the site reader. All post-baseline measurements were to be performed 
using the same tumors and methods as the baseline assessment.  
 
 


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3. STUDY OBJECTIVES  
An interim analysis was conducted after 197 deaths were observed resulting in the early 
termination of the study due to futility based on overall survival. Therefore, the originally 
planned protocol efficacy analyses will be modified according to a revised regulatory 
strategy of Orphan Drug Designation for Pexa-Vec for the treatment of HCC, as the 
originally planned efficacy analyses may no longer be meaningful, while modified ad hoc 
analyses for efficacy endpoints to support Orphan Drug (OD) approval will be added. 
  
3.1 OD Primary Objectives  
The OD primary objective of this study is to determine radiographic responses for 
patients treated with Pexa-Vec followed by sorafenib (Arm A) versus Sorafenib (Arm 
B) based on central assessments using mRECIST for HCC for the following endpoints:  
o Time To Progression (TTP): Time from randomization to the date of first 
documented radiographic tumor progression; TTP does not include deaths.  If a 
patient has not had a TTP event at the cut-off date for analysis, TTP will be 
censored at the date of last evaluable tumor assessment before the cut-off. 
o Overall Response (ORR): Proportion of patients whose best overall response 
during their participation in the study is either CR or PR.  The best overall response 
is the best response recorded from the randomization until disease progression.  
o Disease Control Rate (DCR): Proportion of patients whose best overall response 
during their participation in the study is either CR, PR, or SD 
o Time to Tumor Marker Elevation (TTME): Time from randomization to the date 
of registered elevation of tumor marker of Alpha Fetal Protein (AFP) increase of 
>400 ng/ml.  
 


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3.2 OD Secondary Objectives  
The OD secondary objectives of this study are: 
• 
To determine the overall survival (OS) of 2 treatment arms. 
• 
To determine Progression Free Survival (PFS) of 2 treatment arms. 
• 
To determine the safety profiles of the 2 treatment arms. 
• 
To determine the Quality of Life (QoL) of the 2 treatment arms. 
 
3.3 Exploratory Objectives 
Exploratory objectives are: 
• 
To evaluate the effect of treatment with Pexa-Vec followed by sorafenib (Arm A) 
versus sorafenib (Arm B) on the following endpoints (based on central assessments 
for radiology endpoints): 
o Time to Initial Response (TIR): Time from randomization until the first documented 
response (CR or PR). 
o Tumor size over time by reference to the sum of the longest diameters of the target 
lesions at screening. 
o Duration of Response (DoR): Time (in months) from the first AFP decrease to 
disease progression (per mRECISIT/RECSIT1.1 or AFP increase>400 ng/mL) or 
death due to underlying cancer. To evaluate the efficacy of Pexa-Vec with respect 
to TTP, ORR, DCR and TTME in subgroups of patients (if the number of patients 
in each subgroup is sufficient) as defined in Section 8.8.3.3. 
• 
To determine radiographic responses in the 2 treatment arms using RECIST 1.1 
based on central assessments for OD primary and secondary efficacy endpoints: 
TTP, ORR, DCR and PFS 
• 
To determine the Time to Symptomatic Progression (TSP) of the 2 treatment arms. 
• 
To evaluate the efficacy of Pexa-Vec with respect to TTP and TTME in patients 
subdivided according to the objective response (CR or PR) at 3 months. 
• 
To determine changes in laboratory parameters in the 2 treatment arms including 
standard laboratory parameters, AFP and CD4, CD8 counts. 


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• 
To evaluate the efficacy of Pexa-Vec with respect to TTP and TTME by reference to 
the date of introduction of sorafenib. 
• 
To evaluate the efficacy of Pexa-Vec with respect to TTP and TTME by reference to 
the date of the introduction of subsequent anti-cancer treatment. 


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4. OVERALL STUDY DURATION 
Overall study duration will consist of an active study participation phase (which includes 
the Treatment Phase, Long-Term Follow-Up Visits, End of Treatment Visit, Safety Follow-
Up, and PFS visits (if applicable)) and a survival follow-up phase (consisting of patient 
and/or caregiver contact every 4 weeks). 


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5. TREATMENT PLAN 
5.1 Randomization 
Randomization was conducted in a 1:1 ratio (Pexa-Vec followed by sorafenib versus 
sorafenib).  The randomization was performed in each subgroup of patients according to 
their region (Asian or Non-Asian).  In each subgroup, randomization using a dynamic 
stochastic minimization procedure for the following factors was applied:  
• 
Center 
• 
Main etiology:  
o Hepatitis C, 
o Hepatitis B,  
o Alcohol, 
o Other reasons (such as hemochromatosis, Wilson’s disease, type 2 diabetes, 
NASH)  
• 
Presence of extrahepatic disease: Yes vs No 
• 
Vascular invasion: Yes vs No 
• 
Performance Status (PS):  0 vs 1 
• 
AFP levels:  <200 vs 200-400 vs >400 ng/mL 
The dynamic minimization used a stochastic treatment allocation algorithm based on the 
variance method as proposed by Pocock and Simon (Pocock 1975).  
 
5.2 Duration of Treatment 
The duration of treatment lasts from the first study treatment administration (Pexa-Vec or 
sorafenib) until the last study treatment administration. 
 


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6. DEFINITION OF THE POPULATIONS TO BE ANALYZED 
6.1 Intent-To-Treat (ITT) Population 
The ITT population will comprise all randomized patients.  Following the ITT principle, 
patients will be analyzed according to the treatment and stratum they were assigned to 
at randomization. The ITT population will be the primary population for efficacy analyses 
and for summaries of demographic and Baseline variables. 
 
6.2 Safety Population  
The safety population will comprise all patients who received at least one dose of   study 
treatment (Pexa-Vec or sorafenib).  The safety population will be the population for safety 
and drug exposure analyses and patients will be analyzed according to the treatment they 
received.  
 
6.3 Per Protocol (PP) Population 
The PP population will comprise all patients from the ITT population without any major 
protocol deviations (refer to Section 6.4) who have completed a minimum exposure 
requirement.  In Arm A, the minimum exposure is at least one Pexa-Vec injection. In Arm 
B, the minimum exposure is at least 2 consecutive weeks of sorafenib.  However, if a 
patient progressed as per Investigator radiology data, discontinued for adverse event 
(AE) or died before the minimum exposure requirement could be met, that patient will still 
be included in the PP population. 
If a patient discontinued treatment for trial termination before the minimum exposure 
requirement could be met, that patient will still be eligible for inclusion in the PP population. 
Additional supply of sorafenib allowed after trial termination (i.e. 2 Aug) should not be 
counted for the minimum exposure, only the doses on or before August 2, 2019 will be 
counted in the minimum exposure for PP population. 
Patients will be analyzed according to the treatment arm and stratum that they were 
assigned to at randomization. 
 


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6.4 Protocol Deviations 
Protocol deviation will be classified as minor or major.  A major deviation may lead to 
exclusion of patient from the PP population, only: 
• 
If the protocol deviation is very likely to confound the scientific analysis of the primary 
efficacy endpoint or if it precludes any meaningful efficacy assessment, 
• 
If it is in direct conflict with the population definition given in the title of the study (i.e., 
patient diagnosis, stage of disease or use of prior treatment does not correspond to 
the intended patient population to be studied). 
The status of the major/minor protocol deviations will be reviewed by the Sponsor during 
the Protocol Deviations review meetings.  Major protocol deviations may include, but are 
not limited to, the following: 
• 
unmet inclusion exclusion criteria, at study inclusion or before each Pexa-Vec 
administration as described in the protocol, 
• 
the intake of a medication contraindicated in the protocol, 
• 
a major change in the administration schedule or dosage of Pexa-Vec or sorafenib, 
• 
the maintenance in the study of a patient who meets study withdrawal criteria, 
• 
a major non-compliance of a patient to the sorafenib treatment (< 80% or >120%)  


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7. STATISTICAL DESIGN 
7.1 Sample Size Determination 
Sample size was originally designed by comparing the overall survival in the Pexa-Vec 
arm (Arm A, Pexa-Vec followed by sorafenib) with the sorafenib arm (Arm B). Based on 
the aforementioned assumptions and 1:1 randomization, a total of 474 events of death 
should be observed to reject the null hypothesis of no Pexa-Vec effect with a power of 
86% (assuming that HR = 1 for the first 6 months and 0.6 thereafter) using a stratified log-
rank test at a 1-sided cumulative 2.5% level of significance.   
More information about the original construction of the design with EAST® 6.3 is provided 
in the analysis plan prepared for the interim analysis. 
As the study terminated early after first interim analysis, the final analysis will be based 
on actual number of subjects and events observed as of the study cut-off date for each 
individual subject.  
 
7.2 Coding Dictionaries 
All AEs and medical history will be coded using the most up to date version of Medical 
Dictionary for Regulatory Activities (MedDRA, updated twice a year).  All concomitant 
medications will be coded using the World Health Organization Drug Dictionary 
(WHODRUG). 
 
7.3 Missing Data 
Measurements that were not performed or not recorded are treated as missing data.  No 
imputation will be done for missing data, excepted for missing and incomplete dates for 
AE, concomitants medications (CMD), historical data, death or last contact.  Missing data 
will be noted as missing in appropriate tables/listings.  
Only birth year and age at randomization are collected. A data quality check will be 
programmed to ensure the duration between the randomization and birth years is 
equivalent to the patient’s reported age, otherwise a query will be issued.    
All laboratory parameters will be expressed in the International System (SI) of units. 
Laboratory values recorded as “value < x” or “value > x” will be handled as equal to: 


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• 
x – 0.001 if value recorded as “value < x” 
• 
x + 0.001 if value recorded as “value > x” 
For the calculation of descriptive parameters and for the value derived in standard units. 
In individual listings they will be presented as reported. 
 
Missing and incomplete dates for AE, CMD, historical data, death or last contact will be 
imputed as outlined below. 
Imputation Rules for Partial or Missing Stop Dates for AE, CMD and medical history: 
• 
If the month and year are present, impute the day by the last day of that month. 
• 
If only the year is present, impute by December 31st of that year. 
• 
If the stop date is entirely missing, assume the event or medication is ongoing. 
 
Imputation Rules for Partial or Missing Start Dates for AE, CMD and medical history: 
• 
If the month and year are present, impute the day by the first day of that month.  If 
the month and year are the same as those of the date of first dose, impute the day 
with the day of first dose (Pexa-Vec or sorafenib). 
• 
If only the year is present, impute by January 1st.  If the year is the same as the year 
of the date of first dose, impute by the date of the first dose. 
• 
If the start date is entirely missing, impute by the date of the first dose (Pexa-Vec or 
sorafenib). 
 
Imputation Rules for Partial Dates for Death or Date of Last Contact: 
• 
If the month and year are present: 
o If the month of the event is not the same as previous contact, impute the day by 
the first day of that month; otherwise impute the date of the previous contact. 
• 
If only the year is present: 
o It the year of the event is not the same as previous contact, impute by January 1st 
of that year; otherwise impute the date of the previous contact. 


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The previous contact date will be defined at the last complete assessment date based on 
the definition of date of last contact in Section 7.4.1 using the latest complete date. 
In patient data listings, dates will be displayed as reported.  For the calculation of duration, 
the formula (end date - start date + 1) will be used. 
 
7.4 Definitions and Derived Variables 
The following conventions will be used: 
• 
1 month corresponds to 365.25/12 = 30.4375 days. 
• 
1 year corresponds to 365.25 days. 
 
7.4.1 Definitions 
Baseline 
• 
Baseline for efficacy evaluations:  the last available assessment before or at date of 
randomization.  In the context of baseline definition, the efficacy evaluations include 
in particular tumor evaluations, measures for the stratification, biomarkers, and 
Quality of Life. 
• 
Baseline for safety evaluations:  the last available assessment before or at date of 
start of study treatment. 
 
Last Contact 
The last contact date will be derived for patients not known to have died at the analysis 
cut-off using the latest date among the following: 
• 
All assessment dates (e.g., vital signs assessment, performance status assessment 
and also assessment date in third-party data such as tumor imaging, central 
laboratory, electrocardiogram [ECG], etc.) 
• 
Medication dates including study medication or concomitant medications 
• 
AE dates 
• 
Last contact date collected 
• 
Randomization date 


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The last contact date will be used for censoring of patients in the analysis of time to event. 
 
Date of Treatment 
• 
Start date of Pexa-Vec:  the date of first injection is derived as the first date when a 
nonzero dose of Pexa-Vec was administered and recorded on dose administration 
electronic case report form (eCRF) page. 
• 
End date of Pexa-Vec:  the date of last injection is derived as the last date when a 
nonzero dose of Pexa-Vec was administered and recorded on dose administration 
eCRF page. 
• 
Start date of sorafenib:  the date of first administration of sorafenib is derived as the 
first date when a nonzero dose of sorafenib was administered and recorded on dose 
administration eCRF page. 
• 
End date of sorafenib:  the date of last administration of sorafenib is derived as the 
last date when a nonzero dose of sorafenib was administered and recorded on dose 
administration eCRF page. With the early termination of study, Sorafenib was 
administrated orally at the daily dose of 400mg twice daily (BID) until patient no 
longer clinically benefits from the treatment. SillaJen continued providing Sorafenib 
till Oct 31, 2019.  
• 
Start date of study treatment:  the date of first administration of study treatment is 
derived as the first date when a nonzero dose of any component (Pexa-Vec or 
sorafenib) of study treatment was administered and recorded on dosing 
administration eCRF page.  
• 
End date of study treatment:  the date of last administration of study treatment is 
derived as the last date when a nonzero dose of any component (Pexa-Vec or 
sorafenib) of study treatment was administered and recorded on dosing 
administration eCRF page. On the date of early termination of study, patients 
awaiting re-treatment of Pex-Vec were be given Sorafenib in the next visit (2 weeks 
after the last Pex-Vec). And sorafenib was continued till no longer benefit for patients 
or Oct 31, 2019, the last date the sponsor provided Sorafenib. 
  


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Study Day 
Study Day 1 is defined as the start date of study treatment. Other study days are defined 
relative to the Study Day 1 with Day 2 being the day after Study Day 1 and Day -1 being 
the day prior to Study Day 1. 
For all assessments, study day will be calculated using Day 1 as the origin, i.e., if date of 
assessment is on or after Day 1, the study day will be calculated as (date of assessment) 
– (start date of study treatment) +1; and if date of assessment is before Day 1, the study 
day will be calculated as (date of assessment) – (start date of study treatment).   
 
Cut-Off Date for Analysis 
Cut-off date for subjects that have not completed the study follow-up period will be based 
on their date of dose on or before August 2, 2019 (date of the letter sent to investigators 
terminating treatment + 28 days) or the start date of sorafenib administration, whichever 
comes earlier. The final analysis will be based on events/evaluations that occur on or 
before that cut-off date. The events/evaluations after that cut-off date will be included in 
listings, but not in analyses or summaries (eg considered as censored for time-to-event 
analyses). This cut-off date will also be applied for safety summaries.  
Only data with an assessment date or event start date (e.g., vital sign assessment date 
or start date of an AE) prior to or on the cut-off date will be included in the statistical 
analysis.  (Example:  If cut-off date is 15JUN2016 then an AE starting on 15JUN2016 or 
before will be reported, whereas an AE with start date on 16JUN2016 or after will not be 
reported). 
All AE or concomitant medications with start date before or on the cut-off date will be 
reported no matter if the end date is before or after cut-off date. If the end date is missing, 
then the AE will be reported as ‘ongoing’. The cut-off date will not be imputed and 
therefore will not appear in the listings. 
If it is required to impute an end date to be able to perform a specific analysis (e.g., for a 
dose administration record with missing end date or end date after the cut-off date, the 
cut-off date will be imputed as an end date to allow for calculation of treatment exposure 
duration and dose intensity), the imputed date will be displayed and flagged in the listings. 
 


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Radiographic Definitions 
• 
Overall response assessment:  Overall time point tumor response is defined by 
either RECIST 1.1 (Eisenhauer 2009) or mRECIST for HCC. mRECIST for HCC is 
an adaptation of RECIST guideline which was developed for the evaluation of tumor 
response in patients with HCC (Forner 2009; Llovet 2008). 
o Response will be assessed with RECIST 1.1 on central evaluation. 
o Response will be assessed with mRECIST for HCC centrally only.  
More details about these evaluation methods are provided in Section 11.1.   
• 
Disease progression:  as documented on tumor assessment according to RECIST 
1.1 (resp. mRECIST)  
• 
Determination of missing adequate tumor assessments (TAs):  The ‘missing 
adequate TA’ is defined as TA not done or TA with overall response equal to 
‘Unknown’.  For the sake of simplicity, the ‘missing adequate TA’ will also be referred 
to as ‘missing TA’.  For PFS or TTP censoring rule, an exact rule to determine 
whether there is no, one or two missing TAs is needed.  This rule will be based on 
the distance between the last adequate TA date and the event date.  If the distance 
is larger than threshold Day 1 or Day 2 then the analysis will assume one or 
2 missing TAs, respectively.  The threshold Day 1 will be defined as the protocol 
specified interval between the TAs plus the protocol-allowed window around the 
assessments.  Similarly, the threshold Day 2 is defined as 2 times the protocol 
specified interval between the TAs plus the protocol allowed window around the 
assessments as described in Table 1. 
Table 1: 
Tumor Assessment Threshold 
Timing from Start 
Date of Study 
Treatment 
Tumor Assessment 
Schedule as Per 
Protocol 
Day 1 
Day 2 
Before 55 weeks 
Every 6 weeks ±1 week 
6+2*1 = 
8 weeks 
(2*6)+2*1 = 14 weeks 
From 55 weeks to 
67 weeks 
 
12+2*1 = 
14 weeks 
(6+12)+2*1 = 
20 weeks 
After 67 weeks 
Every 12 weeks ± 1 week 
12+2*1 = 
14 weeks 
(2*12)+2*1 = 
26 weeks 
Disease Progression: 


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If a disease progression event is observed after 2 or more missing or non-evaluable tumor 
assessments, then the date of progression will be censored at the latest occurring 
evaluable tumor assessment; for a progression observed after a single missing or non-
evaluable tumor assessment, the actual date of disease progression will be used. 
Best Overall Response (BOR): 
Tumor response status will be evaluated at screening and every 6 weeks until first 
occurrence of documented progression.  Beyond 12 months of treatment, the evaluation 
will be performed every 12 weeks. 
The best overall response is the best response recorded from the randomization until 
disease progression. The best overall response for each patient is determined from the 
sequence of overall lesion responses according to the following rules:  
o Complete Response (CR): at least one determination of CR. 
o Partial Response (PR): at least one determination of PR and no determination of 
CR. 
o Stable Disease (SD): at least one determination of SD and no determination of CR 
or PR. 
o Progressive Disease (PD): at least one determination of PD and no determination 
of CR, PR or SD. 
o Non-Evaluable (NE): no determination of CR, PR, SD or PD. 
A best overall response NE is observed in case of: 
o No post-baseline assessment, 
o All post-baseline assessments are NE. 
Measurable disease at baseline: 
Even though the eligibility criteria require measurable disease at baseline, patients 
without measurable disease can still be present in the data.  One reason might be a 
simple violation of inclusion criteria.  A strict adherence to the ITT principle requires 
including these patients in the analysis.  Sensitivity analyses will be used to check the 
influence thereof (repeating the analysis while excluding these subjects) if more than 
5% of randomized patients didn’t have baseline measurable disease. 
Target tumor response will always be Not Evaluated (NE) due to missing baseline 


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measurements.  Therefore, a complete response, partial response or stable disease 
cannot be assigned in these cases.  However, a disease progression (PD) can still be 
determined from non-target tumors or from new tumors. 
As a result, the overall tumor responses will always be NE until PD occurs.  The PFS 
or TTP censoring and event date options will depend on how many NEs precede the 
PD. 
Symptomatic Progression 
• 
Event of symptomatic progression: a decrease of 4 points or more from baseline in 
the Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom 
Index 8 (FHSI-8) questionnaire or a decrease in ECOG performance status to 4, or 
death 
• 
Last evaluable symptomatic assessment: last assessment where either FHSI-8 or 
ECOG performance status are non-missing 
 
7.4.2 Derived Variables 
The following variables will be calculated.  Note that the list is not exhaustive and that 
further variables might be added: 
 
Duration of Treatment 
• 
Duration of Pexa-Vec exposure (days) = (End date of Pexa-Vec treatment) – (Start 
date of Pexa-Vec treatment) + 14 
• 
Duration of sorafenib exposure (days) = (End date of sorafenib treatment) – (Start 
date of sorafenib treatment) + 1 
• 
Duration of study treatment exposure (days) = (End date of study treatment) – (Start 
date of study treatment) + 1 (if last treatment is Sorafenib) or 14 (if last treatment is 
Pexa-Vec).  
• 
BSA (Mosteller formula) = Square root[Weight(kg)*Height(cm)/3600] 
 
Definitions related to efficacy endpoints 
• 
Time to Progression (months) = [date of first disease progression – date of 
randomization + 1]/30.4375 if the patient has progressed. Or [date of last evaluable 


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tumor assessment – date of randomization + 1]/30.4375 if the patient has not 
progressed (i.e., TTP time is censored). 
Individual patient’s TTP will be censored if no progression is observed at the cut-off 
date for analysis. The censoring date will be the date of the last evaluable tumor 
assessment before the cut-off date. 
If a TTP event is observed after two or more missing or non-evaluable tumor 
assessments, then the date of progression will be censored at the latest occurring 
evaluable tumor assessment before missing assessments; for a progression observed 
after a single missing or non-evaluable tumor assessment, the actual date of disease 
progression will be used. 
Patients with no post baseline tumor assessments will be censored at the 
randomization date for TTP. 
• 
Time to Tumor Marker Elevation (TTME) = [date of registered elevation of tumor 
marker (AFP increase >400 ng/mL) – date of randomization + 1]/30.4375 if the 
patient has a TTME. Or [Date of last non-missing AFP value – date of randomization 
+ 1]/30.4375 if the patient does not have TTME.  
• 
Overall response rate (ORR) = Proportion of patients whose BOR during their 
participation in the study is either CR or PR. 
• 
Disease Control Rate (DCR) = Proportion of patients whose BOR is either CR, PR 
or SD.  
• 
Overall survival (months) = [Date of death from any cause – date of randomization 
+ 1]/30.4375 if the patient has an available date of death. Or [Date of last contact – 
date of randomization + 1]/30.4375 if the patient does not have a date of death (i.e. 
survival time is censored) 
• 
Progression free survival (months) = [MIN (date of first disease progression, date of 
death due to any cause) – date of randomization + 1]/30.4375 if the patient has a 
PFS event. Or [Date of last evaluable tumor assessment – date of randomization + 
1]/30.4375 if the patient does not have PFS event (i.e., PFS time is censored) 
Individual patient’s PFS will be censored if no progression or death is observed at the 
cut-off date for analysis.  The censoring date will be the date of the last evaluable 
tumor assessment before the cut-off date. 
If a PFS event is observed after 2 or more missing or non-evaluable tumor 


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assessments, then the date of progression will be censored at the latest occurring 
evaluable tumor assessment before missing assessments; for a progression observed 
after a single missing or non-evaluable tumor assessment, the actual date of disease 
progression will be used. 
Patients with no post baseline tumor assessments who do not die will be censored at 
the randomization date for PFS. 
• 
Time to Initial Response (TIR): [First date of CR or PR – date of randomization + 
1]/30.4375.  Patients who did not achieve a response will be censored at last 
adequate tumor assessment date otherwise and calculated as [date of last evaluable 
tumor assessment – date of randomization + 1]/30.4375.  
• 
Duration of overall response (weeks) = [MIN (date of disease progression, date of 
death from underlying disease) – First date of CR or PR (whichever occurs the first)) 
+ 1]/7. Or [Date of last evaluable tumor assessment – First date of CR or PR 
(whichever occurs the first) + 1]/7 if the patient does not have disease progression 
or death from underlying disease (i.e., DoR is censored). This variable is only 
calculated for patients whose best overall response was CR or PR. 
• 
Time to Symptomatic Progression (TSP): [date of first event of symptomatic 
progression – date of randomization + 1]/30.4375 if the patient has progressed, or 
[date of last evaluable symptomatic assessment – date of randomization + 
1]/30.4375 if the patient does not progressed (i.e., TSP time is censored). 
If a patient has not had a TSP event at the cut-off date for analysis, TSP will be 
censored at the date of last evaluable tumor assessment before the cut-off. 
If a progression is observed after 2 or more missing or non-evaluable FHSI-8 or ECOG 
assessments, then the date of progression will be censored at the latest occurring 
FHSI-8 or ECOG assessment before missing; for a progression observed after a 
single missing or non-evaluable FHSI-8 or ECOG assessment, the actual date of 
symptomatic progression will be used. 
 
Definitions Related to Safety Endpoints 
Laboratory data: All laboratory data will be converted into SI units and when applicable 
the severity grade calculated using appropriate common terminology for adverse events 
(Common Terminology Criteria for Adverse Events; CTCAE version 4.03). A severity 


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grade of 0 will be assigned when the value is within normal limits.  
• 
Related to study drug will include the following responses on the CRF:  possibly, 
probably and definitely. CRF terms unrelated and remotely will be considered 
unrelated to study drug. 


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8. STATISTICAL METHODS 
8.1 General Principles 
Continuous variables will be presented by descriptive statistics including the number of 
observations (N), arithmetic mean (Mean), standard deviation (sd), minimum (MIN), 
median (Median) and maximum (MAX).  Minimum and maximum will be presented to the 
same precision as the raw data.   Mean and median will be presented with one more 
decimal place and standard deviation to 2 more decimal places than the original collected 
value. 
Categorical variables (such as gender, race etc.) will be summarized by contingency 
tables containing the frequency (N) and percentage (%).  Percentages will be based on 
all available observations. 
P-values will be presented with 4 decimal places. P-values that are rounded to 0.0000 
will be presented as “< 0.0001”, and that are rounded to 1 will be presented as “> 0.9999”. 
Statistical summaries described in this plan will be produced using SAS® software 
version 9.2 or higher. 
 
8.2 Patient Enrollment and Disposition 
The number of screening failure patients and reasons for screening failure will be 
summarized.  A patient listing will be provided with the reason of screening failure. 
The disposition data will be presented by patient and treatment arm in data listings and 
the following items will be presented by treatment arm in a summary table on the ITT 
population: 
• 
The number of patients randomized 
• 
The number of patients included in each study population 
• 
The number of patients excluded from the Per-Protocol population and reasons for 
exclusion  
• 
The number of patients who have completed 
o The end of treatment visit 
o The safety follow-up visit 


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• 
The number of patients who discontinued Pexa-Vec (Arm A) and reasons for 
discontinuation of Pexa-Vec 
• 
The number of patients who discontinued sorafenib (Arm A or Arm B) and reasons 
for discontinuation of sorafenib 
• 
The number of patients who discontinued sorafenib before or after progression 
radiographic and/or clinical, whichever is first documented 
• 
The number of patients who were followed for progression free survival after end of 
study treatment, 
• 
The number of patients who were followed for overall survival after end of study 
treatment,  
• 
The number of patients who discontinued the study during the follow-up for overall 
survival and reasons for discontinuation during this follow-up (e.g., LFU, withdrawal 
of consent). 
• 
The number of subjects whose study participation was terminated due to study 
closure (for subjects ongoing as of August 2, 2019), which includes: 
o Patients whose study participation was terminated without transition onto 
Sorafenib or additional supply of Sorafenib ; 
o Patients transitioned onto Sorafenib or continued Sorafenib. 
 
A listing of the key dates of the study will be provided including: 
• 
The randomization dates 
• 
The date of first, second and third Pexa-Vec injection 
• 
The date of introduction of sorafenib 
• 
The date of end of sorafenib 
• 
The date of progression 
• 
The date of death 
• 
The date of tumor marker elevation of AFP increase > 400 ng/mL.   
 


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8.3 Analysis of Demographic and Baseline Characteristics 
Baseline demographics and disease characteristics will be listed and summarized by 
treatment arm using the ITT population 
 
The following quantitative data will be summarized as continuous variables: 
• 
Age (year), 
• 
Weight (kg), 
• 
Height (cm), 
• 
Body Surface Area (BSA), 
• 
Time from randomization to initial diagnosis (months), 
• 
Baseline tumor size (SLD) based on both mRECIST and RECIST1.1,  
• 
AFP levels (IU/mL) 
The following qualitative data will be summarized as categorical variables: 
• 
Gender,  
• 
Race,  
• 
Ethnicity, 
• 
BCLC stage, 
• 
CLIP scoring, 
• 
Prior therapy of HCC. 
Prognostic factors used for randomization will also be summarized, including: 
• 
Center (Asian vs Non-Asian), 
• 
Etiology (Hep B vs Hep C vs Alcohol vs Other reasons), 
• 
Extrahepatic disease (Yes vs No), 
• 
Vascular invasion (Yes vs No), 
• 
Performance status (0 vs 1) on the ECOG scale, 
• 
AFP (<200 vs 200-400 vs >400 ng/mL). 
 


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8.4 Medical History and Current Medical Condition 
Medical history will consist of any significant conditions or diseases that stopped at or 
prior to the time of signing the informed consent (IC). Current medical conditions are 
significant condition started before IC with ongoing condition, or diseases present at time 
of informed consent through end of study.  
The number and percentage of patients with relevant medical history/current medical 
conditions (coded per MedDRA) will be presented by treatment arm, system organ class 
(SOC) and preferred term (PT) in the ITT population. A listing of patients with relevant 
medical history/current medical conditions will also be provided.  
 
8.5 Minimization/Stratification Factors 
Minimization factors (main etiology, presence of extrahepatic disease, vascular invasion, 
ECOG performance status, AFP levels) are used in randomization to minimize imbalance 
among groups with respect to both the number in each treatment arm and the 
characteristics of each treatment group.  Those factors will not be used in the primary 
efficacy analysis and will be treated as covariates for secondary or sensitivity analyses.  
Region is the only statistical stratification factor and will be used in primary, secondary 
and sensitivity analyses. Frequencies for each stratification and minimization factor 
collected in the IVRS will be summarized by treatment arm.  
Baseline prognostic factors collected on the eCRF will be cross-classified, tabulated and 
listed against the prognostic factors used to randomize patients.  If more than 5% of 
randomized patients are misclassified according to the prognostic factors used in the 
minimization, there will be an additional sensitivity analysis for TTP and TTME which will 
utilize the Cox proportional hazards model, stratified by region with the other minimization 
factors, according to the actual value of the characteristic as recorded in the EDC, as 
covariates. 
 
8.6 Protocol Deviation Summaries 
The number and percentage of patients in the ITT population and excluded from PP 
population with protocol deviations will be tabulated by treatment arm.  The protocol 
deviations will also be summarized by center. 
All protocol deviations will be listed by treatment arm. 


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8.7 Treatments 
8.7.1 Prior and Concomitant Medications 
Any medications (as well as HCC medications) or significant non-drug therapies (such as 
prior radiation therapy, prior HCC surgery, prior HCC local regional therapy) starting and 
ending before Day 1 will be defined as prior medication. Any non-study medication or any 
therapeutic intervention (e.g., surgery, blood transfusion) with a start date is on or after 
Day 1 up to 28 days after the last dose of Pexa-Vec or sorafenib (e.g., up to the safety 
follow-up visit)., inclusive, or with a start date before Day 1 and an end date after Day 1 
or ongoing, will be considered concomitant medication. 
All non-study medication will be coded by Anatomical Therapeutic Chemical (ATC) code 
and PT using the latest version of World Health Organization Drug Dictionary (WHODrug) 
and be summarized in frequency tabulations (subject counts and percentages) by ATC 
forth level, PT, and treatment arm. 
A listing of non-study medication will also be provided, to include dose, unit, frequency, 
route of administration, start and end dates, and reason for use. 
The ITT population will be used for all summaries and listings. 
 
8.7.2 Further Anti-Cancer Therapies 
All anti-cancer therapies given after progressive disease will be coded using the latest 
WHODrug version.  For patients who prematurely discontinued the study treatment (for 
another reason other than progressive disease), all further antineoplastic therapies will 
also be collected and coded in the same way. Anti-
cancer therapies received after the last dose of study medication are recorded at follow 
up visits after end of treatment (EOT), which also include concomitant treatment before t
he initiation of survival follow up visits but after EOT date.     
All anti-cancer therapies will be listed and summarized by active ingredient and treatment 
arm by means of frequency counts and percentages using the ITT population. 
 


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8.7.3 Study Treatment 
Number of Pexa-Vec doses received (partial doses will be counted as one dose) will be 
categorized (0, 1, 2 or 3). Cumulative injection volume for all the injections, and average 
injection volume received for each treatment session will also be summarized. For the 
calculation of average injection volume, a single average value will be computed for each 
patient, and then the average will be computed for each treatment arm. 
Average injection volume received = Cumulative injection volume for all the injections/ 
Number of Pexa-Vec doses received.  
Exposure of sorafenib will be provided by summarizing the duration of exposure and the 
average daily dose (mg/day) by treatment arm.  Number of patients who received the 
planned dose and who had a dose modification during the study will be summarized. For 
the calculation of daily dose (mg/day), a single average value will be computed for each 
patient, and then the average will be computed for each treatment arm. 
Duration of exposure = End date of sorafenib - Start date of sorafenib+1. 
Average daily dose = Cumulative dose taken / Duration of exposure. 
In addition, total duration of study treatment (including Pexa-Vec and sorafenib) will be 
listed and summarized by treatment arm. 
Total duration of study treatment = End date of study treatment - Start date of study 
treatment+1 (or +14 for Pexa-Vec subjects discontinuing prior to receiving Sorafenib). 
A patient’s study drug compliance (%) to sorafenib will be calculated as {(number of 
tablets dispensed - number of tablets returned)/ (number of tablets dispensed)}*100%.  
This compliance will be summarized with descriptive statistics and patient counts within 
compliance categories (<80%, 80 to <100%, 100 to <120%, >=120%). If the number of 
returned tablets and/or the return date are missing, then 100% compliance will be 
assigned for each day up to the number of tablets dispensed, the date of return, or the 
date of last dose, whichever is earliest. The safety population will be used for all 
summaries and listings of study treatment. 
 
8.8 Analysis of Efficacy 
Efficacy analyses will be performed on the ITT population. OD Primary and OD secondary 
endpoints will be repeated using the PP population. A re-randomization test will be 


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performed to obtain one-sided p value, and the re-randomization should be undertaken 
1000 times. Section 11.3 provides details of re-randomization algorithm applied in this 
study. 
Analyses based on radiological endpoints will be performed based on central 
assessments using mRECIST for HCC and will be repeated using central RECIST 1.1 
criteria. 
 
8.8.1 OD Primary Efficacy Endpoint and Analysis 
Primary Analysis 
The primary objective of this study is to determine radiographic responses in the 2 
treatment arms based on central assessments using mRECIST for HCC for the following 
endpoints: Time to progression (TTP), Overall Response (ORR), Disease Control Rate 
(DCR) and Time to Tumor Marker Elevation (TTME).  
 
8.8.1.1 
Time To Progression (TTP) 
TTP is defined as the time from randomization to the date of first documented 
radiographic tumor progression; TTP does not include deaths.  If a patient has not had a 
progression event at the cut-off date for analysis, will be censored at the date of last 
evaluable tumor assessment before the cut-off.  If a progression event is observed after 
2 or more missing or non-evaluable tumor assessments, then the date of progression will 
be censored at the latest occurring evaluable tumor assessments; for a progression 
observed after a single missing or non-evaluable tumor assessment, the actual date of 
disease progression will be used. 
A re-randomization test using stratified log rank test stratified by region will be performed 
to compare the 2 treatment arms.  Estimates of the HRs (Arm A over Arm B) with 95% CI 
will be obtained from a Cox Proportional Hazard (PH) model stratified by region with other 
minimization factors as covariates will also be presented.  
TTP will be presented descriptively for each treatment arm separately using Kaplan-Meier 
curves.  Summary statistics from the Kaplan-Meier distributions will be determined, 
including median TTP and 25% and 75% quartiles with corresponding 95% confidence 
intervals (CIs).  The proportions of patients remaining progression free at 3, 6, 9 and 12 
months, along with 95% CIs will also be provided by treatment arm. 


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Supportive Analysis 
Estimates of the HRs (Arm A over Arm B) with 95% CI for TTP will be obtained from a 
Cox proportional hazard (PH) model stratified by region with, etiology, extrahepatic 
disease, vascular invasion, ECOG performance status and AFP level as covariates in the 
model in the ITT population.  
• 
In order to take the delayed effect into account, the model will allow for a time 
dependent treatment effect which will take the form of a binary time indicator (≤ 6 
months and > 6 months). An interaction test will be conducted to assess the 
statistical significance of the time dependent effect.  
 
Sensitivity Analyses 
• 
An unstratified re-randomization test will be performed to assess the robustness of the 
results. This test will utilize the unstratified log-rank statistic. Hazard ratios (HR), 
together with associated 95% CI, resulting from an unstratified Cox model but with 
region and the remaining minimization factors included in the model as covariates will 
also be presented in the ITT population. 
• 
All analyses for TTP will be repeated except that TTP will not be censored if a 
progression is observed after 2 or more missing or non-evaluable tumor 
assessments.  
 
8.8.1.2 
Overall Response Rate (ORR)  
Overall Response Rate (ORR) is defined as the proportion of patients whose Best Overall 
Response (BOR) is either CR or PR, patients with NE response will be counted in the 
denominator.  
ORR will be presented by treatment arm along with exact 95% CIs.  Difference in ORR 
proportions (with 95% CI) will also be provided.  A Cochran-Mantel-Haenszel test will be 
performed to compare the 2 treatment arms with respect to the ORR at a 1-sided 2.5% 
level of significance. A re-randomization test stratified for region based on the Mantel-
Haenszel Chi-square statistic will be performed to obtain one-sided p-value. 
As a sensitivity analysis, a two-sided Wilson Newcombe 95% CI for the difference in ORR, 
stratified by region will be computed by using the method of Yan and Su (Yan 2010).  


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Patients with BOR ‘NE’ will be summarized by reason for having unknown status. 
 
8.8.1.3 
Disease Control Rate (DCR) 
Disease Control Rate (DCR) is defined as the proportion of patients whose BOR is either 
CR, PR or SD.  
DCR will be presented by treatment arm along with exact 95% CIs.  Difference in 
proportions (with 95% CI) will also be provided.  A Cochran-Mantel-Haenszel test will be 
performed to compare the 2 treatment arms with respect to the DCR at a 1-sided 2.5% 
level of significance. A re-randomization test stratified for region based on the Mantel-
Haenszel Chi-square statistic will be performed to obtain one-sided p-value. 
As a sensitivity analysis, a two-sided Wilson Newcombe 95% CI for the difference in DCR, 
stratified by region will be computed by using the method of Yan and Su (Yan 2010).  
 
8.8.1.4 
Time to Tumor Marker Elevation (TTME) 
Time to tumor marker elevation is defined as time from randomization to the date of 
registered elevation of tumor markers (AFP) with increase of >400 ng/mL. If a patient is 
alive or if the patient has no tumor marker increase of >400 ng/mL at the cut-off date for 
analysis, TTME will be censored at the date of last AFP record before the cut-off.  
TTME will be summarized by treatment arm.  A Kaplan-Meier curve will be constructed 
for each treatment arm.  Median TTME and 25% and 75% quartiles will be presented 
along with 95% CIs for each treatment arm.  In addition, the Kaplan-Meier estimates with 
95% CIs at 3, 6, 9 and 12 months will be presented by treatment arm. Numbers of patients 
at risk will also be displayed at monthly intervals below the time axis for each of the two 
treatment groups and censored observations will be marked by notches on the curves.  
 
Supportive Analysis 
Estimates of the HRs (Arm A over Arm B) with 95% CI for TTME will be obtained from a 
Cox proportional hazard (PH) model stratified by region with, etiology, extrahepatic 
disease, vascular invasion, ECOG performance status and AFP level as covariates in the 
model in the ITT population.  


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• 
In order to take the delayed effect into account, the model will allow for a time 
dependent treatment effect which will take the form of a binary time indicator (≤ 6 
months and > 6 months). An interaction test will be conducted to assess the 
statistical significance of the time dependent effect.  
Sensitivity Analysis 
• 
An unstratified re-randomization test will be performed for TTME to assess the 
robustness of the results. This test will utilize the unstratified log-rank statistic.  
• 
Hazard ratios (HR), together with associated 95% CI, resulting from an unstratified 
Cox model but with region and the remaining minimization factors included in the 
model as covariates will also be presented in the ITT population. 
• 
Analysis for TTME will be repeated by excluding patients with two consecutive 
missing AFP values before cut-off date in ITT population. 
 
8.8.2 Secondary Efficacy Endpoints and Analyses 
Secondary efficacy endpoint analyses include overall survival (OS) analysis, progression free 
survival analysis (PFS).  
 
8.8.2.1 
Overall Survival Analysis (OS)  
Overall survival between Arm A (Pexa-Vec followed by sorafenib) and Arm B (sorafenib) will 
be compared using a stratified re-randomization test.  This test will utilize the stratified 
log-rank statistic stratified by region. 
Overall survival will be presented descriptively for each treatment arm using a Kaplan-
Meier curve.  Summary statistics from the Kaplan-Meier distribution will be determined, 
including median overall survival and 25% and 75% quartiles with corresponding 95% 
CIs.  The proportions of patients alive at 6, 9, 12, 18, and 24 months, along with 
corresponding 95% CIs, will also be provided by treatment arm in the ITT population. 
Numbers of patients at risk will also be displayed at monthly intervals below the time axis 
for each of the two treatment groups and censored observations will be marked by 
notches on the curves 
 


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Handling of Missing Values/Censoring/Discontinuations 
The survival status of all patients will be determined at the cut-off date.  Patients without 
a known date of death on or before the cut-off date will be censored at the date of their 
last contact. 
 If a patient withdraws early, overall survival will not be censored at the date of withdrawal 
unless this is the date they were last known to be alive.   
The number of overall survival observations that are censored will be summarized by 
treatment arm, according to the reason for censoring.  
 
Supportive Analysis 
Estimates of the HRs (Arm A over Arm B) with 95% CI will be obtained from a Cox 
proportional hazard (PH) model stratified by region with, etiology, extrahepatic 
disease, vascular invasion, ECOG performance status and AFP level as covariates in 
the model in the ITT population.  
 
Sensitivity Analysis 
• 
An unstratified re-randomization test will be performed to assess the robustness of 
the results. This test will utilize the unstratified log-rank statistic. 
• 
Hazard ratios (HR), together with associated 95% CI, resulting from an unstratified 
Cox model but with region and the remaining minimization factors included in the 
model as covariates will also be presented in the ITT population. 
 
8.8.2.2 
Progression Free Survival (PFS) 
PFS is defined as the time from randomization to the date of first documented 
radiographic tumor progression or death due to any cause, whichever occurs first.  If a 
patient has not had a PFS event at the cut-off date for analysis, PFS will be censored at 
the date of last evaluable tumor assessment before the cut-off.  If a PFS event is observed 
after 2 or more missing or non-evaluable tumor assessments, then the date of 
progression will be censored at the latest occurring evaluable tumor assessments; for a 
progression observed after a single missing or non-evaluable tumor assessment, the 
actual date of disease progression will be used. 
A re-randomization test using stratified log rank test stratified by region will be performed 


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to compare the 2 treatment arms.  Estimates of the HRs (Arm A over Arm B) with 95% CI 
will be obtained from a PH model stratified by region with other minimization factors as 
covariates will also be presented. 
PFS will be presented descriptively for each treatment arm separately using Kaplan-Meier 
curves.  Summary statistics from the Kaplan-Meier distributions will be determined, 
including median PFS and 25% and 75% quartiles with corresponding 95% CIs.  The 
proportions of patients remaining progression free at 3, 6, 9, 12, 18 and 24 months, along 
with 95% CIs will also be provided by treatment arm. 
 
Sensitivity Analyses 
• 
An unstratified re-randomization test will be performed to assess the robustness of 
the results. This test will utilize the unstratified log-rank statistic. Hazard ratios (HR), 
together with associated 95% CI, resulting from an unstratified Cox model but with 
region and the remaining minimization factors included in the model as covariates 
will also be presented in the ITT population. 
• 
Analyses will be repeated in the same way except that PFS will not be censored if a 
progression is observed after 2 or more missing or non-evaluable tumor 
assessments. 
 
 
 
8.8.3 Exploratory Efficacy Endpoints and Analyses 
Analyses performed based on central assessments using mRECIST for HCC will be 
repeated using RECIST 1.1 based on both local and central assessments in the ITT 
population.  
 
8.8.3.1 
Time to Initial Response 
The Time to Initial Response (TIR) is defined as the time from randomization until the first 
documented response (CR or PR).  Patients who did not achieve a response will be 
censored at last adequate tumor assessment date otherwise. 
TIR will be summarized by treatment arm.  A Kaplan-Meier curve will be constructed for 
each treatment arm.  Median TIR and 25% and 75% quartiles will be presented along 
with 95% CIs for each treatment arm.  In addition, the Kaplan-Meier estimates with 95% 


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confidence intervals at 3, 6, 9 and 12 months will be presented by treatment arm. Number 
of patients at risk will also be displayed at monthly intervals below the time axis for each 
of the two treatment groups and censored observations will be marked by notches on the 
curves. 
 
8.8.3.2 
Time to Symptomatic Progression (TSP) 
Time to Symptomatic Progression (TSP) is defined as the time from randomization until 
the first documented event of symptomatic progression denoted as a decrease of 4 points 
or more from baseline in the Functional Assessment of Cancer Therapy (FACT) 
Hepatobiliary Symptom Index 8 (FHSI-8) questionnaire or a decrease in ECOG 
performance status to 4, or death.  If a patient has not had a TSP event at the cut-off date 
for analysis, TSP will be censored at the date of last evaluable tumor assessment before 
the cut-off.  If a progression is observed after 2 or more missing or non-evaluable FHSI-
8 or ECOG assessments, then the date of progression will be censored at the latest 
occurring FHSI-8 or ECOG assessment before missing; for a progression observed after 
a single missing or non-evaluable FHSI-8 or ECOG assessment, the actual date of 
symptomatic progression will be used. 
TSP will be presented descriptively for each treatment arm separately using Kaplan-Meier 
curves.  Summary statistics from the Kaplan-Meier distributions will be determined, 
including median TSP and 25% and 75% quartiles with corresponding 95% CIs.  The 
proportions of patients remaining progression free at 3, 6 and 9 months along with 95% 
CIs will also be provided by treatment arm. 
 
8.8.3.3 
Duration of Response (DoR) 
Duration of Response (DoR) applies only to patients whose best overall response is CR 
or PR.  The DoR is defined as the time (in months) from the first AFP decrease to disease 
progression (per mRECISIT/RECSIT1.1 or AFP increase>400 ng/mL) or death due to 
underlying cancer.  If a patient is alive or if the cancer has not progressed at the cut-off 
date for analysis, DoR will be censored at the date of last evaluable tumor assessment 
before the cut-off. 
If a progression is observed after 2 or more missing or non-evaluable tumor assessments, 
then the date of progression will be censored at the latest occurring evaluable tumor 
assessment before missing assessments; for a progression observed after a single 


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missing or non-evaluable tumor assessment, the actual date of disease progression will 
be used. 
DoR will be summarized by treatment arm.  A Kaplan-Meier curve will be constructed for 
each treatment arm.  Median DoR and 25% and 75% quartiles will be presented along 
with 95% CIs for each treatment arm.  In addition, the Kaplan-Meier estimates with 95% 
CIs at 3, 6, and 9 months will be presented by treatment arm. Numbers of patients at risk 
will also be displayed at monthly intervals below the time axis for each of the two treatment 
groups and censored observations will be marked by notches on the curves. 
 
8.8.3.4 
Tumor Size Over Time 
Tumor size is defined as the sum of the longest diameters (SLD), calculated by the sum 
of the longest diameters (LDs) of viable enhancing hepatic target tumors plus LDs of any 
non-nodal extrahepatic target tumors plus the short axis diameters of any nodal target 
tumors. For each time point, SLD will be calculated along with the relative change from 
baseline.  
A repeated measurements analysis model (implemented via SAS PROC MIXED), that 
includes terms of treatment arm, baseline stratification factors, baseline value and visit 
(as a factor) as fixed effect, with a general (unstructured) residual variance-covariance 
matrix, will be used to compare the 2 treatment arms with respect to changes in the tumor 
size longitudinally over time. Treatment*visit interaction will be used to investigate the 
possibility of time-dependent treatment effect. A heterogeneous order-1 autoregressive 
variance-covariance structure will be used in case of problems of convergence of the 
model with a general structure.  Means estimated by the model (with 95% CI associated) 
at each visit will be summarized for each treatment arm. In case of interaction 
Treatment*Visit is significant, Tukey post-hoc tests, to adjust for p-values and confidence 
intervals for visit comparisons to baseline, will be performed to compare the 2 arms at a 
given visit. 
Waterfall plots will be given per treatment arm.  These plots will display the best 
percentage change from baseline in the sum of the longest diameter of target tumors for 
each patient. 
8.8.3.5 
 Efficacy in Subgroups of Patients   
The purpose of these subgroup efficacy analyses is to assess the consistency of 


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treatment effect across potential or expected prognostic factors. If there are too few 
events for a meaningful analysis of a particular subgroup (i.e., less than 10 events in a 
subgroup), the relationship between that subgroup and endpoint will not be analyzed and 
descriptive summaries will be provided instead. 
The homogeneity of the treatment effect for Pexa-Vec will be evaluated in subgroups of 
patients (if the number of patients is sufficient, see above) according to the following 
criteria: 
Baseline categorical variables: 
• 
Region (Asia or non-Asia), 
• 
Countries, 
• 
Main etiology, 
• 
Presence of extrahepatic disease,  
• 
Performance Status (PS) on ECOG scale (0, 1), 
• 
AFP levels (<200 or ≥200 ng/mL, <400 or ≥400 ng/mL), 
• 
Gender, 
• 
Macroscopic vascular invasion, 
• 
Cirrhosis, 
• 
BCLC stage (B or C), 
• 
Child Pugh (A5 or A6), 
• 
Prior therapy of HCC, 
• 
Histological grade. 
 
Post-Baseline categorical variables: 
• 
Whether subject received anti-cancer therapy after last dose of study medication 
(based on those therapies recorded on the survival follow-up CRF) (Yes or No)  
• 
Type of anti-cancer therapy type received after discontinuation of study treatment 
(top 3 types) 
• 
Number of Pexa-Vec doses received (1, 2 or 3) 
• 
Exposure duration of Sorafenib (quartiles) 


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• 
Treatment compliance to Sorafenib (<80%, 80 to <100%, >=100%). 
 
Continuous baseline variables: 
• 
Age, 
• 
Baseline SLD, 
• 
AFP, 
• 
Time since initial diagnosis. 
 
For continuous variables, subgroups will be defined using quartiles (Q1, Median or Q3) 
calculated using baseline values measured in all randomized patients. 
In these subgroups, TTP and TTME will be analyzed using a Cox PH model (stratified by 
Region, except when looking at the factors for Region and for country) including only the 
treatment term as an independent variable.  In addition, a forest plot presenting HR (with 
95% CI) will be provided for each subgroup. For each of the factors listed above, a p-
value for interaction will be obtained from the stratified Cox PH model (stratified by 
Region, except when looking at the factors for Region and for country) by including terms 
for treatment, factor and treatment by factor interaction. These p-values for interaction will 
be displayed on the Forest plot. 
Subgroup analysis will be performed for ORR and DCR using Cochran-Mantel-Haenszel 
test (stratified by Region, except when looking at the factors for Region and for country) 
including only the treatment term as an independent variable to compare the 2 treatment 
arms at a 1-sided 2.5% level of significance. In addition, a forest plot presenting difference 
in rates (with 95% CI) will be provided for each subgroup.  
Subgroups based on compliance and exposure will be summarized for the corresponding 
treatment group only. 
Subgroup analyses will be performed in both ITT and PP population. 
 
8.8.3.6 
Efficacy with Other Date of Introduction as a Reference 
Efficacy of Pexa-Vec will be evaluated with respect to TTP and TTME by reference to the 
date of introduction of sorafenib (instead of the date of randomization). Patients who did 


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not receive sorafenib will be excluded from the analysis.   
Efficacy of Pexa-Vec respect to TTP and TTME will also be evaluated by reference to the 
date of introduction of subsequent anti-cancer treatment (instead of the date of 
randomization) in the same way as specified above. Subjects with events occurring prior 
to induction of subsequent anti-cancer therapy will be excluded from the analysis 
A Kaplan-Meier curve will be constructed for each treatment arm.  Median TTP and TTME 
and 25% and 75% quartiles will be presented along with 95% CIs for each treatment arm.  
In addition, the Kaplan-Meier estimates with 95% CIs at 3, 6, 9 and 12 months will be 
presented by treatment arm. Numbers of patients at risk will also be displayed at monthly 
intervals below the time axis for each of the two treatment groups and censored 
observations will be marked by notches on the curves. 
Analysis will also be conducted in PP population.  
 
8.8.3.7 
Efficacy with Respect to Objective Response 
Efficacy of Pexa-Vec will be evaluated with respect to TTP and TTME in patients 
subdivided according to the presence or not of an objective response (CR or PR at 3 
months 
Estimates of the HRs (Arm A over Arm B) with 95% CI will be obtained from a Cox 
Proportional Hazard (PH) model stratified by region and according to objective response 
(CR or PR) at 3 months.  
Analysis will also be conducted in PP population.  
8.8.3.8 
Clinical and Efficacy Laboratory Evaluations 
Clinical laboratory parameters include AFP and CD4/CD8 counts. 
In addition, during the study, samples will be archived to further assess immune 
parameters and identify potential biomarkers or biomarker ‘profiles’ of patient populations 
most likely to benefit from treatment with Pexa-Vec. 
Relationship between Pexa-Vec efficacy and clinical laboratory parameters at single time 
points and over time will be described. 
These analyses will include but will not be restricted to: 


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• 
The investigation of the correlation between parameters at baseline 
• 
The correlation of each baseline or post baseline value with clinical endpoint 
• 
Descriptive changes of parameters from baseline to post treatment 
• 
Correlation of the change from baseline with clinical endpoint 
8.9 Analysis of Safety 
Safety analyses will be based on the safety population.  The safety summary tables will 
include all safety assessments collected from the first administration of any study 
treatment up to 28 days after end date of any study treatment.  All safety data will be 
listed and those collected later than 28 days after end date of study treatment will be 
flagged in the listings.  
8.9.1 Adverse Events 
All AE tables will be presented with number and percentage of patients and number of 
events for each treatment arm.  The percentage of patients will be based on all treated 
patients within the treatment arm.  The numbers on which the percentages are based will 
be indicated in the headings of the columns. 
Data will be presented by SOC and PT using MedDRA.  MedDRA SOC and PT terms 
within system organ class will be sorted by descending frequency in the overall group.  
PTs or SOCs with the same frequency will be sorted alphabetically. 
The CTCAE grades will always be displayed in the sequence: Total, Grade 1 (Mild), 
Grade 2 (Moderate), Grade 3 (Severe), Grade 4 (Life-threatening) and Grade 5 (Death). 
A patient with multiple occurrences of an AE will be counted only once in the AE category. 
A summary of treatment-emergent adverse events will be provided by treatment arm 
including the number (and percentage) of patients with: 
• 
At least one AE, AE related to Pexa-Vec only, AE related to sorafenib only, AE 
related to both sorafenib and Pexa-Vec, AE related to Pexa-Vec (no matter if related 
to sorafenib) or AE related to sorafenib (no matter if related to Pexa-Vec) 
• 
At least one SAE, SAE related to Pexa-Vec only, SAE related to sorafenib only, SAE 
related to both sorafenib and Pexa-Vec, SAE related to Pexa-Vec (no matter if 
related to sorafenib), SAE related to sorafenib (no matter if related to Pexa-Vec) 
• 
At least one AE leading to discontinuation 


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All AEs, AEs leading to discontinuation of study treatment (overall and by component: 
Pexa-Vec or sorafenib), serious AEs (SAE) will be listed and summarized by SOC and 
PT, intensity (based on the NCI CTCAE v4.03), relationship to study treatment (Pexa-Vec 
only, sorafenib only, at least to Pexa-Vec or at least to sorafenib), relationship to IT 
procedure (intratumoral administration of Pexa-Vec) and treatment arm.  In patients with 
multiple occurrences of the same AE, the AE with the maximum grade will be presented 
in table.   An additional table will be presented for AEs leading to dose modification of 
sorafenib. 
Written narratives will be produced for all SAEs and pregnancies and unexpected or other 
important AEs that are judged to be of special interest because of their clinical importance.  
For example, any problem during the pregnancy and/or its outcome should be reported 
as an AE or a SAE. Spontaneous or induced abortions as well as ectopic pregnancy 
should be considered as serious. Any problem concerning the newborn should also be 
reported as an AE or SAE.  
SAEs occurring after signing the Inform Consent Form (ICF) but before starting study 
treatment, including those observed in patients randomized but never treated with the 
Investigational Medicinal Product (IMP), will be listed separately from those occurring 
after treatment start.  
Individual AE listings will be provided including patient identifiers, all data given on the AE 
CRF page (including the verbatim term), MedDRA system organ class, MedDRA 
preferred term, duration of AE (stop date -  start date + 1, or ongoing) and the study day 
of AE start (start date – day 1 date + 1).  Listings for AEs will be sorted by treatment 
group, patient identifier, start date and preferred term.  
 
8.9.2 Deaths 
AEs leading to death will be listed and summarized by System Organ Class (SOC), 
Preferred Term (PT), and treatment arm, relationship to study treatment (Pexa-Vec or 
sorafenib) and relationship to procedure (IT administration of Pexa-Vec). 
A summary of AEs leading to death will be provided by treatment arm including the 
number (and percentage) of patients with: 


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• 
At least one AE leading to death, AE leading to death related to Pexa-Vec only, AE 
leading to death related to sorafenib only, AE leading to death related to both 
sorafenib and Pexa-Vec, AE leading to death related to Pexa-Vec (no matter if 
related to sorafenib), AE leading to death related to sorafenib (no matter if related to 
Pexa-Vec) 
A listing will also be provided.  
 
8.9.3 Laboratory Abnormalities 
The summaries will include all laboratory assessments collected from the first 
administration of any study treatment and no later than 28 days after end date of study 
treatment.  All laboratory assessments will be listed and those collected later than 28 days 
after end date of study treatment will be flagged in the listings. 
All laboratory values will be converted into SI units and when applicable, the severity 
grade calculated using appropriate common terminology criteria for AEs (CTCAE, version 
4.03).  A severity grade of 0 will be assigned when the value is within normal limits. 
A listing of laboratory values will be provided by laboratory parameter, patient and 
treatment arm.  A separate listing will display notable laboratory abnormalities (i.e., newly 
occurring CTCAE Grade 3 or Grade 4 laboratory toxicities).  The frequency of laboratory 
abnormalities will be displayed by parameter and treatment arm using the following 
summaries: 
• 
A Shift table using CTCAE grades to compare baseline to the worst post-baseline 
value will be produced for hematology and biochemistry laboratory parameters with 
CTCAE grades.  Note that for parameters with 2 directions abnormalities 
(hypo/hyper), both will be presented. 
 
8.9.4 Other Laboratory Data 
Other laboratory data (e.g., vital signs, ECG, ECOG, AFP, CD4/CD8 count) will be listed 
and summarized using descriptive statistics by visit.  Change from baseline will also be 
included in the descriptive statistics summary.  In addition, shift tables from baseline to 
subsequent visits will be presented for ECG, ECOG. 
Vital sign assessments are performed in order to characterize basic body function.  The 
parameters collected in this study are:  height (cm), weight (kg), heart rate (beats per 


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minute) and systolic (SBP) and diastolic blood pressure (DBP) (mmHg). 
Proportion of patients who have SBP drop below 90, 80, 70, and 60 mmHg after IT 
session will be summarized at each visit and during the study.   
Proportion of patients who have fever peak above 38°C and 39°C after IT session will be 
summarized at each visit and during the study.  Time to fever and duration of fever above 
38°C and 39°C after each IT session will be summarized using descriptive statistics.  The 
fever will be categorized into 4 categories; 
o Grade 1: >38°C - <=39°C  
o Grade 2:  >39°C - <=40°C 
o Grade 3: >40°C for under 24 hours 
o Grade 4: >40°C for over 24 hours 
The frequency of fever grade after IT section will be summarized at each visit and during 
the study. 
 
8.10 Analysis of Quality of Life 
Quality of life (QoL) will be analyzed in the ITT population. 
 
8.10.1 Questionnaires 
QoL will be measured using the validated questionnaires, FACT-Hep and EQ5D-3L 
(Herdman 2011; Scalone 2013), to evaluate differences in patient-reported outcomes 
between the 2 treatment arms.  
Patients will complete the FACT-Hep, a 45-item questionnaire designed to measure 
Health-Related Quality of Life (HRQoL) in patients with HCC.  The FACT-Hep consists of 
27-item FACT-General (FACT-G), which assesses generic HRQoL concerns using 
4 subscales (physical, social/family, emotional, functional wellbeing), and the 18-item 
hepatobiliary subscale, which evaluates specific symptoms of hepatobiliary cancer and 
side effects of treatment. 
Patient utility will be assessed with the EQ5D-3L questionnaire. 
The EQ5D-3L is composed of a descriptive system (5 domains) and a visual analog scale 


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(VAS). The 5 domains consist of anxiety/depression, self-care, mobility, pain/discomfort 
and usual activities.  Each domain has 3 levels of response; no problem (coded as 1), 
some problems (coded as 2) and extreme problems (coded as 3).  The VAS measures a 
person’s self-rated health ranging from 0 (worst state of health imaginable) to 100 (best 
state of health imaginable). A health state is defined in terms of a 5-digit code.  Health 
state code 22113, for example, would translate to some problems with mobility and self-
care, no problems with performing usual activities.  EQ5D-3L health states may be 
converted to a single index (known as a utility) by applying values (weights) to each level 
in each dimension.  The utility is estimated by subtracting the suitable weight from 1, the 
value for full health (e.g. 11111).    
 
8.10.2 Statistical Methods 
The number of patients with QoL data and the number of patients missing or expected to 
have QoL assessments will be summarized by each treatment arm for scheduled 
assessment time points. 
Descriptive statistics will be used to summarize the individual item domains (EQ5D-3L) 
and sub-scale scores (FACT-Hep) of QoL data at each scheduled assessment time point.  
Patients will be included if they completed at least one questionnaire item at each 
scheduled assessment time point.  Individual item domains (EQ5D-3L) and of sub-scale 
scores (FACT-Hep) will be presented in listings. 


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9. CHANGE IN PLANNED ANALYSIS 
The study was terminated early due to futility, and thus the plan for final analysis requires 
adjustment. Per Orphan Drug Approval Letter from the Office of Orphan Products 
Development/FDA (Designation #13-3942) dated 2013-May-06, the final analysis will be 
planned to appropriately evaluate the benefit-risk for the treatment of patients with HCC. 
The primary and secondary objectives will be replaced by endpoints supporting orphan 
drug approval as detailed in section 3. 


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10. REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur 
J Cancer. 2009;45:228–47. 
Forner A, Ayuso C, Varela M, Rimola J, Hessheimer AJ, de Lope CR, et al. Evaluation of 
tumor response after locoregional therapies in hepatocellular carcinoma: are response 
evaluation criteria in solid tumors reliable? Cancer 2009;115:616–23. 
Gordon LKK and DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70:659–63. 
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20:1727–3. 
Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu A, et al. Design and 
endpoints of clinical trials in hepatocellular carcinoma. JNCI 2008;100:698–711. 
O'Brien PC and Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 
1979;35:549–56. 
Pocock SJ and Simon R. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics. 1975;31:103–15. 
Scalone L, Ciampichini R, Fagiuoli S, Gardini I, Fusco F, Gaeta L, et al. Comparing the 
performance of the standard EQ-5D 3L with the new version EQ-5D 5L in patients with 
chronic hepatic diseases. Qual Life Res. 2013;22:1707–16. 
Yan X and Su XG. Stratified Wilson and Newcombe Confidence Intervals for Multiple 
Binomial Proportions. Stat Biopharm Res 2010;2;329–35. 


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11. APPENDICES 
 
11.1 Tumor Response Evaluation by mRECIST 
To assess tumor response, the sum of the longest diameters for all target lesions will be 
calculated at baseline and throughout the study.  At each assessment, response is 
evaluated first separately for the target lesions and non-target lesions identified at 
baseline.  These evaluations are then used to calculate the overall lesion response 
considering the target and non-target lesions as well as the presence or absence of new 
lesions. 
 
11.1.1 Target Tumors 
Target tumors show a well delineated area of viable (contrast enhancement in the arterial 
phase) tumor that is at least 1 cm in LD.  Target tumors should be selected on the basis 
of their size (tumors with the LD which are able to be reproducibly measured across time 
points) and are preferred to be within the liver for mRECIST for HCC.  However, target 
tumors may be selected outside of the liver if they meet criteria established by mRECIST 
for HCC for target tumors.  When extrahepatic target tumors are selected, the contrast-
enhancement characteristics are not taken into account and only LD of the tumor is 
measured.  Up to a maximum of 10 tumors, and a maximum of 5 tumors per organ, 
representative of all involved organs will be identified as target tumors by the IER, and 
will be recorded and measured at baseline by the site reader. 
All post-baseline measurements must be performed using the same tumors and methods 
as the baseline assessment. 
Response assessments for target tumors are defined as: 
• 
Complete Response (CR):  Disappearance of all IT arterial-enhancement in all 
Target tumors and the disappearance of all non-enhancing Target tumors. 
• 
Partial Response (PR):  At least 30% decrease in the SLD of Target tumors, taking 
as reference the baseline SLD of Target tumors. 
• 
Progressive Disease (PD):  Radiographic tumor progression for target tumors 
requires an increase in the SLD of target tumors of at least 20% taking as reference 
the smallest sum of diameters of target tumors recorded since the treatment started 
(this includes the baseline sum if that is the smallest on study).   


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• 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for partial response, nor 
sufficient increase to qualify for progressive disease, taking as reference the 
smallest SLD while on study (including Baseline). Contingent upon minimum 
duration of 6 weeks from enrollment. 
• 
Non-Evaluable (NE):  The Reviewer is not able to evaluate Target tumors due to 
inadequate imaging technique or inadequate coverage. Rules for selecting non-
evaluable include the following: 
1. All Target tumors are not evaluable.  
2. Or, if at least 1 Target tumor is not evaluable, the Target tumor SLD is still 
calculated using the remaining evaluable/measureable Target tumors.  The only 
acceptable assessment in this situation is progressive disease or non-evaluable.  
If the SLD of Target tumors has increased at least 20% from nadir or the IPTP 
(depending on the situation) then the response is progressive disease.  Any other 
calculated result gives an assessment of non-evaluable. 
NOTE: SLD = sum of the LDs of viable enhancing hepatic target tumors plus LDs of any non-
nodal extrahepatic target tumors plus the short axis diameters of any nodal target 
tumors) will be calculated. 
 
11.1.2 Non-Target Tumors 
Tumors with the following characteristics are defined as Non-Target Tumors by mRECIST 
for HCC:  Infiltrative-type HCC (with ill-defined borders which are not suitable for accurate 
and repeat measurements) and tumors that are <1 cm in LD.   
All other tumors (or sites of disease) including pathological lymph nodes should be 
identified as non-target tumors and should also be recorded at baseline.  Measurements 
are not required, and these tumors should be followed as ‘present’, ‘absent’, or in rare 
cases ‘unequivocal progression’. 
Furthermore, for the purposes of this trial, special assessments are recommended for the 
following: 
Malignant portal vein thrombosis should be considered a non-measurable tumor due to 
the difficulty of performing reliable repeat measurements of a malignant thrombus. 
Porta hepatis lymph node can be considered as malignant if the lymph node short axis is 
at least 20 mm.  


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Ascites, pleural effusion, and pericardial effusion:  these may not be used to assess 
response as non-target tumors, nor may they be selected as evidence of new disease as 
radiographic progression.  They may not be used due to the incidence of therapeutic fluid 
removal and benign occurrence of these fluid collections which makes them unreliable as 
a marker of disease evolution. 
Response assessments for non-target tumors are defined as: 
• 
Complete Response (CR):  Disappearance of all non-target tumors. 
• 
Stable Disease (SD):  Persistence of 1 or more non-target tumors or IT arterial 
enhancement in non-target tumors. 
• 
Progressive Disease (PD):  Unequivocal progression of existing non-target tumors 
or the appearance of one or more new tumors (see below) is also considered 
progression.   
• 
Non-Evaluable (NE):  Reviewer is not able to evaluate non-target tumors due to 
inadequate imaging technique or inadequate coverage. 
 
Rules for selecting non-evaluable for non-target tumors include the following: 
1. 
All non-target tumors are not evaluable. 
2. 
Or, if at least 1 non-target tumor is not evaluable and no other non-target tumor 
demonstrates unequivocal progression, the assessment is “NE” 
3. 
If at least 1 non-target tumor is not evaluable and at least 1 other non-target tumor 
demonstrates 
unequivocal 
progression, 
the 
assessment 
is 
“unequivocal 
progression.” 
 
11.1.3 New Tumors 
New tumors in the liver are defined as being undetectable at Baseline, and subsequently 
becoming evident and having characteristic vascular features of HCC: arterial 
hypervascularization with washout in the portal venous, or the late phase of dynamic 
contrast imaging, if available.  
New tumors outside the liver are defined as being undetectable at baseline and are 
subsequently clearly tumor.  


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New Tumor Progressive Disease (PD): 
• 
Intrahepatic 
 
To qualify for immediate tumor progression at the present time point (images should be 
sent for immediate independent confirmation of progression): 
The new tumor must be ≥1 cm AND meet all of the following characteristics: 
1. 
Hypervascular in the arterial phase 
2. 
Area of arterial enhancement is 1 cm or larger 
3. 
Demonstrates washout in portal- or late venous phase 
 
Tumors that do not meet the criteria above can qualify for progression if: 
The new tumor is ≥1 cm AND the grows at least 1 cm on the next sequential scan (images 
would be sent at this second time point for independent confirmation of progression) 
• 
Extrahepatic 
If a newly detected lesion is obviously a tumor, progression criteria is met at the current 
time point (images should be sent for immediate independent confirmation of 
progression). 
The evaluation of overall response at each assessment is a composite of the target 
lesions response, non-target lesions response and presence of new lesions as shown in 
Table 2. 
 
Table 2:  
Overall Response Assessment in mRECIST; Responses for All Possible 
Combinations of Tumor Responses in Target and Non-target Lesions with or 
without the Appearance of New Lesions 
Target Tumors 
Non-target Tumors 
New Tumors 
Time Point 
Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
CR 
Not evaluated (NE) 
No 
PR 


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Target Tumors 
Non-target Tumors 
New Tumors 
Time Point 
Response 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
NE 
Non-PD or NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
11.2 Tumor Response Evaluation by RECIST 1.1 
11.2.1 Measurability of Tumor 
All measurements should be recorded in metric notation (mm).  At baseline, tumor 
lesions/lymph nodes will be categorized as measurable or non-measurable.  Lymph 
nodes that have a short axis <10 mm at baseline are considered non-pathological and 
should not be recorded or followed.  If no measurable lesions are identified at baseline, 
the patient will not be allowed to enter the study. 
For tumor lesions:  the longest diameter in the plane of measurement has to be recorded 
with a minimum size of 10 mm by CT scan when CT scan slice thickness is no greater 
than 5 mm. 
For nodal lesions:  at baseline and in the follow-up, only the short axis of lymph node 
will be measured and followed.  To be considered pathologically enlarged and 
measurable, a lymph node must be >15 mm in short axis when assessed at baseline. 
Non measurable lesions are defined as all other lesions present at baseline, including 
small lesions (longest diameter <10 mm or pathological lymph node with ≥10 mm to 
<15 mm short axis) as well as truly non measurable lesions. 
 
11.2.2 Target / Non Target Tumors 
Each lesion reported must be uniquely and sequentially numbered on the eCRF, even if 
it resides in the same organ, from baseline and throughout the study.  For the evaluation 
of lesions at baseline and throughout the study, the lesions are classified as target and 
non-target lesions. 


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11.2.3 Target Tumors 
Target tumors should be selected based on their size (tumors with the LD which are able 
to be reproducibly measured across time points) and are preferred to be within the liver.  
However, target tumors may be selected outside of the liver.  Up to a maximum of 5 
tumors, and a maximum of 2 tumors per organ (except for the liver where 5 tumors can 
be selected as non-target for the purpose of this trial), representative of all involved 
organs will be identified as target tumors and will be recorded and measured at baseline 
by the site reader. 
Selection of tumors outside the liver is patient to Sponsor’s approval. 
All post-baseline measurements must be performed using the same tumors and methods 
as the baseline assessment. 
Response assessments for target tumors are defined as: 
• 
Complete Response (CR): Disappearance of all target tumors. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
• 
Partial Response (PR): At least 30% decrease in the SLD of target tumors, taking 
as reference the baseline SLD of target tumors. 
• 
Progressive Disease (PD): Radiographic tumor progression for target tumors 
requires an increase in the SLD of target tumors of at least 20% taking as reference 
the smallest sum of diameters of target tumors recorded since the treatment started 
(this includes the baseline sum if that is the smallest on study).  
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for partial response, nor 
sufficient increase to qualify for progressive disease, taking as reference the 
smallest SLD while on study (including baseline). Contingent upon minimum 
duration of 6 weeks from enrollment. 
• 
Non-Evaluable (NE): Progression has not been documented and one or more target 
lesions have not been assessed or have been assessed using a different method 
than baseline. Rules for selecting non-evaluable include the following: 
1. 
All target tumors are not evaluable.  
2. 
Or, if at least 1 target tumor is not evaluable, the target tumor SLD is still 


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calculated using the remaining evaluable/measureable target tumors. The only 
acceptable assessment in this situation is progressive disease or non-
evaluable. If the SLD of target tumor has increased at least 20% from nadir 
(including baseline if it is the nadir) then the response is progressive disease. 
Any other calculated result gives an assessment of non-evaluable. 
NOTE: 
SLD = sum of the LDs of viable enhancing hepatic target tumors plus LDs of any non-
nodal extrahepatic target tumors plus the short axis diameters of any nodal target 
tumors will be calculated. 
 
11.2.4 Non-Target Tumors 
All other lesions, including pathological lymph nodes, are considered non-target lesions.  
Measurements of these lesions are not required and these lesions should be followed as 
“present”, “absent”, “worsening” or in rare cases “unequivocal progression” (as defined in 
the below note) throughout the study.  Multiple non-target lesions involving the same 
organ can be assessed as a group and recorded as a single item (i.e., multiple enlarged 
pelvic lymph nodes).  Each non-target lesion identified at baseline should be assessed at 
each subsequent evaluation and be recorded in the eCRF.  
Furthermore, for the purposes of this trial, special assessments are recommended for the 
following: 
Malignant portal vein thrombosis should be considered a non-measurable tumor due to 
the difficulty of performing reliable repeat measurements of a malignant thrombus. 
Porta hepatis lymph node can be considered as malignant if the lymph node short axis is 
at least 20 mm.  
Ascites, pleural effusion, and pericardial effusion: these may not be used to assess 
response as non-target tumors, nor may they be selected as evidence of new disease as 
radiographic progression.  They may not be used due to the incidence of therapeutic fluid 
removal and benign occurrence of these fluid collections which makes them unreliable as 
a marker of disease evolution. 
Response assessments for non-target tumors are defined as: 
• 
Complete Response (CR): Disappearance of all non-target tumors. All lymph nodes 
must be non-pathological in size (<10 mm short axis). 
• 
Incomplete Response / Stable Disease (SD): Neither CR nor PD 


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• 
Progressive Disease (PD): Unequivocal progression of existing non-target tumors  
• 
Non-Evaluable (NE): Progression has not been documented and one or more 
non-target lesions have not been assessed or have been assessed using a different 
method than baseline not allowing a reliable comparison. Rules for selecting non-
evaluable for non-target tumors include the following: 
1. 
All non-target tumors are not evaluable. 
2. 
Or, if at least 1 non-target tumor is not evaluable and no other non-target tumor 
demonstrates unequivocal progression, the assessment is “NE” 
3. 
If at least 1 non-target tumor is not evaluable and at least 1 other non-target 
tumor demonstrates unequivocal progression, the assessment is “unequivocal 
progression.” 
NOTE:  
To achieve “unequivocal progression” on the basis of the non-target disease, there 
must be an overall level of substantially worsening in non-target disease such that, 
even in the presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy.  A “modest” increase in the 
size of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status.  The designation of progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease will therefore be 
extremely rare. 
 
11.2.5 New Tumors 
The appearance of new lesion is always associated with PD.  A lesion identified on a 
follow-up assessment in an anatomical location that was not scanned at baseline is also 
considered a new lesion.  If a new lesion is equivocal, for example because of its small 
size, continued therapy and follow-up evaluation will clarify if it represents truly new 
disease.  If at the next scheduled assessment, PD is confirmed, the date of progression 
would be the earlier date when PD was suspected. 
 
New Tumor Progressive Disease (PD): 
If a newly detected lesion is obviously a tumor, progression criteria is met at the current 
time point.  The evaluation of overall response at each assessment is a composite of the 
target lesions response, non-target lesions response and presence of new lesions as 
shown in Table 3. 


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Table 3:  
Overall Response Assessment in RECIST 1.1; Responses for All Possible 
Combinations of Tumor Responses in Target and Non-Target Lesions with or 
without the Appearance of New Lesions 
Target Tumors 
Non-target Tumors 
New 
Tumors 
Overall Reponses 
CR 
CR 
No 
CR1 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Non-PD or not all evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR1 
SD 
Non-PD or not all evaluated 
No 
SD1,2 
Not all 
evaluated 
Non-PD 
No 
NE1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, non-
evaluable 
1 
this overall lesion response also applies when there are no non-target lesions identified at baseline. 
2 
once confirmed PR is achieved, all these assessments are considered PR. 
If no non-target lesions are identified at baseline, the non-target lesion response at each 
assessment will be considered “not applicable” (NA). 
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of CR depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate / biopsy) to confirm CR.  It 
may be sometimes reasonable to incorporate Fluorodeoxyglucose Positron Emission 
Tomography (FDG-PET) scanning to complement CT in assessment of progression 
(especially in case of possible “new” lesion) or in case where a residual radiographic 
abnormality is thought to represent fibrosis or scarring. 
For equivocal findings of PD (e.g., very small and uncertain new lesions, cystic changes 
or necrosis in existing lesions) treatment may continue until the next scheduled 
assessment. 


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11.3  Re-randomization Algorithm  
11.3.1 Introduction  
The purpose of re-randomization is to minimize imbalance in the distribution of subjects 
in each treatment group within the level of prognostic factors. For each re-randomization, 
subjects will be reassigned to treatment groups Pexa-Vec followed by Sorafenib or 
Sorafenib using Pocock and Simon non-deterministic dynamic randomization algorithm, 
which has been used for subject randomization in the IRT system. Total 1000 
randomizations will be performed independently. For the quality control perspective, the 
random uniform numbers U are pre-specified. A permutation test will be performed for 
efficacy analysis based on the 1000 re-randomizations. For each re-randomization, a log-
rank test will be applied to compare the time to event of two treatment groups. Let 𝑇𝑇𝑖𝑖, 𝑖𝑖=
1, … ,1000 be the test statistics for 1000 re-randomizations, and 𝑇𝑇𝑜𝑜𝑜𝑜𝑜𝑜 be the test statistic 
base on the observed data. An identity function ϕ (∙) is defined as, 
𝜙𝜙 (𝑇𝑇𝑖𝑖) = ൜1  𝑖𝑖𝑖𝑖 𝑇𝑇𝑖𝑖≥𝑇𝑇𝑜𝑜𝑜𝑜𝑜𝑜
0  𝑖𝑖𝑓𝑓 𝑇𝑇𝑖𝑖< 𝑇𝑇𝑜𝑜𝑜𝑜𝑜𝑜 
The p-value of permutation test equals ∑
𝜙𝜙 (𝑇𝑇𝑖𝑖)
1000
𝑖𝑖=1
/1000. 
 
11.3.2 Dynamic Randomization Algorithm 
Each patient will be re-randomized to different treatment based on minimization factor, 
weight, degree of imbalance, total amount of imbalance, and choice of probability of 
assignment. 
11.3.2.1 Minimization Factor 
There are six minimization factors specified in protocol. The weight and level of each 
minimization factor are determined by SillaJen and listed in Table 4.  
Table 4 minimization factors Weight 
Minimization Factor 
Factor Description 
Minimization Factor Weight 
1 
Center 
1 
2 
Main Etiology 
2 
3 
Extrahepatic Disease 
2 
4 
Vascular Invasion 
2 
5 
ECOG Performance Status 
1 
6 
AFP Level 
1 


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11.3.2.2 Degree of Imbalance 
For each patient, the degree of imbalance  𝑑𝑑𝑖𝑖𝑖𝑖, 𝑖𝑖= 1, … ,6, 𝑎𝑎𝑎𝑎𝑎𝑎 𝑘𝑘= 1,2 for each treatment 
groups within each minimization factor is assessed using the range of patient counts 
across treatment groups within the new patient’s minimization factor level. For the i-th 
minimization factor, i = 1, 2, … , 6  , 
• 
𝑑𝑑𝑖𝑖1 = |𝑥𝑥𝑗𝑗𝑗𝑗1 + 1 −𝑥𝑥𝑗𝑗𝑗𝑗2| , for potential assignment to Pexa-Vec followed by Sorafenib 
• 
𝑑𝑑𝑖𝑖2 = |𝑥𝑥𝑗𝑗𝑗𝑗1 −𝑥𝑥𝑗𝑗𝑗𝑗2 + 1| , for potential assignment to Sorafenib 
Where 𝑥𝑥𝑗𝑗𝑗𝑗1 is the number of subjects with level 𝑗𝑗 of minimization factor 𝑖𝑖 who have been 
assigned to treatment Pexa-Vec followed by Sorafenib and 𝑥𝑥𝑗𝑗𝑗𝑗2 is the number of subjects 
with level 𝑗𝑗 of minimization factor 𝑖𝑖 who have been assigned to treatment Sorafenib. 
11.3.2.3 Total Amount of Imbalance 
For each possible treatment assignment, the resulting score of total amount of imbalance 
𝐺𝐺𝑘𝑘 is the summation of weighted degree of imbalance 𝑑𝑑𝑖𝑖𝑖𝑖,  
• 
𝐺𝐺𝑘𝑘= ∑
𝑤𝑤𝑖𝑖
6
𝑖𝑖=1
𝑑𝑑𝑖𝑖𝑖𝑖, 𝑘𝑘= 1, 2 
11.3.2.4 The Choices of Probability of Assignment 
The probability of assignment to treatment with lowest 𝐺𝐺𝑘𝑘 is 𝑝𝑝1, the probability to the other 
treatment is 𝑝𝑝2 = 1 −𝑝𝑝1. For SillaJen Hep024, we use fixed probability 0.6 for 𝑝𝑝1. In the 
event that the 𝐺𝐺𝑘𝑘 are tied, the probability of assignment to each treatment is 0.5. 
11.3.2.5 Assign Treatment 
A random number, U, is taken as the next number generated by the uniform random 
number generated in SAS.  
• If  𝑈𝑈≤𝑝𝑝1 then new patient is randomized to Pexa-Vec followed by Sorafenib 
• If 𝑈𝑈> 𝑝𝑝1and 𝑈𝑈≤1 then the new patient is randomized to Sorafenib 
 
 
 
11.3.3 Implement the Algorithm 
Step 1.  A dataset PARM will be created to include all the key information for the re-
randomization.  
Parameter 
Value 
Number of Iteration 
1000 


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Number of Treatment 
2 
Maximum Sample Size 
600 
Uniform Random Seed 
1000 of Uniform seeds 
Number of Minimization Factor 
6 
Weight of Minimization Factor 
1, 2, 2, 2, 1, 1 
Distance Function to Measure Imbalance 
Range 
Total Amount of Imbalance 
Weighted Sum 
Choice of Probability 
0.6 
Probability of Tie 
1/2 
 
Step 2.  Read in minimization factors data FACTOR from clinical database 
Step 3.   Read in uniform randomization numbers  
Step 3.  Use Macro to %RERANDOM to implement the re-randomization algorithm  
 
11.3.4 Output Result 
The %RERANDOM will generate 2 output datasets: TRACE, STATISTICS.  
TRACE:  contains all the detail information for each re-randomization output.  It contains 
the degree of imbalance minimization factor value, total amount of imbalance, choice of 
probability, and treatment assigned to subjects.  
STATISTICS: contains all the statistics value per each re-randomization and P-value of 
the permutation test based on the formula in section 11.3.1.