A Randomized, Double-blind, Phase 3 Efficacy Trial of PROSTVAC-V/F +/- GM-CSF in Men With Asymptomatic or Minimally Symptomatic Metastatic Castrate-Resistant Prostate Cancer
Phase: PHASE3
Conditions: Prostate Cancer Metastatic
Sponsor: Bavarian Nordic

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PROSTVAC-V/F 
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Protocol Title 
 
A Randomized, Double-blind, Phase 3 Efficacy Trial of 
PROSTVAC-V/F ± GM-CSF in Men With Asymptomatic or 
Minimally Symptomatic Metastatic, Castrate-Resistant 
Prostate Cancer 
Protocol Number  
BNIT-PRV-301 
IND No. / OBA Protocol Number  
BB-IND 13946 / #1104-1101 
NCT Number: 
NCT01322490 
EudraCT No. 
2010-021196-85 
Investigational Product 
PROSTVAC-V/F  
Sponsor  
 
Bavarian Nordic, Inc. 
CRO 
Medical Monitor 
Drug Safety 
Bavarian Nordic, Inc. 
Study Protocol 

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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 7 
1.0 
BACKGROUND AND RATIONALE ................................................................... 16 
1.1 
Rationale .................................................................................................. 16 
1.2 
Background .............................................................................................. 16 
1.3 
Placebo Rationale .................................................................................... 21 
1.4 
Summary of Findings from Human Clinical Studies ................................. 22 
1.5 
Safety of Poxviral Vectors ........................................................................ 24 
1.6 
Potential Benefits and Risks to Human Subjects ..................................... 27 
1.7 
Rationale for Double-Blinding .................................................................. 28 
2.0 
NAME AND DESCRIPTION OF STUDY AGENTS ............................................ 29 
2.1 
Formulation, Packaging, and Labeling ..................................................... 29 
2.2 
Investigational Drug Product (PROSTVAC-V/F) ...................................... 29 
2.3 
GM-CSF ................................................................................................... 30 
2.4 
PROSTVAC-V/F Placebo:  Empty fowlpox vector ................................... 31 
2.5 
GM-CSF Placebo ..................................................................................... 31 
3.0 
STUDY OBJECTIVES AND ENDPOINTS ......................................................... 32 
3.1 
Study Objectives ...................................................................................... 32 
3.2 
Study Endpoints ....................................................................................... 33 
4.0 
INVESTIGATIONAL PLAN ................................................................................ 34 
4.1 
Study Design ........................................................................................... 34 
4.2 
Sample Size ............................................................................................. 34 
4.3 
Selection of Study Population .................................................................. 34 
4.4 
Targeted Enrollment of Minorities ............................................................ 35 
4.5 
Method of Assigning Subjects to Treatment Groups ................................ 35 
4.6 
Inclusion Criteria ...................................................................................... 35 
4.7 
Exclusion Criteria ..................................................................................... 36 
5.0 
SAFETY MONITORING ..................................................................................... 38 
5.1 
Data Monitoring Committee (DMC) .......................................................... 38 
5.2 
Dose-limiting Toxicities and Trial Stopping Rules .................................... 38 
5.3 
Emergency Unblinding Of Treatment Assignment (If Applicable) ............ 39 
5.4 
Removal of Subjects from Therapy or Assessment ................................. 39 
5.5 
Replacement Policy ................................................................................. 40 

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6.0 
STUDY TREATMENTS ...................................................................................... 41 
6.1 
Investigational Study Drug Accountability ................................................ 41 
6.2 
Assessment of Study Drug Compliance................................................... 41 
6.3 
Disposal of Drug Supplies ........................................................................ 41 
6.4 
PROSTVAC-V/F ...................................................................................... 42 
6.5 
GM-CSF ................................................................................................... 42 
6.6 
Subject Instructions and Supplies ............................................................ 43 
6.7 
Dose Reductions and Contraindications for PROSTVAC-V/F ................. 43 
6.8 
Procedures for Potential Serious Vaccinia Reaction ................................ 43 
6.9 
Concomitant and Excluded Medications .................................................. 44 
6.10 
Overdose ................................................................................................. 44 
7.0 
STUDY PROCEDURES BY STUDY PERIOD ................................................... 45 
7.1 
Screening Assessments (Days –28 –1) ................................................... 45 
7.2 
Day 1 (Day of first dose of PROSTVAC-V/F or placebo), Week 1 ........... 46 
7.3 
Week 3 Through Week 21 (booster vaccinations) ................................... 47 
7.4 
End-of-Treatment Visit – Week 25 or When A Subject Discontinues 
Treatment ................................................................................................ 48 
7.5 
Assessments During Long-Term Follow-Up ............................................ 49 
7.6 
Safety Assessments ................................................................................ 50 
7.7 
Biological and Immune Response Assessments ..................................... 50 
7.8 
Laboratory Tests and Radiological Assessments .................................... 50 
8.0 
ADVERSE EVENTS ........................................................................................... 52 
8.1 
Investigator’s Responsibilities .................................................................. 52 
8.2 
Definition of Adverse Events (AE) ............................................................ 52 
8.3 
Definition of Expected and Unexpected Events ....................................... 53 
8.4 
Collecting and Recording Adverse Events ............................................... 54 
8.5 
Assessment of Relationship to Study Drug (Causality) ............................ 56 
8.6 
Severity of Adverse Events (Grading) ...................................................... 56 
8.7 
Dose Modifications for Toxicity ................................................................ 57 
8.8 
Definition of Serious Adverse Events ....................................................... 57 
8.9 
Definition of Unexpected Serious Adverse Events ................................... 58 
8.10 
Definition of Suspected Adverse Reaction ............................................... 58 
8.11 
Documenting and Reporting of Adverse Events and Serious Adverse 
Events ...................................................................................................... 59 
8.12 
Adverse Event Reporting Period .............................................................. 60 

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8.13 
Assessment of Adverse Events ............................................................... 60 
8.14 
Serious Adverse Events ........................................................................... 60 
8.15 
Treatment and Follow-up of Adverse Events or Serious Adverse 
Events ...................................................................................................... 61 
9.0 
STATISTICAL CONSIDERATIONS ................................................................... 62 
9.1 
Study Design ........................................................................................... 62 
9.2 
Randomization ......................................................................................... 62 
9.3 
Analysis Sets ........................................................................................... 62 
9.4 
Primary Efficacy Analysis ......................................................................... 63 
9.5 
Trial Size .................................................................................................. 63 
9.6 
Secondary Efficacy Endpoint ................................................................... 63 
9.7 
Safety Analyses ....................................................................................... 64 
9.8 
Interim Analyses ...................................................................................... 64 
10.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ................. 66 
10.1 
Regulatory and Ethical Compliance ......................................................... 66 
10.2 
Institutional Review Board (IRB), Research Ethics Board (REB), and 
Independent Ethics Committee (IEC) Approval ....................................... 66 
10.3 
Institutional Biosafety Committee (IBC) (where applicable) ..................... 66 
10.4 
Informed Consent .................................................................................... 67 
11.0 
CONTROL AND QUALITY ASSURANCE ......................................................... 68 
11.1 
Protected Subject Health Information Authorization ................................ 68 
11.2 
Study Files and Record Retention ........................................................... 68 
11.3 
Case Report Forms and Record Maintenance ......................................... 69 
11.4 
Study Monitoring/ Audit Requirements..................................................... 69 
11.5 
Investigator Responsibilities .................................................................... 70 
11.6 
Sponsor Responsibilities .......................................................................... 70 
11.7 
Financial Disclosure ................................................................................. 70 
11.8 
Liability and Clinical Trial Insurance ......................................................... 71 
11.9 
Protocol Amendments.............................................................................. 71 
12.0 
PUBLICATION OF STUDY RESULTS .............................................................. 72 
12.1 
Study Discontinuation .............................................................................. 72 
13.0 
REFERENCES ................................................................................................... 73 
14.0 
APPENDICES .................................................................................................... 80 
14.1 
Schedule of Events .................................................................................. 80 
14.2 
NIH RAC Appendix B (excerpt) ................................................................ 82 

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14.3 
Criteria of Progression for Trial Eligibility by PCWG2 (2007) ................... 83 
14.4 
ECOG Performance Status Criteria ......................................................... 84 
14.5 
NYHA Classification – The Stages of Heart Failure ................................. 85 
14.6 
NCI Common Terminology Criteria for Adverse Events (NCI CTCAE v 
4.0)........................................................................................................... 86 
14.7 
FACT-P Quality of Life Questionnaire ...................................................... 87 
14.8 
BPI-SF Quality of Life Questionnaire ....................................................... 90 
14.9 
EQ-5D-3L Quality of Life Questionnaire................................................... 92 
14.10 Vial and Carton Labels............................................................................. 94 
14.11 List of Research Centers ......................................................................... 97 
14.12 Rationale and Changes ........................................................................... 97 
 
LIST OF TABLES 
 
Table 9-1 
Adverse Event Grading Criteria ..................................................................56 
 
 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE(s) 
Adverse Event(s) 
ALT (SGPT) 
Alanine aminotransferase 
APC 
Antigen presenting cell 
AST (SGOT) 
Aspartate aminotransferase 
AWE 
Alive Without Event 
BN 
Bavarian Nordic A/S (Kvistgaard, Denmark) 
BN-B 
Bavarian Nordic, Berlin 
BNI 
Bavarian Nordic, Inc, formerly known as BNIT 
BNIT 
BN ImmunoTherapeutics, Inc. 
BP 
Blood pressure 
BPI-SF 
Brief Pain Inventory – Short Form 
BSL 
Biological Safety Level 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CRF 
Case report form 
CT 
Computerized tomography 
CTC 
Circulating tumor cell 
CTCAE 
Common Toxicity Criteria for  Adverse Events 
CTL 
Cytotoxic T-lymphocyte 
DLT 
Dose-limiting toxicity 
DMC 
Data Monitoring Committee 
ECOG  
Eastern Cooperative Oncology Group  
ECG 
Electrocardiogram 
EM 
Erythema multiforme 
ePIP 
electronic Protocol Inquiry Platform 
EV 
Eczema vaccinatum 
FACT-P 
Functional Assessment of Cancer Therapy - Prostate 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GM-CSF 
Granulocyte macrophage-colony stimulating factor 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HR 
Hazard ratio 
IAP 
Interim Analysis Plan 

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IBC 
Institutional Biosafety Committee 
ICAM-1 
Intercellular adhesion molecule -1 
ICH 
International Conference on Harmonization 
IDT 
IDT Biologika, GmbH 
IND 
Investigational new drug 
Inf.U 
Infectious units 
IRB/EC 
Institutional Review Board/ Ethics Committee 
IU 
IVRS 
IWRS 
International unit 
Interactive voice response system 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LFA-3 
Leukocyte function associated antigen-3 
LLN 
Lower limit of normal 
LTFU 
Long-Term Follow-Up 
mCRPC 
metastatic Castration-Resistant Prostate Cancer 
MHC 
Major histocompatibility complex 
MRI 
Magnetic Resonance Imaging  
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute-Common Toxicity Criteria for Adverse Events 
NYHA 
New York Heart Association 
PAP 
Prostatic acid phosphatase 
PBMCs 
Peripheral blood mononuclear cells 
PCWG2 
Prostate Cancer Clinical Trials Working Group 2 
PEI 
Paul-Ehrlich-Institut 
PFS 
Progression-free survival 
PI 
Principal Investigator 
PVG 
Pharmacovigilance Group 
PROSTVAC 
PROSTVAC™, PROSTVAC-V/F, PROSTVAC™-V/F + TRICOM™ 
PS 
Performance status 
PSA 
Prostate-specific antigen 
PV 
Progressive vaccinia 
PVE 
Post-vaccinial encephalitis 
QoL 
Quality of Life 
RAC 
Recombinant DNA Advisory Committee 
RR 
Respiration rate 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious adverse event 

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sc 
Subcutaneous 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAA 
Tumor-associated antigen 
TRICOM 
TRICOM™, Triad of costimulatory molecules 
TTP 
Time to tumor progression 
ULN 
Upper limit of normal 
VIG 
Vaccinia immune globulin 
VS 
Vital signs 

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Protocol Synopsis 
Protocol Title 
 
A Randomized, Double-blind, Phase 3, Efficacy Trial of 
PROSTVAC-V/F ± GM-CSF in Men With Asymptomatic or 
Minimally Symptomatic Metastatic, Castrate-Resistant  Prostate 
Cancer 
Protocol Number  
BNIT-PRV-301 
IND No. / OBA Protocol Number  
NCT Number: 
EudraCT No. 
BB-IND 13946 / #1104-1101 
NCT01322490 
2010-021196-85 
Investigational Product 
PROSTVAC-V/F 
Sponsor  
Bavarian Nordic, Inc. 
Indication 
For the treatment of subjects with asymptomatic or minimally 
symptomatic, metastatic castration-resistant prostate cancer 
CRO 
Planned Sample Size  
1,200 subjects (approximately) 
Planned Number of Centers  
250 – 300 centers worldwide 
Study Type 
Pivotal 
Study Phase  
Phase 3 
Medical Monitor  
Drug Safety 

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PROTOCOL SYNOPSIS 
Background and 
Rationale 
 
PROSTVAC™ (PROSTVAC-V and PROSTVAC-F; PROSTVAC-V/F) is a novel 
candidate prostate cancer immunotherapy for the treatment of prostate cancer. It is 
a viral vector based product that is administered in seven subcutaneous (sc) 
vaccinations, over a five month period. In a randomized controlled Phase 2 trial, 
PROSTVAC therapy was associated with a prolongation of survival in men with 
metastatic castration-resistant prostate cancer (mCRPC). 
 
PROSTVAC is a PSA (prostate-specific antigen)-based immunization strategy. It is 
intended to generate immune responses to prostate specific antigens and prostate 
cancer cells. It uses poxviral vectors to introduce modified prostate-specific antigen 
(PSA) to the patient in an immunogenic manner to break self-tolerance, and 
thereby induce immune responses directed against prostate cancer cells. 
 
PROSTVAC is comprised of two component viral vectors; a recombinant vaccinia 
(PROSTVAC-V) and a recombinant fowlpox (PROSTVAC-F) virus to be used 
sequentially in a heterologous prime-boost vaccination regimen. Both viruses 
contain four human genes: prostate-specific antigen (PSA) and three genes 
encoding human immunological costimulatory molecules: B7.1, intercellular 
adhesion molecule-1 (ICAM-1), and leukocyte function-associated antigen-3 (LFA-
3) (designated TRIad of COstimulatory Molecules or TRICOM). The simultaneous 
expression of PSA and TRICOM enhances the immune response. The PSA 
transgene is modified at one amino acid (I155L), to enhance binding and 
immunogenicity of a particular peptide epitope in human leukocyte antigen (HLA-
A2)-expressing patients. 
 
PROSTVAC-V/F is the outcome of more than 15 years of poxviral vector 
development and evaluation by the National Cancer Institute (NCI), the former 
Therion Biologics Corporation, and Bavarian Nordic, Inc. Over 570 patients have 
been treated with related PSA-containing poxviral vectors, and over 300 patients 
have been treated with the current PROSTVAC-V/F product. A large database 
exists from safety evaluations in animals and humans for PROSTVAC-V/F. (see 
Investigator’s Brochure)  
 

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Study Design 
BNIT-PRV-301 is a randomized, placebo-controlled, multi-center, multi-country, 
Phase 3 efficacy trial of PROSTVAC-V/F in men with asymptomatic or minimally 
symptomatic, metastatic, castration-resistant prostate cancer. It is a 3-arm study 
and will evaluate overall survival in two separate comparisons, PROSTVAC-V/F 
plus GM-CSF versus control, and PROSTVAC-V/F without GM-CSF versus control. 
Subjects will be randomized with equal probability into one of three double-blind 
arms.  The intended interventions for randomized subjects are: 
(Arm V+G) 
PROSTVAC-V/F plus GM-CSF 
(Arm V) 
PROSTVAC-V/F plus GM-CSF placebo 
(Arm P) 
Double placebo (empty fowlpox vector / plus GM-CSF placebo) 
The trial interventions will consist of a single subcutaneous (sc) immunization of 
PROSTVAC-V or placebo in Week 1, followed by 6 PROSTVAC-F or placebo sc 
immunizations administered in Weeks 3, 5, 9, 13, 17, and 21.   
 
Each immunization will be accompanied by administration of low dose GM-CSF or 
placebo on the day of immunization and for the subsequent 3 days (sc injection at 
same site, within 5 mm). 
Study Objectives  
Primary Efficacy Objectives:  
To ascertain whether the overall survival of subjects randomized to Arm V+G 
(PROSTVAC-V/F plus GM-CSF) or to Arm V (PROSTVAC-V/F) is superior to that 
from subjects randomized to Arm P (placebo control). 
Secondary Efficacy Objective: 
To ascertain whether a greater proportion of subjects randomized to Arm V+G or 
Arm V remain event-free (radiological progression, pain progression, chemotherapy 
initiation, or death) at 6 months (or early termination) as compared to the subjects 
randomized to Arm P.  
Safety Objectives: 
To further characterize the safety and tolerability of PROSTVAC immunotherapy. 
Exploratory Objectives: 
To model radiological disease status over the first year of study participation.  
To ascertain whether a greater proportion of subjects randomized to either 
Arm V+G or Arm V remain event-free (radiological progression) 6 months post 
End-of-Treatment visit (using scans at End-of-Treatment visit as a new baseline) as 
compared to the subjects randomized to Arm P. This analysis will include all 
subjects, and the HLA-A2-expressing subgroup. 
To assess the role of post-treatment anti-cancer therapies as an alternative 
explanation for observed survival differences. 
To ascertain whether the overall survival of HLA-A2-expressing subjects 
randomized to Arm V+G, or Arm V is superior to that from HLA-A2-expressing-
subjects randomized to Arm P.   
To compare arms with respect to immune response to immunizing antigen (PSA), 
as well as to non-vaccine-contained prostate antigens, and tumor-associated 
antigens, and assess whether immune responses are prognostic and/or predictive. 

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To evaluate for baseline biomarkers which are prognostic and/or predictive of long- 
term survival outcome. 
To compare arms with respect to vaccine effects on circulating tumor cell (CTC) 
levels (US sites). 
Study Type  
Pivotal 
Methodology 
• 
Subcutaneous immunizations  
o 
PROSTVAC-V or placebo administered in Week 1 
o 
PROSTVAC-F or placebo administered in Weeks 3, 5, 9, 13, 17, and 21.   
Trial Population  
Subjects with asymptomatic or minimally symptomatic, metastatic prostate cancer 
who have progressed despite surgical castration or androgen suppression therapy. 
Subjects will have evidence of radiological disease progression, or PSA disease 
progression as described in Prostate Cancer Clinical Trials Working Group 2 
(PCWG2) criteria, after being treated with androgen suppression therapy or 
complete androgen blockade and withdrawal. 
Sample Size  
It is projected that approximately 1,200 subjects (400 subjects per arm), will be 
required for evaluation of the primary objective (overall survival). Analysis will 
require 534 events per each overall efficacy comparison.  Arm V+G subjects 
versus all Arm P subjects, and separately all Arm V subjects versus all Arm P 
subjects.  
Duration of Study  
This trial entails the following three phases: Screening, Treatment, and Long-Term 
Follow-Up.  
Screening Phase: Week -4 – 0 
Screening procedures have to be completed no more than 4 weeks prior to first 
planned dose. 
Treatment Phase:  Weeks 1 – 25 
Treatment (5 mos), including vaccination at Weeks 1, 3, 5, 9, 13, 17, and 21 
followed by  End-of-Treatment (Week 25)/Early Termination visit. 
Due to the delayed effect of vaccine induced immunotherapy, PSA and radiological 
progression may be expected during the treatment phase of the trial, and is not a 
cause for stopping vaccination. Subjects who progress clinically (pain) during 
treatment, or who progress rapidly as measured by PSA-DT <1 month will be 
counseled with respect to alternative treatment options. If subjects choose to 
initiate alternative therapy, vaccination will be discontinued.  Subjects who stop 
treatment will continue in the Long-Term Follow-Up phase. 
Long-Term Follow-Up Phase (LTFU): 
After completing the End-of-Treatment/Early Termination visit, all subjects will 
automatically enter the Long-Term Follow-Up phase that extends until 12 months 
after the required number of 534 events for each between-arm comparison is 
realized. Subject health status, disease status, and subsequent prostate cancer 
therapies will be collected at each 6 month visit.  
Summary of 
Eligibility Criteria 
. 
Men ≥ 18 years of age with documented asymptomatic or minimally 
symptomatic  metastatic castration-resistant prostate cancer 
. 
Castrate level of testosterone: <50 ng/dl 

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. 
PSA (or radiological) progression during androgen-suppression or blockade 
therapy and withdrawal 
. 
ECOG PS of 0, or 1 
. 
Life expectancy ≥1 year 
. 
Chemotherapy naïve  
. 
Subjects requiring scheduled opioid narcotics for cancer-related pain are 
excluded 
. 
Subjects with rapidly progressing disease (estimated PSA-DT <1 month), 
visceral metastases, or with elevated LDH or elevated alkaline phosphatase 
(≥2xULN) are excluded 
. 
Adequate bone marrow, hepatic, and renal function 
. 
No significant cardiovascular disease 
. 
No contraindication for vaccinia immunization 
Concomitant Therapy  
. 
Subjects will be on concomitant androgen suppression therapy with a GnRH 
agonist or antagonist 
. 
Subjects may be on concomitant drugs to prevent bone loss or skeletal-related 
events, including bisphosphonates and denosumab 
. 
Subjects may receive palliative radiotherapy during the trial 
Excluded Therapy 
Chemotherapy:  Concomitant use of chemotherapy is not allowed during the 
Treatment phase (approximately 5 months) of this trial.   
Concurrent immunotherapy or immunosuppressive therapy 
Anti-cancer radionuclides:  Concomitant use of anti-cancer radionuclides is not 
allowed during the Treatment phase of this trial. 
Secondary hormonal therapies: Concomitant use of supplementary hormonal 
treatments is not allowed during the Treatment phase of this trial. 
Corticosteroids: Concomitant chronic use of systemic corticosteroids is not 
allowed during the Treatment phase of the study. The use of inhaled 
corticosteroids, nasal sprays, and topical creams for small body areas is allowed. 
 
Dose and 
Administration  
PROSTVAC-V/F is provided at the following doses based on the doses of 
PROSTVAC-V/F used in the randomized controlled Phase 2 trial of 122 men, 
TBC-PRO-002. 
• 2 x 108 Infectious Units (Inf.U)/0.5 ml for vaccinia (PROSTVAC-V). 
• 1x 109 Inf.U/0.5 ml for fowlpox (PROSTVAC-F). 
• 1x 109 Inf.U/0.5 ml for placebo (empty fowlpox vector). 
 
PROSTVAC-V/F is administered by sc injection with the following schedule: 
• 1 PROSTVAC-V (or placebo) priming vaccination (Week 1) 

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• 6 PROSTVAC-F (or placebo) booster vaccinations (Weeks 3, 5, and then 9, 
13, 17, and 21) 
 
GM-CSF is provided at 100 μg per sc injection (on Days 1 – 4) for each 
vaccination.  GM-CSF placebo is bacteriostatic saline for injection and is delivered 
on the same schedule. 
Statistical Methods  
Statistical success with respect to the primary objective is defined as success for 
either of the following comparisons: 
 
• Superiority of Arm V+G over Arm P for all subjects randomized to these 
arms. 
• Superiority of Arm V over Arm P for all subjects randomized to these arms. 
 
The significance levels to be used for the analyses associated with these two 
comparisons will protect the overall study type I error probability to be one-sided 
0.025 or less. The possibility of delayed vaccine effect is taken into account in 
computing the required number of deaths, (as modeled from the randomized 
Phase 2 trial). The projected trial size is 400 subjects per arm (approximately 
1,200 subjects) with at least 85% power, and the final analyses will be event-
driven and take place when 534 deaths have been realized for the comparisons 
involving all subjects randomized (Arm V+G versus Arm P, and separately Arm V 
versus Arm P).  
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Rationale 
Bavarian Nordic, Inc. (BNI) previously known as BN ImmunoTherapeutics, Inc. (BNIT) is developing 
PROSTVAC-V/F for the treatment of prostate cancer (Madan 2009). The PROSTVAC vaccine product is 
comprised of two biologic agents, PROSTVAC-V and PROSTVAC-F. These are two different poxvirus 
vectors, recombinant vaccinia and fowlpox viruses, respectively, encoding the genes for prostate-specific 
antigen (PSA) with the L155 mutation in combination with a triad of human costimulatory molecules, B7.1, 
ICAM-1, and LFA-3 (TRICOM™; TRICOM). They are used to introduce tumor-associated antigens 
(TAAs) and costimulatory molecules into patients with metastatic prostate cancer. The vaccinia and 
fowlpox viruses encoding PSA and TRICOM are used in a prime-boost vaccination regimen to optimize 
immune responses against prostate cancer tumor cells. 
The proposed treatment is a PSA -based immunization strategy. PROSTVAC-V/F is a viral vector-based 
product that is administered over seven subcutaneous vaccinations, over a five month period. It is 
intended to generate immune responses to prostate specific antigens and prostate cancer cells. It uses 
poxviral vectors to introduce modified PSA to the patient in an immunogenic manner to break self-
tolerance and generate immune responses directed against prostate cancer cells.  A double-blind 
randomized Phase 2 trial found longer survival for men randomized to receive PROSTVAC-V/F, where an 
overall median survival of 16.6 months was noted for control vector-treated subjects versus 25.1 months 
for PROSTVAC-V/F-treated subjects, hazard ratio 0.56 (95%CI 0.38-0.88), and p=0.006.  
PROSTVAC-V/F is an outcome of more than 15 years of poxviral vector development and evaluation by 
the NCI, the former Therion Biologics Corporation (Therion), and BNI. Over 570 patients have been 
treated with related PSA-containing poxviral vectors, and over 300 patients have been treated with the 
current PROSTVAC-V/F regimen. A large database (see Investigator’s Brochure) exists from safety 
evaluations in animals and in humans for PROSTVAC-V/F. BNIT-PRV-301 will evaluate the efficacy of 
PROSTVAC-V/F in men with asymptomatic or minimally symptomatic, metastatic castration-resistant 
prostate cancer (mCRPC). 
1.2 
Background 
1.2.1 
PROSTVAC-V/F Development Program 
Bavarian Nordic A/S (BN), 
, is the parent company of BNI, and is now the sole 
manufacturer of PROSTVAC-V/F. BN has manufactured poxviral-based products since 1995, ranging 
from bench-scale through commercial, and has the experience and technical expertise to culture the 
vaccine vectors, and to produce final frozen liquid formulations.  The manufacturing technology and 
methodology originally developed at Therion have been transferred and further developed 
 
. Phase 3 clinical trial material will be 
manufactured 
. 

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The plan for the continued clinical development of PROSTVAC-V/F in men with mCRPC is informed in 
particular by the Phase 2 study conducted under former BB-IND 10428.  This study in metastatic disease 
demonstrated that (i) recombinant vaccinia and fowlpox viruses are well tolerated vectors for 
administration to subjects with prostate cancer, and (ii) prolonged survival is achieved in subjects treated 
with PROSTVAC-V/F versus subjects administered the control.  
The planned Phase 3 clinical program to be conducted by BNI will include one well-powered, randomized, 
placebo-controlled, double-blind, multi-center, multi-country trial designed to evaluate PROSTVAC-V/F 
with and without GM-CSF for the treatment of mCRPC. This trial will be conducted globally. 
1.2.2 
Prostate Cancer 
Prostate cancer is the second leading cause of cancer deaths in men in the United States.  According to 
the American Cancer Society, approximately 200,000 new diagnoses of, and 28,000 deaths from prostate 
cancer occur each year in the United States (Jemal 2009). Up to one-third of patients with localized 
disease will fail local therapy within 10 years (as evidenced by a rising PSA) (Pound 2001, Freedland 
2007). Patients with recurrent disease generally undergo hormone suppression therapy, with medical or 
surgical castration. Unfortunately, in most cases, this is eventually followed (after good response for 
several years) by progressive disease. Castration-resistant prostate cancer (CRPC) is characterized by 
disease that is uncontrolled despite low levels of testosterone and/or the presence of androgen receptor 
antagonist treatment (Rini 2002).  
Upon the development of metastasis, overall survival is approximately 1–3 years. Taxane-based 
chemotherapy (docetaxel) and Provenge™ (Provenge, sipuleucel-T) are the only approved agents for the 
first-line treatment of patients with metastatic disease that have shown a prolonged survival benefit.  
Prostate cancer has been shown to be generally poorly responsive to chemotherapy. Taxotere 
chemotherapy has a beneficial effect on survival of approximately 3 months (Tannock 2004, Petrylak 
2004, Berthold 2008). Cabazitaxel-based chemotherapy also offers an apparent 2-3 month improved 
survival in a second-line setting (after docetaxel chemotherapy) (DeBono 2010). However, as with many 
other cytolytic agents, the impact on the patient’s quality of life is significant. More recently, abiraterone 
(an androgen hormone synthesis inhibitor) has also been shown to prolong median survival by 
approximately 4 months, and has been approved for use in second-line setting (De Bono 2011). 
Provenge has shown a beneficial survival benefit of approximately 4 months (Kantoff 2010, NEJM). 
Provenge, while having a comparatively favorable safety profile with a slightly better survival benefit, 
requires extensive processing during the treatment regimen and, therefore, has practical limitations. 
Consequently, therapies that could significantly improve the therapeutic benefit (survival and safety) as 
well as practical use of that observed with chemotherapy and Provenge, respectively, are urgently 
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1.2.3 
Prostate Cancer Immunotherapy 
Therapeutic cancer vaccines have been investigated in both castration-sensitive and castration-resistant 
disease (Schlom 2007). Prostate cancer is an ideal candidate for treatments that stimulate the immune 
system to target cancer cells. Prostate cancer may progress slowly (even in advanced disease), allowing 
time for the immune system to be stimulated, and to mount an active immune response. It is a poorly 
chemosensitive disease, so patients are generally not heavily pretreated with cytotoxic agents, and their 
immune systems are more intact. Prostate cells have a unique and specific marker, prostate-specific 
antigen (PSA), which is secreted into the blood, and can be detected with even low levels of tumor 
burden.  Several other gene products are unique to prostate cells, and prostate cancer cells over-express 
tumor-associated antigens (TAA), making for multiple targets suitable for immunotherapy responses 
(Cunha 2006, Bradford 2006). Many patients with prostate cancer have low levels of cytolytic T-cells 
capable of recognizing PSA, and this minimal response can be enhanced with immune stimulation by 
therapeutic cancer vaccines (Chakraborty 2003). Finally, because the prostate is a nonessential organ, 
targeting PSA- or TAA-specific immune cells to prostatic tissue is unlikely to have a significant negative 
clinical impact.  
The first FDA approved prostate cancer immunotherapy, Provenge (sipuleucel-T), is now available 
(approved 29 April 2010). However Provenge is available only in the United States. Provenge is a cell-
based vaccine consisting of autologous PBMCs that have been activated ex-vivo with a recombinant 
protein representing a fusion of PAP (prostatic acid phosphatase) and GM-CSF. Early clinical work 
demonstrated prolongation of overall survival (Small 2006), and up-regulations of cellular immunity and 
reductions in PSA and PAP levels (Patel 2008). The Phase 3 IMPACT study of 512 subjects with 
metastatic castration-resistant prostate cancer met its primary endpoint of prolongation of overall survival. 
Provenge was approved for use in metastatic castration-resistant prostate cancer based on an increase 
in median survival of 4.1 to 4.5 months (Kantoff 2010).  
1.2.4 
PSA as a Target Antigen 
PSA is a promising target antigen for immunotherapy of prostate cancer. PSA is a ~34,000 dalton 
glycoprotein that is produced in normal, benign, and cancerous prostate epithelia, but not in other normal 
tissues (Wang 1982, Lilja 2008). Because PSA is expressed essentially only in prostatic epithelial cells 
(normal and malignant), and the prostate gland is nonessential, this antigen is an enticing choice. The 
fact that PSA is secreted and not membrane-bound limits its use as a target for humoral immunity, but not 
its use as a target of specific cellular immune system attack. Cells, including tumor cells, present 
endogenously expressed proteins on their surface in the form of peptide-major histocompatibility 
complexes (MHC). Cytotoxic T-lymphocytes (CTLs) recognize and are activated by specific peptides in 
the context of the appropriate MHC class I molecule on antigen-presenting cells (APC). This activation 
can in turn lead to killing of tumor targets by the peptide-specific CTLs. 
The use of PSA as a target to elicit tumor-specific T-cell-mediated lysis has been validated in vitro. 
Correale et al. demonstrated in vitro killing of a PSA-peptide-pulsed HLA-A2+ human cell line by a PSA-

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specific human CTL cell line, and lysis was blocked by an antibody directed against MHC class I 
molecules (Correale 1997). It has also been shown that PSA-specific CTLs could be generated that lyse 
PSA-expressing prostate cancer cells (Correale 1997, 1998).  The identification of these peptide epitopes 
further provides a means of identifying cytolytic T-cells resulting from immunization as an in vitro 
monitoring tool. 
1.2.5 
PSA-3-epitope modification 
Protein antigens are presented to CTLs as small peptides (approximately 9–10 amino acids long) bound 
to class I molecules of the MHC. One strategy to increase the immunogenicity of a self-antigen such as 
PSA is to modify selected epitopes within the protein sequence to enhance their binding to MHC class I 
alleles. The stabilized binding enables more sustained and potent immune cell activation. One such 
epitope, designated PSA-3 (amino acids 154–163), which is specific for the MHC class I A2 allele, was 
modified by the introduction of a single amino acid change (I to L) at position 2 in the epitope (designated 
L155) (Correale 1998, Terasawa 2002). A number of in vitro studies suggest that PSA carrying this 
modification will be more immunogenic in HLA-A2 individuals than the native (unmodified) PSA 
polypeptide (Correale 1998, Terasawa 2002). 
1.2.6 
Poxviral Vaccine Approach 
Poxviruses are large multi-enveloped DNA viruses which encode about 200 genes.  Poxviral vectors are 
able to accommodate multiple transgenes, and are able to deliver PSA and multiple immunostimulatory 
genes directly or indirectly to APCs.  The activated APCs process and present the PSA antigen, leading 
to PSA specific T-cell activation (Essajee 2004, Schlom 2008).  PSA as a soluble protein is weakly 
immunogenic, especially in the tumor-bearing host. Vaccine strategies must induce greater activation of 
T-cells than is being achieved endogenously in the host. The poxviral system achieves this by generating 
a natural inflammatory context for facilitating activation of immune cells, and inducing PSA-specific 
immune responses. Extensive pre-clinical studies in experimental murine models have demonstrated the 
therapeutic utility of using poxviral vaccines to break tolerance (Bernards 1987, Irvine 1993, Kass 1999).  
Another advantage of poxviral vaccines is that they are well tolerated by the patients. The relative safety 
of PSA-based poxviral vectors has been well established in previous trials (Madan 2009, Kantoff 2010, 
Kaufman 2004, Arlen 2007). 
1.2.7 
Vaccinia Virus 
Vaccinia virus has been used for over 200 years as a vaccine for smallpox and has a well-established 
safety and adverse event (AE) profile (Casey 2005, Poland 2005).  The virus actively replicates in human 
cells, and generates a strong inflammatory response, resulting in the presentation of high levels of 
antigen to the immune system over a period of one to two weeks, supporting a potent immune 
stimulation.  Subsequently, the immune response specific to vaccinia then eliminates the virus. Host 
immune responses to vaccinia restrict its replication and thus limit its ability to be re-used for subsequent 

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vaccinations. Consequently, vaccinia-based vaccines, although potent immunological priming agents, can 
be used to immunize an individual only once or twice.   
1.2.8 
Fowlpox Virus 
Fowlpox virus is a member of the genus Avipox, which is evolutionarily divergent from vaccinia virus and 
serologically non cross-reactive (Taylor 1988, Beukema 2006). Immune responses to vaccinia are 
essentially non cross-reactive with fowlpox, and do not block infection and immunization with fowlpox-
based vectors. Hence vaccinia-primed immune responses can be boosted with fowlpox vectors.  In 
addition, fowlpox vectors do not replicate in human cells (only in avian cells), and are therefore much less 
of a safety risk than vaccinia-based vectors. Fowlpox vectors mediate a limited infection in human cells, 
with early viral and transgene expression, but late gene expression is blocked, and no infectious particles 
are produced. Thus minimal viral surface antigen is made, and minimal neutralizing antibody immune 
responses are induced.  This enables multiple boosting with the fowlpox-based vectors. 
1.2.9 
Prime-Boost 
Recombinant vaccinia and fowlpox vectors are most effective when used in combination in prime-boost 
regimens. By priming with recombinant vaccinia virus and then boosting repeatedly with the 
corresponding recombinant fowlpox virus, maximum immune responses to the expressed tumor antigens 
can be obtained. This phenomenon has been demonstrated in animal models (Hodge 1997, Dale 2006) 
and has been supported by the results from the completed Phase 1 and Phase 2 trials conducted by the 
National Cancer Institute (NCI), Eastern Cooperative Oncology Group (ECOG), and Therion. 
1.2.10 
TRICOM- costimulatory molecules 
Destruction of immunological targets requires T-cell lymphocyte recognition, via the T-cell receptor, of 
antigenic peptides presented in the context of MHC molecules on APCs. In addition to this antigen-
specific signal, a second, antigen-independent signal is required for T-cell activation (Boussiotis 1995, 
Hodge 2006). This second signal is provided by the interaction of specific ligands on the T-cell surface 
with “costimulatory” molecules expressed on APCs. The most extensively studied pathway of 
costimulation is that involving the interaction of the costimulatory molecule B7.1 expressed on APCs with 
CD28 and CTLA4 on the T-cell (Sharpe 2002, Riley 2005).  A number of additional costimulatory 
molecules on APCs have been identified; these include ICAM-1 and LFA-3, whose ligands are LFA-1 and 
CD2, respectively, on the surface of T-cells (Wingren 1995, Lebedeva 2005, Wang 2008).  
Proper engagement of the T-cell receptor and costimulatory receptor requires the expression of both 
antigen and costimulatory molecules, respectively, in the same cell. Therefore, co-expression of 
costimulatory molecules using a single recombinant vector presents the potential of cooperation among 
these proteins to enhance T-cell activation. Recombinant vectors co-expressing three costimulatory 
molecules, LFA-3, ICAM-1, and B7.1, designated TRICOM™ (TRICOM), have been shown to have 
synergistic effects on antitumor responses as compared to vectors expressing individual costimulatory 
molecules (Hodge 1999). Mice immunized with a recombinant vaccinia virus co-expressing 

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carcinoembryonic antigen (CEA) and murine TRICOM exhibited greater immune responses and anti-
tumor responses than mice immunized with a recombinant vaccinia virus co-expressing CEA and murine 
B7.1.  Enhanced anti-tumor immunity was also observed in mice that were transgenic (tolerant) for CEA 
(Hodge 1999). PROSTVAC-V and PROSTVAC-F have, therefore, been designed to simultaneously 
express PSA together with B7.1, LFA-3, and ICAM-1. 
1.2.11 
GM-CSF 
Granulocyte macrophage colony-stimulating factor (GM-CSF) has been shown to enhance antigen 
processing and presentation by dendritic cells (DC). GM-CSF affects many immunologic processes, 
including increasing expression of class II MHC molecules, augmenting the primary antibody response, 
and inducing localized inflammation when administered by injection (Warren 2000, Chang 2004). GM-
CSF has the ability to promote local DC differentiation, maturation, and subsequent migration to regional 
lymph nodes. Antigens released by target cells, such as those from tumors, are likely to be taken up and 
processed by DCs and presented to T-cells, thereby inducing the activation of a cellular immune 
response. These immunologic properties of GM-CSF have made this cytokine a potentially attractive 
adjuvant candidate for vaccines. Indeed, use of both recombinant human (rhu) GM-CSF and the 
recombinant poxviruses expressing GM-CSF has been shown to enhance immunological effects of 
vaccines in both non-clinical (Kass 2001) and clinical studies (Marshall 2000). GM-CSF was administered 
as an adjuvant to the PROSTVAC-V/F vaccine in the randomized, placebo controlled Phase 2 trial, and 
the positive outcome of this trial supports its use in this Phase 3 trial. 
More recent data have however, challenged the benefits of GM-CSF.  A recent review of approximately 
14 different human clinical cancer vaccine studies that employed GM-CSF as an adjuvant (Parmiani, 
2007) concluded that the studies reviewed provided limited evidence to justify the use of GM-CSF as an 
adjuvant and might be even detrimental under certain conditions. There is also growing evidence that 
systemic use of GM-CSF can compound tumor-mediated immune suppression by acting as a growth 
factor for myeloid-derived suppressor cells (MDSC) (Talmadge, 2007).  Lastly, in a small Phase 2 trial of 
PROSTVAC-V/F conducted by the NCI, GM-CSF use was not associated with any dramatic clinical 
benefit.  However, only eight subjects per arm were compared (GM-CSF, no GM-CSF, FPV-GM-CSF, 
FPV-GM-CSF high dose), making firm conclusions difficult. Together these data support going forward 
with a third arm of the trial comparing PROSTVAC-V/F without GM-CSF to control. 
1.3 
Placebo Rationale  
BNIT-PRV-301 will utilize a placebo control in order to fulfill the double-blind design of the study.  In a 
double-blind trial, neither the investigator nor the subject has knowledge of the treatment being 
administered. This study design is utilized in order to control variables that could be caused by knowledge 
of treatment assignment, either on the part of the investigator or the subject.  In order to ensure a double-
blind design, a study protocol must carefully account for all circumstances in which the Investigator or 
subject could obtain knowledge of treatment assignment. One of the most obvious requirements to 
maintain a blind is ensuring that study drug administration is perceived as identical across study arms.  

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This protocol design minimizes the risk of bias and enhances the impartial analysis of the study drug 
versus placebo effect. However, it is important to note that in case this information is required for safety 
purposes it will be provided in an expedited manner. 
In minimally symptomatic metastatic prostate cancer there is no standard of care.  Most patients and 
physicians utilize chemotherapy when the disease has become symptomatic, or has taken on accelerated 
kinetics. These patients are excluded from this trial (BNIT-PRV-301). The side effect profile of 
chemotherapy and its associated risks have favored later use of chemotherapy, where the potential for 
pain relief shifts the risk-benefit profile.  Immunotherapy is a promising approach in this early stage of 
metastatic prostate cancer.  Although promising, sipuleucel-T is not widely available, and has logistic and 
cost concerns. 
In BNIT-PRV-301 the placebo will be an empty viral vector.  Tissue culture adapted fowlpox virus, the 
same host strain as used in PROSTVAC-F will be used.  This vector is non-replicating in humans and has 
minimal safety risk. In addition, the cutaneous injection site reactions (and side effect profiles) are 
overlapping (and generally indistinguishable) with subcutaneously administered vaccinia (PROSTVAC-V).  
Thus this vector forms an ideal placebo. It has no known effects on cancer progression, and is not 
expected to have any significant effects on its own. It is manufactured by the same process as 
PROSTVAC-V and PROSTVAC-F, and has the same look and feel of the other investigational vaccine 
vectors. 
1.4 
Summary of Findings from Human Clinical Studies 
Clinical investigation of the PROSTVAC-V/F vaccine product was initiated in 2002 by Therion in the 
United States under BB-IND 10428. Therion manufactured all PROSTVAC-V/F product and conducted 
two clinical trials on PROSTVAC-V/F, including a Phase 1 trial evaluating the safety and immunogenicity 
of PROSTVAC-V/F in 10 subjects, and a randomized, placebo-controlled Phase 2 trial evaluating the 
safety and efficacy (as defined by time-to-progression; TTP) of PROSTVAC-V/F in approximately 125 
men with castration-resistant metastatic prostate cancer. Both trials were conducted in the US only. 
Therion also manufactured the PROSTVAC-V/F product for all the NCI and ECOG trials. 
1.4.1 
Poxviral PSA Vaccine Clinical Trials 
The use of poxviral vectors to stimulate an immune response to PSA has been evaluated in several 
clinical trials. In a Phase 1 clinical trial using an earlier version of a PSA-based vaccine (devoid of any 
costimulation), Eder et al. used three monthly vaccinations of recombinant vaccinia (rV)-PSA (Eder, 
2000).  Six out of 10 subjects with rising PSA following local therapy who received the highest tested 
dose, with GM-CSF, had a time of PSA progression of greater than six months. Four of these 6 subjects 
still showed no progression, with the longest time of follow-up greater than 24 months. This was 
suggested to be evidence of clinical activity (Eder 2000). Five of 7 HLA-A2+ subjects in this final dose 
level had at least a 2-fold increase in PSA-specific T-cells in peripheral blood mononuclear cells (PBMCs) 
as a result of vaccination, as measured by the ELISPOT assay, indicating that tolerance to self-antigens 

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could be circumvented with these vaccine strategies. Another Phase 1 study of rV-PSA also 
demonstrated that immune responses could be elicited in subjects with metastatic hormone-refractory 
prostate cancer and that immune cells taken from these subjects could specifically lyse PSA-expressing 
cancer cells in vitro (Gulley 2002).   
ECOG previously conducted and reported a randomized Phase 2 study in which 64 subjects with rising 
PSA following definitive local therapy with no evidence of disease on imaging studies were randomized to 
receive four vaccines with rV-PSA (designated V) and/or rF-PSA (designated A for avipox) (Kaufman 
2004). The arms were thus VAAA, AAAA and AAAV.  PSA progression-free survival (PFS) was about 9 
months in the latter arm, and about 18 months in the VAAA arm, lending further support to the use of 
vaccinia priming and avipox vector boosting.  
Vaccinia and fowlpox vectors containing the gene for human PSA with a single amino acid substitution 
(designated PSA (L155)) along with genes encoding TRICOM have been tested in two fully accrued 
Phase 1 clinical trials with 25 subjects with metastatic prostate cancer (Arlen 2007, DiPaola 2006).  There 
were no dose-limiting toxicities on these studies attributed to vaccine. One of these studies in subjects 
with mCRPC has shown that subjects treated with PSA/TRICOM who were evaluable for immune 
response had an increase in PSA-specific T-cells after treatment; and 9 of 15 subjects had decreases in 
PSA velocity (Arlen 2007). 
The Therion-sponsored Phase 2 trial randomized subjects with mCRPC 2:1 in favor of vaccine vs. an 
empty fowlpox vector as control. 125 subjects with mCRPC and Gleason scores ≤ 7 were enrolled  
(122 treated). Subjects randomized to receive vaccine (82 subjects) were given subcutaneous rV-PSA-
TRICOM prime with monthly boosts of rF-PSA-TRICOM, while control subjects (40 subjects) were given 
subcutaneous injections of fowlpox. Although no difference in TTP was seen in the short-term, in an 
interim analysis at two years of follow-up, median overall survival was 24.4 months in the vaccine arm 
compared to 16.6 months in the control arm, suggesting that although disease progression occurred at 
similar times in both groups, there appeared to be a long-term benefit for some subjects treated with 
PSA/TRICOM (Schlom 2008, Kantoff 2006).  
The overall survival results after a final survey (median follow-up 4 years) were recently completed.  The 
formal overall survival update revealed that PROSTVAC-V/F immunotherapy was associated with a 
significant survival benefit. PROSTVAC-V/F-treated subjects had a longer median survival (25.1 months 
versus 16.6 months controls), and an increased survival at 3 years post study (25 of 82 subjects, 30%; 
versus 7 of 40 control subjects, 17%).  Statistical analysis of the Kaplan-Meier curves revealed an 
estimated hazard ratio of 0.56 (95% CI 0.37-0.85), and a stratified log rank of P=0.006 (Kantoff 2010).  
In an NCI Phase 2 study (NCI no.5911) of PSA/TRICOM, 32 subjects with metastatic CRPC were treated 
with an rV-PSA-TRICOM prime and monthly boosts of rF-PSA-TRICOM. In that trial, 47% of subjects had 
a decrease in PSA velocity, 38% had a PSA decline.  Median time to progression was 2.8 months.  One 
subject at 8 months experienced a decrease in his hilar adenopathy associated with declining PSA  
(> 30%). He remained on study for 12 months. Another subject had a decrease of 29% in his adenopathy 

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(by RECIST) associated with a decline in his PSA (> 30%). Another subject who enrolled on study with a 
super-scan on bone scan had a >70% decline in his PSA and remains on trial more than 4 years after 
enrollment. Overall, 13 of 29 evaluable subjects had a > 2-fold increase in PSA-specific T-cells.   
In addition, 5 subjects had a > 6-fold increase in PSA-specific T-cells, which was associated with a trend 
to improved overall survival (p = 0.055) (Madan 2008, Gulley 2009).  
1.4.2 
Clinical Safety of Recombinant Poxvirus-Based Vaccines 
Since 1991, 10 recombinant vaccinia-based vaccines and 8 recombinant fowlpox-based vaccines 
produced by Therion for the treatment of various cancers have been evaluated in human clinical trials 
sponsored by CTEP, DCTD, NCI. Over 1,000 cancer subjects, most with metastatic disease, have been 
treated to date with these poxvirus-based vaccines in 29 CTEP-sponsored or Therion-sponsored clinical 
trials (Kaufman 2004). These trials represent a large component of the relevant safety database that 
supports the initiation of the proposed Phase 3 trial of PROSTVAC-V/F. Significant safety experience in 
humans includes: (a) vaccinia- and/or fowlpox-based vaccines safely administered by a variety of routes 
including intradermal (by injection or scarification), subcutaneous (sc), intramuscular (im), intravenous 
(iv), and intra-tumoral at doses up to 2 x 109 Inf. U. (vaccinia) or 6 x 109 Inf. U. (fowlpox); (b) vaccinia-
based and fowlpox-based vaccines containing costimulatory molecules, alone or in combination with CEA 
or PSA antigens, administered without serious adverse effects, as outlined below. 
Poxviral vectors containing PSA, either alone or with B7.1 or TRICOM, have been evaluated in 13 
different Phase 1 (5 trials) and 2 (8 trials) comprising over 400 vaccinated subjects with advanced 
prostate cancer. In addition, there are three other fully enrolled, and two open studies using PROSTVAC-
V/F treatment, for an additional 100 treated subjects.  There have only been two serious adverse events  
thought to be possibly due to the PROSTVAC-V/F treatment (both in the same subject): the subject had a 
myocardial infarction and it was found that he had Grade 4 thrombotic thrombocytopenic purpura, thought 
to be possibly related to study drug, approximately 3.5 weeks after receiving the fourth dose of his 
vaccine. This resolved with therapeutic apheresis treatment, however, the subject continued to do poorly 
(for a more detailed description of this case, see Investigator’s Brochure). Thrombotic thrombocytopenic 
purpura has not been reported as an adverse event in large scale studies of smallpox vaccination with 
vaccinia. 
1.5 
Safety of Poxviral Vectors 
1.5.1 
Vaccinia Virus 
Vaccinia virus causes a transient infection, with elimination of viral components over several weeks. Host 
cells infected with vaccinia virus are short lived (days) and die by a mixed form of apoptosis/necrosis. 
Vaccinia replicates in the cytoplasm of infected cells, and viral DNA does not integrate into the host cell 
DNA.  Vaccinia virus is known to be shed from the wound site in traditional dermal scarification based 
vaccination.   

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The use of vaccinia virus for worldwide eradication of smallpox provides a safety database with number of 
observations in the millions. Geographical differences in strains of vaccinia virus used as well as 
differences in reporting practices, diagnostic and follow-up criteria between countries are a cause of some 
discrepancies in the incidences of adverse events reported, but the overall picture of vaccinia virus safety 
is very well known.  An additional set of data is provided by recent vaccination campaign of military and 
civilian vaccinations in the US. 
A number of events post vaccination are expected and considered to be normal: fever, myalgia, 
headache, fatigue, chills, nausea, soreness and erythema at the vaccination site, local lymphadenopathy.  
Satellite lesions around the vaccination site have been reported as well as local edema. These symptoms 
are self-limiting, last for around three weeks after vaccination and rarely are a cause for serious concern 
(Frey 2002, Fulginiti 2003). Mild adverse reactions that can occur post vaccination are bacterial 
superinfection of vaccination site, erythema multiforme (EM) and generalized vaccinia. Superinfection is a 
rare event with incidence from 0.14 to 55 cases per million according to different reports (Vellozzi 2004).  
EM most often presents as papules, plaques or urticaria which may be symmetrical, may involve palms 
and soles.  EM resolves spontaneously and requires no special care. A development of Stevens-Johnson 
syndrome with mucosal involvement is extremely rare, with only one case noted in the 2003-2004 
vaccination campaign in the US (<1 per 1,000,000) (Fulginiti 2003, Neff 2008). 
Generalized vaccinia results from viremic spread of vaccinia virus from the vaccination site.  It presents 
as a generalized rash, which behaves like the vaccination site lesion, progressing through papular, 
vesicular, pustular and scab-forming stages. The incidence is difficult to assess, since historically there 
was no strict definition to distinguish generalized vaccinia from other conditions where rash is a dominant 
symptom (severe chickenpox, smallpox, eczema vaccinatum, EM).  Retrospective analysis of 2002 – 
2004 vaccinations suggests an incidence of ~50 cases per 1,000,000 (Bryant-Genevier 2006).  The rash 
appears within a week after vaccination and resolves within a week. Most instances do not require 
specific therapy (Fulginiti 2003). 
Some of the post-vaccinia adverse events, although very rare, are serious and potentially life-threatening.  
They are described as follows. 
Progressive vaccinia (PV) is the most serious complication known. It was almost always fatal prior to the 
introduction of vaccinia immune globulin (VIG). PV occurs predominantly in persons with T-cell 
deficiencies or receiving treatments that result in T-cell deficiencies. The primary vaccination site fails to 
heal leading to a severe local reaction with necrosis, and viremic spread of vaccinia leads to generalized 
appearance of new lesions without reactive immunoinflammatory response (Bray 2003, Fulginiti 2003). 
PV is extremely rare; historical incidence is in the order of 1 case per 1,000,000.  There were no reports 
of PV in the military and civilian vaccines in 2002 – 2004 vaccination campaigns (Neff 2008). 
Eczema vaccinatum (EV) manifests as rash (papular, vesicular, pustular, erosive) that can be localized or 
generalized and predominantly occurs in the areas that have been affected by lesions of atopic dermatitis 
or other eczematous skin condition.  Historically it occurred at a rate of ~1 case per 25,000 vaccinations. 

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EV can occur in a vaccine recipient as well as in susceptible individuals in close contact. Two cases of EV 
from transmission have been recently reported both in children of recently vaccinated US military 
personnel (Lederman 2008, Vora 2008). In the military vaccination program in the US there were no 
reports of EV among 450,239 vaccinees, probably due to careful screening for contraindications 
(Grabenstein 2003).  Review of civilian vaccinations did not detect any cases of EV (Velozzi 2004). EV 
can be prevented by thorough screening of at-risk individuals and education on importance of avoiding 
contacts with such persons and proper hygiene.  
Postvaccinial encephalitis (PVE) historical case-fatality rate is 25%. The historical (1963 – 1968) reported 
frequency of PVE in United States was reported at 2.9 cases per 1,000,000 (Aragon 2003). PVE has 
higher prevalence and mortality rate in children compared to adults. Higher historical rates were reported 
in Europe compared to United States. Variability is attributed to differences in case definitions, clinical 
evaluations and differences in vaccine strains used by different countries (Sejvar 2005). Pathogenesis is 
still under investigation, although several compelling theories focus on autoimmune mechanism. Aside 
from vaccinia, measles and rabies vaccines have known association with PVE, as well as other viral and 
bacterial infections (Benneto 2004, Menge 2007). Review of 2002 – 2004 vaccinations in US reported 
three cases of PVE for the rate of 5 per 1,000,000. 
Recent vaccination campaign in the US revealed a higher than historically observed incidence of 
myo/pericarditis in vaccinees. Predominant symptoms were chest pain, shortness of breath and fatigue, 
typically mild and transient. Among military contingent, 88% of cases occurred in men with the incidence 
of 16.11 per 100,000 for primary vaccines and 2.07 per 100,000 in revaccinees (Arness 2004). In civilian 
population women accounted for 67% of cases and the majority of events (86%) were reported in 
revaccinees (Casey 2005, Sniadack 2008). Variability between the two sets of data may be explained by 
differences in demographics of vaccinees, case detection, ascertainment and reporting practices (Morgan 
2008). Myo/pericarditis has been long associated with a number of viral infections, although there are 
very few reports of confirmed viremia. A few cases of myo/pericarditis have been reported following DTP 
and influenza vaccinations (de Meester 2000, Boccara 2001). It is currently assumed that injury to the 
heart post viral infection is more of an immune inflammatory than direct nature (Cassimatis 2004, 
Feldman 2000). 
Review of data from 2002 – 2004 vaccinations in US reported ~1 case of autoinoculation per 6,500 
vaccinations with 17% of ocular cases, none with corneal involvement (Neff 2008).  Vaccinia keratitis is 
the most serious consequence of autoinoculation, since lesions on the cornea threaten eyesight. 
Diseased or injured conjunctiva and cornea may increase the risk of this complication.  Vaccinia keratitis 
will respond to treatment with topical antiviral agents and interferon and can be prevented with use of 
occlusive bandages over the scarification site and by subject education (Fulginiti 2003). 
Transmission of vaccinia to close contacts is another known complication.  Contact vaccinia may manifest 
as progressive vaccinia, eczema vaccinatum or accidental infection of eye, mouth, genital areas.  Review 
of several national and state surveys between 1962 and 1968 gives frequency for EV at 8 - 27 per 

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1,000,000 and for accidental infections at 3 - 44 per 1,000,000 (Neff, 2002).  The rate of contact vaccinia 
in 2002 – 2004 was <10 cases per 100,000. Education of vaccinees in proper care for the vaccination 
site, proper hand hygiene and avoidance of contact with at risk individuals seems to be a reasonable and 
effective prophylactic against contact vaccinia. 
PROSTVAC-V/F immunization is subcutaneously administered, which greatly reduces injection site 
reactions, and skin surface wound formation/viral shedding. PROSTVAC-V/F is also given to vaccinia pre-
immune persons.  Both of these factors reduce the potential for inadvertent infection versus traditional 
smallpox vaccine programs. 
1.5.2 
Fowlpox Virus 
Fowlpox virus has been investigated and used in vaccine design for at least two decades. As a pox virus, 
it offers the advantages of a large genome but provides an additional safety assurance by not being able 
to replicate in mammalian cells. Fowlpox virus-based vaccines have been tested in both animals and 
humans for HIV, malaria and cancer. No safety concerns have been raised and the adverse events 
associated with the use of fowlpox vector have been limited to mild injection site reactions  
(Beukema 2006, Webster 2006). 
1.6 
Potential Benefits and Risks to Human Subjects 
The intent of vaccination with PROSTVAC-V/F is to induce an immune response to prostate-specific 
antigen (PSA), and other prostate- and tumor-specific antigens.  In the randomized, placebo controlled 
Phase 2 trial; an over-all survival benefit among patients who received PROSTVAC-V/F was observed.  It 
is unknown whether PROSTVAC-V/F will provide this benefit to subjects participating in this trial, as this 
product is still currently in development. Benefits of this trial also include the potential boosting (or 
acquisition) of protective immunity against smallpox. 
Based on clinical experience with PROSTVAC-V/F in Phase 2, adverse reactions are expected to be 
minimal. A local injection site reaction is typical, and comparable to those seen with other modern 
vaccines. Potential adverse reactions attributable to the administration of PROSTVAC-V/F at ≥ 50% 
frequency include injection site reactions (pain, swelling, induration, and redness), and at ≥ 10% 
frequency include headache, fatigue, myalgia, and nausea; the majority of events of Grade 1 and 2 in 
severity. 
The priming vaccination with PROSTVAC-V is with a vaccinia-based replicating virus. Special wound 
precautions are required. The vaccinia virus has been used in millions of people to eliminate smallpox.  In 
this trial it is given subcutaneously, not by dermal scarification, and local injection site reactions are much 
less severe, and viral shedding is minimal.  However, there are still risks of inadvertent infection of other 
body sites (through scratching), or transfer of infection to others. Special bandage precautions are 
required, and subjects need to avoid contact with small children <3 years of age, individuals who are 
immunocompromised or are receiving immunosuppressive therapies, and pregnant or lactating women 

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(for 3-4 weeks). With smallpox vaccine programs in vaccinia-naïve subjects immunized by dermal 
scarification, inadvertent inoculation occurred approximately 1/6,000 vaccinations. Subjects in this trial will 
be given detailed instructions on proper care of the injection site and rules of hygiene to prevent 
inadvertent inoculations and transmission of vaccinia virus. 
In the recent series of military and civilian vaccinations, vaccinia immunization has been reported to 
induce myopericarditis. Symptoms of chest pain were typically mild and transient, but occurred in 1/1,000 
subjects.  The incidence of this complication is lower in re-vaccinees. To prevent potential exacerbation of 
existing chronic problems, this protocol excludes subjects with known history of heart disease from 
participating in the trial. In addition, there are rare risks of severe and possibly life-threatening adverse 
reactions. These include eczema vaccinatum (~1/25,000, usually with history of underlying skin disorder) 
or progressive vaccinia infections (~1/300,000, usually with underlying immunodeficiency), or post 
vaccinial encephalitis (~1/500,000, usually infants or small children). These were observed after the 
administration of conventional smallpox vaccines, and have not been seen in prior studies of 
PROSTVAC-V/F or related PSA (or other tumor antigen-containing vaccinia virus vaccines) administered 
to vaccinia pre-immune cancer subjects Under the proposed protocol, age restriction, exclusion of all pre-
existing conditions with features of immune suppression and skin disorders minimize the risk of such rare 
complications. 
During study treatments, subjects will be under the continuous care of the investigator and his/her staff 
and will be assessed for adverse events which will be recorded in the subject’s CRF. SAEs must be 
reported to BNI or its designee within 24 hours of discovery. To minimize risk, potential subjects who have 
a known allergy to eggs, egg products, aminoglycoside antibiotics or GM-CSF, or other pre-existing 
medical conditions known to be risk factors for SAEs will be excluded from participation. 
In view of the anticipated mild side effects, the potential risks for the subject seem to be limited and to 
justify the potential benefit of participating in this trial. 
1.7 
Rationale for Double-Blinding 
This study has been designed to be double-blinded despite having an objectively ascertained primary 
endpoint (survival) for the following reasons: 
• 
There will be no study defections due to randomization disappointment (so subjects randomized 
to placebo will not quit the study). 
• 
There will be no difference in use of post-treatment anti-cancer therapies or concomitant 
therapies due to knowing the intervention being delivered. 
• 
There will be no difference in the interpretation of biomarkers or lab tests due to knowing the 
intervention being delivered. 
• 
The between-arm comparison of adverse events will not be corrupted by knowing the intervention 
being delivered. 

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2.0 
NAME AND DESCRIPTION OF STUDY AGENTS 
2.1 
Formulation, Packaging, and Labeling 
The PROSTVAC-V/F study vaccines, including placebo, are manufactured at 
 
 in compliance with current good manufacturing practices (cGMPs). The 
formulations do not contain adjuvants or preservatives. 
 
 
 the vials are sealed with rubber injection stoppers and 
plastic/aluminum flip-caps, and a label is affixed to the vial.  PROSTVAC-V/F study vaccine vials are then 
packaged in 6-vial cartons with an outer carton label. 
GM-CSF (Leukine®: 250 μg, lyophilized) will be purchased from licensed, US pharmacy wholesalers. 
Lyophilized GM-CSF is reconstituted with 1.0 mL bacteriostatic water for injection.  GM-CSF vials will not 
be relabeled, and will be packaged in 5-vial cartons with an outer carton label. 
GM-CSF placebo is bacteriostatic sodium chloride for injection and will be purchased from licensed, US 
pharmacy wholesalers.  GM-CSF placebo vials will not be relabeled, and will be packaged in 25-vial trays 
with a label. 
Examples of carton and vial labels are included in Appendix 14.10. 
2.2 
Investigational Drug Product (PROSTVAC-V/F) 
PROSTVAC-V/F is comprised of two components. PROSTVAC-V is a replication-competent vaccinia 
virus which has been engineered to encode the sequences for a modified human prostate-specific 
antigen (PSA) and a triad of co-stimulatory molecules (TRICOM). PROSTVAC-F is a fowlpox virus which 
does not replicate in human cells and has been engineered to encode the same sequences present in 
PROSTVAC-V. A full description of the PROSTVAC-V/F product and PROSTVAC-V/F pre-clinical and 
clinical support are contained in the Investigator’s Brochure. 
Study vaccine for this trial contains no preservatives or adjuvants and is supplied in single-dose 2 ml 
clear, borosilicate glass injection vials with rubber injection stoppers covered by a plastic-aluminum flip 
cap.  
Active Ingredient:  
PROSTVAC-V: PROSTVAC-V-PSA-TRICOM in aqueous solution for injection 
 
PROSTVAC-F: PROSTVAC-F-PSA-TRICOM in aqueous solution for injection 
 
Product Description:  PROSTVAC-V/F is comprised of two recombinant pox viruses: a recombinant 
vaccinia virus (PROSTVAC-V) and a recombinant fowlpox virus (PROSTVAC-F).  
 
 
 
 
 

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Dose:   
0.5 ml containing at least 2 x 108 Infectious Units (Inf.U) PROSTVAC-V 
 
0.5 ml containing at least 1 x 109 Inf.U PROSTVAC-F 
Route of Administration:  
Subcutaneous injection  
Storage*: 
−70°C or below  
There is no pre-treatment regimen for PROSTVAC-V/F. 
* Storage conditions and stability claims for the final PROSTVAC-V/F product are based on long-term 
manufacturing experience with PROSTVAC-V/F by Therion, the initial manufacturer. The stability data for 
PROSTVAC-V/F shows virus titer stability for four years when stored at −80°C (± 10°C). 
Regimen of Administration: Doses of PROSTVAC-V/F or placebo will be drawn into labeled syringes by 
an independent, unblinded research pharmacist or designee for use by the clinic staff.  PROSTVAC-V will 
be administered by the study staff once by sc injection on one side (upper arm or upper outer thigh) 
during Week 1. PROSTVAC-F will be administered by the study staff six times by sc injection during 
Weeks 3, 5, 9, 13, 17, and 21. Vaccination with PROSTVAC-F will begin on one side (upper arm or upper 
outer thigh), and subsequent immunization sites should be rotated to the opposite side and/or limb if 
possible.  
2.3 
GM-CSF 
GM-CSF (Leukine®: 250 μg, lyophilized) will be purchased from licensed, US pharmacy wholesalers and 
labeled appropriately for the study. Lyophilized GM-CSF will be reconstituted using 1.0 ml of room 
temperature bacteriostatic water for injection (USP-grade or equivalent). Product reconstituted with 
bacteriostatic water for injection is stable for 20 days if stored between 2 and 8°C in the original vial. See 
product label for information related to product description and formulation. Doses of GM-CSF of 100 μg 
each will be drawn into labeled syringes by an independent, unblinded research pharmacist or designee 
for use by the clinic staff or by individual subjects for home injection (subjects enrolled in France must 
return to the clinic to receive GM-CSF injections). 
Dose:  
 
0.40 ml (100 μg) GM-CSF 
Route of administration:  
Subcutaneous injection  
Storage: 
 
2 - 8°C (lyophilized and reconstituted); Up to 4 days at 2 - 8°C when in 
syringes 
Regimen of administration:  
GM-CSF will be injected sc by the study staff on the day of vaccine or 
placebo administration and for the subsequent 3 days, within 
approximately 5 mm of the injection site by the study staff, the subject, 
or subject’s caregiver (subjects enrolled in France must return to the 
clinic to receive GM-CSF injections). 

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2.4 
PROSTVAC-V/F Placebo:  
Empty fowlpox vector 
The PROSTVAC-V/F placebo will be provided in blinded vials matched to active product.  The same 
placebo will be used for both vaccinia and fowlpox PROSTVAC-V/F components.  
Dose:  
0.5 ml containing at least 1 x 109 Inf.U 
Route of administration:  
Subcutaneous injection  
Storage: 
–70˚C or below 
Regimen of administration:  
PROSTVAC-V placebo will be administered once by sc injection by the 
study staff in the upper arm or upper outer thigh during Week 1. 
PROSTVAC-F placebo will be administered by the study staff six times 
by sc injection during Weeks 3, 5, 9, 13, 17, and 21. Vaccination with 
PROSTVAC-F placebo will begin on one side (upper arm or upper 
outer thigh), and subsequent immunization sites should be rotated to 
the opposite side and/or limb if possible. 
2.5 
GM-CSF Placebo 
GM-CSF placebo will consist of USP-grade or equivalent bacteriostatic sodium chloride (saline) for 
injection.  Doses of GM-CSF placebo will be drawn into labeled syringes by an independent, unblinded 
research pharmacist or designee for use by the clinic staff or by individual subjects for home injection 
(subjects enrolled in France must return to the clinic to receive GM-CSF placebo injections). 
Dose: 
0.40 ml injection of bacteriostatic sodium chloride (saline) for injection 
Route of administration:  
Subcutaneous injection  
Storage: 
Room temperature when in vials; Up to 4 days at 2-80 C when in 
 
syringes 
Regimen of administration:  
GM-CSF placebo will be administered sc on the day of 
 
PROSTVAC-V/F or PROSTVAC-V/F placebo vaccination by the study 
 
staff and for the subsequent 3 days, within approximately 5 mm of the 
 
PROSTVAC-V/F or PROSTVAC-V/F placebo vaccination site by the 
 
study staff, the subject, or the subject’s caregiver (subjects enrolled in 
 
France must return to the clinic to receive GM-CSF placebo injections). 
 
 

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3.0 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 
Primary Efficacy Objective  
To ascertain whether the survival of subjects randomized to Arm V+G (PROSTVAC-V/F plus GM-CSF) or 
to Arm V (PROSTVAC-V/F) is superior to that from subjects randomized to Arm P (placebo control). 
3.1.2 
Secondary Efficacy Objective 
To ascertain whether a greater proportion of subjects randomized to Arm V+G or to Arm V remain event-
free at six months (or early termination) as compared to the subjects randomized to Arm P.  
3.1.2.1 
Definition of Event (To be Used in Secondary Endpoint)  
Progression events will be defined as: 
• 
Radiographic progression 
o 
Two new lesions on bone scan, new metastases on CT scans*, or an increase size of 
nodal lesions per RECIST 1.1.  
• 
Pain progression 
o 
Introduction of scheduled opioid narcotics for cancer-related pain control. 
• 
Initiation of chemotherapy 
• 
Death 
* For subjects with allergies to contrast agents, MRIs for abdomen and pelvis may be performed.  Only in 
cases where MRI is unavailable may a non-contrast CT be performed. For subjects enrolled in Germany, 
MRI must be used as the primary imaging modality. 
Radiographic progression will be assessed by bone scan at 3 and 6 months, and by CT scan (or MRI for 
subjects in Germany) at 6 months (and at the time of progression, or any time during the treatment period 
if clinically indicated). For secondary endpoint analysis, baseline scans and 6 month scans (or early 
termination scans) will be compared by central radiology review. Bone scan and CT (or MRI for subjects 
in Germany) data will be archived up to five years past the end of the trial. 
In addition, for an exploratory endpoint, we will assess radiological progression at 12 months (6 months 
post End-of-Treatment visit) by comparison with the 6 month scans (from End-of-Treatment visit or early 
termination).  This will attempt to define effects on secondary progression, and characterize delayed 
effects of investigational vaccine therapy. 

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3.1.3 
Safety Objective 
To further characterize the safety and tolerability of PROSTVAC-V/F immunotherapy, characterize type 
and number of AEs compared to placebo. 
3.1.4 
Exploratory Objectives 
To model secondary radiological disease progression over the first year of study participation.  
To ascertain whether a greater proportion of subjects randomized to either Arm V+G or Arm V remain 
event-free (radiological progression) six months post End-of-Treatment visit (using scans at End-of-
Treatment visit as a new baseline), as compared to the subjects randomized to Arm P.  This analysis will 
include all subjects, and separately the HLA-A2-expressing subgroup. 
To assess the role of post-treatment anti-cancer therapies as an alternative explanation for observed 
survival differences.  
To ascertain whether the survival of HLA-A2-expressing subjects randomized to Arm V+G, or Arm V is 
superior to that from HLA-A2-expressing-subjects randomized to Arm P.  
To ascertain whether a greater proportion of HLA-A2 expressing subjects randomized to Arm V+G or to 
Arm V remain event-free at six months as compared to the HLA-A2 expressing subjects randomized to 
Arm P. 
To compare arms with respect to immune response to immunizing antigen (PSA), as well as to non-
vaccine containing prostate antigens, and tumor-associated antigens, and assess whether immune 
responses are prognostic and/or predictive. 
To evaluate for baseline biomarkers which are prognostic and/or predictive of long term survival outcome. 
To compare arms with respect to vaccine effects on circulating tumor cell (CTC) levels (US sites only). 
3.2 
Study Endpoints 
3.2.1 
Primary Efficacy Endpoint 
The primacy efficacy endpoint for the trial is overall survival. 
3.2.2 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint for the study is the proportion of event-free subjects (radiological 
progression, pain progression, chemotherapy initiation, or death) at six months (or early termination) 
compared to placebo.  

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4.0 
INVESTIGATIONAL PLAN 
4.1 
Study Design 
BNIT-PRV-301 is a randomized, placebo-controlled, multi-center, multi-country, Phase 3 efficacy trial of 
PROSTVAC-V/F in men with asymptomatic or minimally symptomatic, metastatic, castration-resistant 
prostate cancer. Subjects will be randomized with equal probability (1:1:1) to one of three double-blind 
arms; two investigational arms (Arm V+G; Arm V), and a control arm (Arm P). The study will consist of 
three periods: a Screening phase, followed by Treatment, and subsequently Long-Term Follow-Up 
(LTFU) phases. 
The intended intervention in Arm V+G is PROSTVAC-V/F plus GM-CSF; Arm V intended intervention is 
PROSTVAC-V/F plus GM-CSF placebo, whereas the intended intervention in Arm P is vaccine placebo 
plus GM-CSF placebo. The trial interventions will consist of a single sc immunization of PROSTVAC-V or 
placebo in Week 1, followed by six PROSTVAC-F or placebo immunizations administered in Weeks 3, 5, 
9, 13, 17, and 21.  Each immunization will be accompanied by administration of sc GM-CSF or placebo 
on the day of immunization and for the subsequent three days (sc injection within 5 mm of the original 
PROSTVAC V/F or placebo injection site).  The Treatment phase of this trial lasts for five months and is 
followed by an End-of-Treatment visit at Week 25. During the Treatment phase, subjects will continue to 
be treated with vaccination therapy or placebo through PSA and/or radiological progression. 
Following the completion of the Treatment phase (after the last dose of PROSTVAC-V/F + GM-CSF or 
placebo or early termination of treatment) of the trial, all subjects will automatically enter the LTFU phase 
with study visits occurring every six months. During LTFU subjects will receive standard-of-care treatment 
as determined by the Principal Investigator or treating physician. The appropriate timing and the nature of 
any subsequent treatment will be at the discretion of the Principal Investigator or treating physician. All 
treatments for mCRPC subsequent to the Treatment phase of the trial will be documented in the CRF. 
This comprehensive data will be collected until study closure, death, or until a subject withdraws from the 
study.  
The primary endpoint for the study is overall survival. All subjects will be followed for 12 months after the 
required number of 534 events for each between-arm comparison is realized.  
4.2 
Sample Size 
This study will evaluate approximately 1,200 subjects (400 subjects/arm) with a 1:1:1 randomization of 
PROSTVAC-V/F plus or minus GM-CSF versus placebo control plus GM-CSF placebo. 
4.3 
Selection of Study Population 
All subjects will be men ≥ 18 years old with asymptomatic or minimally symptomatic, metastatic CRPC. 
Subjects will have progressive disease following androgen suppression or complete blockade therapy, or 
surgical castration; and will be chemotherapy naïve for metastatic prostate cancer. Subjects must be 

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vaccinia experienced (previous smallpox vaccination). Subjects must have a castrate testosterone level of 
<50 ng/dl at study entry. 
For subjects on anti-androgens, a 6-week washout is required (4 weeks if on flutamide).  
Prospective subjects may be screened from hospital or clinic records or databases, or may be new 
patients. At the discretion of the institution, subjects may be recruited by advertisements, on-line, in 
newsletters or journals, flyers, or on radio provided the content and distribution is approved by BNI and by 
the IRB/EC prior to use or release. BNI will list the study on the government website, 
www.clinicaltrials.gov. 
4.4 
Targeted Enrollment of Minorities 
Attempts will be made (in the US) to specifically enroll minority subjects up to the level of representation 
in the general US population. Cities with high minority populations will be specifically targeted for center 
recruitment, as will study centers serving primarily minority populations; e.g., Historically Black Colleges 
and Universities. Attempts will be made to tailor advertising and recruitment tools to minority groups and 
to enlist the help of subject advocacy groups in high minority population centers. 
4.5 
Method of Assigning Subjects to Treatment Groups 
This study is double-blind and placebo-controlled. Enrollment will be randomized with equal probability to 
each of three double-blinded arms: two investigational arms (Arm V+G or Arm V) and a control arm (Arm 
P). The intended interventions associated with the arms are: active treatment with PROSTVAC-V/F + 
GM-CSF (Arm V+G); PROSTVAC-V/F + GM-CSF placebo (Arm V); or placebo control (Arm P).  Block 
randomization will be used to randomly assign subjects in a 1:1:1 manner.  Randomization will be 
stratified according to the following two factors, PSA (equal and above or below 50 ng/ml) and LDH 
(equal and above or below 200 U/mL).  
4.6 
Inclusion Criteria 
Eligible subjects must meet all the following criteria (there will be no exemptions for Inclusion/Exclusion 
criteria): 
1. Signed Informed Consent.  
2. Men, ≥18 years of age with documented asymptomatic or minimally symptomatic metastatic 
castration-resistant prostate cancer.  
3. Castrate testosterone level < 50 ng/dl. 
4. Documented progressive disease post-surgical castration or during androgen suppression 
therapy, or during complete androgen blockade therapy and withdrawal. Documented by either 
criterion a (Radiological progression), OR criterion b (PSA progression). 

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a. Radiological progression defined as any new/enlarging bone metastases or new/enlarging 
lymph node disease, consistent with prostate cancer. 
OR 
b. PSA progression defined by sequence of rising values separated by > 1 week (2 separate 
increasing values) over a threshold minimum of 2.0 ng/ml. (PCWG2 PSA eligibility criteria). 
5. Chemotherapy naïve. No prior chemotherapy for metastatic prostate cancer. Neo-adjuvant or 
adjuvant chemotherapy for primary prostate cancer is permissible if >3 years prior.   
6. Vaccinia-experienced (previous smallpox vaccination). 
7. ECOG Performance Score of 0 or 1. 
8. Life expectancy ≥ 1 year. 
9. Bone Marrow function: 
• 
Absolute neutrophil count ≥ 1,500/mm3 
• 
Hemoglobin ≥ 10 g/dL  
• 
Platelet count ≥ 100,000/mm3 
10. Hepatic Function: 
• 
AST and ALT ≤ 2.5 times upper limit of normal (ULN) 
• 
Bilirubin ≤ 1.5 times ULN 
11. Renal Function: 
• 
Creatinine ≤ 2.0 times ULN 
12. Currently using a GnRH agonist or antagonist (unless surgically castrated). 
4.7 
Exclusion Criteria 
Subjects with any of the following will be excluded from enrollment: 
1. Cancer-related pain requiring scheduled opioid narcotics for control (as needed, ≤ 2x per week is 
allowed). 
2. Metastasis to organ systems other than lymph nodes and/or bone. 
3. LDH ≥ 2 times ULN. 
4. Alkaline phosphatase ≥ 2 times ULN. 

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5. Estimated PSA doubling time of <1 month as established within 6 months of the anticipated first 
dose of vaccine or placebo.  A minimum of 3 PSA level determinations, at least 2 weeks apart 
(over a 6 month time-period), are required for assessment. 
6. Concurrent or prior Provenge (sipuleucel-T) immunotherapy for prostate cancer. 
7. Receipt of an investigational agent within 30 days (or 60 days for an antibody-based therapy) of 
the first planned dose of PROSTVAC-V/F. There is no exclusion to previous experimental therapy 
provided dosing/treatment is completed at least 30 days prior to the first planned dose of vaccine 
unless otherwise noted. 
8. History of prior malignancies other than prostate cancer within the past 3 years, excluding 
successfully resected basal or squamous cell carcinoma of the skin. 
9. Congestive heart failure (NYHA Class II, III, or IV), unstable angina, ventricular or 
hemodynamically significant atrial arrhythmia, or cardiovascular disease such as stroke or 
myocardial infarction (current or within the past 6 months). 
10. Confirmed positive for HIV, hepatitis B, and /or hepatitis C. 
11. Prior solid organ or bone marrow transplant. 
12. Immunodeficiency or splenectomy. 
13. Chronic immunosuppressive therapy within 30 days of screening. 
14. Inflammatory eye disease requiring steroid treatment. 
15. Chronic administration (defined as daily or every other day for continued use > 14 days) of 
systemic corticosteroids within 28 days of the first planned dose of PROSTVAC-V/F. Use of 
inhaled steroids, nasal sprays, and topical creams for small body areas is allowed. 
16. History of or active autoimmune disease (e.g., autoimmune neutropenia, thrombocytopenia, or 
hemolytic anemia, systemic lupus erythematosis, Sjogren’s syndrome, scleroderma, myasthenia 
gravis, Goodpasture’s syndrome, Addison’s disease, Hashimoto’s thyroiditis, or Graves disease).  
Persons with vitiligo are not excluded. Diabetics are not excluded if the condition is well 
controlled. 
17. Known allergy to eggs, egg products, aminoglycoside antibiotics (for example, gentamicin or 
tobramycin), or GM-CSF. Subjects with a known or suspected allergy to radiological contrast 
agents are eligible, but this must be noted in the subject’s medical history and in the chart notes. 

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18. History of atopic dermatitis or active skin condition (acute, chronic, exfoliative) that disrupts the 
epidermis. 
19. Previous adverse reactions to smallpox vaccination. 
20. Unable to avoid close contact or household contact with the following high-risk individuals for 
three to four weeks after the Day 1 vaccination or until the vaccination site heals completely: (a) 
children ˂ 3 years of age, (b) pregnant or nursing women, (c) individuals with prior or concurrent 
extensive eczema or other eczemoid skin disorders, or (d) immunocompromised individuals, such 
as those with HIV. 
21. Significant medical abnormality (defined as a pre-existing condition AE/condition ≥ Grade 3 
according to NCI CTCAE v 4.0 and any condition which, in the opinion of the investigator, would 
prevent full participation in this trial (including the Long-Term Follow-Up), or would interfere with 
the evaluation of the trial endpoints. 
22. Study personnel. 
5.0 
SAFETY MONITORING 
5.1 
Data Monitoring Committee (DMC) 
An independent Data Monitoring Committee will be established to ensure subject safety, to consider 
subject risks against the potential for meeting trial objectives, and to provide recommendations to BNI 
with respect to the conduct and analysis of the trial. The DMC will operate independently of BNI with the 
exception of the administration of compensation to the DMC members for DMC-related activities and non-
voting activities such as clinical trial conduct updates. The voting members of the DMC will be a multi-
disciplinary group that may include representative physicians who treat the type of subjects entered onto 
this trial; one or more individuals with statistical expertise; and if appropriate, one or more biological 
scientists. The DMC will meet either by phone or in person and will be provided with all available pertinent 
subject data in a manner specified in the approved Charter. An Executive Summary of Committee 
recommendations generated at each meeting will be forwarded to all IRBs/ECs as requested or required. 
Minutes of the closed sessions will be held in confidence by the DMC or its designee until the official 
close of the trial. The exact constitution and conduct of the DMC will be ultimately governed by the 
approved Charter. A vital status sweep will be performed in conjunction with each DMC meeting to 
ensure the most current data is being reviewed. 
5.2 
Dose-limiting Toxicities and Trial Stopping Rules 
5.2.1 
Dose-limiting Toxicities 
For the purposes of this trial, a dose-limiting toxicity (DLT) is defined as any anaphylactic reaction, a full-
thickness ulceration/necrosis, or any AE ≥ Grade 3 definitely related to study drug with the following 
exceptions: 

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• 
Local injection site reactions lasting < 72 hours: pain, redness, swelling, induration, or 
pruritus 
• 
Systemic injection reactions lasting < 72 hours: fever; myalgia, headache, nausea, 
fatigue 
Study drug should be discontinued for the subject in the case of a definitely related anaphylactic reaction 
or full-thickness ulceration/necrosis. Re-exposure to study drug after development of other related AE ≥ 
Grade 3 should only occur if the event resolved or is reduced to grade 1 toxicity. 
5.2.2 
Trial Stopping Rules 
In the event of a death definitely related to study drug within 24 hours of vaccination or ≥ 3 definitely 
related SAEs (per 20 patients) at any time after receiving study drug during the treatment period, dosing 
will halt immediately and the DMC will be consulted. All data will be reviewed prior to any further dosing, 
and dosing will not continue until the DMC agrees that it is safe to continue. At the discretion of the DMC, 
the FDA or other Health Regulatory Agencies may be consulted. The decision to permanently halt the trial 
may only be made by BNI Executive Committee. 
5.3 
Emergency Unblinding Of Treatment Assignment (If Applicable) 
All investigational vaccine products for this study have been packaged and labeled in a blinded fashion. 
GM-CSF will be labeled for investigational use as required by the local and regional Health Authorities, 
Lyophilized GM-CSF is not packaged and labeled in a blinded fashion. Reconstituted GM-CSF or GM-
CSF placebo in single-use syringes is blinded. Unblinding by study site personnel for adverse events 
should only be performed in emergencies where knowledge of the subject’s treatment assignment is 
essential for further management of the subject’s medical care.  Unblinding a subject’s treatment 
assignment under any other circumstances will be considered a protocol violation.  The Principal 
Investigator is strongly encouraged to contact the BNI Medical Monitor before unblinding any subject’s 
treatment assignment, but must at least do so within 1 working day after the unblinding.  Although the 
Medical Monitor should be contacted the subject’s treatment code should not be communicated to the 
Medical Monitor. Emergency unblinding for adverse events will be performed through an interactive voice-
response system (IVRS).  All calls resulting in an unblinding event are recorded and reported by the 
IVRS.  Emergency unblinding must also be documented at the study site.  The Medical Monitor will 
receive notification of unblinding from IVRS but will not be notified of the subject’s treatment assignment. 
5.4 
Removal of Subjects from Therapy or Assessment 
Subjects may withdraw consent for participation in the study at any time without prejudice.  Additionally, 
the investigator may withdraw a subject if, in his/her clinical judgment, it is in the best interest of the 
subject or if the subject cannot or will not comply with the protocol. Wherever possible, the End-of-Study 
tests and evaluations listed in Section 7.4 should be carried out at the time the subject withdraws or 
whenever the Investigator feels that the subject will be unable to make any further visits. 

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If a subject fails to return for the necessary visits or discontinues prematurely from the study, a genuine 
effort must be made to determine the reason why. If the subject or his designated contact is unreachable 
by telephone, the minimum of a registered letter should be sent requesting that contact be made with the 
Investigator (or designee) to report survival information. Every attempt possible to obtain follow-up blood 
samples for safety and immune monitoring should be made. Request for an autopsy, autopsy report and 
death certificate when/if the subject expires while on trial should be pursued. 
BNI may discontinue individual subjects, study arms, individual study centers, or the entire study at any 
time provided sufficient time is given to ensure subject safety. 
5.4.1 
Clinical or Kinetic Progression: Removal of Subjects from Therapy 
Subjects who experience a significant clinical progression during the treatment phase (i.e., before last 
vaccination is received) will be counseled to seek alternative therapy.  Significant clinical progression is 
defined by the need to institute scheduled narcotic pain relief measures for cancer-related pain, or 
acceleration of tumor growth kinetics by PSA (PSA doubling time <1 month). Such subjects are allowed to 
continue vaccine therapy at the discretion of the PI if the decision is made not to seek alternative anti-
cancer treatment(s). If subjects choose to initiate alternative anti-cancer treatment, vaccination will be 
discontinued. All subjects will continue on study and will be followed for survival and safety per protocol.  
5.4.2 
Biochemical or Radiological Progression: Continuation of Therapy 
Vaccination may take several months to induce an immune response.  PSA declines and radiological 
responses are infrequent, and the expectation is for a slowing of ongoing disease progression. Due to the 
delayed effect of vaccine induced immunotherapy, PSA progression and radiological progression may be 
expected during the treatment phase of the trial, and are not a cause for stopping vaccination.  Continued 
vaccination to maximize immune response is believed to be beneficial based on earlier clinical trials. 
5.5 
Replacement Policy 
5.5.1 
Subjects 
No subjects will be replaced in this study.  All subjects who receive at least one dose of PROSTVAC-V/F 
or placebo will be considered evaluable and will be included in all appropriate analyses as described in 
Section 9.0. 
5.5.2 
Research Centers 
Centers will be opened only after all requirements for documentation have been met as defined by 
Appendix M (M-I-C-1) of the NIH Guidelines for Research Involving Recombinant DNA Molecules (April 
2002) or the appropriate regional or national guidelines outside the United States. If an approved 
institution declines further participation or is dropped for any reason, or if enrollment lags, new centers 
may be added under the same restrictions. 

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6.0 
STUDY TREATMENTS 
6.1 
Investigational Study Drug Accountability  
Prior to study start, each Investigator will provide the actual location (facility, room number, and 
freezer/refrigerator number, if any) and identify the pharmacist, study coordinator, sub-investigators, or 
other personnel who will have access to the drug, and if different from above, any personnel who will 
have preparation, administration, receipt and disposal responsibilities of the study drug. It should be 
noted that reconciliation of PROSTVAC-V/F and GM-CSF vials will be performed by an independent 
unblinded monitor in order to keep the study monitor blinded.  
Accurate records of dates, quantities and the lot or vial numbers of all study drug received, to whom 
dispensed (subject-by-subject accounting), and accounts of any product accidentally wasted or 
intentionally disposed of must be maintained.  The disposal of all used, partially used, or wasted study 
drug vials and syringes must be performed in accordance with the hospital or institution’s drug disposal 
policy for infectious medical waste.  Used vials will not be retained by the pharmacy for drug 
accountability. The institution’s policy for disposal must be kept in the Pharmacy Manual and a copy 
provided to BNI. 
Accountability records must be maintained and readily available for inspection by representatives of BNI 
or designee and are open to inspection by regulatory authorities at any time. 
6.2 
Assessment of Study Drug Compliance  
Accountability and reconciliation of drug dispensing and administration compliance will be assessed by 
review of adequate drug dispensing (including return) records performed periodically by the unblinded 
monitor. 
A drug dispensing log must be kept current and will be reviewed periodically throughout the study by the 
unblinded monitor. 
6.3 
Disposal of Drug Supplies 
Local or institutional regulations require immediate disposal of used study drug.  The investigational site 
staff is to destroy any dispensed study drug vials and syringes in accordance with the institution’s policy. 
Source document verification will be performed on the remaining inventory and reconciled against the 
documentation of quantity shipped, dispensed, and disposed. Each research center must provide BNI a 
statement of the institutional policy and procedures for disposing of material with a Biosafety rating of 
RG2 (Appendix 14.2; RAC Guidelines 2002, Appendix B or equivalent outside the United States) and the 
institution’s policy and procedures for disposal of hazardous waste or biologic products.  A copy of the 
policy must be placed in the Pharmacy Manual and provided to BNI.  
At the conclusion of the Treatment phase of the study, all unused vaccine, GM-CSF, and placebo 
supplies (collectively, study medication) will be either disposed of on site or by a licensed facility 

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contracted by the site following final reconciliation. Subjects who received home-injections will be 
instructed to return all used and unused GM-CSF syringes to the site for disposal (not applicable to 
subjects enrolled in France as they must return to the clinic to receive GM-CSF injections). BNI or its 
designee will provide logs to each site pharmacy for recording IP dispensing (subject ID, date, disposal, 
etc.). Sites may use their own logs provided the required data is adequately captured. 
6.4 
PROSTVAC-V/F  
PROSTVAC-V is considered a BSL-2 agent; PROSTVAC-F is considered BSL-1 (but may be considered 
BSL-2 outside the United States, depending on country specific requirements). All vaccines in this trial 
should be handled using standard infection control procedures and study staff should wear personal 
protection consisting of at least a lab coat, gloves, and protective eyewear when handling  
PROSTVAC-V/F. More complete instructions and guidelines are included in the Study Instruction Manual 
and Pharmacy Manual.  
PROSTVAC-V/F is prepared in a phosphate-buffered saline (PBS) with 10% glycerol and stored at -70˚C 
or colder until the day of use. Once used and accounted for, vials should be disposed of according to 
institutional standards, local and occupational safety guidelines. 
There is no pre-treatment regimen for PROSTVAC-V/F. 
PROSTVAC-V/F should not be mixed with any other medicinal product.  Refer to the pharmacy manual 
for instructions regarding administration. 
Subjects should remain in the clinic for at least 30 minutes following administration of PROSTVAC-V/F or 
placebo for observation for signs of adverse reactions. 
6.5 
GM-CSF 
GM-CSF (sargramostim; Leukine®) is a glycosylated, recombinant human GM-CSF manufactured by 
Genzyme Corporation.  GM-CSF is an altered form of the native molecule; the position 23 arginine has 
been replaced with a leucine to facilitate expression. Leukine is preserved with benzyl alcohol and 
provided in vials containing 250 μg of lyophilized product. GM-CSF is reconstituted using USP 
bacteriostatic water for injection (1.0 ml per vial). Refer to the Pharmacy Manual for instructions regarding 
administration). 
If the subject or their caregiver is proficient at self injection (as determined by the study staff), (s)he may 
be provided with the pre-filled syringes of GM-CSF (or placebo) for self injection for each of 3 consecutive 
days following the day of vaccination. If the subject or their caregiver is unable or does not wish to self 
inject, the subject must return to the clinic for three consecutive days following the vaccination to receive 
the GM-CSF or placebo (subjects enrolled in France must return to the clinic for three consecutive days 
following the vaccination to receive GM-CSF or placebo).  

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Site personnel are instructed to query subjects self-injecting GM-CSF for compliance and record the 
outcome in the subject’s chart. 
6.6 
Subject Instructions and Supplies 
Subjects, and if possible, subject caregivers, should be educated as to the care of the injection site, 
including proper bandage changing, bathing, possible side effects, and minimization of contact with at-risk 
individuals. Subjects will be provided with injection site care ‘kits’ containing, for example; instruction 
sheets, disposable gloves, absorbent toweling, alcohol swabs, non-adherent Telfa-type bandages, band-
aids, zip-lock biohazard bags for disposal of used bandages and gloves, pre-filled syringes for home 
injection of GM-CSF or placebo, a cold pack, a sharps container, and contact information for the study 
personnel (not applicable to subjects enrolled in 
as they must return to the clinic to receive GM-
CSF injections). Subjects should be instructed to return the zip-lock biohazard bag containing all used 
supplies at their next clinic visit. 
6.7 
Dose Reductions and Contraindications for PROSTVAC-V/F 
There are no dose reductions for this study. Subjects who experience intolerable reactions will be 
discontinued from treatment but will remain on study and be followed for safety, immune status, and 
survival per protocol. PROSTVAC-V/F will be discontinued as defined in Section 5.4.  Subjects 
discontinued from further vaccination should remain on study and continue to be followed for safety, 
immune status, and survival per protocol. 
For acute illnesses (fever, infectious disease, respiratory insufficiency, chest pain, angina, etc.) present at 
the time of a scheduled vaccination, the vaccination can be delayed until symptoms subside, the 
underlying process is treated or resolves, or the subject may be withdrawn at the discretion of the 
Investigator. If vaccinations are delayed due to acute illness, timing for scheduled assessments and 
remaining vaccinations should be reestablished according to the original Schedule of Events  
(Appendix 14.1) as soon as possible. 
6.8 
Procedures for Potential Serious Vaccinia Reaction 
The Investigator must notify an Infectious Disease Specialist in the 
Pharmacovigilance Group (PVG) 
if there is a suspected serious vaccinia reaction as soon as possible, but no later than 24 hours after 
he/she becomes aware. The Investigator should contact the BNI study Medical Monitor if there are 
specific questions in regard to the potential vaccinia reaction.  A swab of the suspected lesion may be 
obtained from the study subject for confirmatory testing prior to administration of VIG. The Investigator 
should refer to the Management Plan for Potential Serious Vaccinia Reaction for recognition, diagnosis 
and treatment of a rare potential serious vaccinia reaction.  This plan also describes when VIG is 
indicated for use and administration procedures.  For further information or for a supply of VIG in the 
United States, contact the Centers for Disease Control at (877) 554-4625. For centers outside the United 
States, VIG suppliers (where known) are listed in the Study Instruction Manual. The Investigator should 
refer to the Management Plan for Potential Serious Vaccinia Reaction.  If VIG treatment is warranted, the 

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person receiving VIG must sign the Consent Form to Administer Vaccinia Immune Globulin (VIG) PRIOR 
to administration of VIG. 
6.9 
Concomitant and Excluded Medications 
6.9.1 
Concomitant Medications: 
Subjects will be on concomitant androgen suppression therapy with a GnRH agonist or antagonist, unless 
surgically castrated.  Subjects may also be on concomitant drugs to prevent bone loss or skeletal-related 
events, including bisphosphonates and denosumab. Subjects may receive palliative radiotherapy during 
the trial. 
6.9.2 
Excluded Medications: 
During the Treatment phase of the study (approximately 5 months) all medications required for the health 
of the subject are allowed with the following exceptions: 
• 
Concurrent chemotherapy  
• 
Concurrent 
immunotherapy 
(e.g. 
sipuleucel-T, 
etc.) 
or 
immunosuppressive 
therapy  
(e.g. etanercept, natalizumab, etc.)  
• 
Concurrent anti-cancer radionuclides 
• 
Concurrent systemic corticosteroid use (daily or every other day for continued use  
> 14 days) 
• 
Concomitant use of secondary anti-cancer hormonal treatments (e.g. abiraterone) 
6.10 
Overdose 
Because PROSTVAC-V and PROSTVAC-F are provided in single-dose vials there is no potential for an 
overdose.  The highest single dose of PROSTVAC-V (2x108 Inf. U.) or PROSTVAC-F (1x109 Inf. U.) used 
in human studies did not show any dose-limiting toxicity.  
Because the GM-CSF dose on this study is approximately five times lower than the approved therapeutic 
dose, there is no potential for an overdose.  Possible side effects with the use of standard dosage are 
described in the commercial product insert (see the Pharmacy Manual). 

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7.0 
STUDY PROCEDURES BY STUDY PERIOD 
7.1 
Screening Assessments (Days –28 –1) 
Screening activities must be completed within 28 days prior to the first dose of any study medication 
unless noted. Assessments will be done over one or more visits and are to be completed prior to dosing. 
Subjects requiring anti-androgen wash-out specifically for this protocol should be consented prior to 
beginning withdrawal of therapy. No other screening procedures should be performed until it is clear that 
the subject is eligible as defined in Sections 4.6 and 4.7.  Subjects requiring wash-out and re-testing will 
be asked to re-sign an informed consent form prior to any additional screening procedures. Screening 
assessments performed greater than 28 days prior to first dose will need to be repeated except as 
specified below.  Subjects must be entered into IVRS after signing Informed Consent and prior to any 
screening procedures being initiated. 
For the purposes of this trial, one month = 4 weeks = 28 ± 3 days. 
After signing the Informed Consent, Screening assessments will include: 
1. Complete medical history, including smallpox vaccination history 
2. Prostate cancer history (primary diagnosis, progression history, treatments received; procedures 
undergone) 
3. Concomitant medications (all drugs currently being taken, all drugs prescribed during the past 
month, and all over-the-counter drugs or supplements (excluding vitamins) taken for ≥5 
consecutive days during the past month) 
4. Complete physical examination (PE) including vital signs (VS; sitting blood pressure [BP], heart 
rate, respiration rate [RR]), temperature, height and weight 
5. ECOG performance status 
6. 12-lead ECG 
7. Blood samples will be obtained for: 
a. Hematology (CBC and differential, RBC with indices, platelet count). 
b. Serum chemistry (BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, LDH, 
sodium, potassium, chloride, bicarbonate, calcium and glucose). 
c. Testosterone level. 
d. C-reactive protein. 
e. Cardiac markers (CK, CK-MB, Troponin T and I). 
f. 
Coagulation panel (PT (INR)/PTT). 
g. Serum PSA and PAP (prostatic acid phosphatase) levels. 

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h. Virology (HIV, HepBsAg, HepC) unless known negative within previous 2 months. 
8. Urinalysis (dipstick and microscopy). 
9. Bone scan, if not performed within 3 months of the start of screening. 
10. CT scan with contrast* (abdomen and pelvis) if not performed within 3 months of the start of 
screening. 
*For subjects with allergies to contrast agents, MRIs for abdomen and pelvis may be performed.  Only in 
cases where MRI is unavailable may a non-contrast CT be performed.  For subjects enrolled in Germany, 
MRI must be used as the primary imaging modality. 
7.2 
Day 1 (Day of first dose of PROSTVAC-V/F or placebo), Week 1 
Subjects must be randomized and the first dosing date entered and confirmed in IVRS prior to any 
Week 1 procedures being performed.  Treatment assignment must be obtained through IVRS prior to 
dosing. 
During Week 1 of the Treatment phase of this study, the following procedures will be performed and 
dosing will occur as follows  
To be performed PRIOR to administration of study drug: 
1. Adverse events (AEs) should be sought by non-directive questioning of the subject, self-reported, 
and/or directly observed at each clinic visit during the treatment phase of the study. 
2. Concomitant medications will be reviewed and any new medications recorded 
3. QoL (FACT-P, BPI-SF and EQ-5D-3L) where translations are available  
4. Abbreviated physical exam, consisting of VS, temperature, and weight. Only significant changes 
in PE from Screening will be recorded. 
5. ECOG performance status 
6. Immune monitoring assessments are to be collected prior to first dose only after a subject is 
deemed eligible for the study by all other criteria.  Blood sample collection will include:  
a. Serum for immune and biomarker status  
b. Peripheral blood RNA//biomarker analysis  
c. Immune functional assay (
) 
d. CTC quantification (
) 
7. Blood samples will be obtained for: 
a. Hematology (CBC with differential, RBC with indices, platelet count) 

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b. Serum Chemistry (BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, LDH, 
sodium, potassium, chloride, bicarbonate, calcium and glucose).  
c. Serum PSA and PAP levels 
d. HLA-A2 typing 
Dosing is to occur, as follows: 
a. Day 1 for PROSTVAC-V or placebo (subcutaneous)* 
b. Days 1, 2, 3, and 4 for GM-CSF or placebo (subcutaneous) 
* Subjects should remain in the clinic for at least 30 minutes following administration of PROSTVAC-V or 
placebo for observation of adverse reactions. 
7.3 
Week 3 Through Week 21 (booster vaccinations) 
During the 21-week Treatment phase of this study, the study visits will occur on Weeks 3, 5, 9, 13, 17 and 
21 (± 3 days for each individual visit). Medication assignment must be obtained through IVRS prior to 
dosing for each week of booster vaccinations.  The following procedures will be performed and dosing will 
occur as follows: 
To be performed PRIOR to administration of study drug: 
1. Adverse events (AEs) should be sought by non-directive questioning of the subject, self-reported, 
and/or directly observed at each clinic visit during the treatment phase of the study. 
2. Concomitant medications will be reviewed and recorded at all visits. 
3. Abbreviated physical exam (consisting of VS, temperature, and weight). Only significant changes 
in PE from Screening will be recorded  
4. ECOG performance status 
5. Blood samples, except for Week 3, will be obtained for: 
a. Hematology (CBC with differential, RBC with indices, platelet count) 
b. Serum Chemistry (BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, LDH, 
sodium, potassium, chloride, bicarbonate, calcium and glucose).  
c. Serum PSA and PAP levels (Weeks 5, 9, 13, 17, and 21) 
6. Bone scan 
• 
Week 13 only 
7. CT scan with contrast* (abdomen and pelvis):  
• 
Week 13, only if clinically indicated 

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Dosing is to occur, as follows: 
a. Day 1 of each week: PROSTVAC-F or placebo** 
b. Days 1, 2, 3 and 4 of each week: GM-CSF or placebo 
* For subjects with allergies to contrast agents, MRIs for abdomen and pelvis may be performed.  Only in 
cases where MRI is unavailable may a non-contrast CT be performed.  For subjects enrolled in 
Germany, MRI must be used as the primary imaging modality. 
**Subjects should remain in the clinic for at least 30 minutes following administration of PROSTVAC-F or 
placebo for observation of adverse reactions. 
7.4 
End-of-Treatment Visit – Week 25 or When A Subject Discontinues Treatment 
The End-of-Treatment visit is approximately 4 weeks ± 3 days after the last injection of vaccine or 
placebo.  The tests and evaluations listed for the End-of-Treatment/Early Termination Visit should be 
carried out at the time of any premature subject withdrawal (subject- or investigator-directed) or whenever 
the investigator feels that the subject will be or is unable or unwilling to make any further visits. If a 
subject discontinues treatment early for any reason, every attempt should be made to document the 
reason for the discontinuation.   
Any subject who requests to stop study treatment or has been withdrawn from study treatment before 
completion of the protocol-specified treatment duration will be strongly encouraged to complete the 
evaluations below, and encouraged to participate in the Long-Term Follow-Up Phase of the study 
provided the subject has not withdrawn full consent.  
1. Adverse events – will be collected by non-directive questioning, self-reported or directly observed 
occurring since last visit, and discuss and/or resolve any previously reported or ongoing events. 
2. Concomitant medications – record all medications being taken currently and record all previously 
taken, but discontinued drugs. 
3. QoL (FACT-P, BPI-SF and EQ-5D-3L) where translations are available  
4. Complete PE including VS, sitting BP, heart rate, RR, temperature, and weight 
5. ECOG performance status 
6. Blood samples will be obtained for: 
a. Hematology (CBC and differential, RBC with indices, platelet count) 
b. Serum chemistry (BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, LDH, 
sodium, potassium, chloride, bicarbonate, calcium and glucose) 
c. Coagulation panel (PT/(INR) / PTT) 
d. C-reactive protein 

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e. Serum PSA and PAP 
f. 
Serum for immune and biomarker status 
g. Peripheral blood RNA/biomarker analysis  
h. CTC quantification (US sites only) 
i. 
Immune functional assays (US sites only) 
7. Urinalysis 
8. 12-lead ECG 
9. Bone scan 
10. CT scan with contrast* (abdomen and pelvis)  
* For subjects with allergies to contrast agents, MRIs for abdomen and pelvis may be performed.  Only in 
cases where MRI is unavailable may a non-contrast CT be performed.  For subjects enrolled in 
Germany, MRI must be used as the primary imaging modality. 
7.5 
Assessments During Long-Term Follow-Up 
The Long-Term Follow-Up (LTFU) phase begins immediately after the End-of-Treatment visit regardless 
of the total number of vaccinations actually received by a subject. The first visit is 6 calendar months ± 14 
days after the End-of-Treatment visit with consecutive visits every 6 months ± 14 days thereafter.  
Subjects who progress prior to or during the LTFU phase will continue to be followed for survival and as 
described below until study closure or death.  
First LTFU visit at 6 Months ± 14 Days from the End-of-Treatment visit 
1. Concomitant medications (limited to the treatment of prostate cancer therapy). All previously 
recorded medication entries should be reviewed for stop dates. 
2. Prostate cancer treatment update for procedures, including interim unscheduled laboratory tests 
and/or radiological assessments. 
3.  Update for newly diagnosed autoimmune disease. 
4. Physical exam (limited to assessment of subject’s prostate cancer status including prostate 
cancer progression), vital signs, and weight. 
5. QoL (FACT-P, BPI-SF and EQ-5D-3L) 
6. Blood samples obtained for: 
i. Serum for immune and biomarker status. 
ii. Peripheral blood RNA/biomarker analysis 
iii. CTC quantification (US sites only) 
iv. PSA and PAP 

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v. Immune functional assays (US sites only) 
7. CT* and bone scan 
* For subjects with allergies to contrast agents, MRIs for abdomen and pelvis may be performed. Only in 
cases where MRI is unavailable may a non-contrast CT be performed.  For subjects enrolled in 
, MRI must be used as the primary imaging modality. 
Subsequent LTFU visits thereafter (every 6 Months ± 14 Days, phone call is acceptable) 
1. Survival status 
2. Any anti-prostate cancer therapy 
3. Update for newly diagnosed autoimmune disease 
7.6 
Safety Assessments  
Subjects will be followed during the Treatment phase of the study for any signs or symptoms of treatment-
emergent toxicity by means of an abbreviated physical exam, hematology, serum chemistry panels, ECG, 
and recording of AEs and concomitant medications. 
7.7 
Biological and Immune Response Assessments 
To evaluate biological responses to vaccinations, serum as well as whole blood samples will be collected 
from all enrolled subjects at Screening, End-of-Treatment visit, and the first LTFU visit. Serum samples 
may be analyzed for immune and biomarker status, such as the development of antibodies to the vaccinia 
and fowlpox virus vectors, the PSA insert, other prostate specific antigens, tumor associated antigens, 
changes in cytokine and chemokine expression and circulating tumor markers. In addition, whole blood 
will be drawn into tubes containing an RNA preservative, which will allow for possible future analysis of 
selected tumor and immune cell gene expression profiles by quantitative PCR as well as other methods.  
Circulating tumor cell (CTC) characterization and immune functional analysis will only be performed for 
the subjects in the United States. Whole blood will be collected for the enumeration of CTC levels and for 
the isolation of peripheral blood mononuclear cells (PBMCs) for immune functional assays. PBMCs will be 
evaluated for PSA antigen-specific responses by ELISPOT and flow cytometric-based methods. 
Determinant spreading to other prostate antigens and tumor-associated antigens will also be examined. 
All evaluations will be performed at laboratories using standardized procedures. Subject samples may be 
kept for up to one year past the end of the trial for assay development, implementation, and data review. 
These described analyses may generate a large dataset that could potentially enable the identification of 
new potential biomarkers of disease prognosis and/or vaccine response. 
7.8 
Laboratory Tests and Radiological Assessments 
Samples of blood and urine will be obtained for the tests listed in the Schedule of Events. On the day of 
vaccination all samples will be collected prior to vaccine/placebo administration. Follow-up samples will 
be obtained as clinically indicated. All lab report print-outs will be collected and kept with the appropriate 

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source documents. Total blood volumes collected for the study will remain within Red Cross guidelines, 
which specify, “450 ± 50 mL of blood may be collected every 8 weeks.”   

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8.0 
ADVERSE EVENTS  
For the purposes of this trial, “study vaccine” is defined as PROSTVAC-V/F. Study medication is defined 
as study vaccine, GM-CSF, or placebo. 
8.1 
Investigator’s Responsibilities  
Investigators are responsible for monitoring the safety of subjects who have entered this study and for 
assuring appropriate medical care is provided. In addition, investigators are responsible for alerting BNI or 
its designee to any event that seems unusual, even if the event may be considered an unanticipated 
benefit to the subject, and for reporting the event on the appropriate CRF or safety report form.  
Investigators are responsible for providing subjects who experience adverse events, especially SAEs that 
cause subjects to discontinue participation in the study, with appropriate medical care. Frequency of 
follow-up of any particular adverse event is left to the discretion of the investigator.  Duration of follow-up 
and requirement for immediate SAE reporting (within 24 hours of becoming aware of the event) are 
described below. 
8.2 
Definition of Adverse Events (AE) 
An AE is any untoward (unfavorable, harmful, or pathologic) medical occurrence in a subject administered 
a pharmaceutical (investigational) product even if the event does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not related to the medicinal (investigational) product (ICH E2A II/A/1, 
21 CFR 312.32).   
For the purpose of this clinical study, adverse events include only treatment-emergent events which are 
either new or represent detectable exacerbations of pre-existing conditions. Adverse events may include, 
but are not limited to: 
1. Subjective or objective symptoms spontaneously offered by the subject and/or observed by the 
Investigator or study staff including laboratory abnormalities of clinical significance.  Any adverse 
events experienced by the subject through the completion of final study procedures. 
2. AEs not previously observed in the subject that emerge during the protocol-specific AE reporting 
period, including signs or symptoms associated with metastatic castration-resistant prostate 
cancer that were not present before the AE reporting period 
3. Complications that occur as a result of protocol-mandated interventions 

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For the purposes of this study, the following exceptions to the definitions above will NOT be considered 
an Adverse Event: 
Pre-existing condition: A pre-existing condition (documented on the medical history CRF) is not 
considered and AE unless the severity, frequency, or character of the event worsens during the study 
period.  
Preplanned hospitalization: A hospitalization planned before signing the informed consent form is not 
considered an SAE, but rather a therapeutic intervention. However, if during the pre-planned 
hospitalization an event occurs, which prolongs the hospitalization or meets any other SAE criteria, the 
event will be considered an SAE. Surgeries or interventions that were under consideration, but not 
performed before enrollment in the study will not be considered serious if they are performed after 
enrollment in the study for a condition that has not changed from its baseline level. Hospitalizations for 
social reasons or due to long travel distances are also not SAEs.  Diagnostic testing and procedures: 
Testing and procedures should not be reported as adverse events or serious adverse events, but rather 
the cause for the test or procedure should be reported. 
8.3 
Definition of Expected and Unexpected Events 
8.3.1 
Expected Events 
Expected events are those that have been previously identified as resulting from administration of the 
investigational product.  For the purpose of this study, an adverse event is considered expected when it 
appears in the current adverse event list, the Investigator’s Brochure, the package insert or is included in 
the informed consent document as a potential risk.  An event will be considered expected if the event is 
thought to be related to a study procedure, and the event occurs with reasonable frequency and similar 
intensity in the day-to-day care of a patient with prostate cancer treated with GnRH agonists or 
bisphosphonates.  Examples of adverse events that are expected during the course of treatment for 
prostate cancer with GnRH agonists include, but are not limited to malaise/fatigue, hot flashes/sweating, 
gynecomastia, testicular atrophy or pain, impotence, and clinically significant and non-significant 
alterations in laboratory parameters including transient increases in testosterone levels. For subjects 
taking bisphosphonates (e.g., Zometa), expected events would include flu-like symptoms (fever, chills, 
myalgia, fatigue), injection site redness, swelling, and pain (for injection or infusion-delivered 
bisphosphonates); joint and/or muscle pain; osteonecrosis of the jaw, and renal insufficiency. Expected 
events associated with GM-CSF (at therapeutic doses) include mild to moderate headache, fever, 
arthralgia, chills, and myalgia. Injection site reactions such as pain, redness, swelling, induration, and 
pruritus, or systemic injection reactions such as fever ≥ 104°F; myalgia, headache, nausea, fatigue lasting 
less than 72 hours are expected events for PROSTVAC-V/F. 
If, however, the investigator considers an expected event to be unexpectedly severe or more frequent 
than usual for a patient with prostate cancer treated with GnRH agonists/antagonists, GM-CSF, or 
bisphosphonates, the event will be captured on the AE CRF (see below). Similarly, if the event is 

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associated with PROSTVAC-V/F, and is unexpectedly severe, such as a dose-limiting toxicity, it will also 
be recorded on the AE CRF. 
8.3.2 
Unexpected Events  
Unexpected events are those considered unexpected when it varies in nature, intensity or frequency from 
the information provided in the current adverse event list, the Investigator’s Brochure, the package insert 
or when it is not included the informed consent document as a potential risk.  An event will be considered 
to be unexpected for GnRH agonist/antagonist, GM-CSF, or bisphosphonate therapy or a study 
procedure if it is not identified in the package insert, or is unexpectedly more severe or more frequent 
than events described in the package insert, or is related to PROSTVAC-V/F (with the exceptions for 
injection site and systemic reactions as noted above). 
8.4 
Collecting and Recording Adverse Events 
The Investigator will monitor the occurrence of adverse event for each subject during the course of the 
study. All AEs (as defined above) reported by the subject, observed by the Investigator, or documented in 
medical records will be listed on the AE CRF, whether believed by the Investigator to be related or 
unrelated to the study vaccine.  
All AEs must be reviewed, graded and causality determined by an Investigator listed on the form FDA 
1572 at the research center reporting the event(s). Collection of adverse events begins at the time the 
subject signs informed consent and continues for 28 days following administration of the last dose of 
study medication. 
Adverse event terms should be recorded concisely, using acceptable medical terms. When possible, a 
diagnosis (i.e., disease or syndrome) rather than the component signs and symptoms should be recorded 
on the CRF (e.g., congestive heart failure rather than dyspnea, rales, and cyanosis).  However, signs and 
symptoms considered unrelated to syndromes or diseases are to be recorded as individual adverse 
events on the CRF (e.g., if congestive heart failure and severe headache are observed at the same time, 
each event is to be recorded as an individual adverse event). Only abnormal laboratory values that result 
in clinical sequelae or require medication for treatment should be recorded as an adverse event. The 
adverse event should not be recorded as a procedure or clinical measurement (i.e., a laboratory or vital 
sign). The underlying reason for the procedure or the abnormal clinical measurements, and, whenever 
possible, a diagnosis, should be recorded.  The diagnosis should be recorded; not the individual lab test 
name. 
Death is considered to be an outcome of an adverse event. The cause of death should be recorded on 
the AE CRF (e.g., congestive heart failure with an outcome of death rather than the term “death”). 

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8.4.1 
Progression of Underlying Malignancy 
It is anticipated that a proportion of subjects will experience disease progression. When clinical disease 
progression is identified, the clinical event which marks or identifies the disease progression should be 
reported as the adverse event term for standard AE reporting, including SAE reporting, per ICH 
definitions of AE and SAE as reviewed in Section 8.2 and Section 8.8 of this protocol, respectively. 
For the purpose of this study, progression of underlying malignancy is not considered an (S)AE. 
Hospitalization, prolonged hospitalization, or death due solely to the progression of underlying malignancy 
will be captured on the AE CRF, but may NOT be reported as an SAE. Clinical symptoms of progression 
may be reported as AEs if they cannot be determined to be exclusively due to the progression, or if they 
do not fit the expected pattern of progression for prostate cancer.  
Symptomatic deterioration may occur in the absence of radiographic evidence of tumor progression in 
some subjects. Alternatively, the disease progression may be so evident that the investigator may elect 
not to perform further assessments. In such cases, the determination of clinical progression is based on 
symptomatic deterioration. In these cases, efforts should be made to quantitatively document the 
progression of the underlying malignancy to the extent possible.  
If there is any uncertainty about an adverse event being due to the progression of prostate cancer, it 
should be reported as an (S)AE. 
8.4.2 
Pregnancy of a Female Partner 
For the purposes of this study, pregnancy of a female partner will be captured using a modified SAE 
report form, however; the event is not considered an SAE and will be reported to the appropriate 
regulatory authorities in the annual safety update. Partner pregnancies will be followed through the term 
of the pregnancy or pregnancy termination and the birth of the child after the female partner has signed 
the Pregnant Partner Informed Consent Form.  Subjects and their partners will be counseled as to any 
possible known risks to either the partner or the child. 
8.4.3 
Accidental Transmission of Vaccinia Virus 
Accidental transmission of vaccinia virus to a clinic staff member or a member of the subject’s family or 
personal contacts must be reported to the Investigator as soon as possible, but no later than 24hours 
after he/she becomes aware.  The Investigator must notify an Infectious Disease Specialist in the 
 
Pharmacovigilance Group (PVG) if there is a suspected serious vaccinia reaction as soon as possible, 
but no later than 24 hours after he/she becomes aware.. The Investigator should contact the BNI study 
Medical Monitor if there are specific questions in regard to the potential vaccinia reaction.  A swab of the 
suspected lesion may be obtained from the study subject for confirmatory testing prior to administration of 
VIG. The Investigator should refer to the Management Plan for Potential Serious Vaccinia Reaction for 
recognition, diagnosis and treatment of a rare potential serious vaccinia reaction.  This plan also 
describes when VIG is indicated for use and administration procedures.  For further information or for a 

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supply of VIG in the United States, contact the Centers for Disease Control at (877) 554-4625. For 
centers outside the United States, VIG suppliers (where known) are listed in the Study Instruction Manual. 
The Investigator should refer to the Management Plan for Potential Serious Vaccinia Reaction.  If VIG 
treatment is warranted, the person receiving VIG must sign the Consent Form to Administer Vaccinia 
Immune Globulin (VIG) PRIOR to administration of VIG. 
8.5 
Assessment of Relationship to Study Drug (Causality) 
Investigators are required to assess the causal relationship (i.e., whether there is reasonable possibility 
that the study drug caused the event) using the following definitions:  
Unrelated: Another cause of the adverse event is more plausible; a temporal sequence cannot be 
established with the onset of the adverse event and administration of the investigational product; or, 
a causal relationship is considered biologically implausible.  
Possibly Related: There is clinically plausible time sequence between onset of the adverse event 
and administration of the investigational product, but the adverse event could also be attributed to 
concurrent or underlying disease, or the use of other drugs or procedures. Possibly related should 
be used when the investigational product is one of several biologically plausible adverse event 
causes. 
Definitely Related: The adverse event is clearly related to use of the investigational product.  
8.6 
Severity of Adverse Events (Grading) 
Adverse events will be categorized and graded by the Investigator using standard terminology for grading 
the severity (intensity) of the AE. This study will use the NCI Common Terminology Criteria for Adverse 
Events (NCI CTCAE v 4.0) five-point scale, Grades 1 to 5 with unique clinical descriptions of severity for 
each referenced AE.A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  A hard copy will be provided 
by BNI upon request. 
Should a subject experience any AE not listed in the CTCAE v4.0, the following grading system should be 
used to assess severity:   
Table 9-1 
Adverse Event Grading Criteria 
CTCAE Grade 
Equivalent To: 
Definition 
Grade 1 
Mild AE 
Experiences which are usually transient, requiring no special 
treatment, and no disruption of normal daily activity 
Grade 2 
Moderate AE  
Experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily 
activities, but are usually ameliorated by simple therapeutic 
measures 

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Grade 3 
Severe AE 
Experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usually daily activity, and require systemic 
drug therapy or other treatment  
Grade 4 
Life threatening 
/ disabling AE 
Experience which causes the subject to be in imminent danger of 
death  
Grade 5  
Death related to 
AE 
Experiences resulting in subject death  
8.7 
Dose Modifications for Toxicity 
There are no dose reductions or modifications for dose toxicity for PROSTVAC-V/F. If subjects 
experience intolerable toxicities due to PROSTVAC-V/F, they will be removed from treatment and will be 
immediately rolled over onto the Long-Term Follow-Up (LTFU) phase of the study and followed for safety 
and vital status per protocol. 
8.8 
Definition of Serious Adverse Events 
Note: The terms “severe” and “serious” are not synonymous. Severity (or intensity) refers to the grade of 
an AE (see below). “Serious” is a regulatory definition. A serious adverse event (experience) or reaction is 
an untoward medical occurrence that at any dose: 
• 
Results in death (i.e., the AE actually causes or leads to death) 
• 
Is life-threatening (with regards to determining if an AE is serious, “life-threatening” is defined 
as an AE in which the subject was at risk of death at the time of the event.  It does not refer to 
an event which hypothetically might have caused death if it were more severe. If either the 
Investigator or the Sponsor believes that an AE meets the definition of life-threatening, it will 
be considered life-threatening). 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions) 
• 
Results in a congenital anomaly/birth defect 
• 
Is medically significant 
Medical and scientific judgment should be exercised in deciding whether other situations, such as 
important medical events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in 
the definition above, should also be considered serious.  Examples of such events are intensive treatment 
in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization; or development of drug dependency or drug abuse). Given the Investigator’s 

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perspective may be informed by having actually observed the event, the Sponsor is likely to have broader 
knowledge of the drug and its effects to inform its evaluation of the significance of the event, if either the 
Sponsor or the Investigator believes that the event is serious, the event will be considered serious. 
For the purposes of this trial, death is an expected outcome of disease progression and/or sequelae and 
will not be considered an SAE.  Death due to causes other than underlying disease progression should 
be reported on the AE and SAE page and should also be reported on the CRF death page.  
For the purposes of this trial, the following will NOT be considered SAEs: 
• 
Hospitalizations < 24 hours, or for planned surgeries or procedures. 
• 
Progression of underlying malignancy as a stand-alone event term; clinical events 
associated with disease progression should be reported as AEs or SAEs as applicable. 
• 
Death due to progression of underlying malignancy 
8.9 
Definition of Unexpected Serious Adverse Events 
An unexpected SAE is one in which the specificity or severity is not consistent with the current applicable 
product information (Investigators’ Brochure or drug prescribing label), or one that has not been observed 
previously (rather than from the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product). 
8.10 
Definition of Suspected Adverse Reaction 
The FDA has published guidance on the reporting of SAEs (Safety Reporting requirements for INDs and 
BA/BE studies, December 2012).  This document directs Sponsors to consider more carefully the adverse 
events that are reported in an expedited (urgent) fashion to the FDA.  Key elements of this guidance are 
outlined below: 
The guidance defines any adverse event for which there is a “reasonable possibility” that the drug caused 
the adverse event as a Suspected Adverse Reaction.  
“Reasonable Possibility”, for the purposes of safety reporting, means there is evidence to suggest a 
causal relationship between the drug and the adverse event.  Examples of evidence that would suggest a 
causal relationship between the drug and the adverse event are: 
• 
A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (e.g., angioedema, blood dyscrasias, rhabdomyolysis, hepatic injury, 
anaphylaxis, and Stevens-Johnson Syndrome).  
• 
One or more occurrences of an event that is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (e.g., include tendon 
rupture or heart valve lesions in young adults, or intussusception in healthy infants).  If the 
event occurs in association with other factors strongly suggesting causation (e.g., strong 
temporal association, event recurs on rechallenge), a single case may be sufficiently 

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persuasive; but often, more than one occurrence (from one or multiple studies) would be 
needed before the Sponsor could make a determination of whether the drug caused the 
event.  
• 
An aggregate analysis of specific events that can be anticipated to occur in the study 
population independent of drug exposure.  Such events include known consequences of the 
underlying disease or condition under investigation (e.g., symptoms or disease progression), 
or events unlikely to be related to the underlying disease or condition under investigation, but 
commonly occur in the study population independent of drug therapy (e.g., cardiovascular 
events in an elderly population).  An aggregate analysis (across studies) will identify those 
events that occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
This definition of “suspected adverse reaction” and the application of the “reasonable possibility” causality 
standard is considered to be consistent with the concepts and discussion about causality in the 
International Conference on Harmonization (ICH) E2A guidance. 
8.11 
Documenting and Reporting of Adverse Events and Serious Adverse Events  
The Investigator is responsible for ensuring that all AEs and SAEs that are observed or reported during 
the study, as outlined in the prior sections, are recorded on the CRF.   
An event may qualify for expedited reporting to worldwide regulatory authorities if it is a Serious Adverse 
Event, Serious Adverse Drug Reaction or Suspected Unexpected Serious Adverse Reaction (SUSAR) in 
line with relevant legislation, including the European Commission Clinical Trials Directive (2001/20/EC). 
Expectedness of SAEs will be determined by BNI using the reference safety information specified in the 
Investigator’s Brochure. All investigators will receive a safety letter notifying them of relevant SUSAR 
reports.  
In accordance with the European Commission Directive 2001/20/EC, BNIT or designee will notify the 
relevant Ethics Committees in concerned Member States of applicable SUSARs as individual notifications 
or through a periodic line listing. 
The Sponsor makes the determination of expedited reporting of an SAE to Regulatory Authorities.  
Regulatory Authorities, Institutional Review Boards/Research Ethics Boards/Independent Ethics 
Committees (IRBs/REBs/IECs), and Principal Investigators will be notified of SAEs in accordance with 
applicable requirements (e.g., GCPs, ICH guidelines, national regulations, and local requirements).  The 
Investigator is responsible for complying with the responsible IRB/IEC’s procedures of adverse event 
reporting.  It is the responsibility of the Investigator to promptly inform the relevant IRB/IEC of these new 
adverse events/risks to subjects, in accordance with the US FDA Code of Federal Regulations (CFR) 21 
CFR 312.66.  

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BNI has an internal medical safety review committee that will review and evaluate accumulating safety 
data from the entire clinical trial database for PROSTVAC-V/F at appropriate intervals (e.g., quarterly) to 
identify new safety signals or increased frequency of events.     
8.12 
Adverse Event Reporting Period 
The AE reporting period for this study begins with signing of the informed consent and ends 28 days 
following administration of the last dose of study medication.  If an SAE is present at the EOT Visit, the 
SAE (and associated AEs and concomitant medications) should be followed to resolution or until the 
Investigator assesses the subject as stable, or the subject is lost to follow-up or withdraws consent.  
Resolution/stable means the subject has returned to baseline state of health or the Investigator does not 
expect any further improvement or worsening of the event. 
New SAEs will be collected until 28 days following administration of the last dose of study medication . If 
an SAE comes to the attention of the investigator after the end of the study, information regarding the 
SAE should be collected and reported only if assessed as possibly or definitely related by the 
investigator. 
8.13 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time points during the 
study.  All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, clinically significant laboratory test, or other 
means will be recorded in the subject’s medical record and on the AE CRF and, when applicable, on the 
Serious Adverse Event (SAE) report form. 
Each recorded AE or SAE will be described by its duration (i.e., start and end dates), severity, regulatory 
seriousness criteria (if applicable), suspected relationship to the investigational product, and any actions 
taken. 
Any SAE that occurs after the subject signs informed consent and until 28 days following administration of 
the last dose of study medication, irrespective of the treatment received by the subject, must be reported 
to the 
PVG within 24 hours of the investigator learning of the event.  
8.14 
Serious Adverse Events 
BNI is required to expedite to worldwide regulatory authorities reports of Serious Adverse Events, Serious 
Adverse Drug Reactions or Suspected Unexpected Serious Adverse Reactions (SUSARs) in line with 
relevant legislation, including the European Commission Clinical Trials Directive (2001/20/EC); therefore, 
BNI (or the CRO on the behalf of BNI) must be notified immediately regarding the occurrence of any SAE 
or SADR that occurs after the subject consents to participate in the study, including SAEs/SADRs 
resulting from protocol-associated procedures as defined in relevant legislation including 2001/20/EC, 
performed from screening onwards. 

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All SAEs (initial and follow-up information) will be reported electronically through 
 Remote Data 
Capture (RDC) platform within 24 hours of the discovery of the event or information.  Manual SAE report 
forms are available in the Study Instructions Manual, however manual SAE report forms may be faxed to 
PVG only in the event RDC is not functioning, and must be entered into RDC when it becomes 
available.  The Sponsor may request follow-up and other additional information from the Investigator 
(e.g., hospital admission/discharge notes and laboratory results).  
All deaths should be reported with the primary cause of death as the AE term, as death is typically the 
outcome of the event, not the event itself.  The primary cause of death on the autopsy report should be 
the term reported.  Autopsy and postmortem reports must be forwarded to the Sponsor’s Medical Monitor, 
or designee, as outlined above. 
If study drug is discontinued because of an SAE, this information must be included in the SAE report. 
Investigators must report SAEs to their governing IRBs/ECs in writing as soon as possible and in 
accordance with national and local laws and regulations. 
8.15 
Treatment and Follow-up of Adverse Events or Serious Adverse Events 
From the time the subject signs informed consent until 28 days after the last vaccination, all untoward 
medical events (as defined in Section 8.2 and exceptions as noted in Section 8.4) will be documented as 
(S)AEs through the Treatment phase of the study or through the last visit of the Treatment phase of the 
study for subjects who withdraw early.  
All (S)AEs assessed as not related to study vaccine will be followed as clinically indicated until resolved, 
stabilized, or if non-resolving, until 28 days after the last vaccination, whichever comes first.  If a clear 
explanation is established, it should be recorded on the CRF. 
If an SAE is assessed as possibly or definitely related to study vaccine, it must be followed until either the 
event has resolved, stabilized, or is deemed to be non-resolvable by the investigator. 

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9.0 
STATISTICAL CONSIDERATIONS 
The full details of the trial planning computations and planned analyses are contained in a separate 
Statistical Analysis Plan. Key features are summarized below. This study will be monitored by an 
independent Data Monitoring Committee and the charter for this committee is based on FDA guidance. 
9.1 
Study Design 
This 1,200 subject (approximately) study is a randomized, double-blind, placebo-controlled, three-arm 
clinical trial. The primary endpoint is survival time or time to the most recent knowledge of “known to be 
alive” (censored time). Zero time is defined as the date of randomization. 
Subjects will be randomly partitioned with equal probability into one of three double-blinded arms, an 
investigational arm where the intended intervention is vaccine (PROSTVAC-V/F) plus GM-CSF (Arm 
V+G), an investigational arm where the intended intervention is vaccine (PROSTVAC-V/F) with placebo 
GM-CSF (Arm V), and a control arm where the intended intervention is an empty fowlpox vector and 
placebo GM-CSF (Arm P). 
(Arm V+G) 
PROSTVAC-V/F plus GM-CSF 
(Arm V) 
PROSTVAC-V/F plus GM-CSF placebo  
(Arm P) 
Double placebo (empty fowlpox vector / plus GM-CSF placebo). 
The association of intervention to arm will be hidden from clinical personnel and subjects by using a 
coded identifier for each intervention preparation to be administered. Specifically, the arm designators 
shown above (V+G, V, and P) are for statistical purposes. 
9.2 
Randomization 
Block randomization will be used to randomly assign subjects in a 1:1:1 manner.  Randomization will be 
stratified by PSA (equal and above, or below 50 ng/mL), and LDH (equal and above, or below 200 u/L).  
Subjects will be randomized through IVRS/IWRS. 
9.3 
Analysis Sets 
Three analysis sets are defined for this trial.  The Intent-to-Treat set (ITT) includes all subjects who are 
randomized. The full analysis set (FAS) includes all subjects initiating study intervention. The safety 
analysis set includes all subjects initiating study intervention.  The FAS and safety analysis set are the 
same. 
All efficacy analyses will be performed on the ITT set and the FAS.  Subjects will be analyzed and 
summarized based on the arm into which they were randomized.  Efficacy analysis performed on the ITT 
analysis set will be considered to be the primary indicator of efficacy. Analysis performed on the FAS will 
be considered to be supportive. 

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All safety analyses will be performed on the Safety set. 
9.4 
Primary Efficacy Analysis 
Two main overall comparisons of survival time are planned: A comparison between Arm V+G and Arm P, 
and a comparison between Arm V and Arm P.  Thus two separate tests will be assessed, and success for 
the trial is defined as meeting statistical criterion for either of the following comparisons. 
• 
Superiority of Arm V+G over Arm P for all subjects randomized to these arms. 
• 
Superiority of Arm V over Arm P for all subjects randomized to these arms. 
The overall type one error probability (alpha error) for the whole study is designed as a one sided 
P=0.025. There are two main overall comparisons, which therefore necessitate a type one error 
probability to 0.0125 for each comparison based on using a Bonferroni correction.  
The primary analysis methodology will be the stratified log rank test. 
9.5 
Trial Size 
The Arm P reference data for planning this trial is specified as a median survival of 22 months based on 
the placebo arm of Dendreon D9902B. Based on exponential assumptions the corresponding hazard rate 
is 0.3781 and the corresponding three-year survival is 32.2%. 
The hazard ratio to be used in the specific alternative hypotheses used to compute trial size is specified 
to be 0.68 for the main comparisons, that is, a 32% smaller hazard rate in Arm V+G or Arm V as 
compared to Arm P. This hazard ratio is based on hazard ratio estimates from the previously completed 
randomized Phase 2 trial with an allowance that the Phase 2 trial likely provides an over-optimistic 
estimate of the true hazard ratio. The hazard ratio estimate from the Phase 2 trial was 0.56, and was 
approximately 0.5 when delayed effect is taken into account (depending on the characterization of the 
delayed effect). 
Simulations project that 534 events for each between-arm comparison are required for a minimum of 85% 
power to detect a 32% lower hazard rate.  These calculations have taken in to consideration a delayed 
treatment effect (as found in the randomized phase 2 study).  If there is less delayed effect the power will 
be greater.  The projection for the time to realize the required number of deaths for final analysis is 4.6 
years following the start of accrual. 
9.6 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is a binary assessment for Alive without Event (AWE) at six months (or 
early termination). The event is any of the following on or before six months: radiological progression, 
pain progression, chemotherapy initiation, or death. Subjects without an event prior to six months will 
have an evaluation for event at six months. Subjects without event who are not evaluated at six months 
(or early termination) will be assumed to have had an event. Thus, each subject will be defined as AWE = 

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1 if the subject is alive and free of event at six months (or early termination) and AWE = 0 otherwise. 
AWE will have a realization for every subject and therefore is amendable to an intent-to-treat analysis. 
The same two comparisons as done for survival will be done for AWE, using the same significance levels.  
For each comparison the proportions of subjects in each arm for which AWE = 1 will be compared. The 
probability is 90% or greater that this statistical test will be significant if the true proportion difference is 
0.1375 or greater.  The critical difference is 0.092 if the control arm proportion is 0.5. 
9.7 
Safety Analyses 
The primary safety analysis set will be all subjects initiating study intervention. The primary focus will be a 
between-arm comparison of the frequency and severity of safety events without attribution. Supporting 
analyses will be comparisons of subjects according to intervention received and attribution. 
Adverse events will be summarized and tabulated by severity and by relationship to study intervention 
(attribution). The original terms used by investigators to identify AEs in the CRFs will be translated into 
preferred terms using current MedDRA Thesaurus. The AEs will be grouped by MedDRA preferred terms 
into frequency tables according to body system. The number and percentage of subjects experiencing 
adverse events will be tabulated by body system/preferred term and treatment. When an AE occurs more 
than once, the maximum severity and causality will be listed only once. Additionally, SAEs and AEs that 
are possibly or probably related to study intervention will be summarized separately.  Data listings of all 
AEs will be provided by individual subject. 
9.8 
Interim Analyses 
An interim analysis plan (IAP) is included in the SAP for this study.  Interim analyses are executed by 
 a Contract Research Organization that acts as the independent statistician 
and assessed by the DMC as described in the DMC Charter.  At each interim analysis, both unblinded 
(closed) and blinded (open) interim analysis reports will be provided to the DMC, while the sponsor will 
only receive an open (blinded) report unless one of the criteria is met.  Even in this case, the DMC will 
use its discretion regarding the communications of results to the sponsor, with patient safety balanced 
against benefit being the primary concern.   
The IAP was designed to detect early evidence of both efficacy and futility.  Interim analyses for the two 
comparisons of overall survival described in Section 9.4 are to be executed at 40%, 60%, and 80% of 
information times, corresponding to 214, 321, and 427 deaths per comparison.  The final analysis will be 
completed when 534 deaths per comparison have occurred.  To maintain an overall one-sided type I error 
probability of 0.0125 per comparison, the one-sided significance criteria using one-sided O’Brien-
Flemming boundaries for early detection of efficacy analyses are 0.000135, 0.00147, 0.00501, 
respectively, with the adjusted final analysis to use 0.01063.  The significance level to be used for 
detection of futility at each interim analysis is 0.00001.  This futility significance level was chosen in order 

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to provide a balance between the sought for estimated probability of detecting futility and protecting 
against falsely detecting futility.   
 

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10.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS  
10.1 
Regulatory and Ethical Compliance 
This clinical study was designed and will be implemented in accordance with the protocol, the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local regulations (including 
US Code of Federal Regulations Title 21 and European Directive 2001/20/EC), and with the ethical 
principles laid down in the Declaration of Helsinki.  
10.2 
Institutional Review Board (IRB), Research Ethics Board (REB), and Independent Ethics 
Committee (IEC) Approval 
The Investigator will submit this protocol, the informed consent, Investigator Brochure, and any other 
relevant supporting information (e.g., all advertising materials or materials given to the subject during the 
study) to the appropriate IRB/REB/IEC for review and approval before study initiation.  Amendments to 
the protocol and informed consent form must also be approved by the IRB/REB/IEC before the 
implementation of changes in this study. 
The Investigator is responsible for providing the IRB/REB/IEC with any required information before or 
during the study, such as SAE expedited reports or study progress reports. 
The IRB/REB/IEC must comply with current United States (US) regulations (§21 CFR 56) (unless a 
waiver to the IRB requirements of the 1572 has been obtained) as well as country-specific national 
regulations and/or local laws. 
The following documents must be provided to BNI or its authorized representative before entering 
subjects in this study: (1) a copy of the IRB/REB/IEC letter that grants formal approval; and (2) a copy of 
the IRB/REB/IEC-approved ICF.  
10.3 
Institutional Biosafety Committee (IBC) (where applicable) 
This protocol and any accompanying material provided to the subject (such as subject information sheets, 
Informed Consent Form, or descriptions of the study used to obtain informed consent) will be submitted 
by BNI and/or the site to a legally constituted and chartered Institutional Biosafety Committee (IBC). 
Additional materials, such as the Investigator’s Brochure, will be submitted to the IBC according to the 
specific Committee and federal (United States’ National Institutes of Health or foreign equivalent) 
requirements. Each site will be approved by the IBC in accordance with local procedures and country-
specific regulatory requirements. Documentation of IBC approval must be in place prior to drug shipment 
to the site. 
At the discretion of the specific IBC and within federal requirements, IBC oversight of individual sites may 
be terminated provided (1) all subjects at that site have completed dosing by at least 28 days, and (2) all 
investigational materials have been fully accounted for and either returned to BNI, destroyed on site, or 

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shipped to a duly licensed destruction facility and a shipping and inventory reconciliation records have 
been filed in the Pharmacy Manual. 
10.4 
Informed Consent 
The informed consent form (ICF) and process must comply with the United States regulations  
(§ 21 CFR Part 50) as well as country specific national regulations and/or local laws.  The ICF will 
document the study-specific information the Investigator or his/her designee provides to the subject and 
the subject’s agreement to participate.   
The Investigator, or designee (designee must be listed on the Delegation of Authority log), must explain 
in terms understandable to the subject the purpose and nature of the study, study procedures, anticipated 
benefits, potential risks, possible adverse effects, and any discomfort participation in the study may entail.  
This process must be documented in the subject’s source record.  Each subject must provide a signed 
and dated informed consent before any study-related (nonstandard of care) activities are performed (such 
as screening).  The original and any amended signed and dated consent forms must remain in each 
subject’s study file at the study site and be available for verification by study monitors at any time.  A copy 
of each signed consent form must be given to the subject at the time that it is signed by the subject. 

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11.0 
CONTROL AND QUALITY ASSURANCE 
11.1 
Protected Subject Health Information Authorization  
Information on maintaining subject confidentiality in accordance to individual local and national subject 
privacy regulations must be provided to each subject as part of the informed consent process (refer to 
Section 10.4) either as part of the informed consent form or as a separate signed document (for 
example, in the US, a site-specific Health Insurance Portability and Accountability Act [HIPAA] consent 
may be used).  The Investigator or designee must explain to each subject that for the evaluation of study 
results, the subject’s protected health information obtained during the study may be shared with BNI and 
its designees, regulatory agencies, and IRBs/REBs/IECs.  As the study Sponsor, BNI will not use the 
subject’s protected health information or disclose it to a third party without applicable subject 
authorization.  It is the Investigator’s or designee’s responsibility to obtain written permission to use 
protected health information from each subject.  If a subject withdraws permission to use protected health 
information, it is the Investigator’s responsibility to obtain the withdrawal request in writing from the 
subject and to ensure that no further data will be collected from the subject.  Any data collected on the 
subject before withdrawal will be used in the analysis of study results. 
During the review of source documents by the monitors or auditors, the confidentiality of the subject will 
be respected with strict adherence to professional standards and regulations. 
11.2 
Study Files and Record Retention  
The Investigator must keep a record that lists all subjects considered for enrollment (including those who 
did not undergo screening) in the study.  For those subjects subsequently excluded from enrollment, the 
reason(s) for exclusion is to be recorded. 
The Investigator/study staff must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified.  Essential documentation 
includes, but is not limited to, the Investigator’s Brochure, signed protocols and amendments, 
IRB/REB/IEC approval letters (dated), signed FDA Form 1572 and Financial Disclosures, signed ICFs 
(including subject confidentiality information), drug dispensing and accountability records, shipping 
records of investigational product and study-related materials, signed (electronically), dated and 
completed CRFs, and documentation of CRF corrections, SAE forms transmitted to BNI or designee and 
notification of SAEs and related reports, source documentation, normal laboratory values, decoding 
procedures for blinded studies, curricula vitae for study staff, and all relevant correspondence and other 
documents pertaining to the conduct of the study. 
All essential documentation will be retained by the Investigator for at least 2 years after the date the last 
marketing application is approved for the drug for the indication for which it is being investigated and until 
there are no pending or contemplated marketing applications; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after formal discontinuation of clinical 
development of the drug.  

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The Investigator must notify BNI and obtain written approval from BNI before destroying any clinical study 
documents or images (e.g., scan, radiograph, ECG tracing) at any time.  Should an Investigator wish to 
assign the study records to another party or move them to another location, advance written notice will be 
given to BNI.  BNI will inform the Investigator of the date that study records may be destroyed or returned 
to BNI. 
BNI must be notified in advance of, and BNI must provide express written approval of, any change in the 
maintenance of the foregoing documents if the Investigator wishes to move study records to another 
location or assign responsibility for record retention to another party.  If the Investigator cannot guarantee 
the archiving requirements set forth herein at his or her study site for all such documents, special 
arrangements must be made between the Investigator and BNI to store such documents in sealed 
containers away from the study site so that they can be returned sealed to the Investigator for audit 
purposes. 
11.3 
Case Report Forms and Record Maintenance 
Electronic case report forms (eCRFs) will be used to collect the clinical study data and must be completed 
for each enrolled subject with all required study data accurately recorded such that the information 
matches the data contained in medical records (e.g., physicians’ notes, nurses’ notes, clinic charts and 
other study-specific source documents).  Authorized study site personnel (i.e., listed on the Delegation of 
Authority form) will complete eCRFs designed for this study according to the completion guidelines that 
will be provided.  The Investigator will ensure that the eCRFs are accurate, complete, legible, and 
completed within 5 days of each subject’s visit.  At all times, the Investigator has final responsibility for the 
accuracy and authenticity of all clinical data. 
The eCRFs exists within an electronic data capture (EDC) system with controlled access managed by 
BNI or its authorized representative for this study.  Study staff will be appropriately trained in the use of 
eCRFs and application of electronic signatures before the start of the study and before being given 
access to the EDC system.  Original data and any changes of data will be recorded using the EDC 
system, with all changes tracked by the system and recorded in an electronic audit trail.  The Investigator 
attests that the information contained in the eCRFs is true by providing electronic signature within the 
EDC system.  After database lock, the Investigator will receive a copy of the subject data (e.g., paper, 
CD-ROM or other appropriate media) for archiving at the study site. 
11.4 
Study Monitoring/ Audit Requirements  
Representatives of BNI or its designee will monitor this study until completion.  Monitoring will be 
conducted through personal visits with the Investigator and site staff, remote monitoring, as well as any 
appropriate communications by mail, fax, email, or telephone.  The purpose of monitoring is to ensure 
that the study is conducted in compliance with the protocol, standard operating procedures (SOPs), and 
other written instructions and regulatory guidelines, and to ensure the quality and integrity of the data.  
This study is also subject to reviews or audits. 

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To assure the accuracy of data collected in the CRFs, it is mandatory that the monitor/auditor have 
access to all original source documents, including all electronic medical records (EMR) at reasonable 
times and upon reasonable notice.  During the review of source documents, every effort will be made to 
maintain the anonymity and confidentiality of all subjects during this clinical study.  However, because of 
the experimental nature of this treatment, the Investigator agrees to allow the IRB/REB/IEC, 
representatives of BNI, its designated agents and authorized employees of the appropriate Regulatory 
Authority to inspect the facilities used in this study and, for purposes of verification, allow direct access to 
the hospital or clinic records of all subjects enrolled into this study.  A statement to this effect will be 
included in the informed consent and permission form authorizing the use of protected health information. 
BNI or its authorized representative may perform an audit at any time during or after completion of this 
study.  All study-related documentation must be made available to the designated auditor.  In addition, a 
representative of the FDA or other Regulatory Agencies may choose to inspect a study site at any time 
before, during, or after completion of the clinical study.  In the event of such an inspection, BNI will be 
available to assist in the preparation.  All pertinent study data should be made available as requested to 
the Regulatory Authority for verification, audit, or inspection purposes. 
11.5 
Investigator Responsibilities 
A complete list of Investigator responsibilities are outlined in the clinical trial research agreement and the 
Statement of Investigator FDA Form 1572, both of which are signed by the Investigator before 
commencement of the study.  In summary, the Investigator will conduct the study according to the current 
protocol; will read and understand the Investigator’s Brochure; will obtain IRB/REB/IEC approval to 
conduct the study; will obtain informed consent from each study participant; will maintain and supply to 
the Sponsor or designee, auditors and regulatory agencies adequate and accurate records of study 
activity and drug accountability for study-related monitoring, audits, IRB/REB/IEC reviews and regulatory 
inspections; will report SAEs to the Sponsor or designee and IRB/ REB/IEC according to the specifics 
outlined in this protocol; will personally conduct or supervise the study; and will ensure that colleagues 
participating in the study are informed about their obligations in meeting the above commitments. 
11.6 
Sponsor Responsibilities  
A complete list of the Sponsor responsibilities is outlined in the clinical trial research agreement and in the 
laws and regulation of the country in which the research is conducted.  In summary, the Sponsor will 
select qualified Investigators, provide them with the information they need to properly conduct the study, 
ensure adequate monitoring of the study, conduct the study in accordance with the general investigational 
plan and protocols and promptly inform Investigators, health and regulatory agencies/authorities as 
appropriate of significant new adverse effects or risks with respect to the drug. 
11.7 
Financial Disclosure 
A separate financial agreement will be made between each Principal Investigator and BNI or its 
authorized representative before the study drug is delivered. 

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For this study, each Investigator and Sub-investigator (as designated on the FDA 1572 form) will provide 
a signed Financial Disclosure Form in accordance with § 21 CFR 54.  Each Investigator will notify BNI or 
its authorized representative of any relevant changes during the conduct of the study and for 1 year after 
the study has been completed. 
11.8 
Liability and Clinical Trial Insurance 
In the event of a side effect or injury, appropriate medical care as determined by the 
Investigator/designee will be provided. 
If a bodily injury is sustained, resulting directly from the use of the study drug, BNI will reimburse for 
reasonable physician fees and medical expenses necessary for treatment of only the bodily injury which 
is not covered by the subject’s medical or hospital insurance, provided that the injury is not due to a 
negligent or wrongful act or omission by the Investigator/study staff.  The Informed Consent Form will 
include a description of this reimbursement policy, incorporating country-specific national regulations 
and/or local laws.  Financial compensation for lost wages, disability or discomfort due to the study is not 
available. 
Clinical trial insurance has been undertaken according to the laws of the countries where the study will be 
conducted.  An insurance certificate will be made available to the participating sites at the time of study 
initiation upon request. 
11.9 
Protocol Amendments 
BNI will initiate any change to the protocol in a protocol amendment document.  The amendment will be 
submitted to the IRB/REB/IEC together with, if applicable, a revised model informed consent form (ICF).  
Written documentation of IRB/REB/IEC and required site approval must be received by BNI before the 
amendment may take effect at each site.  Additionally under this circumstance, information on the 
increased risk and/or change in scope must be provided to subjects already actively participating in the 
study, and they must read, understand and sign any revised ICF confirming willingness to remain in the 
trial. 
No other significant or consistent change in the study procedures, except to eliminate an immediate 
hazard, shall be effected without the mutual agreement of the Investigator and BNI. 

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12.0 
PUBLICATION OF STUDY RESULTS  
BNI may use the results of this clinical study in registration documents for Regulatory Authorities in the 
United States or abroad.  The results may also be used for papers, abstracts, posters or other material 
presented at scientific meetings or published in professional journals or as part of an academic thesis by 
an Investigator.  In all cases, to avoid disclosures that could jeopardize proprietary rights and to ensure 
accuracy of the data, BNI reserves the right to preview all manuscripts and abstracts related to this study, 
allowing BNI sufficient time to make appropriate comments before submission for publication. 
In most cases, the Principal Investigators at the sites with the highest accruals of eligible subjects shall be 
listed as lead authors on manuscripts and reports of study results.  This custom can be adjusted upon 
mutual agreement of the authors and BNI. 
12.1 
Study Discontinuation  
The Sponsor reserves the right to terminate the study at any time.  Should this be necessary, both the 
Sponsor and the Investigator will arrange discontinuation procedures.  In terminating the study, the 
Sponsor and the Investigator will assure that adequate consideration is given to the protection of the 
subjects’ interests. 

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13.0 
REFERENCES 
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prostate-specific antigen in advanced prostate cancer. Clin Cancer Res 2000;6(5):1632-1638. 

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26. Essajee S and Kaufman HL. Poxvirus vaccines for cancer and HIV therapy. Expert Opin Biol Ther 
2004;4(4):575-588. 
27. Feldman A.M., McNamara D. Myocarditis. NEJM 2000:343 (19):1388-1398. 
28. Freedland SJ and Moul JW. Prostate specific antigen recurrence after definitive therapy.  J Urol. 
2007 Jun;177(6):1985-1991. 
29. Frey SE, Newman FK, Cruz J, et al. Dose-related effects of smallpox vaccine. NEJM 
2002;346(17):1275-1280. 
30. Fulginiti VA, Papier A, Lane JM, et al. Smallpox Vaccination: A Review, Part I. Background, 
Vaccination Technique, Normal Vaccination and Revaccination, and Expected Normal Reactions.  
CID 2003:37:241-250. 
31. Fulginiti VA, Papier A, Lane JM, et al. Smallpox Vaccination: A Review, Part II. Adverse Events. 
CID 2003:37:251-271. 
32. Grabenstein JD. US military Smallpox Vaccination Program Experience. JAMA 2003:289:3278-
3282. 
33. Gulley J, Chen AP, Dahut W, et al. Phase I study of a vaccine using recombinant vaccinia virus 
expressing PSA (rV-PSA) in patients with metastatic androgen-independent prostate cancer. 
Prostate 2002;53(2):109-117. 
34. Gulley JL, Arlen PM, Madan, et al.  Immunologic and prognostic factors associated with overall 
survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer.  
Cancer Immunol Immunother. 2010.59(5):663-674. 
35. Hodge JW, McLaughlin JP, Kantor JA, et al. Diversified prime and boost protocols using 
recombinant vaccinia virus and recombinant non-replicating avian pox virus to enhance T-cell 
immunity and antitumor responses. Vaccine, 1997. 15(6-7):759-768. 
36. Hodge, JW, Sabzevari H, Yafal AG et al.  A triad of costimulatory molecules synergize to amplify 
T-cell activation. Cancer Res, 1999. 59(22):5800-5807. 
37. Hodge JW, Greiner JW, Tsang KY, et al. Costimulatory molecules as adjuvants for 
immunotherapy.  Front Biosci. 2006 Jan 1;11:788-803. 
38. Irvine K, Kantor J, and Schlom J. Comparison of a CEA-recombinant vaccinia virus, purified CEA, 
and an anti-idiotypic antibody bearing the image of a CEA epitope in the treatment and prevention 
of CEA-expressing tumors. Vaccine Res 1993;2:79-94. 

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39. Jemal, A, Siegel, R, Ward, et al.  Cancer Statistics, 2009.  CA Cancer J Clin, 2009; 59:225-249. 
40. Kantoff P, Glode L, Tannenbaum S, et al. Randomized, double-blind, vector-controlled study of 
targeted immunotherapy in patients with hormone-refractory prostate cancer [abstract]. J Clin 
Oncol 2006;24(18S):2501. 
41. Kantoff PW, Schuetz TJ, Blumenstein BA, et al.  Overall survival analysis of a Phase II 
randomized controlled trial (RCT) of a poxviral-based PSA-targeted immunotherapy in metastatic 
castration-resistant prostate cancer. J Clin Oncol 2010 Mar 1 (28):1109-1105. 
42. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant 
prostate cancer. N Engl J Med 2010: 363 (5): 411-422. 
43. Kass E, Panicali DL, Mazzara G, et al.  Granulocyte/macrophage-colony stimulating factor 
produced by recombinant avian poxviruses enriches the regional lymph nodes with antigen-
presenting cells and acts as an immunoadjuvant.  Cancer Res. 2001 Jan 1;61(1):206-214. 
44. Kass E, Schlom J, Thompson J, et al. Induction of protective host immunity to carcinoembryonic 
antigen (CEA), a self-antigen in CEA transgenic mice, by immunizing with a recombinant 
vaccinia-CEA virus. Cancer Res 1999;59(3):676-683. 
45. Kaufman H, DiPaola R, Mehren MV, et al. Safety profile of therapeutic pox virus-based vaccines 
for cancer. J Clin Oncol 2004;22(14S):2513. 
46. Kaufman HL, Wang W, Manola J, et al.  Phase II randomized study of vaccine treatment of 
advanced prostate cancer (E7897): a trial of the Eastern Cooperative Oncology Group.  J Clin 
Oncol. 2004 Jun 1;22(11):2122-2132. 
47. Lebedeva T, Dustin ML, and Sykulev Y.  ICAM-1 co-stimulates target cells to facilitate antigen 
presentation.  Curr Opin Immunol. 2005 Jun;17(3):251-258. 
48. Lederman E, Miramontes R, Openshaw J, et al. Eczema vaccinatum resulting from the 
transmission of vaccinia virus from a smallpox vaccinee: An investigation of potential fomites in 
the home environment. Vaccine:2008:doi:10.1016/j.vaccine.2008.11.019. 
49. Lilja H, Ulmert D, and Vickers AJ.  Prostate-specific antigen and prostate cancer: prediction, 
detection and monitoring.  Nat Rev Cancer. 2008 Apr;8(4):268-278. 
50. Madan R, Gulley J, Dahut W, et al. Overall survival (OS) analysis of a phase II study using a pox 
viral-based vaccine, PSA-TRICOM, in the treatment of metastatic, castrate-resistant prostate 
cancer (mCRPC): implications for clinical trial design [abstract]. J Clin Oncol 2008;26(20S):3005. 

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51. Madan RA, Arlen PM, Mohebtash M, et al.  Prostvac-VF: a vector-based vaccine targeting PSA in 
prostate cancer.  Expert Opin. Investig. Drugs.  2009 Jul:18(7):1001-1011. 
52. Marshall JL, Hoyer RJ, Toomey MA, et al. Phase I study in advanced cancer patients of a 
diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and 
recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune 
responses. J Clin Oncol, 2000: 18 (23): 3964 – 3973. 
53. Menge T, Kieseier BC, Nessler S, et al. Acute Disseminated Encephalomyelitis: an Acute Hit 
Against the Brain. Curr Opin Neurol 2007:20:247-254. 
54. Morgan J, Roper MH, Sperling L, et al. Myocarditis, Pericarditis, and Dilated Cardiomyopathy 
after Smallpox Vaccination among Civilians in the United States, January-October 2003. CID 
2008:46 (Suppl 3):S242-S250. 
55. Neff JM, Lane JM, Fulginiti VA, et al. Contact Vaccinia – Transmission of Vaccinia From Smallpox 
Vaccination. JAMA 2002:288:1901-1905. 
56. Neff J, Modlin J, Birkhead GS, et al. Monitoring the Safety of a Smallpox Vaccination Program in 
the United States: Report of the Joint Smallpox Vaccine Safety Working Group of the Advisory 
Committee on Immunization Practices and the Armed Forces Epidemiological Board. CID 
2008:46:S258-270. 
57. Parmiani G, Castelli C, Pilla L, et al. Opposite immune functions of GM-CSF administered as 
vaccine adjuvant in cancer patients. Ann Oncol 2007:18 (2):226-232. 
58. Patel HP, Kockler DR. Sipuleucel-T: A Vaccine for Metastatic, Asymptomatic, Androgen-
Independent Prostate Cancer. Ann Pharmacother 2008:42:91-8. 
59. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with 
mitoxantrone and prednisone for advanced refractory prostate cancer.  N Engl J Med 2004 Oct 
7;351(15):1513-1520. 
60. Poland GA, Grabenstein JD, and Neff JM.  The US smallpox vaccination program: a review of a 
large modern era smallpox vaccination implementation program. Vaccine. 2005 Mar 18:23(17-
18):2708-2781. 
61. Pound CR, Brawer MK, and Partin AW. Evaluation and treatment of men with biochemical 
prostate-specific antigen recurrence following definitive therapy for clinically localized prostate 
cancer.  Rev Urol. 2001 Spring;3(2):72-84. 
62. Riley JL and June CH.  The CD28 family: a T-cell rheostat for therapeutic control of T-cell 
activation.  Blood. 2005 Jan 1;105(1):13-21. 

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63. Rini BI and Small EJ. Hormone-refractory Prostate Cancer. Curr Treat Options Oncol. 2002 
Oct;3(5):437-46. 
64. Schlom J, Arlen PM, and Gulley JL. Cancer vaccines: moving beyond current paradigms. Clin 
Cancer Res 2007;13(13):3776-3782. 
65. Schlom J, Gulley JL, and Arlen PM.  Paradigm shifts in cancer vaccine therapy.  Exp Biol Med 
(Maywood). 2008 May;233(5):522-534. 
66. Sejvar JJ, Labutta RJ, Chapman LE, et al. Neurologic Adverse Events Associated With Smallpox 
Vaccination in the United States, 2002 2004. JAMA 2005:294:2744-2750. 
67. Sharpe AH and Freeman GJ.  The B7-CD28 superfamily.  Nat Rev Immunol. 2002 Feb;2(2):116-
126. 
68. Small EJ, Schellhammer PF, Higano CS, et al.  Placebo Controlled Phase III Iummunologic 
Therapy with Sipuleucel-T (APC8015) in Patients with Metastatic, Asymptomatic Hormone 
Refractory Prostate Cancer. JCO 2006:24 (19): p. 3089-3094. 
69. Sniadack M.M. et al. Follow-up of Cardiovascular Adverse Events after Smallpox Vaccination 
among Civilians in the United States, 2003. CID 2008:46 (Suppl 3): S251-S257. 
70. Talmadge GE. Pathways mediating the expansion and immunosuppressive activity of Myeloid-
derived suppressor cells and their relevance to cancer therapy. Clin Cancer Res 
2007;13(18):5243-5244. 
71. Tannock IF, de Wit R, Berry WR, et al. TAX 327 Investigators.  Docetaxel plus prednisone or 
mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004 Oct 
7;351(15):1502-1512. 
72. Taylor, J, Weinberg R, Languet B, et al. Fowlpox virus based recombinant vaccines. Technol Adv 
Vaccine Devel. 1988. 33(3): p. 321-324. 
73. Terasawa H, Tsang KY, Gulley J, et al.  Identification and characterization of a human agonist 
cytotoxic T-lymphocyte epitope of human prostate-specific antigen.  Clin Cancer Res 2002 
Jan;8(1):41-53. 
74. Vellozzi C, Averhoff F, Lane JM, et al. Superinfections Following Smallpox Vaccination 
(Vaccinia), United States: Surveilance January 2003 through January 2004. CID 2004:39:1660-
1666. 
75. Vora S, Damon I, Fulginiti V, et al. Severe Ecxema Vaccinatum in a Household Contact of a 
Smallpox Vaccinee. DID:2008:46:1555-1561. 

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76. Wang Y., Shibuya K, Yamashita Y, et al.  LFA-1 decreases the antigen dose for T cell activation 
in vivo.  Int Immunol 2008 Sep;20(9):1119-1127. 
77. Wang, UC, Kuriyama M, Papsidero LD, et al. Prostate antigen of human cancer patients. Meth 
Cancer Res 1982. 19:179-197. 
78. Warren TL and Weiner GJ.  Uses of granulocyte-macrophage colony-stimulating factor in vaccine 
development.  Curr Opin Hematol. 2000 May;7(3):168-173. 
79. Webster DP, Dunachie S, McConkey S, et al. Safety of recombinant fowlpox strain FP9 and 
modified vaccinia virus Ankara vaccines against liver-stage P.falciparum malaria in non-immune 
volunteers. Vaccine 2006:24:3026-3034. 
80. Wingren AG, Parra E, Varga M, et al.  T cell activation pathways: B7, LFA-3, and ICAM-1 shape 
unique T cell profiles.  Crit Rev Immunol. 1995;15(3-4):235-253. 
Relevant Guidelines 
• 
United States Pharmacopoeia 
• 
European Pharmacopoeia 
• 
United States Requirements for Drugs and Biologics (21CFR Parts 200 (Drugs) & 21CFR 
Parts 600 (Biologics), 2008). 
• 
Guidance on the Development of Vaccinia Virus Based Vaccines Against Smallpox 
(EMEA/CPMP/1100/02), 2002. 
• 
Recommendations for the Production and Quality Control of Smallpox Vaccine, Revised 
2003 (WHO Technical Report Series. No 926), 2004. 
• 
Safety Reporting Requirements for INDs and BA/BE Studies, December 2012 

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14.0 
APPENDICES 
14.1 
Schedule of Events 
All Treatment Visits have a ± 3 day  
window 
LTFU Visits have a +14 day window 
Screening 
Treatment 
Long-Term Follow-Up 
Week 
1 
3 
5 
9 
13 
17 
21 
25 
1st visit (6 
mos after 
EoT) 
 
Every 
subsequent 
6 mos16* 
  
Day  –28 – –1 
 
 
 
 
 
 
 
EoT 
 
 
Dosing: PROSTVAC-V or placebo1 
 
X 
 
 
 
 
 
 
 
 
 
Dosing:  PROSTVAC-F or placebo1 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
GM-CSF or placebo2 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Immune Monitoring** 
 
 
 
 
 
 
 
 
 
 
 
Immune/Biomarker Status 
 
X 
 
 
 
 
 
 
X 
X 
 
Peripheral Blood RNA 
 
X 
 
 
 
 
 
 
X 
X 
 
Tumor CTC (US sites only) 
 
X 
 
 
 
 
 
 
X 
X 
 
Immune function (US sites only) 
 
X 
 
 
 
 
 
 
X 
X 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Prostate Cancer History 
X 
 
 
 
 
 
 
 
 
 
 
Prostate Cancer Treatment Update 
 
 
 
 
 
 
 
 
 
X 
X 
Complete Physical Exam3 
X 
 
 
 
 
 
 
 
X 
 
 
Abbreviated Physical Exam4 
 
X 
X 
X 
X 
X 
X 
X 
 
X13 
X13 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Autoimmune Disease Status  
 
 
 
 
 
 
 
 
 
X14 
X14 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X15 
 
ECG 
X 
 
 
 
 
 
 
 
X 
 
 
Quality of Life Questionnaire*** 
 
X 
 
 
 
 
 
 
X 
X 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
HLA-A2 typing 
 
X 
 
 
 
 
 
 
 
 
 
PSA and PAP 
X 
X8 
 
X 
X 
X 
X 
X 
X 
X 
 
Testosterone 
X 
 
 
 
 
 
 
 
 
 
 
Hematology6  
X 
X8 
 
X 
X 
X 
X 
X 
X 
 
 
Serum Chemistry7 
X 
X8 
 
X 
X 
X 
X 
X 
X 
 
 
Cardiac Markers9 
X 
 
 
 
 
 
 
 
 
 
 
HIV, HBsAg, HepC10 
X 
 
 
 
 
 
 
 
 
 
 
PT(INR)/PTT 
X 
 
 
 
 
 
 
 
X 
 
 
C-Reactive Protein 
X 
 
 
 
 
 
 
 
X 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
X 
 
 

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14.1 
Schedule of Events (Continued) 
All Treatment Visits have a ± 3 day  
window 
LTFU Visits have a +14 day window 
Screening 
Treatment 
Long-Term Follow-Up 
Week 
1 
3 
5 
9 
13 
17 
21 
25 
1st visit  
(6 mos 
after EoT) 
 
Every 
subsequent 6 
mos16* 
Radiology Assessments 
 
 
 
 
 
 
 
 
 
 
 
Bone Scan 
X11 
 
 
 
 
X 
 
 
X 
X 
 
CT Scan with contrast (pelvis and 
abdomen)**** 
X11 
 
 
 
 
X12 
 
 
X 
X 
 
 
* 
Until 12 months after the projected number of events is realized or death, whichever is first. 
** 
Immune monitoring samples should be collected only after a patient is eligible by all other criteria and prior to the first dose 
of study drug (US Only). 
*** 
QOLs include: FACT-P, BPI-SF, and EQ-5D-3L to be performed at Week 1 and Week 25 during the Treatment Phase and 
at Month 6 during the LTFU Phase. 
**** 
For subjects enrolled in Germany, MRI must be used as the primary imaging modality 
1. 
Subject should remain in the clinic for at least 30 minutes following administration of 
PROSTVAC-V/F/ placebo for observation of adverse reaction. 
2. 
GM-CSF or placebo will be administered the day of vaccination and following 3 consecutive days.  
3. 
A Complete Physical Examination will include, at a minimum, the general appearance of the 
subject, height (screening only) and weight, and examination of the skin, eyes, ears, nose, throat, 
lung, heart, abdomen, extremities, musculoskeletal system, genitourinary system, nervous 
system, and lymphatic system 
4. 
Abbreviated physical examinations will be driven by problems or issues identified during the 
Treatment Phase and during the LTFU Phase that have changed since Screening 
5. 
Vital signs will include including sitting BP, heart rate, RR, temperature, and weight 
6. 
Hematology: CBC with differential, RBC with indices, platelets 
7. 
Serum chemistry: BUN, creatinine, ALT, AST, alkaline phosphatase, total bilirubin, LDH, sodium 
potassium, chloride, bicarbonate, calcium and glucose 
8. 
Blood samples do not need to be repeated at Day 1, if screening samples were run within 7 days 
of the visit 
9. 
Cardiac Markers (CK, CK-MB, Troponins T and I) 
10. 
Virology testing required unless known negative within the previous 2 months 
11. 
Baseline Bone Scan and CT Scan of the abdomen and pelvis (if not performed within 3 months of 
the start of Screening); for subjects with allergies to contrast agents, MRIs for abdomen and 
pelvis may be performed.  Only in cases where MRI is unavailable may a non-contrast CT be 
performed. 
12. 
If clinically indicated  
13. 
Survival status update per Section 7.5 
14. 
 Update only newly diagnosed autoimmune disease.  
15. 
Only treatments for prostate cancer should be captured during the LTFU Phase. 
16. 
After the initial LTFU visit, all subsequent follow-up LTFU visits can be conducted by phone if the 
subject cannot visit the clinic. 

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14.2 
NIH RAC Appendix B (excerpt) 
Appendix B - Table 1.  Basis for the Classification of Biohazardous Agents by Risk Group (RG) 
Risk Group 1 (RG1) 
Agents that are not associated with disease in healthy adult humans  
Risk Group 2 (RG2) 
Agents that are associated with human disease which is rarely serious and for 
which preventive or therapeutic interventions are often available 
Risk Group 3 (RG3) 
Agents that are associated with serious or lethal human disease for which 
preventive or therapeutic interventions may be available (high individual risk but 
low community risk) 
Risk Group 4 (RG4) 
Agents that are likely to cause serious or lethal human disease for which 
preventive or therapeutic interventions are not usually available (high individual 
risk and high community risk) 
Appendix B-I. Risk Group 1 (RG1) Agents 
RG1 agents are not associated with disease in healthy adult humans. 
Appendix B-II. Risk Group 2 (RG2) Agents 
RG2 agents are associated with human disease which is rarely serious and for which preventive or 
therapeutic interventions are often available. 
Those agents not listed in Risk Groups (RGs) 3 and 4 are not automatically or implicitly classified in RG1 
or 2; a risk assessment must be conducted based on the known and potential properties of the agents 
and their relationship to agents that are listed. 
 
 

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14.3 
Criteria of Progression for Trial Eligibility by PCWG2 (2007) 
Variable 
PCWG2 (2007) 
PSA 
Obtain sequence of rising values at a minimum of 1-week intervals 
 
2.0 ng/mL minimum starting value 
 
Estimate pretherapy PSA-DT if 3 or more values available 4 or more weeks apart 
 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patient with progressive 
prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical 
Trials Working Group. J clin Oncol 2008;26:1148-59. 
 
 

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14.4 
ECOG Performance Status Criteria 
 
These scales and criteria are used by doctors and researchers to assess how a patient's disease is 
progressing, assess how the disease affects the daily living abilities of the patient, and determine 
appropriate treatment and prognosis. They are included here for health care professionals to access.  
 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.  
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert 
Comis M.D., Group Chair. 
 
 

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14.5 
NYHA Classification – The Stages of Heart Failure 
In order to determine the best course of therapy, physicians often assess the stage of heart failure 
according to the New York Heart Association (NYHA) functional classification system. This system relates 
symptoms to everyday activities and the patient's quality of life. 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency at rest. If any physical activity  
 
 
 

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14.6 
NCI Common Terminology Criteria for Adverse Events (NCI CTCAE v 4.0) 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
A hard copy of the CTCAE version 4.0 can be found in the Study Instruction Manual. 
 
 

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14.7 
FACT-P Quality of Life Questionnaire 
 

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14.8 
BPI-SF Quality of Life Questionnaire 
 

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14.9 
EQ-5D-3L Quality of Life Questionnaire 
 
 
 

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14.10 
Vial and Carton Labels 
Labels are provided as reference only and are provided as examples.  Specific label text and language 
may vary depending on country. 
Labeling for Phase III PROSTVAC-V Outer carton label (Vaccinia)  
 
 
 
Labeling for Phase III PROSTVAC-V and placebo vials:   
 
Vial label:  (All vial numbers shown are for demonstration purposes only) 
 
 

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Labeling for Phase III PROSTVAC-F Outer carton label (Fowlpox) 
 
 
 
Labeling for Phase III PROSTVAC-F and placebo vials:   
 
Vial label:  (All vial numbers shown are for demonstration purposes only) 
 
 
 
 
 
 

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Labeling for Phase III GM-CSF Outer carton label 
Bacteriostatic 0.9% Sodium Chloride for Injection, USP,  
Secondary Package Label (for tray containing 25 vials, booklet label text) 
 

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Version 2.7, 08 February 2017  
CONFIDENTIAL AND RESTRICTED 
97 
Amend 7 
Disclosure requires written consent from Bavarian Nordic, Inc. 
 
14.11 
List of Research Centers 
A list of participating centers will be available on www.clinicaltrials.gov, or upon request to BNI. Actual 
centers may change over time. Additional sites may be identified and held in reserve in the event that 
some of the original sites discontinue participation, or if enrollment is slower than expected. 
14.12 
Rationale and Changes 
14.12.1 
Rationale 
The main reason for this administrative amendment is to address feedback from the 
 
, who requested that the study protocol be updated to contain details regarding the 
Interim Analyses described in the Statistical Analysis Plan for this study.  There is no impact to study 
design, conduct, or endpoints as a result of the language provided in Section 9.8, Interim Analyses.   
In addition, the sponsor address and medical monitor have been updated. 
14.12.2 
Changes 
General changes: 
• 
Update Sponsor Address and Medical Monitor name 
• 
Addition of Section 9.8, Interim Analyses and Section 14.12, Rationale and Changes 
• 
Updated Abbreviation list 
New text contained in the new Section 9.8, Interim Analyses is provided below 
An interim analysis plan (IAP) is included in the SAP for this study.  Interim analyses are 
executed by 
 a Contract Research Organization that acts as 
the independent statistician and assessed by the DMC as described in the DMC Charter.  
At each interim analysis, both unblinded (closed) and blinded (open) interim analysis 
reports will be provided to the DMC, while the sponsor will only receive an open (blinded) 
report unless one of the criteria is met.  Even in this case, the DMC will use its discretion 
regarding the communications of results to the sponsor, with patient safety balanced 
against benefit being the primary concern.   
The IAP was designed to detect early evidence of both efficacy and futility.  Interim 
analyses for the two comparisons of overall survival described in Section 9.4 are to be 
executed at 40%, 60%, and 80% of information times, corresponding to 214, 321, and 
427 deaths per comparison.  The final analysis will be completed when 534 deaths per 
comparison have occurred.  To maintain an overall one-sided type I error probability of 
0.0125 per comparison, the one-sided significance criteria using one-sided O’Brien-

Protocol BNIT-PRV-301; Amendment 7 
PROSTVAC-V/F 
 
Version 2.7, 08 February 2017  
CONFIDENTIAL AND RESTRICTED 
98 
Amend 7 
Disclosure requires written consent from Bavarian Nordic, Inc. 
 
Flemming boundaries for early detection of efficacy analyses are 0.000135, 0.00147, 
0.00501, respectively, with the adjusted final analysis to use 0.01063.  The significance 
level to be used for detection of futility at each interim analysis is 0.00001.  This futility 
significance level was chosen in order to provide a balance between the sought for 
estimated probability of detecting futility and protecting against falsely detecting futility.