Clinical trial NCT02506114
Conditions: Prostatic Neoplasms
Keywords: prostate
Sponsor: Lawrence Fong
Start date: 2016-10-06; Completion date: 2020-04-22
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicentered, open label, randomized phase II trial of PROSTVAC or ipilimumab or the combination of PROSTVAC and ipilimumab as neoadjuvant therapy in patients with localized prostate cancer. Eligible patients will be randomized to PROSTVAC monotherapy (Arm A), ipilimumab monotherapy (Arm B), or combination therapy with both PROSTVAC and ipilimumab (Arm C), prior to RP. In arms A and C, PROSTVAC-V will be administered subcutaneously as the primary vaccine on Day 1, which will be followed 2 weeks later with a series of 2 PROSTVAC-F subcutaneous administrations, given 3 weeks apart. In arms B and C, ipilimumab will be administered twice, at a dose of 3mg/kg, 3 weeks apart. In the combination arm, ipilimumab administration will coincide with the PROSTVAC-F administration. In arm B, ipilimumab will begin on Day 1. In all three arms, radical prostatectomy (RP) will occur 21 days, or three weeks, following final treatment administration of PROSTVAC or ipilimumab. No further therapy will be administered on study following RP.

Detailed description:

Arms: arm 1: PROSTVAC-V: 2 x 10\^8pfu; subcutaneous; Day 1. PROSTVAC-F: 1 x 10\^9pfu; subcutaneous; Days 15, and 36. arm 2: Ipilimumab: 3 mg/kg; intravenously; Days 1 and 21. arm 3: PROSTVAC-V: 2 x 10\^8pfu; subcutaneous; Day 1. PROSTVAC-F: 1 x 10\^9pfu; subcutaneous; Days 15, and 36. Ipilimumab: 3 mg/kg; intravenously; Days 15 and 36.
Interventions: intervention 1: PROSTVAC V/F intervention 2: Ipilimumab
Intervention descriptions: intervention 1: PROSTVAC-V/F is a prostate-specific antigen(PSA)-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 PSA to the patient in an immunogenic manner to break self-tolerance, and thereby induce immune responses directed against prostate cancer cells. intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed. 
AN OPEN LABEL, RANDOMIZED PHASE 2 TRIAL OF PROSTVAC AND 
IPILIMUMAB AS MONOTHERAPY OR IN COMBINATION FOR MEN 
WITH LOCALIZED PROSTATE CANCER UNDERGOING RADICAL 
PROSTATECTOMY 
Protocol Number:  CC#14559 
Study Drugs:  PROSTVAC and IPILIMUMAB 
Version Number: 2.0 
Version Date:  July 10, 2018 
IND Number:  16241 
Principal Investigator (Sponsor-Investigator) 
Lawrence Fong, MD 
University of California, San Francisco 
 
 
 
Statistician 
Li Zhang, PhD 
Pharmacist 
Zoe Ngo, Pharm.D. 
Revision History 
Version 2.0 
07-10-18
Version 1.9 
07-05-17
Version 1.8 
02-02-17
Version 1.7 
11-05-15
Version 1.6 
01-28-15
Version 1.5 
12-04-14
Version 1.4 
09-22-14
Version 1.3 
07-23-14
Version 1.2 
07-17-14
Version 1.1 
07-01-14
Version 1.0 
03-14-14
NCT# 02506114


 
 
Protocol Signature Page 
Protocol No.: 14559 
Version Date: 07/10/2018 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Committee on Human Research (CHR), and Data Safety Monitoring Committee 
(DSMC).  
2. I will conduct the study in accordance with applicable CHR requirements, Federal 
regulations, and state and local laws to maintain the protection of the rights and welfare of 
study participants.  
3. I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol.  
4. I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in 
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the 
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In 
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website.  
5. I agree to maintain adequate and accurate records in accordance with CHR policies, 
Federal, state and local laws and regulations. 
UCSF Principal Investigator / Study Chair 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 
 
 


 
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Protocol CC#: 14559 
Phase II – PROSTVAC, IPILIMUMAB 
 
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Abstract 
Title 
An open-label, randomized phase II trial of PROSTVAC and ipilimumab (as 
monotherapy and in combination) as neoadjuvant treatment for men with localized 
prostate cancer (PC) undergoing radical prostatectomy (RP). 
Patient 
population 
Prostate cancer patients undergoing RP 
Rationale for 
Study 
30-40% of patients who undergo RP with curative intent for their localized PC 
experience relapse of their disease. Therefore, improved therapeutic approaches are 
needed in this patient population. Enhancing the immune system’s response to the 
tumor may improve long-term outcomes following RP. 
 
PROSTVAC is a vaccine therapy consisting of two recombinant viral vectors that 
may generate systemic immune responses to PSA, and has been shown to improve 
overall survival in a randomized, placebo-controlled and blinded phase II trial. 
PROSTVAC is well tolerated, with most adverse events (AEs) related to mild 
injection site reactions and only a subset of patients showing other mild systemic 
AEs such as fatigue.  
 
CTLA-4 is negative regulatory molecule that is upregulated when the antigen-specific 
T-cell is activated, which may blunt the immune system’s response to malignancy. 
ipilimumab is a human anti-CTLA-4 monoclonal antibody designed to stimulate 
immune responses. It has obtained regulatory approval for the treatment of 
metastatic melanoma, and demonstrated clinical activity in prostate cancer. 
 
We hypothesize that PROSTVAC and ipilimumab can each induce specific immune 
response in the primary tumor as well as in peripheral blood, and that in combination, 
IPILIMUMAB may augment the T cell-mediated immune response generated by 
PROSTVAC by blocking the inhibitory signal of the CTLA-4 checkpoint. 
 
Primary 
Objective 
 
To assess the immunologic impact induced within the prostate by 
neoadjuvant administration of PROSTVAC OR ipilimumab OR the 
combination in men with localized PC undergoing RP, as measured by 
CD3+ T cell tumor infiltration. 
Secondary 
Objectives 
 
To characterize T cell subsets and NK cells infiltrating the prostate after 
neoadjuvant administration of PROSTVAC OR ipilimumab OR the 
combination. 
 
To measure the treatment-induced effects on circulating T cells following 
neoadjuvant PROSTVAC OR ipilimumab OR the combination of PROSTVAC 
and ipilimumab. 
 
To assess the safety of PROSTVAC OR ipilimumab OR the combination in 
the neoadjuvant setting.  


 
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Exploratory 
Objectives 
 
To examine the effects of neoadjuvant PROSTVAC OR ipilimumab OR the 
combination on systemic antigen-specific immune responses. 
 
To assess various immune monitoring parameters of cellular and humoral 
immune response following neoadjuvant PROSTVAC OR ipilimumab OR the 
combination in blood and in the tumor. 
 
To determine the impact of neoadjuvant PROSTVAC OR ipilimumab OR the 
combination on PD-L1 expression in patients with localized PC. 
 
To determine the clinical benefit of neoadjuvant PROSTVAC OR ipilimumab 
OR the combination in patients with localized prostate cancer measured by: 
o 
PSA response 
o 
Pathologic response 
Study Design 
Open label randomized phase II trial of PROSTVAC and Ipilimumab prior to RP. 
There will be three arms in the study: 1) PROSTVAC alone, 2) Ipilimumab alone, 3) 
PROSTVAC + ipilimumab. To compare the immune response following treatment, 
tissue from the prostatectomy specimen will be compared with tissue from the core 
biopsy specimen obtained prior to treatment, with each subject serving as his own 
control. The immune response of each arm as well as in aggregate will be compared 
with a reference control group. Figure 1 presents a schematic of the study design.  
Number of 
patients 
42 (14 patients in each arm) 
Duration of 
Therapy 
Patients will be randomized to receive PROSTVAC or ipilimumab alone, or the 
combination of PROSTVAC and ipilimumab, and will undergo RP 12 weeks after start 
of therapy. 
Duration of 
Follow up 
All subjects will be followed for 1 year following RP. 
Duration of 
study 
The study will conclude when all enrolled patients have been followed for 1 year 
following RP. The estimated duration of study, from start of enrollment to final study 
report is 2 years. 
Study Drugs 
PROSTVAC (Bavarian-Nordic) is a therapeutic cancer vaccine. Two component viral 
vectors (PROSTVAC-V, a recombinant vaccinia vector, and PROSTVAC-F, a 
recombinant fowlpox vector) are used together in a prime-boost vaccination regimen. 
Both vectors co-express a human PSA gene and genes encoding three human 
immunological costimulatory molecules: B7.1, intercellular adhesion molecule-1 
(ICAM-1), and leukocyte function-associated antigen-3 (LFA-3). 
Ipilimumab (Yervoy, Bristol-Myers Squibb) is a human immunoglobulin G-1 kappa 
monoclonal antibody that targets cytotoxic T lymphocyte-associated antigen-4 
(CTLA-4). Ipilimumab was the first in a class of therapies targeting T cell activation 
and regulation to be licensed in the broad category of agents known as immune 
checkpoint inhibitors, based on improved overall survival in patients with metastatic 
melanoma. 


 
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Safety 
Assessments 
Safety will be assessed by reviewing adverse events (AEs), laboratory evaluations, 
and by physical examination. The NCI CTCAE v4.03 will be used. All AEs and serious 
AEs (SAEs), with the exception of those considered related to RP, will be recorded 
on case report forms (CRFs) from enrollment through 12 weeks post-surgery 
Efficacy 
Assessments 
For the primary endpoint, the change in the number of CD3+ T cell infiltration within 
prostate tissue between the biopsy and RP specimen will be quantified using 
immunohistochemistry (IHC), with a positive result if there is ≥2 fold increase in the 
number of CD3+ T cell infiltration. 
As secondary endpoints we will look at changes in T cell subsets by IHC in the 
tissue and circulating T cells by flow cytometry. We will assess the toxicities 
according to NCI CTCAE v.4.03 
Unique 
Aspects of this 
Study 
This is the first study to: 1) evaluate the safety of systemic PROSTVAC or ipilimumab 
monotherapy, or the combination of PROSTVAC and ipilimumab, in the neoadjuvant 
setting in prostate cancer patients; 2) evaluate their direct effect both systemically, 
and in the tumor microenvironment. The secondary and exploratory studies will 
enhance the understanding of the immune effects of these therapeutic modalities. 
 
 
 
 
 
 
 
 
 


 
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Figure 1 
Study Schema  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F/U: at 9 weeks, 6 months, and 12 
months following RP 


 
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List of Abbreviations 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CBC 
Complete blood cell (count) 
CHR 
Committee on Human Research (UCSF IRB) 
CR 
Complete response 
CRC 
Clinical Research Coordinator 
CRADA 
Cooperative Research and Development Agreement 
CRF 
Case report form 
CT 
Computerized tomography 
CTCEA 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trial Management System 
DFS 
Disease-free survival 
DLT 
Dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBeAg 
Hepatitis B “e” antigen 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HDFCCC 
Helen Diller Family Comprehensive Cancer Center 
HGB 
Hemoglobin 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IND 
Investigational new drug application 
IP 
Investigational product 
irAE 
Immune related adverse event 
IRB 
Institutional Review Board 
IV 
Intravenous 


 
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List of Abbreviations 
LDH 
lactate dehydrogenase 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
ORR 
Overall response rate 
PC 
Prostate cancer 
PD 
Disease progression 
PK 
Pharmacokinetics 
PO 
Per os (by mouth, orally) 
PR 
Partial response 
PRC 
Protocol Review Committee (UCSF) 
QOL 
Quality of Life 
RBC 
Red blood cell (count) 
SD 
Stable disease 
SD 
Standard deviation 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
TRICOM 
TRIad of COstimulatory Molecules 
TAA 
Tumor associated antigen 
ULN 
Upper limit of normal 
WBC 
White blood cell (count) 
 
 


 
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Table of Contents 


 
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Protocol Signature Page ......................................................................................................... 2 
Abstract 
3 
List of Abbreviations ................................................................................................................ 7 
Table of Contents .................................................................................................................... 9 
1 
Introduction .................................................................................................................. 14 
1.1 
Background on Indication .................................................................... 14 
1.2 
PROSTVAC ......................................................................................... 14 
1.2.1 Preclinical studies: PROSTVAC ....................................................... 15 
1.2.2 Clinical studies: PROSTVAC ............................................................ 15 
1.3 
Ipilimumab ........................................................................................... 16 
1.3.1 Preclinical studies ............................................................................. 17 
1.3.2 Clinical studies: Non-prostate cancer patients .................................. 17 
1.3.3 Ipilimumab in prostate cancer patients ............................................. 18 
1.3.4 Safety: Ipilimumab at 3 mg/kg .......................................................... 20 
1.4 
Rationale for the Proposed Study ........................................................ 22 
2 
Objectives of the Study ................................................................................................ 23 
2.1 
Primary ................................................................................................ 23 
2.2 
Secondary ............................................................................................ 23 
2.3 
Exploratory Objectives, Other Assessments ........................................ 23 
2.4 
Endpoints ............................................................................................. 23 
2.4.1 Primary Endpoint .............................................................................. 23 
2.4.2 Secondary Endpoints ....................................................................... 23 
2.4.3 Exploratory Endpoints ...................................................................... 24 
3 
Study Design ................................................................................................................ 25 
3.1 
Characteristics ..................................................................................... 25 
3.2 
Number of Subjects ............................................................................. 25 
3.3 
Eligibility Criteria .................................................................................. 25 
3.3.1 Inclusion Criteria ............................................................................... 26 
3.3.2 Exclusion Criteria.............................................................................. 26 
3.4 
Duration of Therapy ............................................................................. 28 
3.5 
Duration of Follow Up and Removal from Assessment. ....................... 29 
3.6 
Randomization Procedures .................................................................. 29 
3.7 
Study Timeline ..................................................................................... 29 
3.7.1 Primary Completion .......................................................................... 29 
3.7.2 Study Completion ............................................................................. 29 
4 
Study Drugs ................................................................................................................. 29 
4.1 
Description, Supply and Storage of Investigational Drugs ................... 29 
4.1.1 PROSTVAC ...................................................................................... 29 
4.1.2 Investigational Drug #2: PROSTVAC-F [PROSTVAC-F/TRICOM; 
Recombinant Fowlpox-PSA (L155)/TRICOM; NSC 717171] ....................... 32 
4.2 
Viral shedding: PROSTVAC ................................................................ 32 
4.3 
Safe handling of recombinant vaccinia virus vaccine ........................... 33 
4.4 
Safe handling of recombinant fowlpox vaccine .................................... 33 
4.4.1 Investigational Drug #3: Ipilimumab (Yervoy®, BMS) ........................ 33 
4.4.2 Provision of Drugs ............................................................................ 34 
4.5 
Drug Accountability .............................................................................. 34 
4.6 
Drug Ordering ...................................................................................... 34 


 
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Table of Contents 
4.7 
Packaging and Labeling of Study Drugs .............................................. 35 
5 
Treatment Plan ............................................................................................................. 35 
5.1 
Dosage and Administration .................................................................. 35 
5.1.1 Criteria for study arm discontinuation ............................................... 36 
5.2 
Criteria for stopping treatment ............................................................. 36 
5.2.1 Criteria for holding/skipping ipilimumab ............................................ 36 
5.3 
Radical Prostatectomy ......................................................................... 37 
5.4 
Dose Modifications............................................................................... 37 
5.5 
Monitoring and Toxicity Management of PROSTVAC and ipilimumab. 37 
5.5.1 Management of PROSTVAC injection site reactions ........................ 37 
5.5.2 Management of PROSTVAC-related systemic adverse events ........ 38 
5.6 
Monitoring and Toxicity Management of Ipilimumab ............................ 38 
5.6.1 General Guidelines for Managing Toxicity ........................................ 38 
5.6.2 Hypersensitivity Reactions ............................................................... 39 
5.6.3 Management of Hepatotoxicity ......................................................... 40 
5.6.4 Treatment of Ipilimumab-Related Isolated Drug Fever ..................... 40 
5.6.5 Immune Related Toxicity .................................................................. 40 
5.6.6 Criteria for stopping ipilimumab ........................................................ 41 
6 
Study Procedures and Observations ............................................................................ 42 
6.1 
Schedule of Procedures and Observations .......................................... 42 
6.1.1 Pretreatment Period ......................................................................... 42 
6.1.2 Treatment Period, ARMS A&C ONLY .............................................. 44 
6.1.3 Treatment Period, ARM B ONLY ...................................................... 45 
6.1.4 Study Procedures: Radical Prostatectomy (ALL ARMS: 21 days 
following final dose of PROSTVAC and/or Ipi) ............................................. 46 
6.1.5 Early Termination Visit (All ARMS) ................................................... 47 
6.1.6 Follow-up Study Procedures: (ALL ARMS, 9 weeks  following RP (+/- 
7 days)) ........................................................................................................ 47 
6.1.7 Post-treatment/Follow Up Visits (ALL ARMS, 6 and 12 months 
following RP (+/- 7 days)) ............................................................................ 48 
6.1.8 Discontinuation of Therapy ............................................................... 48 
6.2 
Usage of Concurrent/Concomitant Medications ................................... 53 
6.3 
Dietary Restrictions .............................................................................. 53 
6.4 
Prohibited Medications ......................................................................... 53 
6.5 
Restricted Medications ......................................................................... 53 
7 
Reporting and Documentation of Results ..................................................................... 53 
7.1 
Evaluation of Activity ............................................................................ 53 
7.1.1 Primary endpoint: Immunohistological Characterization of CD3
+ T 
Cell Infiltration within Prostate Tissue. ......................................................... 53 
7.1.2 Secondary and exploratory endpoints. ............................................. 54 
7.1.3 PSA .................................................................................................. 54 
7.1.4 Pathologic Response ........................................................................ 54 
7.2 
Evaluation of Safety ............................................................................. 54 
7.3 
Definitions of Adverse Events .............................................................. 55 
7.3.1 Adverse event .................................................................................. 55 


 
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7.3.2 Adverse reaction............................................................................... 55 
7.4 
Recording of an Adverse Event ........................................................... 56 
7.5 
Follow-up of Adverse Events ............................................................... 57 
7.6 
Adverse Events Monitoring .................................................................. 57 
7.7 
Expedited Reporting ............................................................................ 57 
All non-serious AEs should be transferred to Bavarian Nordic and Bristol-Myers Squibb, Inc. 
(related to ipilimumab), every six months once the case is closed in the UCSF 
safety database. ........................................................................................... 59 
8 
Statistical Considerations and Evaluation of Results .................................................... 59 
8.1 
Study Endpoints ................................................................................... 59 
8.2 
Sample size and power estimate ......................................................... 59 
8.3 
Accrual ................................................................................................. 59 
8.4 
Interim Analyses and Stopping Rules .................................................. 60 
8.5 
Analyses Plans .................................................................................... 60 
8.5.1 Primary Analysis (or Analysis of Primary Endpoint).......................... 60 
8.5.2 Secondary Analyses (or Analyses of Secondary Endpoints) ............ 60 
8.5.3 Exploratory Analyses (or Analyses of Exploratory Endpoints) .......... 61 
8.6 
Reference population ........................................................................... 62 
8.7 
Evaluation of Safety ............................................................................. 62 
9 
Study Management ...................................................................................................... 62 
9.1 
Pre-study Documentation .................................................................... 62 
9.2 
Institutional Review Board Approval .................................................... 63 
9.3 
Informed Consent ................................................................................ 63 
9.4 
Changes in the Protocol ....................................................................... 63 
9.5 
Handling and Documentation of Clinical Supplies ............................... 63 
9.6 
Case Report Forms (CRFs) ................................................................. 64 
9.7 
Registration/Enrollment ........................................................................ 64 
9.8 
Oversight and Monitoring Plan ............................................................. 65 
10 
Protection of Human Subjects ...................................................................................... 65 
10.1 
Protection from Unnecessary Harm ..................................................... 65 
10.2 
Protection of Privacy ............................................................................ 65 
 
Appendix 1 
Performance Status Criteria .......................................................................... 70 
Appendix 2 
Data and Safety Monitoring Plan for a Phase II or Phase III Institutional Study 
 ..................................................................................................................... 71 
Appendix 3 
Clinical Monitoring for Autoimmunity ............................................................. 74 
Appendix 4 
American Urological Association (AUA) symptom ......................................... 76 
Appendix 5 
General recommendations for managements of suspected immune related 


 
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Table of Contents 
adverse events ............................................................................................. 77 
Appendix 6 
Diarrhea Management Algorithm .................................................................. 78 
Appendix 7 
Hepatotoxicity Management Algorithm .......................................................... 79 
Appendix 8 
Endocrinopathy Management Algorithm ....................................................... 81 
Appendix 9 
Prohibited Medications.................................................................................. 82 
 
List of Tables 
Table 1 
Adverse Events: Ipilimumab 3mg/kg in prostate cancer patients ......... 21 
Table 2 
Regimen Description ............................................................................ 36 
Table 3 
Schedule of Study Procedures and Assessments (ARMS A&C) ......... 49 
Table 4 
Schedule of Study Procedures and Assessments (ARM B) ................. 51 
 
List of Figures 
Figure 1 
Study Schema ....................................................................................... 6 
Figure 2 
T-cell activation and mechanism of action of Ipilimumab. .................... 17 
 
 
 
 
 


 
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1 
Introduction 
1.1 
Background on Indication 
Prostate cancer (PC) represents the most common malignancy and the second leading cause of 
cancer-related death in men in Western countries. In the United States, nearly 240,000 new cases 
were diagnosed and 30,000 men died in 2013 (1). While surgery and radiotherapy are potential 
curative treatments in patients with localized PC; treatment failure rates reach 35-40% (2, 3). 
Neoadjuvant approaches with chemotherapy or androgen deprivation therapy (ADT) in 
combination with surgery or radiation have been investigated to reduce treatment failure rates. 
These studies have demonstrated the safety and feasibility of neoadjuvant approaches, and have 
been shown to decrease the proportion of patients with positive margins at surgery (4, 5). 
However, this has not translated into significant benefit at meaningful clinical endpoints such as 
progression-free survival or overall survival (6). Therefore, neoadjuvant therapy remains an 
investigational approach. 
 
The efficacy of immune therapies in the treatment of human malignancies, and the positive impact 
on survival or sipuleucel-T (Sip-T) in men with advanced prostate cancer (7) has led to the 
investigation of the role of immune therapy in the neoadjuvant setting. In a recently completed 
phase II study(8), patients received 3 infusions of Sip-T at 2 week intervals beginning 6-7 weeks 
prior to RP. Preoperative sip-T was safe and tolerable, and did not impact surgery.  Importantly, 
significant increases in CD3+ and CD4+ T cells were observed in the prostatectomy specimens, 
suggesting that a tumor-specific immune response can be induced via this approach (since the 
effect of systemic Sip-T on localized prostate tumor tissue was unknown prior to this study, a 
group of 12 patients who underwent RP without any neoadjuvant therapy were used as a negative 
control to provide confidence that the changes observed were due to treatment effect). 
 
There are multiple strategies for generating therapeutic immune responses, including the use of 
therapeutic vaccines designed to target specific tumor-associated antigens (TAAs) and immune 
checkpoint inhibitors that allow for the expansion of an underlying immune response. Antigen-
specific active immunotherapy is designed to generate immune responses, particularly T cell-
mediated responses, against specific TAAs using vaccines that express one or more of these 
antigens. The identification and isolation of genes encoding TAAs has allowed the development 
of recombinant antitumor vaccines designed to elicit immune responses to one or more antigens 
known to be expressed by a particular tumor type.  
 
1.2 
PROSTVAC 
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 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.  Thus the therapy consists of the following: 
 


 
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 
A recombinant vaccinia vector (PROSTVAC-V) as the primary vaccination 
 
A recombinant fowlpox vector (PROSTVAC-F) as subsequent booster vaccinations 
Both vectors contain the transgene to express PSA, as well as transgenes for 3 costimulatory 
molecules: B7.1, intercellular adhesion molecule-1 (ICAM-1), and leukocyte function-associated 
antigen-3 (LFA-3), also known as TRICOM (TRIad of COstimulatory Molecules). The PSA gene 
used in these recombinants has an alteration in a human leukocyte antigen-A2 (HLA-A2) specific 
epitope (replacement of isoleucine with leucine at amino acid position 155; designated L155 
agonist epitope). 
Vaccinia virus has been used for over 200 years as a vaccine for smallpox and has a well-
established safety profile. Productive fowlpox virus infection is restricted in vivo to avian species; 
however, fowlpox mediated gene expression does occur in infected non-avian cells (9). In 
PROSTVAC-V, the recombinant vaccinia virus actively replicates in infected human cells, 
resulting in the presentation of high levels of antigen to the immune system over a period of one 
to two weeks, substantially increasing the potential for immune stimulation. The immune system 
response specific to vaccinia then eliminates the virus. The administration of the recombinant 
fowlpox vector PROSTVAC-F can then stimulate both humoral and cell-mediated immunity to the 
expressed transgene. 
 
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 further supported by results from completed Phase 1 and 
Phase 2 trials (See Section 1.2.2). 
 
1.2.1 Preclinical studies: PROSTVAC 
All components of PROSTVAC, including vaccinia and fowlpox vectors delivering PSA (with the 
L155 mutated agonist epitope), B7.1, ICAM-1, LFA-3 or murine CEA have been tested in various 
combinations in mouse, rabbit and non-human primate models as well as in a number of in vitro 
experiments (10). Recombinant vaccinia and fowlpox vaccines targeting PSA as the tumor 
antigen demonstrated generation predominantly of cell-mediated immune responses to PSA plus 
antigen spreading to additional tumor antigens which resulted in substantial evidence of anti-
tumor activity. Humoral responses to the recombinant vectors and to a much lesser extent to PSA 
were also observed. No biologically significant changes or signs of untoward toxicological effects 
(including immunogenicity, biodistribution, neurovirulence and BBB survival) were noted in either 
rodent or non-human primate safety studies, supporting initiation of human clinical trials (see 
PROSTVAC Investigator Brochure for more detailed information). 
 
1.2.2 Clinical studies: PROSTVAC 
Clinical evaluation of PROSTVAC was preceded by 12 Phase 1 and Phase 2 clinical studies with 
earlier generation vaccinia and fowlpox constructs showing safety and immunogenicity in different 
settings. 
 
Sanda et al (11) evaluated the safety and biologic effects of a single dose vaccinia-PSA (rV-PSA) 
administered in 6 patients with PSA-recurrence after androgen-deprivation interruption. Toxicity 
was minimal, and DLTs were not observed. Variability in the time required for androgen 
restoration (after interruption of androgen deprivation therapy) was observed, with one patient 


 
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showing 30 weeks of undetectable PSA levels after testosterone restoration. Primary anti-PSA 
IgG antibody activity was induced after rV-PSA vaccination in one patient. 
 
Eder et al (12) tested three dose levels of rV-PSA (4-week intervals for a total of three doses), in 
33 advance PC patients, with GM-CSF as immunostimulatory adjunct for the ten patients at the 
highest dose level. No virus-related adverse events appeared, and immunological studies 
demonstrated specific T-cell response to PSA. Certain patients remained without evidence of 
clinical progression for up to 21 months or longer. 
 
Phase I trial: P1-4 studied PROSTVAC (without GM-CSF) in ten patients establishing its safety 
and immunogenicity. Only 1 dose of rV (prime, day 1) followed by 1 dose of rF (booster, day 29) 
was used. There were no SAEs related to the vaccine and anti-vaccinia titers were increased at 
day 15 (seroconversion) and at the end of eight weeks (13). 
 
Phase I/II trial: (NCI sponsored, Protocol 5911, NCT00062153/NCT00060528) studied patients 
without previous chemotherapy; visceral disease and narcotic use for cancer pain were allowed. 
This trial studied different doses of PROSTVAC as well as the effect of GM-CSF and/or rF-GM-
CSF on the immunologic response as an addition to these vaccines. The MTD established in the 
Phase I stage showed no DLT or Grade 3/4 AEs (14). The Phase II portion of the study of 32 
patients showed a median OS of 26.6 months, compared to the predicted median OS by the 
Halabi nomogram of 17.4 months. Overall survival was correlated with the development of this 
immune response, as patients with greater PSA-specific T-cell responses showed a trend (p = 
0.055) toward enhanced survival. There were no SAEs related to PROSTVAC or GM-CSF in this 
study. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-
CSF versus no GM-CSF (15). The PSA-TRICOM vaccine appears to have provided marked 
benefit not apparent during vaccination, but consistent with subsequent development of a 
beneficial immune response (16).  
 
Phase II trial: TBC-PRO-002 (NCT00078585) was a randomized (2:1), double-blind empty 
vector-controlled trial that evaluated the safety and efficacy of PROSTVAC in 125 men with 
castration-resistant metastatic PC patients with no visceral metastases, previous chemotherapy 
nor narcotic use for cancer-related pain (17). Investigational arm consisted in 1 dose of rV (prime, 
day 1) followed by 6 doses of rF (boosters on days 14, 28, 56, 84, 112, 140). PFS (primary 
endpoint) was similar in both arms, but median survival was longer in the investigational arm than 
for the control group (25.1 and 16.6 months, respectively), with an overall hazard ratio of 0.559 
(95% CI 0.367 – 0.852), P=0.0061. The vaccination regimen was well tolerated and safety profile 
was similar for the two treatment groups. 
 
 
In collaboration with the NCI under the CRADA agreement and with NCI cooperative groups, 
clinical experience with PROSTVAC-V and PROSTVAC-F has been evaluated under a variety of 
study designs.  In 2003, the NCI initiated its own BB-IND (10915) on the current PROSTVAC-V 
and PROSTVAC-F product and to date has conducted multiple studies, which cover a range of 
study designs evaluating PROSTVAC-V and PROSTVAC-F in early and late-stage disease and 
in combination with other therapies. 
 
1.3 
Ipilimumab 
Inhibition of immune checkpoints represents another important major strategy in prostate cancer 
immunotherapy (Figure 2). Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a molecular 
“brake” on the immune system. The cell-surface molecule is found on activated T cells and 
interfaces with the B7 ligands, CD80 and CD86, on antigen presenting cells (APCs). CTLA-4 


 
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binds more avidly to the B7 ligands than CD28 receptors, which are responsible for costimulatory 
signaling, and leads to negative regulation of T-cell activation and proliferation. CTLA-4 also is 
expressed constitutively on T-reg cells, which contribute to the induction of peripheral self-
tolerance.  
 
Ipilimumab is a human immunoglobulin G (IgG1)κ anti-CTLA-4 monoclonal antibody (mAb). In 
vitro studies were performed with ipilimumab to demonstrate that it is specific for CTLA-4, actively 
inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any cross-reactivity with human 
B7.1, B7.2 negative cell lines, and stains the appropriate cells without non-specific cross-reactivity 
in normal human tissues, as demonstrated by immunohistochemistry. 
 
Figure 2 
T-cell activation and mechanism of action of Ipilimumab 
 
1.3.1 Preclinical studies 
Complete information on the pre-clinical toxicology studies can be found in the Ipilimumab 
Investigator Brochure (IB). Ipilimumab is a human IgG1, an isotype generally capable of mediating 
CDCC and ADCC, but preclinical studies showed neither of these activities, likely due to a very 
low expression of CTLA-4 on activated T cells. Therefore, these data suggest that ipilimumab 
treatment would not result in depletion of activated T cells in-vivo. Indeed, no depletion of T-cells 
or T-cell subsets were noted in toxicology studies in cynomolgus monkeys, and no mortality or 
signs of toxicity were observed in three independent 14-day intravenous toxicology studies at 
multiple doses up to 30 mg/kg/dose. Ipilimumab was well tolerated alone or in combination in all 
studies. There were no significant changes in clinical signs, body weight values, clinical pathology 
values or T cell activation markers. In addition, there were no significant histopathology changes 
in the stomach or colon. 
1.3.2 Clinical studies: Non-prostate cancer patients 
Ipilimumab has shown to improve overall survival in patients with advanced melanoma 
(unresectable Stage III or Stage IV) previously treated with chemotherapy (18), and in previously 
untreated in combination with chemotherapy (19). These results prompted FDA-approval of 
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In general, the safety profile of ipilimumab administered as single doses of up to 20 mg/kg and 
multiple doses of up to 10 mg/kg every 3 weeks was characterized by adverse reactions that were 
mostly immune in nature. Drug-related SAEs were reported in studies of ipilimumab administered 
as monotherapy, as well as in combination with vaccines, cytokines, chemotherapy, or radiation 
therapy. 
The data on safety of ipilimumab at the dose of 3 mg/kg in phase III trials comes mainly from the 
metastatic melanoma patients enrolled in the above mentioned study of previously treated 
patients (18). Immune-related adverse events (irAE) occurred in approximately 60% of patients 
treated with ipilimumab, of which Grade 3 and 4 were 12.2 and 2.3% respectively, which typically 
did not occur until 3-4 weeks into therapy. Overall, severe or life-threatening (grade 3 or 4) toxicity 
was seen in 10-15%. The phase III trial used a dose of 3 mg/kg of ipilimumab every 3 weeks. 
Grade 4 drug-related toxicities were uncommon (3.8%) and typically immune-related (2.3%).  
A higher incidence of side effects was observed with a dose of 10 mg/kg every 3 weeks in the 
randomized phase II trial that assessed the effects of dose on activity and toxicity. Data from 
other studies in melanoma and prostate cancer patients show that there is an increase in the 
frequency of adverse events at increasing dose levels (20, 21): 
- 
Serious adverse events (35, 49, and 53 %, at 0.3, 3.0, and 10 mg/kg, respectively). 
- 
Immune-related adverse events (26, 56, and 70 %, respectively) and serious (grade 3 to 4) 
immune-related adverse events (0, 7, and 25 %, respectively). 
- 
Adverse events leading to drug discontinuation (13, 10, and 27 %, respectively). 
1.3.3 Ipilimumab in prostate cancer patients 
The first-in-human study of ipilimumab was performed in patients with prostate cancer at UCSF. 
In this initial trial, a single dose of ipilimumab at 3 mg/kg given to patients with CRPC resulted in 
a ≥50% decline in PSA levels in 2 of 14 patients, any of those two having measureable disease. 
This trial showed that a single 3 mg/kg dose of ipilimumab has acceptable pharmacokinetic and 
safety profiles, but also indicated the risk of treatment-related immune events as one patient 
developing grade 3 rash/pruritus requiring systemic corticosteroids (22). 
 
In the setting of prostate cancer, ipilimumab has shown activity across the six other clinical trials 
that have explored its use alone or in combination with other strategies or immune adjuvants: GM-
CSF (23), cancer vaccines like GVAX (24) and PROSTVAC (25), chemotherapy (26), radiation 
(21) and anti-androgen therapy (27). Although the studies are too small to be definitive, these 
trials overall have noted declines in PSA and a low frequency of radiographic responses at doses 
of ipilimumab ≥ 3mg/kg. It is important to note that radiographic responses in metastatic CRPC 
can be difficult to detect because bone metastasis are difficult to measure. Many of these trials 
were looking for the optimal dose and schedule of ipilimumab alone or in combination. 
 
Phase I dose-escalation of Ipilimumab with GM-CSF (23). Up to 24 patients were enrolled in 
this trial where sequential cohorts were treated with increasing doses of ipilimumab, up to 3 
mg/kg. At this dose, 22% of patients experienced a PSA response and 50% had a PSA decline 
of >50%. Subjects experienced irAE in a dose-dependent fashion and also in correlation with 
PSA response. The three subjects that experienced clinical responses also had irAE: grade 3 
pan-hypopituitarism in one, grade 3 colitis in another, and grade 2 rash in the third. All of these 
irAE were clinically manageable with steroids. The combination enhanced the activation of 
circulating CD8+ T cells also in a dose-dependent manner. 
 


 
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Phase II of Ipilimumab (3 mg/kg monthly for four doses) with or without a single dose of 
docetaxel (26) enrolled 43 patients and did not reveal clear difference in safety or PSA response 
(around 15%) between the two groups, and no radiographic responses where seen. Two patients 
in the monotherapy group and one in the combination group had PSA responses. 18 patients 
experienced 52 SAE, 10 of which were attributed to ipilimumab. 
 
Phase II of a single dose of Ipilimumab (3 mg/kg) with ADT vs ADT alone (27). This 
randomized trial enrolled 108 patients and at 3 months, 55% of ipilimumab patients had 
undetectable PSA versus 38 % in the ADT-only arm. In the combination arm, grade 3 or 4 irAEs 
included colitis (4.5%) and diarrhea (4.5%). 
 
Phase I/II testing three different doses (3 mg/kg, 5 mg/kg and 10 mg/kg) with or without 
radiotherapy (21). PSA decline and radiographic responses were observed in all dose cohorts. 
Overall PSA response was 20%. Among 45 patients in the 10-mg/kg group, 8 had PSA declines 
of greater than 50%, 1 had a CR lasting greater than 11.3 months, and 6 had stable disease. 
Immune-related adverse events were similar to those described in previous studies. No difference 
in the number of patients who had a decline in PSA ≥ 50% was seen between patients treated 
with ipilimumab alone (5 out of 16 chemo-naïve patients) versus the ipilimumab and radiotherapy 
(4 out of 15 chemo-naïve patients), and fewer patients in the post-chemotherapy group had a 
decline in PSA ≥ 50% when treated with ipilimumab and radiation (1 out of 14). 
 
Various patterns of PSA decline have been reported, occurring at treatment onset, after a short 
period of stable disease, or within six months after an initial rise in PSA levels. In some cases, 
response to ipilimumab lasted for 1 year or more. These observed patterns do suggest that an 
individual´s immune response to prostate cancer may be dynamic and in some patients durable. 
 
Phase III trial of ipilimumab (10 mg/kg) and radiation versus radiation alone in the 
postdocetaxel setting (NCT00861614, Gerritsen, ESMO 2013) (28). The study's primary 
endpoint of OS did not reach statistical significance with median OS at 11.2 months with 
ipilimumab (n=399) and 10 months with the placebo (n= 400; HR=0.85; 95 % confidence 
interval [CI]=0.72-1.00; p=0.053). Median progression-free survival favored ipilimumab over 
placebo (HR=0.7; 95 % CI=0.61-0.82) as did prostate-specific antigen (PSA) response rates, 
as evidenced by declines of ≥50 % in evaluable patients (13.1 % vs. 5.3 %, respectively). 
Respective 1- and 2-year OS rates for ipilimumab vs placebo were 47% vs 40% and 26% vs 
15%. Median PFS also favored ipilimumab over placebo (HR=0.70; 95%CI=0.61–0.82), as did 
PSA declines of ≥50% in evaluable patients (13.1% vs 5.3%, respectively). Pre-specified 
subset analyses suggest that ipilimumab may be most active in patients with no visceral 
disease and favorable laboratory prognostic factors (eg. decreased alkaline phosphatase, 
elevated hemoglobin). A post hoc analysis in patients who received treatment (n=779; n=387 
for ipilimumab vs n=392 for placebo) showed an improvement in OS which favored ipilimumab 
(HR=0.84; 95%CI=0.71–1.00; p=0.0498). Treatment-related adverse events (AEs) were 
common and mostly immune-related AEs (irAEs). Grade ≥3 irAEs in the ipi vs pbo arms, 
respectively, were GI (18% vs 1%), liver (5% vs 1%), endocrine (2% vs 1%) and dermatologic 
(1% vs 0%); most were reversible using standard ipi management algorithms. Incidences of 
drug-related death and GI perforation were 1% and 0.6%, respectively. 
 
A second phase III study that compares ipilimumab versus placebo in individuals with metastatic 
CRPC who have not already been treated with chemotherapy is ongoing (NCT01057810). 
Combining cancer vaccines and ipilimumab would presumably improve anti-tumor activity by 
amplifying immune responses focused to relevant antigens as demonstrated in mice. 
 


 
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Phase I dose-escalation of ipilimumab (monthly, up to 5 mg/kg, with the expansion cohort 
at 3 mg/kg) with GVAX (24). Five of 28 patients who completed treatment had a ≥ 50% decline 
in PSA, and 12 had stabilization of metastatic bone disease for extended durations (12 to 21 
months) (24). In the escalation cohort (12 patients), 5 patients who received 3 or 5 mg//kg had 
grade ≥2 irAEs (4 had hypophysitis, 1 had sarcoid alveolitis), and in the expansion cohort (16 
patients), 2 patients had grade 2 hypophysitis, 3 had grade 1or 2 colitis and 1 had grade 3 
hepatitis. 
 
Phase I dose-escalation of ipilimumab (monthly, at 1, 3, 5 and 10 mg/kg, up to 6 doses) 
with PROSTVAC and GM-CSF in metastatic CRPC. Twenty-four chemo naïve and 6 
postdocetaxel patients were enrolled in this trial. Five of 9 chemo-naïve patients with mCRPC 
who received 3 or 5 mg/kg of ipilimumab plus PROSTVAC had ≥ 50% declines in PSA (25), and 
4 had stable disease ≥ 6 months, and 2 had unconfirmed partial responses. Overall 14 of 24 
chemotherapy-naïve subjects at any dose level of ipilimumab (1, 3, 5 and 10 mg/kg) showed 
decline in PSA. Physical tumor shrinkage however was infrequent. Nine of 15 receiving 10mg/kg 
of ipilimumab had stable disease ≥ 6 months. No dose-limiting toxicities were recorded and the 
maximum tolerated dose was not exceeded. Toxicities were primarily local grade 1 and 2 
injection-site reactions (three patients with grade 1 events, 26 with grade 2) and immune-related 
adverse events (table 3). Rash was the most common irAE noted mostly in patients receiving 10 
mg/kg ipilimumab. Endocrine irAEs were more common at 5 and 10 mg/kg doses, with grade 2 
and 3 diarrhea or colitis noted at all doses above the lowest (1 mg/kg)) ipilimumab dose. Other 
uncommon irAEs included elevated concentrations of aminotransferases and neutropenia or 
leucopenia. Overall, 21 patients (70%) had a grade 2 or greater irAE, and 8 patients (27%) had 
grade 3 or 4 immune-related adverse events. There were no other non-immune-related grade 4 
toxic effects, and the remaining grade 3 toxic effects were probably related to the accompanying 
irAEs in the same patient. Overall, 14 patients discontinued ipilimumab because of disease 
progression (progressed before the planned initial six doses of ipilimumab) and 13 discontinued 
ipilimumab because of irAEs (median 2 doses, range 1–3); and three received all six planned 
initial doses. Of these toxic effects, six patients had irAEs in the first month of treatment. These 
AEs included rashes in 4 patients (all grade 2) and 2 cases of diarrhea or colitis (grade 2 and 3). 
With the exception of one subject with rash at the 3 mg/kg dose, all other irAEs in the first month 
were at the 10 mg/kg dose. The duration of all irAEs varied on the basis of toxic effects and 
individual patients. For endocrine-related toxic effects, patients had to be placed indefinitely on 
replacement hormones. Two patients were weaned off these treatments. 10 patients with rash 
were treated with supportive measures for a median of 27 days (range 6–138). The duration of 
diarrhea or colitis varied from 2 to 98 days, with a median of 32 days until resolution of symptoms 
to grade 1 or less. The three episodes of raised aminotransferases lasted for 3, 25, and 28 days, 
respectively, and the single episode of grade 4 neutropenia lasted 6 days. 
 
1.3.4 Safety: Ipilimumab at 3 mg/kg 
The majority of data for drug-related AEs come from the studies with metastatic melanoma 
patients, where four doses of ipilimumab was the treatment schema. The most common 
treatment-emergent adverse events (AEs) considered by the investigator to be related to study 
drug in the metastatic melanoma trial (18) were irAEs, which occurred in approximately 60% of 
the patients treated with ipilimumab. The frequency of grade 3-4 immune-related adverse events 
was 10 to 15%. All irAEs occurred during the induction period (within the initial 4 doses). The 
irAEs most often affected the skin and gastrointestinal tract. The median time to the resolution of 
irAEs of grade 2, 3, or 4 was 4.9 weeks (95% CI, 3.1 to 6.4). The most common irAE was diarrhea, 
which occurred at any grade in 27 to 31% of the patients in the ipilimumab treated patients. After 
the administration of corticosteroids, the median time to the resolution of diarrhea of grade 2 or 
higher was 2.3 weeks for 14 of 15 patients. In addition to corticosteroids, 4 patients received 


 
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infliximab (anti–tumor necrosis factor α antibody) for diarrhea of grade 3 or higher or colitis. 
Among the 94 persons who survived for 2 years, residual effects of AEs included those related to 
injection site reactions (16 patients), vitiligo (12), diarrhea or colitis (e.g., proctocolitis with rectal 
pain) (4), and endocrine irAEs (e.g., inflammation of the pituitary) that required hormone-
replacement therapy (8). Ongoing events in the persons who survived for 2 years included rash 
pruritus, diarrhea, anorexia, and fatigue, generally of grade 1 or 2 (in 5 to 15% of the patients) 
and grade 3 leukocytosis (in one patient). There were 14 deaths related to the study drugs (2.1%), 
of which 7 were associated with immune-related adverse events. 
In another study of metastatic melanoma patients comparing three different doses of ipilimumab 
(20), irAEs of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 
3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were 
gastrointestinal irAEs (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg 
group) and diarrhea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg 
group). Overall, grade 3-4 toxicities were seen in 25.4%, 7 % and 0%, respectively. 
Many of the adverse events considered related to ipilimumab may be immune in nature and 
presumably a consequence of the intrinsic biological activity of ipilimumab. An irAE is defined as 
any adverse event associated with drug exposure and consistent with an immune-mediated 
event. Disease progression, infections and other etiologic causes are ruled out or deemed unlikely 
as contributing to the event. Supportive data, such as autoimmune serology tests or biopsies, are 
helpful but not necessary to deem an event an irAE. Events of unclear etiology, which were 
plausibly “immune-mediated” have been conservatively categorized as irAEs even if serologic or 
histopathology data are absent. These irAEs likely reflect a loss of tolerance to some self-antigens 
or an unchecked immune response to gut or skin flora. Some breakthrough of immunity may be 
inseparably linked to the clinical antitumor activity of ipilimumab. Immune-related AEs 
predominately involve the GI tract, endocrine glands, liver or skin. With few exceptions, irAEs 
were clinically manageable and reversible with supportive care or corticosteroids. Management 
algorithms are included in the IB. 
Corticosteroid treatment did not adversely affect antitumor responses in those subjects who had 
both an irAE requiring steroid therapy and an objective tumor response. Systemic corticosteroids 
do not appear adversely associated with ipilimumab-induced clinical response when used to 
manage irAEs in patients with advanced melanoma. Similar results were observed regardless of 
whether mWHO or the novel immune-related response criteria (irRC) (29) were used. Steroids 
can be used promptly to manage severe irAEs and minimize the risk for serious 
complications(30).  
In this study, two doses of ipilimumab will be administered; thus AE data from prior studies 
may not necessarily be applicable. Here, we report the safety for prostate cancer patients treated 
with Ipilimumab monotherapy at 3 mg/kg q3 weeks for up to four doses: 
 
 
 
 
Table 1 
Adverse Events: Ipilimumab 3mg/kg in prostate cancer patients  
 
Small et al 
(single dose) 
 N=14 (31) 
Slovin et al 
(up to 4 doses) 
N=8 (21) 
Diarrhea 
21% 
50% 


 
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Colitis (G3-4) 
NR 
13% 
Nausea 
14% 
38% 
Constipation 
29% 
NR 
Vomiting 
NR 
25% 
Abdominal pain 
21% 
NR 
Fatigue 
29% 
0 
Decrease appetite 
43% 
NR 
Pruritus 
NR 
25% 
Rash 
14% 
13% 
1.4 
Rationale for the Proposed Study 
Results from the PROSTVAC studies Phase I/II trial (Protocol Nº 5911) and the Phase 2 TBC-
PRO-002 suggest that it may confer an advantage in overall survival in subjects with mCRPC. 
Despite limited numbers of patients with noticeable tumor shrinkage, both GVAX and 
PROSTVAC with Ipilimumab showed significant numbers of patients with stabilization of their 
disease that can last for several months, with manageable side effects. The presumptive 
mechanism is that the vaccination activates anti-cancer immune responses, and in particular, 
induces an intratumoral T cell response (32). Additionally, the median overall survival in the 
PROSTVAC/ipilimumab combination trial was 31.8 months (25), a notable duration in mCRPC.  
 
The non-overlapping mechanisms of action of these drugs suggest a potential for combination 
therapy, with the goal of substantially augmenting immune response and ultimately improving 
clinical outcomes. Although cancer vaccines might induce an antigen-specific T-cell response, 
once activated, T cells up-regulate CTLA4, a negative regulatory molecule. Preclinical studies in 
mice have shown that CTLA4 blockade can augment an immune response and increase T cell 
avidity, leading to enhanced T cell-mediated immune responses to the vaccine. The key role of 
CTLA4 in regulating immune response is evident in CTLA4 knockout mice, which cannot 
modulate immune responses (33, 34). 
 
To date, most immunotherapy trials in humans have focused upon assessing immune responses 
in the blood. While circulating tumor-specific T cells have been detected in a number of studies 
(35), they have not consistently been demonstrated to be predictive of clinical outcome. Moreover, 
there is emerging data that antigen-specific T cells can be detected within lymph nodes and 
tumors of melanoma patients (36). 
The underlying hypothesis for this study is that effective immunotherapy induces the 
recruitment of anti-cancer T cells to the tumor. The study is designed to examine whether 
immunization with PROSTVAC, or ipilimumab monotherapy, or PROSTVAC and 
ipilimumab in combination, prior to RP recruits T cells infiltrate PC tissue. Additionally, in a 
slow-developing disease such as PC it may be that an intervention at an early stage of the 
disease, when the tumor load is still minimal, may be beneficial for prevention of recurrence after 
primary treatment. Therefore, we have selected a patient population undergoing curative therapy 
for their disease, with 2 immune therapies that have shown promising clinical activity in patients 
with prostate cancer. PROSTVAC, as discussed above, has been shown to be a safe and well-
tolerated agent; ipilimumab has been shown to be safe and well-tolerated at a dose of 3mg/kg, 
and this dose was chosen in order to mitigate the risks associated with treatment. 


 
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2 
Objectives of the Study 
2.1 
Primary 
 
To assess the immunologic impact induced within the prostate by neoadjuvant 
PROSTVAC or ipilimumab or the combination in men with localized PC undergoing 
RP, as measured by CD3+ T cell tumor infiltration 
2.2 
Secondary 
 
To characterize T cell subsets and NK cells infiltrating the prostate after neoadjuvant 
PROSTVAC or ipilimumab or the combination. 
 
To measure the treatment-induced effects on circulating effector and regulatory T cells 
following neoadjuvant PROSTVAC or ipilimumab or the combination. 
 
To assess the safety of PROSTVAC or ipilimumab or the combination in the 
neoadjuvant setting. 
2.3 
Exploratory Objectives, Other Assessments 
 
To examine the effects of neoadjuvant PROSTVAC or ipilimumab or the combination  
on systemic antigen-specific immune responses. 
 
To assess various immune monitoring parameters of cellular and humoral immune 
response following neoadjuvant PROSTVAC or ipilimumab or the combination blood 
and in the tumor. 
 
To determine the impact of neoadjuvant PROSTVAC or ipilimumab or the combination 
on PD-L1 expression in patients with localized PC. 
 
To determine the clinical benefit of neoadjuvant PROSTVAC or ipilimumab or the 
combination in patients with localized prostate cancer measured by: 
o PSA response 
o Pathologic response 
 
2.4 
Endpoints 
2.4.1 Primary Endpoint 
 
The proportion of subjects who demonstrate a positive response following neoadjuvant 
therapy as measured by change from baseline in CD3+ T cell infiltration within prostate 
tumor tissue by immunohistochemistry (IHC) assessment following treatment. 
2.4.2 Secondary Endpoints 
 
The change in immunologic infiltration in tumor tissue quantitated by IHC assessment 
(e.g. CD4+, CD8+, CD56+, FOXP3, etc.) following neoadjuvant PROSTVAC or 
ipilimumab or the combination 
 
Change in circulating effector and regulatory T cells following neoadjuvant 
PROSTVAC or ipilimumab or the combination by flow cytometry assessment of 
peripheral blood mononuclear cells 
 
Treatment related toxicities according to NCI CTCAE v.4.03 


 
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2.4.3 Exploratory Endpoints  
 
Change in antigen-specific T cell responses in peripheral blood from baseline 
(screening visit) to post-RP (9 weeks post-RP visit) assessed by using a T cell 
proliferation assay, and interferon gamma (IFN-γ) immunospot (ELISPOT) assays. In 
a limited number of patients we will also assess for antigen-specific T cells in tumor 
infiltrating lymphocytes isolated from the RP as fresh tissue is available. 
 
Development of and changes in humoral immune responses in the periphery following 
treatment. This will be evaluated by testing serum with methods such as: 
o Measurement of antibodies to PSA,TAA and the viral vector using 
peptide/protein arrays or standard ELISA assays. 
 
To characterize the frequency of circulating B and T cells induced by neoadjuvant 
PROSTVAC or ipilimumab or the combination in patients with localized prostate 
cancer by flow cytometry. In a limited number of patients we will also assess for 
antigen-specific T cells in tumor infiltrating lymphocytes isolated from the RP as fresh 
tissue is available. 
 
T-cell receptor (TCR) repertoire sequencing following restimulation with prostate 
specific tumor-associated antigens and viral vector specific antigens to evaluate 
clonality of T-cell responses in the periphery. TCR repertoire in the tumor may also be 
evaluated in prostate biopsy samples to allow correlation with responses in the 
periphery.  
 
Change in PD-L1 expression by IHC assessment following neoadjuvant PROSTVAC 
or ipilimumab or the combination  
 
The clinical benefit of neoadjuvant PROSTVAC or ipilimumab or the combination as 
measured by: 
o Proportion of patients with a PSA response (≥30% PSA decline) at the time of 
RP. 
o Proportion of patients with pathologic complete response (pT0) or near 
complete response at the time of RP. 


 
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3 
Study Design 
  
3.1 
Characteristics 
This is a multicentered, open label, randomized phase II trial of PROSTVAC or ipilimumab or the 
combination of PROSTVAC and ipilimumab as neoadjuvant therapy in patients with localized PC. 
Eligible patients will be randomized to PROSTVAC monotherapy (Arm A), ipilimumab 
monotherapy (Arm B), or combination therapy with both PROSTVAC and ipilimumab (Arm C), 
prior to RP. In arm A, PROSTVAC- V will be administered subcutaneously as the primary vaccine 
on Day 1, which will be followed 2 weeks later with a series 2 PROSTVAC-F subcutaneous 
administrations,  given 3 weeks apart (Day 15 and 36). In arm B, Ipilimumab will be administered 
twice, at a dose of 3 mg/kg, 3 weeks apart (Day 1 and 22). In arm C, PROSTVAC will be 
administered in the same schedule as given in arm A; Ipilimumab will be administered on the 
same days as PROSTVAC-F. In all three arms, RP will occur 21 days, or 3 weeks, following the 
final study treatment administration. No further study therapy will be administered following RP.  
 
3.2 
Number of Subjects 
42 subjects will be enrolled and randomized. 
3.3 
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first dose of PROSTVAC and/or 
ipilimumab, and must meet all inclusion and exclusion criteria.  In addition, the patient must be 
F/U: at 9 weeks, 6 months, and 12 
months following RP 


 
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thoroughly informed about all aspects of the study, including the study visit schedule and required 
evaluations and all regulatory requirements for informed consent.  The written informed consent 
must be obtained from the patient prior to enrollment.  The following criteria apply to all patients 
enrolled onto the study unless otherwise specified. 
3.3.1 Inclusion Criteria 
For a subject to be eligible for participation in this study, all of the following criteria must be 
satisfied: 
1. Patients must have histologically confirmed adenocarcinoma of the prostate without 
previous therapy for PC. 
a. Treatment-naïve AND 
b. Undergoing RP as initial, locally definitive therapy for PC AND 
c. Eligible for RP in a 3 month timeframe AND 
d. Able to consent  for RP 
2. Subject’s archival prostate biopsy specimen is available, and subject consents to provide 
tissue for study endpoint analysis. The prostate biopsy slides or blocks must be available 
prior to starting any study treatment. 
3. Age ≥ 18 years 
4. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 
1 (Appendix 1). 
5. Subject has adequate organ function, defined as: 
a. White blood cell (WBC) count ≥ 3,000/mcL 
b. Absolute neutrophil count (ANC) ≥ 1,500/mcL 
c. Platelet count ≥ 100,000/mcL 
d. Hemoglobin (Hgb) ≥ 10.0 g/dL 
e. Creatinine ≤ 1.5x institutional ULN  
f. Total bilirubin ≤ 1.5 x institutional ULN 
g. Alanine aminotransferase (ALT) ≤ 1.5 x institutional ULN 
h. Aspartate aminotransferase (AST) ≤ 1.5 x institutional ULN 
6. No known history of human immunodeficiency virus (HIV) 1 and 2, human T-cell 
lymphotropic virus (HTLV)-I/II, and Hepatitis B and C. 
7. Ability to understand a written informed consent document, and the willingness to sign it. 
8. Because of the unknown potential risk to a gamete and/or developing embryo from these 
investigational therapies, subjects must agree to use adequate contraception (i.e. barrier 
method) for the duration of study participation, and for three months after discontinuing 
therapy. 
 
3.3.2 Exclusion Criteria 
A subject will not be eligible for participation in this study if any of the following criteria apply. 
1. Subject’s biopsy specimen reveals neuroendocrine or small cell features.  


 
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2. Subject has any evidence of metastatic disease (pre-operative staging will be undertaken 
per urologic standard of care) as deemed by the Investigator. 
3. Subject has prior use of any hormones, including luteinizing hormone-releasing hormone 
(LHRH) agonists, ketoconazole, antiandrogens (such as bicalutamide, flutamide, or 
nilutamide), or 5-α-reductase inhibitors. 
4. Subject has prior use of any anti-cancer treatment or product, such as PC-SPES (or any 
other PC-x product: PC-HOPE, PC-CARE, PC-PLUS, etc). 
5. Subject has received prior radiation therapy or chemotherapy for prostate cancer. 
6. Chronic administration (defined as daily or every other day for continuous use >14 days) 
of systemic corticosteroids within 28 days of the first planned dose off PROSTVAC. Use 
of inhaled steroids, nasal sprays, and topical creams for small body areas are allowed. 
7. Active atopic dermatitis or skin condition that disrupts the epidermis  
8. Inflammatory eye disease requiring steroid treatment 
9. History of prior solid organ or bone marrow transplant 
10. Previous history of hypersensitivity to eggs or allergy or untoward reaction to prior vaccinia 
(smallpox) vaccination. 
11. Splenectomy 
12. Subject, or subject’s close household contacts (defined as those who share housing or 
have close physical contact) have any of the following conditions during the screening 
and/or treatment periods:  
a. active or a history of atopic dermatitis, eczema or other eczematoid skin disorders 
that disrupt the epidermis 
b. other acute, chronic or exfoliative skin conditions (e.g., burns, impetigo, varicella 
zoster, severe acne or other open rashes or wounds) until condition resolves 
c. pregnant or nursing 
d. immunodeficient or immunosuppressed (by disease or therapy), including HIV 
infection 
13. Subject’s close household contacts include children less than the age of three 
14. 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, Hashimotos´s thyroiditis, or Graves disease) as determined by the treating 
medical oncologist.".  
a. Persons with vitiligo are not excluded.  
b. Persons with a history of type 1 diabetes are not excluded if the condition is well 
controlled: 
i. Hemoglobin A1C < 7.0, and 
ii. No evidence of end-organ damage due to diabetes, such as diabetic 
retinopathy, nephropathy, or neuropathy 
Persons with type 2 diabetes are not excluded since this is not an autoimmune 
disease, and do not need to meet these criteria. 


 
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c. Persons with hypothyroidism are not excluded if condition is well controlled, and 
condition is due to a non-autoimmune etiology. 
15. Subject has received treatment with any investigational immunotherapy within 2 years 
prior to study screening or has received treatment with any other investigational product 
within 28 days prior to study screening.  
16. Subject has participated in any previous study involving PROSTVAC, Sipuleucel-T or 
ipilimumab, regardless of whether the subject received PROSTVAC, Sipuleucel-T or 
ipilimumab.  
17. Subject has a history of allergic reactions attributed to compounds of similar chemical or 
biologic composition to PROSTVAC or ipilimumab.  
18. Subject has a history of stage III or greater cancer, excluding prostate cancer. Subjects 
with a history of basal or squamous cell skin cancers are allowed, provided that the subject 
was adequately treated and is disease-free at the time of study screening. Subjects with 
a history of stage I or II cancer must have been adequately treated and been disease-free 
for ≥ 3 years prior to study screening.  
19. Subject has any uncontrolled, concurrent illness including, but not limited to the following: 
ongoing or active infection (bacterial, viral, or fungal), symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia, stroke or myocardial infarction within 
6 months, or psychiatric illness that would limit compliance with study requirements.  
20. Subject requires any medical intervention(s) or has any other condition(s) that, in the 
Investigator’s opinion, will 1) make the administration of PROSTVAC or ipilimumab 
hazardous, 2) obscure the interpretation of AEs, 3) compromise adherence with study 
requirements, or 4) otherwise compromise the study’s objectives.  
21. Subject has high-risk features (e.g., based on Gleason score, PSA, clinical stage, % 
positive biopsies), and the treating physician feels the subject should undergo radical 
prostatectomy sooner than planned within the protocol. 
3.4 
Duration of Therapy 
For patients randomized to receive PROSTVAC (arms A and C), PROSTVAC-V will be 
administered as the primary vaccine on Day 1, to be followed 2 weeks later by a series of 
PROSTVAC-F treatments administered on Days 15 and 36; a total of 2 PROSTVAC-F doses will 
be administered.  
For patients randomized to receive ipilimumab alone (arm B), ipilimumab will be administered on 
Days 1 and 22, at a dose of 3mg/kg; thus a total of 2 doses will be administered. 
For those patients randomized to receive the combination (arm C), ipilimumab will be 
administered on Days 15 and 36 (coinciding with PROSTVAC-F administration) at a dose of 
3mg/kg; thus patients will receive 1 dose of PROSTVAC-V, 2 doses of PROSTVAC-F, and 2 
doses of ipilimumab.  
For all patients, RP will be performed 21 days (+/- 7 days) following the final dose of PROSTVAC 
and/or ipilimumab. No further therapy will be administered on study following RP. 
Subjects should remain on study and continue with protocol-specified tests and evaluations 
whenever possible. Subjects will remain on study, including randomization, regardless of RP 
results, initiation of hormonal therapy, chemotherapy, or radiation therapy, or development of 
biochemical failure or metastatic disease. However, should a subject withdraw early from the 
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The Investigator may withdraw a subject from treatment or assessment at any time if, in his or her 
clinical judgment, it is in the best interest of the subject.  
Subjects may discontinue their participation in the trial at any time without prejudice. If a subject 
chooses to withdraw early from the study, the Investigator should make every reasonable attempt 
to ensure that early withdrawal procedures are completed and to determine the reason for 
withdrawal. The date and reason for withdrawal will be recorded in the source documentation and 
on the eCRF.  
 
If the subject fails to respond to requests for follow-up, the clinical site will send a 
registered letter, at the minimum, to the subject requesting contact with the clinic. All 
attempts to resume contact (including copies of written correspondence) will be included 
in the source documentation. Subjects who do not respond to requests for follow-up after 
all reasonable attempts to establish contact will be considered ‘lost to follow-up’. 
3.5 
Duration of Follow Up and Removal from Assessment. 
Following RP, patients will be followed at 9 weeks and at 6 and 12 months. Patients removed 
from study for unacceptable treatment-related AEs will be followed until resolution or stabilization 
of all treatment related adverse events to Grade 2 or lower, until the subject is deemed lost to 
follow-up, or death. 
3.6 
Randomization Procedures 
Once patients have signed the informed consent, patients will be randomized 1:1:1 by stat 
computing software R, package blockrank, to receive PROSTVAC alone, Ipilimumab alone, or 
the combination.  The randomization is done within blocks to ensure that the balance between 
treatments stays close to equal throughout the trial. Randomization must be completed within 
28 days of day 1 of study.  
3.7 
Study Timeline 
3.7.1 Primary Completion 
The study will reach primary completion in 24 months from the time the study opens to accrual. 
3.7.2 Study Completion 
The study will reach study completion 30 months from the time the study opens to accrual.  
4 
Study Drugs 
4.1 
Description, Supply and Storage of Investigational Drugs 
4.1.1 PROSTVAC 
PROSTVAC is a genetically modified organism (GMO) consisting of a live attenuated viral vector-
based vaccine product that is comprised of two component viral vectors (V and F), to be used 
together in a prime (V) – boost (F) vaccination regimen: 
 
PROSTVAC-V: Recombinant vaccinia virus that contains a modified gene encoding human 
prostate-specific antigen (PSA) and genes encoding three human immunological costimulatory 
molecules: B7.1, intracellular adhesion molecule-1 (ICAM-1), and leukocyte function-associated 
antigen-3 (LFA-3) (or TRIad of COstimulatory Molecules, TRICOM™). The PSA gene used in the 
recombinant has an alteration in an HLA-A2 specific epitope (replacement of isoleucine with 
leucine at amino acid position 155; designated L155 agonist epitope). All four genes are inserted 
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PROSTVAC-F: Recombinant fowlpox virus that co-expresses the same four human genes as 
PROSTVAC-V. 
 
Precautions: General Vaccinia and Fowlpox Virus Handling and Disposal Precautions: 
Both PROSTVAC-V and PROSTVAC-F are preparations of live viruses and, therefore, materials 
that may have been exposed to vaccine (empty vials, syringes, swabs, dressings, etc.) should be 
treated as infectious waste and incinerated according to local institutional protocol. 
4.1.1.1 Clinical safety of recombinant poxvirus-based vaccines 
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. 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.  
 
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 (37, 38).  
 
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 (39). 
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) (38). 
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. The rash appears within a week after vaccination and resolves within 
a week. Most instances do not require specific therapy (38).  
 
The parent vaccinia vector Therion used to engineer PROSTVAC was further attenuated from the 
Wyeth strain of vaccinia, with lower neurovirulence than the strains that were used to generate 
most of the smallpox eradication/prevention safety database. Since 1991, ten recombinant 
vaccinia-based vaccines and eight recombinant fowlpox-based vaccines produced by Therion for 
the treatment of various cancers, have been evaluated in human clinical trials sponsored by the 
NCI. Over 1,000 cancer patients, most with metastatic disease, have been treated to date with 
these various poxvirus-based vaccines in NCI-sponsored or Therion-sponsored clinical trials (40) 
and NCI and Therion Annual Reports.  
 
Clinical evaluations of early versions of PSA-containing poxviral vectors involved over 250 
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patients (11, 12, 41). Later, a prime-boost regimen was devised with boosting with fowlpox-PSA 
containing vectors, in two studies, one with 64 patients (40) and another unpublished study of 
approximately 16 patients. The NCI subsequently began a series of trials using additional 
admixed vectors encoding a single costimulatory molecule (B7.1/CD80). These studies involved 
94 patients (42-44). No significant safety issues were identified in these early studies. In addition 
to the two trials conducted by Therion with PROSTVAC-V and PROSTVAC-F (Phase I trial in ten 
patients (13); Phase II trial in 125 patients (17)) there are five other fully enrolled studies (14, 15) 
and one open study using PROSTVAC-V and PROSTVAC-F treatment, for an additional 246 
treated patients (NCI-sponsored studies). 
 
No dose-limiting toxicities were observed in early phase trials. The majority of side effects 
reported across all of the studies involved Grade 1 or 2 injection site reactions; all resolved without 
sequelae. There have been three SAEs thought to be possibly due to the PROSTVAC-V and 
PROSTVAC-F treatment; two occurred in the same patient. This patient experienced myocardial 
infarction and Grade 4 thrombotic thrombocytopenic purpura (TTP), and was discontinued from 
the study. The third SAE was reported from a subject hospitalized and diagnosed with bilateral 
pulmonary embolism. Laboratory evaluations likewise did not reveal any untoward effects of 
treatment.  
 
Additional safety information is described in the Investigator’s Brochure, however no vaccinia-
related complications were noted in any of the PROSTVAC clinical studies 
 
Overall, based on clinical information available today, recombinant poxviral vaccines present a 
beneficial safety profile. 
 
4.1.1.2 Investigational Drug #1: PROSTVAC-V [PROSTVAC-V/TRICOM; 
Recombinant Vaccinia-PSA (L155)/TRICOM; NSC 717170] 
Classification: Vaccine; Genus: Orthopox Virus; Species: Vaccinia. PROSTVAC-V is a purified 
live viral vaccine produced under serum-free conditions in chicken embryo fibroblast (CEF) cells. 
Bulk Drug Substance (BDS) of PROSTVAC-V is formulated with sterile phosphate-buffered 
solution (PBS)/10 % glycerol. 
Mechanism of Action: Vaccinia virus actively replicates in the cytoplasm of human cells, resulting 
in the presentation of high levels of antigen to the immune system over a period of one to two 
weeks, substantially increasing the potential for immune stimulation. A number of studies have 
shown that immunization of mammalian species by recombinant vaccinia virus can stimulate both 
humoral and cell-mediated immunity to the expressed transgene. 
Contraindications: Immune deficiency of any nature, immunosuppression, history or current 
eczema or atopic dermatitis, moderate to severe acute illness (deferral of vaccination), myocardial 
infarction (prior six months), cardiomyopathy, symptomatic CHF, unstable angina  
Availability: Each vial of PROSTVAC-V contains a single dose (2 x 108 infectious units (Inf. U.) 
per 0.50 mL) of PROSTVAC-V in PBS/10% glycerol for subcutaneous injection. The drug product 
contains no adjuvants or preservatives and is supplied in borosilicate (2R) glass vials, which are 
sealed with rubber stoppers and aluminium-plastic closures. 
Storage and handling: Intact vials must be stored at 80°C±10°C.  To date, stability studies 
indicate that when stored at -80°C±10°C PROSTVAC-V is stable for up to 72 months. Once 
thawed, potency can be maintained by storing at 2 – 8°C for up to 24 hours. Vaccinia Virus 
Handling and Disposal Precautions: 
- 
The risk of transmission of recombinant viruses to exposed healthcare workers is very 
low. There have been no cases of transmission to healthcare personnel in any of the 
studies with PROSTVAC-V or related vaccinia-based vaccines. 
- 
Vaccinia virus is classified as a Biosafety Level 2 organism. 


 
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- 
Due to the potential for transmission, healthcare personnel who have direct contact with 
contaminated dressings or other infectious material from participants in clinical studies 
should adhere to appropriate infection control measures (45, 46).  
- 
Those who are pregnant, have exfoliative skin conditions, or are immunocompromised 
should avoid exposure to contaminated dressings or to the inoculation site. 
- 
Use of appropriate infection control measures, such as covering the vaccination site 
(including bandages) and washing hands after contact with the vaccination site, will 
prevent transmission. 
- 
While there is a theoretical risk of exposure through a needle stick or an accidental spill, 
the risk can be further minimized by following safety guidelines. 
 
4.1.2 Investigational Drug #2: PROSTVAC-F [PROSTVAC-F/TRICOM; Recombinant 
Fowlpox-PSA (L155)/TRICOM; NSC 717171] 
Classification: Vaccine; PROSTVAC-F: Genus: Avipox Virus; Species: Fowlpox. PROSTVAC-F 
is a purified live viral vaccine produced under serum-free conditions in CEF cells. Bulk Drug 
Substance (BDS) is formulated with sterile PBS/10 % glycerol. 
Mechanism of Action: Fowlpox virus infects but does not actively replicate in mammalian human 
cells. Immunization with recombinant PROSTVAC-F results in the presentation of high levels of 
antigen to the immune system over a period of several days, substantially increasing the potential 
for stimulation of cell-mediated immune responses. Boosting with PROSTVAC-F has been shown 
to focus the vaccine-associated cell-mediated immune responses to the PSA antigen.  
Contraindications: There are no specific contraindications for PROSTVAC-F, other than those for 
fowlpox immunization and serious intercurrent illness. 
Availability: Each vial of PROSTVAC-F contains a single dose (1 x 109 Inf. U. per 0.50mL) of 
PROSTVAC-F in PBS/10% glycerol. The drug product contains no adjuvants or preservatives 
and is supplied in borosilicate (2R) glass vials, which are sealed with rubber stoppers and 
aluminium-plastic closures. PROSTVAC-F is stored at -70°C or colder. 
Storage and handling: Intact vials must be stored at -80°C±10°C. Once thawed, potency can be 
maintained by storing at 2 – 8°C for up to 24 hours. To date, stability studies indicate that when 
stored at 80°C±10°C, PROSTVAC-F is stable for up to 72 months. Fowlpox Virus Handling 
and Disposal Precautions: Fowlpox virus is classified as a Biosafety Level 1 organism. These 
agents are not known to cause disease in healthy adult humans and are of minimal potential 
hazard to personnel and the environment under ordinary conditions of use. They can be 
handled safely in the laboratory without special apparatus or equipment, using techniques 
generally acceptable for nonpathogenic material.  
 
Safety of Fowlpox vaccination: Fowlpox vectors do not replicate in human cells (only in avian 
cells).). No safety concerns have been raised following recombinant fowlpox administration and 
the adverse events associated with the use of fowlpox vectors have been limited to mild injection 
site reactions (9). 
 
Complete and updated adverse event information is available in the Investigational Drug Brochure 
and/or product package insert. 
 
4.2 
Viral shedding: PROSTVAC 
Vaccinia virus is known to be shed from the wound site in traditional dermal scarification based 
vaccination. Transmission of vaccinia to close contacts is another known complication. Contact 
vaccinia may manifest as progressive vaccinia, eczema vaccinatum (EV) or accidental infection 
of eye, mouth, genital areas. Review of several national and state surveys between 1962 and 


 
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1968 gives frequency for EV at 8 - 27 per 1,000,000 and for accidental infections at 3 - 44 per 
1,000,000 (47). 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 immunization is subcutaneously administered, which greatly reduces injection site 
reactions, and skin surface wound formation/viral shedding.  Both of these factors reduce the 
potential for inadvertent inoculation and contact transmission versus traditional smallpox 
vaccine programs.  
4.3 
Safe handling of recombinant vaccinia virus vaccine  
Special consideration must be given to the nature of the initial vaccine: a recombinant replicating 
vaccinia virus. Subject instruction materials will include detailed descriptions for bandaging, 
bathing, and reporting any possible side effects. Subjects will also be educated regarding 
restrictions on contact with certain classes of individuals (children under the age of 3 years 
pregnant or lactating women, immunocompromised individuals). 
 
PROSTVAC-V is considered a Biosafety Level 2 (BSL2) agent according to the CDC/NIH 
Biosafety in Microbiological and Biomedical Laboratories Manual. Study staff will be provided 
specific instructions for storage, use, and destruction of these materials. All subjects will be dosed 
with the vaccine in the clinic or hospital setting according to local regulations. PROSTVAC-V is 
aseptically vialed at low volume in a sealed vaccine vial. Loading of syringes may be performed 
using standard aseptic methods in a clinical pharmacy. Routine, standard universal precautions 
are required when directly handling the vaccine vials, including the wearing of a lab coat, eye 
protection, and gloves. There is no need to sequester subjects after dosing. Vials and needles 
and syringes may be disposed of as for infectious medical waste according to local regulations.  
 
These recommendations are the same as those for administering smallpox vaccine with 
bifurcated needles. 
 
4.4 
Safe handling of recombinant fowlpox vaccine 
PROSTVAC-F is classified as BSL1 and because it cannot replicate in mammalian cells, no 
special precautions beyond standard, universal precautions for infectious materials are required. 
There are no subject restrictions with respect to activities (such as bathing), personal contact, or 
bandaging required for vaccination with PROSTVAC-F. 
 
4.4.1 Investigational Drug #3: Ipilimumab (Yervoy®, BMS) 
Ipilimumab is available as a sterile solution in the vial is clear and colorless. Ipilimumab is 
administered via intravenous infusion only. 
  
Patients will receive ipilimumab 3 mg/kg IV administered over 90 minutes every 3 weeks for 2 
doses (Arm B: Days 1 and 22; Arm C: Days 15 and 36). Vital signs, including blood pressure, 
heart rate, respiratory rate, temperature and pulse oximetry, will be monitored before ipilimumab 
infusion. 
Classification 


 
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Ipilimumab monoclonal antibody is specific for the CTLA-4 antigen expressed on a subset of 
activated T-cells. CTLA-4 interaction with the B7 molecule, one of its ligands expressed on 
antigen presenting cells, can down-regulate T-cell response. 
Mechanism of Action 
Ipilimumab is thought to act by blocking the interaction of CTLA-4 with the B7 ligand, resulting in 
a blockade of the inhibitory effect of T-cell activation that is created by the CTLA-4/B7 
interaction.  
Storage  
Ipilimumab must be stored in a secure area according to local regulations. The investigator must 
ensure that it is stored at a temperature  2C and  8C. 
Handling 
As with all injectable drugs, care should be taken when handling and preparing ipilimumab. 
Whenever possible, ipilimumab should be prepared in a laminar flow hood or safety cabinet 
using standard precautions for the safe handling of intravenous agents applying aseptic 
technique. Latex gloves are required. If ipilimumab concentrate or solution comes in contact 
with skin or mucosa, immediately and thoroughly wash with soap and water. After final drug 
reconciliation, unused ipilimumab solution should be disposed at the site following procedures 
for the disposal of anticancer drugs. 
4.4.2 Provision of Drugs 
PROSTVAC will be obtained directly from Bavarian Nordic pharmaceutical company as study 
supply.   
PROSTVAC is supplied in single use vials. Each vial of PROSTVAC-V contains a single dose (2 
x 108 infectious units (Inf. U.) per 0.50 mL) of PROSTVAC-V in PBS/10% glycerol. The drug 
product contains no adjuvants or preservatives and is supplied in borosilicate (2R) glass vials, 
which are sealed with rubber stoppers and aluminium- plastic closures. PROSTVAC-V is stored 
at -80°C±10°C  
.  
Each vial of PROSTVAC-F contains a single dose (1 x 109 Inf. U. per 0.50mL) of PROSTVAC-F 
in PBS/10% glycerol. The drug product contains no adjuvants or preservatives and is supplied 
in borosilicate (2R) glass vials, which are sealed with rubber stoppers and aluminium-plastic 
closures. PROSTVAC-F is stored at -80°C±10°C  
. 
Ipilimumab will be obtained from Bavarian Nordic, Inc, as study supply. Ipilimumab is supplied in 
single-use, glass vials as a sterile, colorless solution for intravenous administration containing 
200 mg.   
. 
4.5 
Drug Accountability 
The Investigational Pharmacist will manage drug accountability records. 
4.6 
Drug Ordering 
 
PROSTVAC and ipilimumab will be directly supplied by Bavarian Nordic, Inc. 


 
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4.7 
Packaging and Labeling of Study Drugs 
Drugs will be packaged and labeled per institutional standards, adhering to applicable local and 
federal laws. 
5 
Treatment Plan 
 
5.1 
Dosage and Administration 
PROSTVAC: Treatment will be administered on an outpatient basis as a subcutaneous 
injection. No premedication before the administration of the study drug is required. 
PROSTVAC must only be administered prior to the labeled expiration date. To maintain 
the correct product temperature, the shipping container should not be opened upon 
receipt. PROSTVAC must be stored and frozen in its shipping package, at -80°C±10°C 
until immediately before its use.  PROSTVAC is to be thawed at room temperature for 
approximately 10-15 minutes prior to preparation.  Prior to PROSTVAC administration, 
subjects will be provided written instructions on proper wound care. Subjects will also be 
provided a wound care kit. Administration time will be recorded, as will vital signs within 
30 minutes prior to and after injections. Subjects will be observed for at least 30 minutes 
after receiving the injections. 
Ipilimumab:  will be infused over 90 minutes through a low protein-binding in-line filter 
on an outpatient basis. Flush with NS or D5W at the end of infusion. 
 
F/U: at 9 weeks, 6 months, and 12 
months following RP 


 
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Table 2 
Regimen Description 
Study Drug 
Dose 
Route 
Schedule 
PROSTVAC-V 
(prime) 
2 X 108Inf. U 
SC 
Arms A & C: Day 1 
PROSTVAC-F 
(boost) 
1 X 109Inf. U. 
SC 
Arms A & C: Days 15 and 36 
Ipilimumab 
3 mg/kg 
IV 
Arm B: Days 1 and 22 
Arm C: Days 15 and 36 
 
5.1.1 Criteria for study arm discontinuation 
A treatment arm shall be stopped, if Grade ≥3 treatment-associated AEs occur in ≥2 of the first 6 
patients, or at any point afterwards if Grade ≥3 adverse events are observed in ≥33% of patients. 
Exceptions apply to local injection site AEs and transient (no more than 3 days) fevers, chills, 
myalgias, fatigue, nausea, or dizziness. AEs that are NOT clinically relevant, as per Principal 
Investigator´s assessment, will also be excluded. 
5.2 
Criteria for stopping treatment 
Subjects must discontinue therapy prior to RP if any of the following occurs prior to completion of 
the treatment regimen:  
• The subject develops a concurrent illness that prevents further administration of PROSTVAC;  
• The subject elects not to receive all injections of PROSTVAC or withdraws consent;  
• At the discretion of the Principal Investigator.  
Subjects who receive fewer than planned injections of PROSTVAC or ipilimumab due to any of 
the reasons noted above will continue to be followed post-RP per protocol as summarized in 
Section 3.5.  
5.2.1 Criteria for holding/skipping ipilimumab 
Ipilimumab doses that cannot be given on schedule due to treatment-related AEs will be skipped. 
No dose adjustment or delay will be allowed for treatment-related AEs (Section 5.3 allows a 3 day 
window for drug administration for scheduling issues). Decisions to hold ipilimumab must be made 
on specified safety criteria summarized below. Treatment with ipilimumab will be skipped or 
discontinued if the subject experiences at least one of the following, considered by the investigator 
to be “possibly”, probably” or “definitely” related to ipilimumab: 
 
Any clinically relevant Grade ≥2 non-skin, treatment-related AEs (including irAEs), except 
for laboratory abnormalities and infusion-related reactions.  
 
Any Grade ≥3 treatment-related laboratory non-hematologic abnormalities. 
 
Any AEs, laboratory abnormality or intercurrent illness that, in the judgment of the Principal 
Investigator, presents a substantial risk to the subject with continued dosing. 
 
Please see section 5.6.6 for more details, including section 5.6.6.1 for exceptions. 
 


 
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5.3 
Radical Prostatectomy 
Radical Prostatectomy will be performed at least 14 days but not more than 28 days following the 
last scheduled subcutaneous injection of PROSTVAC-F or ipilimumab. AEs and concomitant 
medications will be evaluated and recorded prior to surgery. Adverse events and concomitant 
medications considered by the Investigator to be related to RP will be recorded in appropriate 
source documentation; however, such AEs and concomitant medications will not be recorded on 
eCRFs. Blood samples for PSA and for immune assays will be collected prior to RP. 
Standard institutional practices for the care and treatment of surgical patients will be followed 
before, during, and after the subject’s RP. Adverse events and concomitant medications 
considered by the Investigator to be related to RP will be recorded in appropriate source 
documentation but will not be recorded on a eCRF. 
Patients will be informed in the written consent that radical prostatectomy may be delayed due to 
adverse events resulting from study treatment, at the discretion of the Investigator and performing 
surgeon.   
5.4 
Dose Modifications 
There are no dose modifications for this study. 
Treatment or visit delays for public holidays or weather conditions do not constitute a protocol 
violation. Should any delay on receiving the treatment of more than 3 days occur due to these 
issues, that dose will be skipped; future treatments will continue according to protocol. 
5.5 
Monitoring and Toxicity Management of PROSTVAC and ipilimumab 
Each patient receiving PROSTVAC and/or ipilimumab will be evaluated for safety.  The safety 
parameters include all laboratory tests and hematological abnormalities, physical findings, and 
spontaneous reports of adverse events reported to the investigator by patients. 
Each patient will be assessed periodically for the development of any toxicity as outlined in 
Section 6 Study Procedures and Observations. Toxicity will be assessed according to the NCI 
CTCAE v4.03. Criteria for stopping treatment will be made according as outlined in Section 5.1.1.  
Acute toxicity will be managed by the treating physician. Further management will depend upon 
the judgment of the clinician and may include Vaccinia immunoglobulin (VIG) as described below. 
5.5.1 Management of PROSTVAC injection site reactions 
Subcutaneous injection may induce a local inflammatory response, and pain at the injection site 
is a commonly reported adverse event. Patients should be carefully assessed for signs of 
bacterial infection. If there is no evidence of bacterial infection, and the pain is determined to be 
due to injection site pain: 
 
Grade 1 injection site pain: should be monitored until resolution. 
 
Grade 2 injection site pain >72 hours: can be treated with acetaminophen 650mg PO q4-
6 hours PRN, and until resolution to grade 1; patient can then be monitored until resolution.  
 
Grade 3 injection site pain: 
o Initiate treatment with immediate release PO opioid/acetaminophen combination 
(oxycodone/acetaminophen; hydrocodone/acetaminophen, 
codeine/acetaminophen) 
o If grade 3 pain is not relieved with treatment as above for >72 hours, patients 
should then start ibuprofen, 600mg PO q6 hours (or equivalent nonsteroidal anti-


 
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inflammatory drug (NSAID)), as needed for pain. The use of ibuprofen (or other 
NSAID) must be reported to the Principal Investigator. 
o If grade 3 pain is not relieved with NSAID treatment for >72 hours, patient should 
then be treated with prednisone 20mg po daily in addition to the NSAID. The use 
of prednisone must be reported to the Principal Investigator. 
o If at any point the pain resolves to grade 1/2, subjects can be treated with 
acetaminophen 650mg q4-6h, and observed until resolution. 
 
5.5.2 Management of PROSTVAC-related systemic adverse events 
Systemic adverse events should be treated according to the investigators discretion. 
 
Pyrexia may be treated with acetaminophen 650mg PO q4-6 hours PRN. If necessary, ibuprofen 
up to 1200 mg daily may be taken until pyrexia resolution. 
 
In the rare, potential event of serious vaccinia virus reaction, treatment of the severe 
complications of vaccinia caused by dissemination of virus (except for complications involving the 
CNS and the cornea) is with Vaccinia immunoglobulin (VIG). VIG is an isotonic sterile solution of 
the immunoglobulin fraction of pooled plasma from individuals inoculated with vaccinia vaccine. 
It is available through the Center for Disease Control (CDC) by calling the Clinician Information 
Line 
 or the Director's Emergency Operations Center (DEOC) 
.  
 
The Investigator must notify an Infectious Disease Specialist 
 
 if there is a suspected 
serious vaccinia reaction as soon as possible but no later than 24 hours after he/she becomes 
aware. A swab from the suspected lesion(s) should be obtained and sent to BioReliance for 
testing (see Appendix 10). 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. 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. 
Recommended dose: I.V.: 6000 units/kg; may repeat dose based on severity of symptoms and 
response to treatment (specific data are lacking); 9000 units/kg may be considered if patient does 
not respond to initial dose. Doses up to 24,000 unit/kg were tolerated in healthy volunteers. 
 
Infusion rate for VIG: Patients ≥50 kg: Infuse at ≤2 mL/minute; Patients <50 kg: Infuse at ≤0.04 
mL/kg/minute. Maximum assessed rate of infusion: 4 mL/minute. Decrease rate of infusion in 
patients who develop minor adverse reactions (eg, flushing) and in patients with risk factors for 
thrombosis/thromboembolism and/or renal insufficiency. 
 
There is no guarantee that VIG will successfully treat indications, but there are no other known 
effective antiviral treatments for vaccinia complications besides supportive care. 
 
5.6 
Monitoring and Toxicity Management of Ipilimumab 
5.6.1 General Guidelines for Managing Toxicity 
Clinical monitoring of autoimmunity should be completed at each MD visit (see Appendix 3). 
Please see section 5.2.1 regarding guideline for holding ipilimumab for treatment-related AEs. 
Management algorithms for AEs associated with ipilimumab (including diarrhea, hepatotoxicity, 


 
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and endocrinopathies) are provided in Appendices 5-8 and in the Investigator’s Brochure. AEs 
must resolve to grade ≤1 or baseline before resuming ipilimumab 
5.6.2 Hypersensitivity Reactions 
Since ipilimumab contains only human protein sequences, it is less likely that any allergic reaction 
will be seen in patients. However, it is possible that infusion of ipilimumab will induce a cytokine 
release syndrome that could be evidenced by fever, chills, rigors, rash, pruritus, hypotension, 
hypertension, bronchospasm, or other symptoms. No prophylactic pre-medication will be given 
unless indicated by previous experience in an individual patient. Reactions should be treated 
based upon the following recommendations or per institutional protocol. 
For mild symptoms (e.g., localized cutaneous reactions such as mild pruritus, flushing, rash): 
 
Decrease the rate of infusion until recovery from symptoms, remain at bedside and 
monitor patient. 
 
Complete the ipilimumab infusion at the initial planned rate. 
 
Diphenhydramine 50 mg IV may be administered at the discretion of the treating physician 
and patients may receive additional doses with close monitoring. 
 
Premedication with diphenhydramine may be given at the discretion of the investigator for 
subsequent doses of ipilimumab. 
For moderate symptoms (any symptom not listed above as mild symptoms; or below as severe 
symptoms, such as generalized pruritus, flushing, rash, dyspnea, and hypotension with systolic 
BP >80 mmHg):  
 
Interrupt ipilimumab. 
 
Administer diphenhydramine 50 mg IV. 
 
Monitor patient closely until resolution of symptoms. 
 
Corticosteroids may abrogate any beneficial immunologic effect, but may be administered 
at the discretion of the treating physician. 
 
Resume ipilimumab infusion after recovery of symptoms. 
 
At the discretion of the treating physician, ipilimumab infusion maybe resumed at one half 
the initial infusion rate, then increased incrementally to the initial infusion rate. If symptoms 
develop after resumption of the infusion, the infusion should be discontinued and no 
additional ipilimumab should be administered that day. 
 
The next dose of ipilimumab will be administered at its next scheduled time and may be 
given with pre-medication (diphenhydramine and acetaminophen) and careful monitoring, 
following the same treatment guidelines outlined above. At the discretion of the treating 
physician additional oral or IV antihistamine may be administered prior to dosing with 
ipilimumab. 
For severe symptoms (e.g., any reaction such as bronchospasm, generalized urticarial, systolic 
blood pressure  80 mm Hg, or angioedema): 
 
Immediately discontinue infusion of ipilimumab, and disconnect infusion tubing from the 
subject. 
 
Consider 
bronchodilators, 
epinephrine 
1 mg 
IV 
or 
subcutaneously, 
and/or 
diphenhydramine 50 mg IV, with solumedrol 100 mg IV, as needed. 


 
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 
Patients should be monitored until the investigator is comfortable that the symptoms will 
not recur. 
 
No further ipilimumab will be administered. 
In case of late-occurring hypersensitivity symptoms (e.g., appearance within one week after 
treatment of a localized or generalized pruritus), symptomatic treatment may be given (e.g., oral 
antihistamine, or corticosteroids). 
5.6.3 Management of Hepatotoxicity 
Liver function tests (AST, ALT, T. bilirubin) will be evaluated for every subject prior to 
administration of ipilimumab. Blood samples must be collected and analyzed at local or central 
labs within 3 days prior to dosing. LFT results must be reviewed by the principal investigator (or 
designee) to meet dosing criteria specifications:  2.5 x ULN for AST, ALT and  1.5 x ULN for T. 
bilirubin unless liver metastases are present in which case LFT  5 x ULN for AST, ALT and T. 
bilirubin  3.0 x ULN) prior to dosing. 
If, during the course of treatment abnormal LFT values are detected, the subject must be 
managed using the hepatotoxicity algorithm section in the appendix 7. 
5.6.4 Treatment of Ipilimumab-Related Isolated Drug Fever 
In the event of isolated fever, the investigator must use clinical judgment to determine if the fever 
is related to the ipilimumab or to an infectious etiology. If a patient experiences isolated drug fever, 
for the next dose, pre-treatment with acetaminophen or non-steroidal anti-inflammatory agent 
(investigator discretion) should be instituted and a repeated antipyretic dose at 6 and 12 hours 
after ipilimumab infusion, should be administered. The infusion rate will remain unchanged for 
future doses. If a patient experiences recurrent isolated drug fever following premedication and 
post dosing with an appropriate antipyretic, the infusion rate for subsequent dosing should be 
decreased to 50% of the previous rate. If fever recurs following infusion rate change, the 
investigator should assess the patient’s level of discomfort with the event and use clinical 
judgment to determine if the patient should receive further ipilimumab. 
5.6.5 Immune Related Toxicity 
Blocking CTLA-4 function may permit the emergence of auto-reactive T cells and resultant clinical 
autoimmunity. Rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis, and hypopituitarism 
were drug-related, presumptive autoimmune events, now termed irAEs, noted in previous 
ipilimumab studies. 
For the purposes of this study, an irAE is defined as an AE of unknown etiology associated with 
drug exposure and consistent with an immune phenomenon. Efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin or other etiologic causes prior to labeling an AE as an irAE. 
Serological, immunological, and histological (biopsy) data should be used to support the diagnosis 
of an immune-mediated toxicity. Suspected irAEs must be documented on an AE or SAE form.  
Patients should be informed of and carefully monitored for evidence of clinically significant 
systemic irAE (e.g., systemic lupus erythematosus-like diseases) or organ-specific irAE (e.g., 
rash, colitis, uveitis, hepatitis or thyroid disease). If an irAE is noted, appropriate work-up 
(including biopsy if possible) should be performed, and steroid therapy may be considered if 
clinically necessary.   
It is unknown if systemic corticosteroid therapy has an attenuating effect on ipilimumab activity. 
However, clinical anti-tumor responses have been maintained in patients treated with 
corticosteroids and discontinued from ipilimumab. If utilized, corticosteroid therapy should be 


 
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individualized for each patient. Prior experience suggests that colitis manifested as ≥ Grade 3 
diarrhea requires corticosteroid treatment. 
The most common immune-related adverse events are dermatologic, endocrine, gastrointestinal, 
and hepatic.  For any suspected immune-related adverse event, begin with the algorithm in the 
Appendix 5.  For diarrhea, hepatotoxicity, or endocrinopathy, this will refer the investigator to a 
more specific algorithm (see Appendix 6 – Appendix 8).  For rash, see the below. 
Grade 3 – skin related AE 
Fatal toxic epidermal necrolysis (TEN) has been reported following a grade 3 skin-related AE, 
which was considered unrelated to ipilimumab on a Bristol-Myers Squibb-sponsored trial.  In 
patients with a drug-related Grade 2 skin immune-mediated toxicity or Grade 3 skin-related 
adverse event, regardless of causality, additional treatment will be delayed until the event 
improves to ≤ Grade 1 severity.  
A dermatologist should evaluate persistent or severe rash or pruritus. A biopsy should be 
performed if appropriate and if possible, photos of the rash should also be obtained. Low grade 
ipilimumab-mediated rash and pruritus were treated with symptomatic therapy (e.g., 
antihistamines). Topical or parenteral corticosteroids may be required for more severe symptoms. 
With the appearance of any generalized rash, concomitant medications (e.g antibiotics, 
anticonvulsants, or proton pump inhibitors) that may be associated with severe skin reactions 
(e.g., Stevens Johnson Syndrome, TEN) should be discontinued and avoided.  Ipilimumab should 
also be held. 
5.6.6 Criteria for stopping ipilimumab 
The following treatment-related non-neurological adverse events require permanent 
discontinuation of ipilimumab: 
 
Any ≥ Grade 2 eye pain or reduction of visual acuity that does not respond to topical therapy 
and does not improve to ≤ Grade 1 severity within 2 weeks of starting therapy, OR requires 
systemic treatment. 
 
Any ≥ Grade 3 bronchospasm or other hypersensitivity reaction. 
 
Any other ≥ Grade 3 non-skin related adverse event with the exception of events listed 
below under “Exceptions to Permanent Discontinuation”. 
 
Any ≥ Grade 4 laboratory abnormalities, except AST, ALT, or Total Bilirubin 
 
AST or ALT > 5 x ULN 
 
Total Bilirubin > 3 x ULN 
 
Any other Grade 4 adverse event  
 
Any adverse event, laboratory abnormality or intercurrent illness, which, in the judgment of 
the investigator, presents a substantial clinical risk to the patient with continued dosing.  
 
The following neurological adverse event requires permanent discontinuation of 
ipilimumab and defines unacceptable neurotoxicity: 
 
Any motor neurologic toxicity >Grade 3 regardless of causality 
 
Any > Grade 3 treatment-related sensory neurologic toxicity 
 


 
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5.6.6.1 Exceptions to Permanent Discontinuation  
 
Potentially reversible inflammation (< Grade 4), attributable to a local anti-tumor reaction and 
a potential therapeutic response. This includes inflammatory reactions at sites of tumor 
resections or in draining lymph nodes, or at sites suspicious for, but not diagnostic of 
metastasis. 
 
Hospitalization for ≤ Grade 2 adverse events where the primary reason for hospitalization is 
to expedite the clinical work-up. 
 
Patients with the following conditions where in the investigator’s opinion continuing study drug 
administration is justified: 
 
Ocular toxicity that has responded to topical therapy. 
Endocrinopathies where clinical symptoms are controlled with appropriate hormone replacement 
therapy. Note: Ipilimumab may not be restarted while the patient is being treated with systemic 
corticosteroids except for patients on stable doses of hormone replacement therapy such as 
hydrocortisone. 
6 
Study Procedures and Observations 
6.1 
Schedule of Procedures and Observations 
The study schematic is presented in Figure 1. A schedule of study visits and required procedures, 
tests, and examinations are presented in Table 3(Arms A and C) Table 4(Arm B). All scheduled 
visits outlined in Table 3 (Arms A and C) Table 4(Arm B) must be conducted at the study site of 
an Investigator, as indicated on Food and Drug Administration (FDA) Form 1572. 
The study-specific assessments are detailed in this section and outlined in Table 3(Arms A and 
C) Table 4(Arm B).  Screening assessments must be performed within 28 days prior to the first 
dose of investigational product.  Any results falling outside of the reference ranges may be 
repeated at the discretion of the investigator. All on-study visit procedures are allowed a window 
of 2 days unless otherwise noted.  Treatment or visit delays for public holidays or weather 
conditions do not constitute a protocol violation. 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.   
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is 
password protected and meets HIPAA requirements. 
6.1.1 Pretreatment Period 
6.1.1.1 Informed consent 
Before initiation of any screening procedures, each prospective subject will be provided a verbal, 
in-depth explanation of the study, requested to read the Institutional Review Board (IRB) approved 
informed consent form (ICF), and encouraged to ask questions. The Investigator must ensure 
that each subject understands how the study will be conducted and how they will participate if 
they so choose. The subject shall be given sufficient time to properly consider the information and 
to make an informed decision regarding consent. Once all questions have been answered and 
the Investigator is assured that the subject understands the implications of study participation, the 
subject will be asked to provide written consent to participate in the study by signing the ICF. The 


 
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Investigator will document the informed consent process in the subject’s medical chart or progress 
notes and will provide a copy of the signed ICF to the subject 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.   
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system is 
password protected and meets HIPAA requirements. 
6.1.1.2 Screening Assessments (ALL ARMS) 
Subject screening evaluations must be performed within 28 days prior to enrollment; however, 
informed consent may be obtained earlier. Written informed consent will be obtained prior to the 
conduct of any study related procedures. At screening, the subject’s name will be entered onto a 
screening log and a unique subject number will be assigned.  
The subject’s medical history and demographic information will be reviewed and recorded. The 
subject’s PSA values following prostate cancer diagnosis will be collected and recorded on a 
eCRF. Each subject will undergo a comprehensive physical examination, including collection of 
vital signs, performed by the Investigator. The subject’s ECOG performance status and American 
Urological Association (AUA) symptom index will be determined (See Appendix 1 and Appendix 
4, respectively).  
After eligibility is confirmed, the subject will be enrolled within 1 week prior to the first scheduled 
administration of study treatment. 
The Screening procedures and assessments must be completed within 28 days of first day of 
infusion (Week 1 Day 1).  
 
Physical examination 
 
Vital signs including blood pressure, heart rate, respiratory rate, temperature, pulse 
oximetry, height, weight 
 
Complete medical history 
 
Baseline conditions assessment 
 
Documentation of disease assessment 
 
ECOG Performance status and International Prostate Symptom Score (IPSS) 
 
Baseline medications taken within 28 days of Day 1 
 
Obtain diagnostic biopsy 
 
Complete blood count (CBC) with differential and platelet count 
 
Blood 
chemistry 
assessment, 
including: 
Alkaline 
phosphatase, 
aspartate 
aminotransferase/alanine 
aminotransferase 
(ALT/AST), 
total 
bilirubin, 
calcium, 
phosphorus, blood urea nitrogen (BUN), creatinine, total protein, albumin, fasting glucose, 
potassium, sodium, chloride, lactate dehydrogenase (LDH), carbon dioxide, Lipase, 
Amylase 
 
TSH and T4 
 
PSA 
 
Immune monitoring 


 
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 
HLA typing 
 
Serum Hepatitis assessment, including Hepatitis B surface antigen (HBsAg), Hepatitis B 
surface antibody (HBsAb), Hepatitis B core antibody (HBcAb), Hepatitis C virus RNA 
 
Urinalysis 
 
ECG 
6.1.2 Treatment Period, ARMS A&C ONLY 
6.1.2.1 Study Procedures: ARMS A&C Day 1: 
 
Before administration of study drug: 
o Physical examination 
o Vital signs including blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry 
o ECOG PS 
o AE assessment 
o Concomitant medications 
o CBC with differential and platelet count 
o Blood chemistry assessment, including: Alkaline phosphatase, ALT/AST, total 
bilirubin, BUN, calcium, phosphorus, creatinine, total protein, albumin, fasting 
glucose, potassium, sodium, chloride, LDH, carbon dioxide, lipase, amylase. 
 
Arms A&C: Dosing of PROSTVAC-V subcutaneously in the right thigh(both study arms) 
o Vital signs including blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry, and weight will be taken within 30 min before dosing of 
PROSTVAC-V. 
 
Following administration of study drug: 
o Vital signs including blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry, and weight will be taken within 30 min after dosing. 
o Observation of adverse events for 30 min in the clinic. 
6.1.2.2 Study Procedures: ARMS A&C, Day 15: 
 
Before administration of study drug: 
o Physical Exam 
o Vital signs including blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry, weight 
o ECOG PS 
o Evaluation of adverse events 
o Concomitant medications 
o CBC with differential and platelet count 
o Blood chemistry assessment, including: Alkaline phosphatase, ALT/AST, total 
bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting 
glucose, potassium, sodium, chloride, LDH, carbon dioxide, lipase, amylase 
o TSH and T4 
o Immune monitoring  


 
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 
Study drug administration 
o Arms A&C: Dosing of PROSTVAC-F subcutaneously in the left thigh 
 
Vital signs including blood pressure, heart rate, respiratory rate, 
temperature, pulse oximetry, and weight will be taken within 30 min 
before dosing of PROSTVAC-F. 
o Arm C: Dosing of Ipilimumab 
 
Following administration of both PROSTVAC-F and Ipilimumab: 
o Vital signs including blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry, and weight will be taken within 30 min after dosing. 
o Observation for adverse events for 30 minutes in the clinic after each drug 
administration. 
6.1.2.3 Study Procedures: ARMS A&C, Day 36: 
 
Before administration of study drug: 
o Physical Exam 
o Vital signs including blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry, weight 
o ECOG PS 
o Evaluation of adverse events 
o Concomitant medications 
o CBC with differential and platelet count 
o Blood chemistry assessment, including: Alkaline phosphatase, ALT/AST, total 
bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting 
glucose, potassium, sodium, chloride, LDH, carbon dioxide, lipase, amylase 
o TSH and T4 
o Immune monitoring 
 
Study drug administration: 
o ARMS A&C: Dosing of PROSTVAC-F subcutaneously in the left arm/shoulder 
 
Vital signs including blood pressure, heart rate, respiratory rate, 
temperature, pulse oximetry, and weight will be taken within 30 min 
before dosing of PROSTVAC-F. 
o ARM C: Dosing of Ipilimumab 
 
Following administration of both PROSTVAC-F and Ipilimumab: 
o Vital signs including blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry, and weight will be taken within 30 min after dosing. 
o Observation for adverse events for 30 minutes in the clinic after each drug 
administration. 
6.1.3 Treatment Period, ARM B ONLY 
6.1.3.1 Study Procedures: ARM B, Day 1: 
 
Before administration of study drug: 
o Physical examination 


 
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o Vital signs including blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry, weight 
o ECOG PS 
o AE assessment 
o Concomitant medications 
o CBC with differential and platelet count 
o Blood chemistry assessment, including: Alkaline phosphatase, ALT/AST, total 
bilirubin, BUN, calcium, phosphorus, creatinine, total protein, albumin, fasting 
glucose, potassium, sodium, chloride, LDH, carbon dioxide, lipase, amylase 
 
Before Dosing of Ipilimumab 
o Vital signs including blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry should be taken within 30 minutes before dosing of Ipilimumab 
 
Dosing of Ipilimumab 
6.1.3.2 Study Procedures: ARM B, Day 22: 
 
Before administration of study drug: 
o Physical Exam 
o Vital signs including blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry, weight 
o ECOG PS 
o Evaluation of adverse events 
o Concomitant medications 
o CBC with differential and platelet count 
o Blood chemistry assessment, including: Alkaline phosphatase, ALT/AST, total 
bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting 
glucose, potassium, sodium, chloride, LDH, carbon dioxide, lipase, amylase 
o TSH and T4 
o Immune monitoring  
 
Before dosing of Ipilimumab 
o Vital signs including blood pressure, heart rate, respiratory rate, temperature, 
pulse oximetry within 30 min of dosing. 
 
Dosing of Ipilimumab 
6.1.4 Study Procedures: Radical Prostatectomy (ALL ARMS: 21 days following 
final dose of PROSTVAC and/or Ipi) 
 
For Arms A&C, Day 57 +/- 7 days 
 
For Arm B, Day 43 +/- 7 days 
 
Radical prostatectomy will be performed by the treating urologic oncologist. 
 
Preoperative Physical exam 


 
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 
Preoperative Vital signs including blood pressure, heart rate, respiratory rate, 
temperature, pulse oximetry 
 
Preoperative Medical history 
 
Immune monitoring (done preoperatively). 
 
Preoperative ECOG PS and IPSS. 
 
Preoperative labs, 
o CBC with differential and platelet count 
o Blood chemistry assessment, including: Alkaline phosphatase, ALT/AST, total 
bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting 
glucose, potassium, sodium, chloride, LDH, carbon dioxide, lipase, amylase 
o TSH and T4 
o PSA 
 
Subjects will have a postoperative telephone follow-up assessment 10-42 days following 
RP as per the treating urologic and medical oncologists’ discretion. At this time the 
following will be performed: 
o Concomitant medications 
o Evaluation of adverse events 
o Postoperative labs may be requested as per the treating urologic and medical 
oncologists’ discretion 
o  
6.1.5 Early Termination Visit (All ARMS) 
To be completed within 7 days for subjects who do not proceed to Radical Prostatectomy. 
 
Physical examination 
 
Vital signs including blood pressure, heart rate, respiratory rate, temperature, pulse 
oximetry 
 
ECOG Performance status 
 
Evaluation of adverse events 
 
Concomitant medications 
 
CBC with differential and platelet count 
 
Blood chemistry assessment, including: Alkaline phosphatase, ALT/AST, total bilirubin, 
calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, potassium, 
sodium, chloride, carbon dioxide, lipase, amylase 
 
PSA 
 
Immune monitoring 
6.1.6 Follow-up Study Procedures: (ALL ARMS, 9 weeks  following RP (+/- 7 days)) 
 
Physical examination 
 
Vital signs including blood pressure, heart rate, respiratory rate, temperature, pulse 
oximetry 
 
ECOG Performance status 


 
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 
Evaluation of adverse events 
 
Concomitant medications 
 
CBC with differential and platelet count 
 
Blood chemistry assessment, including: Alkaline phosphatase, ALT/AST, total bilirubin, 
calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, potassium, 
sodium, chloride, carbon dioxide, lipase, amylase 
 
PSA 
 
Immune monitoring 
 
6.1.7 Post-treatment/Follow Up Visits (ALL ARMS, 6 and 12 months following RP 
(+/- 7 days)) 
Patients will be followed 6 and 12 months following RP, or until disease progression (whichever 
occurs first). The following procedures will be performed at the Follow Up Visit(s): 
 
Physical examination 
 
Vital signs including blood pressure, heart rate, respiratory rate, temperature, pulse 
oximetry 
 
Documentation of disease assessment 
 
ECOG Performance status 
 
Evaluation of adverse events 
 
Concomitant medications 
 
CBC with differential and platelet count 
 
Blood chemistry assessment, including: Alkaline phosphatase, ALT/AST, total bilirubin, 
calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, potassium, 
sodium, chloride, LDH, carbon dioxide, lipase, amylase 
 
PSA 
 
Immune monitoring 
6.1.8 Discontinuation of Therapy 
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests.  Reasons for withdrawing a patient include, but are not limited to, disease 
progression, the occurrence of an adverse event or a concurrent illness, a patient’s request to 
end participation, a patient’s non-compliance or simply significant uncertainty on the part of the 
Investigator that continued participation is prudent.  There may also be administrative reasons to 
terminate participation, such as concern about a patient’s compliance with the prescribed 
treatment regimen. 


 
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Table 3 
Schedule of Study Procedures and Assessments (ARMS A&C) 
Study Day/Visit Day 
Screening 
Day 
-28 to 0 
Day 1 
Day 15 
(± 3 
days) 
Day 36 
(±3 
days) 
Day 57f 
(± 7 
days) 
Early 
Terminatione 
9 wks 
post RP 
(± 7 
days) 
 
6 months 
post RP  
(± 7 days) 
12 months 
post-RP  
(±7 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Baseline conditions 
X 
 
 
 
 
RP 
 
 
 
 
 
AE assessment 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Obtain diagnostic biopsy 
or prostatectomy tissue 
X 
 
 
 
 
X 
 
 
 
 
 
Treatment/Drug 
Administration 
 
 
 
 
 
 
 
 
 
 
 
PROSTVAC – V  
(Arms A&C) 
 
X 
 
 
 
RP 
 
 
 
 
 
PROSTVAC – F  
(Arms A&C) 
 
 
X 
X 
 
 
 
 
 
 
IPILIMUMAB (Arm C 
only) 
 
 
X 
X 
 
 
 
 
 
 
Clinical procedures 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
X 
X 
X 
RP 
X 
X 
 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Disease assessment 
X 
 
 
 
 
 
 
 
X 
X 
Performance status 
X 
Xa 
X 
X 
X 
X 
X 
 
X 
X 
IPSS 
X 
 
 
 
X 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 


 
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Study Day/Visit Day 
Screening 
Day 
-28 to 0 
Day 1 
Day 15 
(± 3 
days) 
Day 36 
(±3 
days) 
Day 57f 
(± 7 days) 
Early 
Terminatione 
9 wks 
post RP 
(± 7 
days) 
 
6 months 
post RP  
(± 7 days) 
12 months 
post-RP  
(±7 days) 
Laboratory procedures 
 
 
 
 
 
 
 
 
 
 
 
CBC w/ Diffb  
X 
Xa 
X 
X 
X 
RP 
X 
X 
 
X 
X 
Blood chemistryb  
X 
Xa 
X 
X 
X 
X 
X 
 
X 
X 
Thyroid Function Tests 
X 
 
X 
X 
X 
 
 
 
 
 
PSA 
X 
 
 
 
X 
X 
X 
 
X 
X 
Hepatitis B, C and HIV 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
HLA Typing 
X 
 
 
 
 
 
 
 
 
 
 
Immune Monitoringc 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
a 
Pre-study clinical (physical exam and performance status) and laboratory parameters are to be measured within 14 days of beginning treatment and do not 
need to be repeated on Day 1. 
b 
CBC with differential and platelet count will be collected prior to study drug(s) dosing.  Blood chemistry assessment, including: Alkaline phosphatase, 
ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, LDH, carbon dioxide, 
lipase, amylase 
c 
Refer to Laboratory Manual for collection procedures. 
d 
Vitals that are to be taken at screening and at every provider visit prior to study drug administration are Blood pressure (diastolic & systolic), Heart Rate, 
Temperature, Respiration, & Pulse Oximetry. Weight is to be measured at screening and prior to Ipilimumab administration. Height is only required at 
screening. See Section 6.1.2 for Vitals schedule before and after study drug administration.   
e 
Early termination visits are to be completed within 7 days for subjects who do not proceed to Radical Prostatectomy. 
f 
Subjects will have routine postoperative follow-up assessments 10-42 days following RP as per urologic oncologist’s discretion. Concomitant medications, 
adverse events, and ECOG performance status should be evaluated. 
 
 


 
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Table 4 
Schedule of Study Procedures and Assessments (ARM B) 
Study Day/Visit Day 
Screening 
Day 
-28 to 0 
Day 1 
Day 22  
(± 3 days) 
Day 43f 
(± 7 days) 
Early 
Terminatione 
9 wks  
post RP  
(± 7 days) 
 
6 months 
post RP (± 
7 days) 
12 months 
post RP  
(± 7 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Baseline conditions 
X 
 
 
 
RP 
 
 
 
 
 
AE assessment 
 
X 
X 
X 
X 
X 
 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
Obtain diagnostic biopsy or 
prostatectomy tissue 
X 
 
 
 
X 
 
 
 
 
 
Treatment/Drug Administration 
 
 
 
 
 
 
 
 
 
IPILIMUMAB  
 
X 
X 
 
RP 
 
 
 
 
 
Clinical procedures 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
X 
X 
RP 
X 
X 
 
X 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
 
X 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
Disease assessment 
X 
 
 
 
 
 
 
X 
X 
Performance status 
X 
Xa 
X 
X 
X 
X 
 
X 
X 
IPSS 
X 
 
 
X 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
Laboratory procedures 
 
 
 
 
 
 
 
 
 
 
CBC w/ Diff b 
X 
Xa 
X 
X 
RP 
X 
X 
 
X 
X 
Blood chemistry b 
X 
Xa 
X 
X 
X 
X 
 
X 
X 
Thyroid Function Tests 
X 
 
X 
X 
 
 
 
 
 
PSA 
X 
 
 
X 
X 
X 
 
X 
X 
Hepatitis B, C and HIV 
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
HLA Typing 
X 
 
 
 
 
 
 
 
 
 
Immune Monitoring c 
X 
 
X 
X 
 
X 
X 
 
X 
X 
a 
Pre-study clinical (physical exam and performance status) and laboratory parameters are to be measured within 14 days of beginning treatment and do not 
need to be repeated on Day 1. 
b 
CBC with differential and platelet count will be collected prior to ipilimumab dose.  Blood chemistry assessment, including: Alkaline phosphatase, ALT/AST, 
total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, fasting glucose, potassium, sodium, chloride, LDH, carbon dioxide, lipase, amylase 
c 
Refer to Laboratory Manual for collection procedures.   


 
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d 
Vitals that are to be taken at screening and at every provider visit prior to ipilimumab administration are Blood pressure (diastolic & systolic), Heart Rate, 
Temperature, Respiration, & Pulse Oximetry. Weight is to be measured at screening and prior to Ipilimumab administration. Height is only required at 
screening. See section 6.1.3 for Vitals schedule before Ipilimumab administration. 
e 
Early termination visits are to be completed within 7 days for subjects who do not proceed to Radical Prostatectomy. 
f 
Subjects will have routine postoperative follow-up assessments 10-42 days following RP as per urologic oncologist’s discretion. Concomitant medications, 
adverse events, and ECOG performance status should be evaluated. 


 
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6.2 
Usage of Concurrent/Concomitant Medications 
Concomitant medications associated with RP will not be recorded on the concomitant 
medication eCRF unless the need for the medication is judged to be at least possibly related to 
treatment with PROSTVAC or ipilimumab or may be immunosuppressive. Concomitant 
medications that are considered by the Investigator to be related to RP will be documented in 
the source documentation but will not be recorded on an eCRF  
. 
6.3 
Dietary Restrictions 
No dietary restrictions to this protocol. 
6.4 
Prohibited Medications  
The following should not be used at any time during the study:  
• Any investigational product other than PROSTVAC or IIpilimumab;  
• Corticosteroid administration (inhaled, intra-articular and topical steroids are allowable) 
• Vaccine therapy  
Additionally, patients in this study may not use vaccines for or prevention of disease (including 
those for common medical conditions, e.g. influenza) while they are participating in this clinical 
study, and for 3 months following the final study treatment. 
6.5 
Restricted Medications  
Hormones, including LHRH agonists, antiandrogens (such as bicalutamide, flutamide, or 
nilutamide), or 5-α-reductase inhibitors may not be administered until after RP. Additionally, 
radiation therapy may not be initiated until after RP. Following RP, subjects may receive hormone 
therapy or radiation therapy as deemed appropriate by their medical professional. Systemic anti-
cancer therapies not listed above should be discussed with the medical monitor prior to initiating 
treatment.  
7 
Reporting and Documentation of Results 
7.1 
Evaluation of Activity 
7.1.1 Primary endpoint: Immunohistological Characterization of CD3
+ T Cell 
Infiltration within Prostate Tissue. 
The primary endpoint response measure will be the change in the number of infiltrating CD3+ T 
cells/µm2 within the prostatic tumor tissue from the diagnostic core biopsy specimens to the post-
treatment prostatectomy tissue specimens, based upon IHC analysis. The infiltrate will be scored 
by the number of CD3+ cells/µm2. Thus, the number of inflammatory cells will be normalized to 
the unit area. Both biopsies and RP specimens will be quantitated with this frequency. For each 
patient, the change in the number of CD3+ T-cell infiltration from the pre-treatment biopsy to post-
treatment prostatectomy tissue specimens will be represented by the ratio of post-treatment 
prostatectomy tissue specimens vs. pre-treatment biopsy. 


 
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7.1.2 Secondary and exploratory endpoints. 
7.1.2.1 Immunohistological characterization of T Cell Subsets and other Immune 
Cells within the Prostate Tissue. 
The change in the number of infiltrating T cells/µm2 of selected subsets (e.g., CD4+, CD8+) within 
the prostatic tumor tissue from the diagnostic core biopsy specimens to the post treatment 
prostatectomy tissue specimens will be assessed, based upon IHC analysis. 
7.1.2.2 Antigen-specific T Cell Immunity in Peripheral Blood 
To assess antigen-specific T cell immunity in the peripheral blood, indicated by the T cell response 
to PSA-3, peripheral blood samples will be collected from subjects at the screening visit, prior to 
RP and at 9 weeks post-RP. The frequency of PSA, TAA and vector specific T cells will be 
enumerated by interferon gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assays using 
established methods (41). 
T-cell proliferation assay will also be measured at the same timepoints the antigen-specific T cell 
response by co-culturing previously cryopreserved PBMCs in triplicate with PSA, TAA, viral vector 
or PHA-L, and assessing with a standardized [3H] thymidine proliferation assay (48),(49). 
7.1.3 PSA 
The utility of a decline in PSA as a marker of response to neoadjuvant therapies is not well 
defined. However, the proportion of patients with PSA response, defined as ≥50% PSA decline, 
will be reported. 
7.1.4 Pathologic Response 
The proportion of patients with pathologic complete response (pT0) at the time of prostatectomy 
will be reported.  
7.2 
Evaluation of Safety 
The following will be collected to evaluate safety:  
 
Adverse events (including SAEs and deaths)  
 
Physical examinations  
 
Vital signs  
 
ECOG performance status  
 
AUA symptom index  
 
Laboratory test results 
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the CTCAE v4.03 for reporting of non-hematologic adverse events and modified 
criteria for hematologic adverse events. 
For multicenter studies, the Principal Investigator at the UCSF Coordinating Center will hold the 
role of Study Chair. The Study Chair is responsible for the overall conduct of the study and for 
monitoring its safety and progress at all participating site.  


 
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7.3 
Definitions of Adverse Events 
7.3.1 Adverse event 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related.  
More specifically, an adverse event can be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, 
without any judgment about causality.  An adverse event can arise from any use of the drug (e.g., 
off-label use, use in combination with another drug) and from any route of administration, 
formulation, or dose, including an overdose.  
7.3.2 Adverse reaction 
An adverse reaction is defined as any adverse event caused by the use of a drug.  Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
7.3.2.1 Suspected  
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship between 
the drug and the adverse event.  A suspected adverse reaction implies a lesser degree of certainty 
about causality than an adverse reaction. 
7.3.2.2 Unexpected  
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the 
investigator brochure or package insert(s), or is not listed at the specificity or severity that has 
been observed, or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the current 
application.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the investigator 
brochure.  For example, a certain number of non-acute deaths in a cancer trial would be 
anticipated as an outcome of the underlying disease, but such deaths would generally not be 
listed as a suspected adverse reaction in the investigator brochure. 
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class effect, 
the first case of angioedema observed with the drug under investigation should be considered 
unexpected for reporting purposes. 


 
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7.3.2.3 Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
 
Death 
 
Life-threatening adverse event 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
7.3.2.4 Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death.  
7.4 
Recording of an Adverse Event 
All grade 3 and above adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of the study drug.  Data about these events and their severity 
will be recorded using the NCI CTCAE v4.0.   
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below:  
Relationship  
Attribution  
Description  
Unrelated to investigational 
drug/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention  
Unlikely 
The AE is doubtfully related to the 
intervention  
Related to investigational 
drug/intervention 
Possible 
The AE may be related to the intervention  
Probable 
The AE is likely related to the intervention  
Definite 
The AE is clearly related to the intervention  
 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions: 


 
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Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 
3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL 
Grade 
4: 
Life-threatening consequences; urgent intervention indicated 
Grade 
5: 
Death related to AE 
7.5 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved.  Patients 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator. 
7.6 
Adverse Events Monitoring  
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®, as noted above. 
The Investigator will assess all adverse events and determine report ability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board, 
the Committee on Human Research (CHR); and, when the study is conducted under an 
Investigational New Drug Application (IND), to the Food and Drug Administration (FDA) if it meets 
the FDA reporting criteria. 
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis.  The Site Committee will 
review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s). 
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
Site Committee meetings. The Site Committee will review and discuss the selected toxicity, the 
toxicity grade, and the attribution of relationship of the adverse event to the administration of the 
study drug(s). 
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and 
discussed at DSMC meetings, which take place every six weeks. 
For a detailed description of the Data and Safety Monitoring Plan please refer to Appendix 2. 
7.7 
Expedited Reporting  
Reporting to the Data and Safety Monitoring Committee 


 
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If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) or 
to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or qualified 
alternate) within 1 business day of knowledge of the event.  The contact may be by phone or e-
mail. 
Reporting to UCSF Committee on Human Research (Institutional Review Board) 
The Principal Investigator must report events meeting the UCSF CHR definition of “Unanticipated 
Problem” (UP) within 5 business days of his/her awareness of the event.  
Expedited Reporting to the Food and Drug Administration 
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32).  
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all 
three definitions:  
 
Suspected adverse reaction 
 
Unexpected 
 
Serious  
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)).  
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)).  
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)).  
Reporting SAEs to Pharmaceutical Companies providing Study Drug 
All expedited SAEs (serious, unexpected and related to study drugs) must be reported to Bavarian 
Nordic. within 24 hours by fax or email to:  
 
Bavarian Nordic 
  
  
Specify: protocol #, subject #, PI name/site#, SAE/onset dates 
 
In addition, all SAEs – serious, unexpected, and related to ipilimumab – must be reported to 
Bristol-Myers Squibb, Inc. within 24 hours by fax or email to: 
 
Bristol-Myers Squibb Company Global Pharmacovigilance & Epidemology Department 
  


 
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Reporting Non-Serious AEs to Pharmaceutical Companies providing Study Drug 
All non-serious AEs should be transferred to Bavarian Nordic and Bristol-Myers Squibb, Inc. 
(related to ipilimumab), every six months once the case is closed in the UCSF safety database.  
 
8 
Statistical Considerations and Evaluation of Results 
8.1 
Study Endpoints 
See section 2.4 for endpoints. 
8.2 
Sample size and power estimate 
The primary endpoint is the proportion of patients who demonstrate a positive response to 
neoadjuvant therapy for each arm of the study. A positive response is defined as a ≥2-fold 
increase in the number of infiltrating CD3+ T cell between the pretreatment biopsy and the post-
treatment RP specimen. A negative response is defined as a <2-fold increase. We expect treated 
patients have more positive responders than the reference cohort with no neoadjuvant treatment 
(see section 8.6); thus we consider the lower threshold for the probability of positive responders 
to be 5%. If the true proportion of positive responders is 25%, with 13 patients in each treatment 
arm, we will have 90% confidence interval of (6.6%, 49.5%). Considering a dropout rate of 7%, a 
total of 42 patients will be accrued to the study. Additionally, with 13 evaluable patients in each 
arm, we have 80% power to detect a significantly different response rate between the PROSTVAC 
and ipilimumab combination arm versus the two monotherapy arms, at a significance level of 0.1, 
if the monotherapy arms have an average response rate of 20% and the combination arm has a 
response rate of 66%. 
Patients who complete screening but withdraw prior to receiving treatment will be replaced. There 
are no stratification factors in this analysis. 
8.3 
Accrual 
It is anticipated that 4 subjects will be enrolled on study each month, with accrual to the study 
completed in approximately 18 months. With 12 months of planned follow-up after RP, the study 
is expected to be completed in 30 months. 


 
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8.4 
Interim Analyses and Stopping Rules 
There will be no formal interim analysis for efficacy performed in this study. Please refer to section 
5.1.1 regarding criteria for stopping treatment for lack of safety. 
8.5 
Analyses Plans 
Safety analyses will be performed on safety-evaluable patients, defined as enrolled patients who 
received any amount of the study treatment. Efficacy analyses will be performed on efficacy-
evaluable patients, defined as safety evaluable patients with measurable disease at baseline. 
Demographic and baseline characteristics will be summarized by arm and overall. In general, 
frequency distribution and percentage will be used to summarize categorical measurements, 
while mean (with standard deviation) and median (with range) will be used to describe symmetric 
and skewed continuous measurements, respectively. Univariate analysis among variables will be 
assessed using the two-sample t-test, Wilcoxon-rank-sum test, Chi-square test, as appropriate. 
8.5.1 Primary Analysis (or Analysis of Primary Endpoint) 
The primary analysis for immune response within the prostate will include all enrolled subjects 
who receive at least 1 dose of PROSTVAC or ipilimumab in any of the treatment arms, and 
undergo RP. Analysis will be done for each arm separately as well as aggregate for all treatment 
arms. 
CD3+ T cell infiltration will be assessed by IHC staining, and quantitated by the number of CD3+ 
T cells/µm2. Therefore, the number of T cells will be normalized per unit area. For the analysis of 
the primary endpoint, T cells will be enumerated from tumor/benign tissue interface (from here on 
referred to as the “tumor interface”). Subjects will be considered to have a “positive” response if 
they exhibit a ≥2-fold increase in CD3+ T cell infiltration, and a “negative” response if they exhibit 
a <2-fold increase. The proportion of patients who have “positive” responses will be reported, with 
95% confidence intervals. Furthermore, the positive response rate will be compared between the 
combination arm vs. the monotherapy arms (pooling the two monotherapy arms together) via two-
sample proportion test. Pairwise comparisons among the three arms will also be performed by 
two-sample proportion test. No multiple testing adjustments will be performed. Additional analyses 
will be performed for assessment of response at the tumor center and benign glands and will be 
reported similarly to the primary endpoint. 
8.5.2 Secondary Analyses (or Analyses of Secondary Endpoints) 
 
T cell tumor infiltration (of selected T cell subsets) will be scored by IHC assessment, and 
scored by the number of T cells/µm2. Therefore, the number of T cells will be normalized 
per unit area. The change in T cell infiltration following neoadjuvant therapy will be 
determined as described above for the primary endpoint. Similar analyses may be 
performed for other immune cells, such as CD4+, CD8+, CD56+, FOXP3, etc. Results will 
be reported as described for the primary endpoint, and T cell infiltration will be reported 
separately for areas of tumor interface, tumor center and benign tissue. 
 
Flow cytometry will be performed in both pre- and post-treatment peripheral blood 
mononuclear cells (PBMC) to determine the change in T cell activation (both Treg and Teffector 
cells) after neoadjuvant therapy. Descriptive statistics for continuous measurements will be 
used to summarize the changes. 
 
Treatment-related toxicities will be assessed according to NCI CTCAE v4.03, for all patients 
who receive at least a single dose of investigational therapy. The distribution for the 


 
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maximum observed grade for each adverse event will be tabulated and reported with 95% 
confidence interval. 
8.5.3 Exploratory Analyses (or Analyses of Exploratory Endpoints) 
 
To characterize antibody responses to a broad panel of antigens, sera will be collected at 
baseline, prior to RP, and  9 weeks following RP, and profiled using spotted antigen array 
(50). After standard preprocess of the protein array data, Cluster and Tree view software will 
be used for unsupervised clustering of the data with Pearson correlation and complete linkage. 
For each array, an antigen is identified as being detected if its value is above the median. To 
determine the number of up- and down-modulated antibodies, the difference in log2 intensity 
values of pretreatment and post-treatment samples will be taken for each patient to identify 
antigens that are detected differentially due to treatment.  
 
Assessment of change from baseline in antigen-specific T-cell immunity in the blood will be 
performed using repeated measure analysis of variance (ANOVA) methods with a mixed 
model approach to allow for a varying number of follow-up measurements. To study the 
change from baseline (screening visit) to post-baseline visits (up to 9 weeks post-RP), the 
mixed model will include four visits (up to 9 weeks post-RP) and subject as a random effect. 
Using polynomial contrast statements, the overall pattern T-cell immunity in the blood (e.g. 
linear) will be investigated. The specific comparison of change in immunity between baseline 
and any specific post-baseline time point will be tested also using linear contrast statements. 
The above analysis will be done for each arm separately as well as aggregately.  
 
Development of and changes in humoral immune responses in the periphery following 
treatment. This will be evaluated by testing serum with methods such as: 
o Measurement of antibodies to PSA, TAA and the viral vector may be performed using 
peptide/protein arrays, standard ELISA assays or flow cytometry to determine 
neutralizing antibody titers. After standard pre-process of the protein array data, 
Cluster and Tree view software will be used for unsupervised clustering of the data 
with Pearson correlation and complete linkage. For each array, an antigen is identified 
as being detected if its value is above the median. To determine the number of up- 
and down-modulated antibodies, the difference in log2 intensity values of pre-
treatment and post-treatment samples will be taken for each patient to identify antigens 
that are detected differentially due to treatment. 
o Measurement of cytokines, chemokines or cancer biomarkers by Luminex multiplex 
analysis will be summarized by descriptive statistics for continuous variables at each 
timepoint for each arm. Furthermore, repeated measure ANOVA methods with a 
mixed model approach to allow for a varying number of follow-up measurements will 
be applied. The specific comparison of change between baseline and any specific 
post-baseline time point will be tested also using linear contrast statements. 
o PD-L1 expression, by IHC assessment, will be scored on a 0-3 scale (0=0-5% staining, 
1=6-33% staining, 2=34-66% staining, 3=67-100% staining). For each subject, the 
change in PD-L1 expression score following neoadjuvant therapy will be calculated for 
exploratory characterization of the impact on PD-L1 in localized prostate cancer. 
Descriptive statistics for categorical measurements will be used to summary the PD-
L1 expression change for each location. Furthermore, univariate analysis (proportion 
test) will be applied to explore the PD-L1 expression score change between locations. 
 
In order to assess the clinical impact of neoadjuvant treatment with PROSTVAC, ipilimumab, 
or the combination or PROSTVAC and ipilimumab: 


 
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o The proportion of patients who achieve a ≥30% decline in PSA at the time of RP 
will be reported with 95% confidence intervals. 
o The proportion of patients with pathologic complete response (pT0) at the time of 
RP will be reported with 95% confidence intervals. 
 
 
T-cell receptor (TCR) repertoire sequencing following re-stimulation on T cells in vitro with 
prostate specific, tumor associated antigens and vector specific antigens to evaluate clonality 
of T-cell responses in the periphery. The responses in the tumor may also be evaluated in 
prostate biopsy samples to allow correlation with responses in the periphery. For each 
individual treatment, the change in tumor-infiltrating TCR between pre-treatment and post-
prostatectomy after treatment will be assessed by calculating the number of unique 
clonotypes comprising the top 25th percentile of cumulative reads after sorting by clone 
abundance. Repertoire change between sequencing experiments will be measured using 
Morisita’s distance. 
8.6 
Reference population 
As discussed in the introduction (section 1.2), in a prior study of neoadjuvant Sip-T, since the 
effect of systemic Sip-T administration on localized prostate cancer was unknown, a negative 
control was felt to be important to be confident that the observed changes in the study population 
were due to treatment effect. Therefore a group of 12 patients, who had undergone RP at UCSF 
without any neoadjuvant therapy, selected prior to undergoing any tissue analyses and matched 
to the study population using the UCSF CAPRA-S score for preoperative risk stratification were 
used as a negative control; these patients were selected from the surgical population at UCSF 
that provide separate, written consent to the use of their RP specimens for research purposes. 
Similarly, in this study, a cohort of 12 patients not treated with any neoadjuvant therapy will be 
used as a negative control, since the effect of neoadjuvant PROSTVAC, ipilimumab, or the 
combination of PROSTVAC and ipilimumab in prostate cancer tissue is unknown. Patients will be 
selected from the RP population at UCSF who have provided separate, written consent to the use 
of their RP specimens for research purposes, and matched to the phase II study population using 
the UCSF CAPRA-S score for preoperative risk stratification. This analysis will provide confidence 
that the changes observed in the prostates of treated patients are due to neoadjuvant treatment 
effect. These 12 patients will not otherwise be included in the analyses as delineated in section 
8.5.  
8.7 
Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of study drug.  The 
study will use the NCI CTCAE v4.03. In addition, safety data will be tabulated in aggregate and 
by treatment group within the safety population. The results will be tabulated for all toxicities 
observed. No statistical testing is planned for AE summaries. 
9 
Study Management 
9.1 
Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable 
regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the Institutional 
Review Board for the protocol, written informed consent form, subject recruitment materials, and 


 
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any other written information to be provided to subjects before any protocol related procedures 
are performed on any subjects.   
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements.  
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable regulatory 
requirements. 
9.2 
Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information related 
to the study (e.g. advertisements used to recruit participants) will be reviewed and approved by 
the UCSF CHR (UCSF Institutional Review Board).  Prior to obtaining CHR approval, the protocol 
must be approved by the Helen Diller Family Comprehensive Cancer Center Site Committee and 
by the Protocol Review Committee (PRC).  The initial protocol and all protocol amendments must 
be approved by the IRB prior to implementation.   
9.3 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation. Participants must 
sign the CHR-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  The 
original signed copy of the consent document must be retained in the medical record or research 
file.  
9.4 
Changes in the Protocol 
Once the protocol has been approved by the UCSF CHR, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the Investigator 
and approved by PRC and the CHR prior to implementation.   
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after implementation.  
The Study Chair and the UCSF study team will be responsible for updating any participating sites. 
9.5 
Handling and Documentation of Clinical Supplies 
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs.  The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included.  The sponsor-
investigator will maintain written records of any disposition of the study drug. 
The Principal Investigator shall not make the investigational drug available to any individuals other 
than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 


 
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9.6 
Case Report Forms (CRFs) 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific electronic Case Report Forms (eCRFs) will document safety and treatment outcomes for 
safety monitoring and data analysis.  All study data will be entered into OnCore® via standardized 
eCRFs in accordance with the CTMS study calendar, using single data entry with a secure access 
account.  The Clinical Research Coordinator (CRC) will complete the eCRFs as soon as possible 
upon completion of the study visit; the Investigator will review and approve the completed eCRFs.  
The information collected on eCRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by UCSF 
personnel.  All source documentation should be kept in separate research folders for each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto eCRFs.  The PI will approve all 
completed eCRFs to attest that the information contained on the eCRFs is true and accurate.  
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the eCRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the eCRFs after that time can only 
be made by joint written agreement among the Study Chair, the Trial Statistician, and the Protocol 
Project Manager. 
Each participating site will complete study specific eCRFs for safety monitoring and data 
analysis.  Each site will enter the study data into OnCore® via standardized eCRFs in 
accordance with the CTMS study calendar, using single data entry with a secure access 
account. The participating site’s Clinical Research Coordinator (CRC) will complete the eCRFs; 
the Investigator will review and approve the completed eCRFs – this process must be 
completed within 5 business days of the visit. Study data from the participating site will be 
reported and reviewed in aggregate with data from patients enrolled at the coordinating center, 
UCSF.  All source documentation and CTMS data will be available for review/monitoring as 
needed. 
9.7 
Registration/Enrollment 
Screening procedures will occur when a subject and investigator signs and dates an informed 
consent form and the subject provides authorization to use protected health information. The 
informed consent form will be completed prior to any study-specific procedures. Screening 
procedures that are standard of care and were performed prior to consent, do not need to be 
repeated if they were conducted within the eligible screening period, unless otherwise specified. 
To initiate enrollment, the investigator will verify eligibility according to all inclusion and 
exclusion criteria and complete the Enrollment Form. All eligible subjects must be centrally 
registered through the UCSF GU Clinical Research Office.  To complete the registration 
process, the study site must fax or email the signed completed study-specific eligibility checklist, 
registration form, all source documents verifying eligibility, any supporting documents, and the 
signed informed consent.  These data must also be entered into the OnCore database.  Once 
the enrollment information is received at UCSF, the Study Chair will review the packet and if 
eligibility is confirmed, he will sign the registration form   and assignment to treatment can occur.  
UCSF will provide the participating site with the signed registration approval.  Subjects failing to 


 
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meet all study eligibility requirements will not be registered.  See Section 3.6 for randomization 
details. 
9.8 
Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring entity 
for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-approved Data 
and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all adverse events and 
suspected adverse reactions considered “serious”.  The DSMC will audit study-related activities 
to ensure that the study is conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant results of the DSMC 
audit will be communicated to the IRB and the appropriate regulatory authorities at the time of 
continuing review, or in an expedited fashion, as applicable.  See Appendix 2 Data and Safety 
Monitoring Plan for a Phase 2 or 3 Institutional Study, for additional information. 
10 
Protection of Human Subjects 
10.1 Protection from Unnecessary Harm  
Each clinical site is responsible for protecting all subjects involved in human experimentation. This 
is accomplished through the CHR mechanism and the process of informed consent. The CHR 
reviews all proposed studies involving human experimentation and ensures that the subject’s 
rights and welfare are protected and that the potential benefits and/or the importance of the 
knowledge to be gained outweigh the risks to the individual. The CHR also reviews the informed 
consent document associated with each study in order to ensure that the consent document 
accurately and clearly communicates the nature of the research to be done and its associated 
risks and benefits.  
10.2 Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the individuals 
described in the informed consent document. 
 
 


 
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Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science (New York, 
NY). 1995 Nov 10;270(5238):985-8. PubMed PMID: 7481803. Epub 1995/11/10. eng. 
34. 
Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of 
CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a 
critical negative regulatory role of CTLA-4. Immunity. 1995 Nov;3(5):541-7. PubMed PMID: 
7584144. Epub 1995/11/01. eng. 
35. 
Keilholz U, Martus P, Scheibenbogen C. Immune monitoring of T-cell responses in 
cancer vaccine development. Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2346s-52s. PubMed 
PMID: 16609057. eng. 
36. 
Le Gal F-A, Widmer VM, Dutoit V, Rubio-Godoy V, Schrenzel J, Walker PR, et al. Tissue 
homing and persistence of defined antigen-specific CD8+ tumor-reactive T-cell clones in long-
term melanoma survivors. J Invest Dermatol. 2007 Mar;127(3):622-9. PubMed PMID: 
17039243. Epub 20061012. eng. 
37. 
Frey SE, Newman FK, Cruz J, Shelton WB, Tennant JM, Polach T, et al. Dose-related 
effects of smallpox vaccine. N Engl J Med. 2002 Apr 25;346(17):1275-80. PubMed PMID: 
11923489. Epub 20020328. eng. 
38. 
Fulginiti VA. Risks of smallpox vaccination. JAMA. 2003 Sep 17;290(11):1452; author 
reply PubMed PMID: 13129976. eng. 
39. 
Vellozzi C, Averhoff F, Lane JM, Wen X, Moore AC, Santibanez S, et al. Superinfection 
following smallpox vaccination (Vaccinia), United States: surveillance January 2003 through 
January 2004. Clin Infect Dis. 2004 Dec 1;39(11):1660-6. PubMed PMID: 15578368. Epub 
20041108. eng. 
40. 
Kaufman HL, Wang W, Manola J, DiPaola RS, Ko Y-J, Sweeney C, 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):2122-32. PubMed 
PMID: 15169798. eng. 
41. 
Gulley J, Chen AP, Dahut W, Arlen PM, Bastian A, Steinberg SM, 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 Oct 1;53(2):109-17. PubMed PMID: 
12242725. eng. 
42. 
Gulley JL, Arlen PM, Bastian A, Morin S, Marte J, Beetham P, et al. Combining a 
recombinant cancer vaccine with standard definitive radiotherapy in patients with localized 
prostate cancer. Clin Cancer Res. 2005 May 1;11(9):3353-62. PubMed PMID: 15867235. eng. 


 
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43. 
Arlen PM, Gulley JL, Todd N, Lieberman R, Steinberg SM, Morin S, et al. Antiandrogen, 
vaccine and combination therapy in patients with nonmetastatic hormone refractory prostate 
cancer. J Urol. 2005 Aug;174(2):539-46. PubMed PMID: 16006888. eng. 
44. 
Madan RA, Gulley JL, Schlom J, Steinberg SM, Liewehr DJ, Dahut WL, et al. Analysis of 
overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with 
vaccine, nilutamide, and combination therapy. Clin Cancer Res. 2008 Jul 15;14(14):4526-31. 
PubMed PMID: 18628467. Pubmed Central PMCID: PMC2682417. eng. 
45. 
Bolyard EA, Tablan OC, Williams WW, Pearson ML, Shapiro CN, Deitchmann SD. 
Guideline for infection control in healthcare personnel, 1998. Hospital Infection Control Practices 
Advisory Committee. Infect Control Hosp Epidemiol. 1998 Jun;19(6):407-63. PubMed PMID: 
9669622. eng. 
46. 
Garner JS. Guideline for isolation precautions in hospitals. The Hospital Infection Control 
Practices Advisory Committee. Infect Control Hosp Epidemiol. 1996 Jan;17(1):53-80. PubMed 
PMID: 8789689. eng. 
47. 
Neff JM, Lane JM, Fulginiti VA, Henderson DA. Contact vaccinia--transmission of 
vaccinia from smallpox vaccination. JAMA. 2002 Oct 16;288(15):1901-5. PubMed PMID: 
12377090. eng. 
48. 
Corradin G, Etlinger HM, Chiller JM. Lymphocyte specificity to protein antigens. I. 
Characterization of the antigen-induced in vitro T cell-dependent proliferative response with 
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70468. eng. 
49. 
Fong L, Brockstedt D, Benike C, Breen JK, Strang G, Ruegg CL, et al. Dendritic cell-
based xenoantigen vaccination for prostate cancer immunotherapy. J Immunol. 2001 Dec 
15;167(12):7150-6. PubMed PMID: 11739538. eng. 
50. 
Kwek SS, Dao V, Roy R, Hou Y, Alajajian D, Simko JP, et al. Diversity of antigen-
specific responses induced in vivo with CTLA-4 blockade in prostate cancer patients. Journal of 
immunology. 2012 Oct 1;189(7):3759-66. PubMed PMID: 22956585. Pubmed Central PMCID: 
3448828. 
 
 
 
 


 
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Appendices 
Appendix 1 Performance Status Criteria 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity 
Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work) 
2 
In bed < 50% of the time 
Ambulatory and capable of all self-care, but unable to 
carry out any work activities 
Up and about more than 50% of waking hours 
3 
In bed > 50% of the time 
Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
5 
Dead 
 
 
 


 
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Appendix 2 Data and Safety Monitoring Plan for a Phase II or Phase III 
Institutional Study 
 
Data and Safety Monitoring Plan for a Phase II or III Institutional Study 
1.         Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study includes:  
 
Review of patient data.  
 
Review of serious adverse events. 
 
Auditing every six months (depending on study accrual). 
 
Minimum of a yearly regulatory audit. 
2. 
Monitoring and Reporting Guidelines 
Investigators will conduct continuous review of data and patient safety and discuss each 
patient’s treatment at monthly site committee meetings.  These discussions are documented in 
the site committee meeting minutes.  The discussion will include the number of patients, 
significant toxicities in accordance with the protocol, and observed responses.   
All institutional Phase II and III studies are designated with a moderate risk assessment (see 
Appendix H).   The data is audited twice per year with twenty percent of the patients monitored 
(or at least three patients if the calculated value is less than three).   
3. 
Review and Oversight Requirements 
 
3.1 
Adverse Event Monitoring  
All Grade 3-5 Adverse Events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of the study 
drug, will be entered into OnCore®, UCSF’s Clinical Trial Management System.   
Adverse Events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) (version 4.03) as developed and revised by the Common Therapy 
Evaluation Program (CTEP) of the National Cancer Institute.  Adverse events are further 
given an assignment of attribution or relationship to treatment or medical procedure.  
Attribution categories are: 
• 
Definite – The adverse event is clearly related to the investigational agent(s) or 
medical procedure. 
• 
Probable – The adverse event is likely related to the investigational agent(s) or 
medical procedure. 
• 
Possible – The adverse event may be related to the investigational agent(s) or 
medical procedure. 


 
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• 
Unlikely – The adverse event is doubtfully related to the investigational agent(s) 
or medical procedure. 
• 
Unrelated – the adverse event is clearly not related to the investigational 
agent(s) or medical procedure. 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the Site Committee meetings.  The Site Committee will review and discuss the 
selected toxicity, the toxicity grade, and the attribution of relationship of the adverse 
event to the administration of the study drug(s). 
3.2 
Serious Adverse Event Reporting  
By definition, an adverse event is defined as a serious adverse event (SAE) according to 
the following criteria: 
• 
Death. 
• 
Life-threatening (i.e. results in an immediate risk of death). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
Permanent or significant disability/incapacity 
• 
Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that 
may require medical or surgical intervention to prevent one of the outcomes 
listed above.  
• 
Event occurring in a gene therapy study. 
• 
Event that changes the risk/benefit ratio of a study. 
• 
Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution. 
Serious Adverse Event reporting will be in accordance with the UCSF IRB Regulations 
and Code of Federal Regulation Title 21 Part 312.32.  The SAE will be reported on a 
Med Watch form.   
UCSF IRB website for guidance in reporting serious adverse events: 
https://irb.ucsf.edu/adverse-event  
FDA website for guidance in reporting serious adverse events: 
www.fda.gov/Safety/MedWatch/HowToReport/default.htm 
Med Watch forms and information: 
www.fda.gov/medwatch/getforms.htm 


 
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All serious adverse events are entered into OnCore®, as well as submitted to the IRB 
(per IRB guidelines) via iMedRIS®.  The SAEs are reviewed and monitored by the Data 
and Safety Monitoring Committee on an ongoing basis and discussed at DSMC 
meetings, which take place every six weeks.  The date the SAE is sent to all required 
reporting agencies will be documented in OnCore®.  
If the SAE involves a subject death, and is determined to be possibly, probably or 
definitely related to the investigational drug or any research related procedure, the event 
must be reported to the DSMC Chair or Vice Chair within 1 business day.   
The reporting procedure is by communication via phone or in person with written 
documentation of the one-on-one communication via e-mail, with a copy of the e-mail to 
the DSMC Manager. 
3.3 
Review of Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported 
in the Investigator Brochure or package insert) is noted in the study, the Principal 
Investigator will notify the DSMC at the time the increased rate is identified.  The report 
will indicate if the incidence of adverse events observed in the study is above the range 
stated in the Investigator Brochure or package insert. 
If at any time the Investigator stops enrollment or stops the study due to safety issues, 
the DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail.  
and the IRB must be notified within 10 business days via an iRIS Reporting Form. 
 
Data and Safety Monitoring Committee Contacts: 
 
 
 
 
 
Box 1705 
UCSF HDFCCC 
San Francisco, CA 94158 
 
DSMC Monitors  
Box 0128 
UCSF HDFCCC 
San Francisco, CA 94143 
 
 
 
 
 
 


 
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Appendix 3 Clinical Monitoring for Autoimmunity 
(to be completed at each MD visit) 
Patient ID________________________ 
 
 
Skin   
 
 
 
 
UCSF MRN ________________________  
Symptoms _____________________ 
 
Signs (include pruritis, vitiligo)_____  
 
 
 
 
 
 
 
_____ no rash 
  
 
 
   
 
 
 
_____ rash; description_____________ 
  
 
 
   
 
 
 
_____ % of body surface  
Hepatic  
 
 
 
 
 
Pulmonary 
 
Symptoms __________________________  
 
Symptoms ____________________ 
Signs ______________________________  
Signs ________________________ 
Labs: _____ AST/SGOT _____ ALT/SGPT _____ Bilirubin (total) _____ ALP 
Gastrointestinal  
 
 
 
 
Rheumatologic 
Symptoms ___________________________ 
 
Symptoms____________________ 
Signs________________________________  
Signs (joint pain swelling; #/location of joints 
involved) ______________ 
_____ no diarrhea 
 
 
 
 
Labs 
_____ increase of < 4 stools/day 
 
      
     
____ ANA (titer, pattern) 
_____ increase of  4-6 stools/day 
 
          ____ RF   
_____ increase of ≥ 7 stools/day, or need        
 Other _______________ 
for parenteral support  
_____ diarrhea requiring ICU admission  
or hemodynamic compromise 
 
 
_____ nausea / vomiting 
Labs 
_____  Stool analysis (include. WBC count) for patients with GI symptoms 
 


 
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Pancreas  
 
 
 
 
 
Renal 
Symptoms ___________________________  
 
Symptoms ___________________ 
Signs  _______________________________  
 
Signs  _______________________ 
Labs: ______ amylase _____ lipase _____glucose Lab: ______ Cr 
Endocrine 
 
 
 
 
 
Hematologic 
Symptoms ____________________________  
 
Symptoms ____________________ 
Signs  ________________________________  
 
Signs  _______________________ 
Labs: ____ TSH; ____T4; ____T3; _____FTI 
 
Labs: ___ WBC; ___ Hgb; ___ Plt; 
___ANC 
Pituitary_______________________________ 
Neurologic 
 
 
 
 
 
Cardiac 
Symptoms ____________________________ 
 
Symptoms ____________________ 
Signs_________________________________ 
 
Signs ________________________ 
 
 


 
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Appendix 4 American Urological Association (AUA) symptom  
  
 


 
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Appendix 5 General recommendations for managements of suspected immune 
related adverse events 
 
 
 
 
 


 
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Appendix 6 Diarrhea Management Algorithm 
 
 
Diarrhea 
GRADE 1 
Increase of < 4 stools per 
day over baseline; mild 
increase in ostomy output 
compared with baseline 
GRADE 2 
Increase of 4-6 stools per 
day over baseline; IV 
fluids indicated < 24 hrs; 
moderate increase in 
ostomy output compared 
to baseline; not 
interfering with ADL 
GRADE 3 
Increase of ≥ 7 stools per 
day over baseline; 
incontinence; IV fluids 
indicated < 24 hrs; 
hospitalization; severe 
increase in ostomy output 
compared to baseline; 
interfereing with ADL 
GRADE 4 
Life-threatenting 
consequences (e.g. 
hemodynamic collapse) 
GRADE 5 
Death 
 


 
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Appendix 7 Hepatotoxicity Management Algorithm  
Situation: rising liver function tests (LFTs) > 8X ULN or suspected immune-mediated hepatitis 
1) Admit subject to hospital for evaluation and close monitoring 
2) Stop further Ipilimumab dosing until hepatotoxicity is resolved. Consider permanent 
discontinuation of Ipilimumab per protocol (Section 6.2.5 of protocol) 
3) Start at least 120 mg methylprednisolone sodium succinate per day, given IV as a single 
or divided dose 
4) Check liver laboratory test values (LFTs, T-bilirubin) daily until stable or showing signs of 
improvement for at least 3 consecutive days 
5) If no decrease in LFTs after 3 days or rebound hepatitis occurs despite treatment with 
corticosteroids, then add mycophenolate mofetil 1g BID per institutional guidelines for 
immunosuppression of liver transplants (supportive treatment as required, including 
prophylaxis for opportunistic infections per institutional guidelines) 
6) If no improvement after 5 to 7 days, consider adding 0.10 to 0.15 mg/kg/day of 
tacrolimus (trough level 5-20 ng/mL) 
7) If target trough level is achieved with tacrolimus but no improvement is observed after 5 
to 7 days, consider infliximab, 5 mg/kg, once 
8) Continue to check LFTs daily for at least 2 weeks to monitor sustained response to 
treatment 
A flow chart of the algorithm is depicted in the following page. 
 
 


 
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Appendix 8 Endocrinopathy Management Algorithm 
 
Footnote 
For numbered footnotes (1,2,3,4), please refer to further explanation and text found in the corresponding dotted line boxes to 
the right side of the algorithm 
 
 


 
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Appendix 9 Prohibited Medications 
All prostate cancer-directed therapies are prohibited, including, but not limited to: 
Leuprolide acetate 
 
Lupron, Eligard 
Goserelin 
 
 
Zoladex 
Degarelix 
 
 
Firmagon 
Bicalutamide  
 
Casodex 
Flutamide 
 
 
Eulexin 
Nilutamide 
 
 
Nilandron 
Ketoconazole (systemic) 
Nizoral 
Docetaxel 
 
 
Taxotere 
Cabazitaxel 
 
 
Jevtana 
Abiraterone acetate 
 
Zytiga 
Enzalutamide  
 
Xtandi 
Sipuleucel-T  
 
Provenge 
Radium-223 
 
 
Xofigo 
Diethylstilbestrol  
 
PC-SPES (or any other PC-X product) 
 
 
 
 
 
 
Any investigation therapy for the treatment of prostate cancer is prohibited. 
Chronic use of prednisone of any corticosteroids (>10mg prednisone daily or its equivalent) is 
prohibited; the chronic use of any chronic immunosuppressant therapy is prohibited.