Clinical trial NCT01875250
Conditions: Prostate Cancer
Keywords: Gene Transfer Androgen Receptor Antagonist PSA Immune Response Immunotherapy
Sponsor: National Cancer Institute (NCI)
Start date: 2013-07-22; Completion date: 2020-02-28
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

\- Enzalutamide is a well tolerated hormone therapy that is used to treat advanced prostate cancer. It is given to help kill cancer cells and limit cancer cell growth. A new possible way of treating prostate cancer is using a therapeutic cancer vaccine (immune stimulating therapy) that may help activate the immune system against the cancer. The immune stimulating vaccine will help white blood cells recognize and kill the cancer cells throughout the body. This vaccine therapy has been tested in hundreds of patients and is very well tolerated. Researchers want to see whether this vaccine, given with enzalutamide, is more effective at treating advanced prostate cancer than enzalutamide alone.

Objectives:

\- To compare the safety and effectiveness of enzalutamide with and without vaccine therapy for advanced prostate cancer.

Key Eligibility:

* Men at least 18 years of age who have advanced castration sensitive prostate cancer.
* Patients must have testosterone within the normal range
* No evidence of metastatic prostate cancer on computed tomography (CT) or Bone scan
* No history of autoimmune diseases
* No previous immunotherapy within 3 years

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies will be used to monitor the cancer before treatment.
* Participants will be separated into two groups. One group will have enzalutamide and the study vaccine. The other group will have enzalutamide alone.
* All participants will take enzalutamide once a day. They will take the drug for 3 months. This form of intermittent therapy is common in this population of patients.
* The vaccine group of participants will receive the new study vaccine. They will have a single injection on the first day of the first study cycle. There will be regular booster injections afterward. There will be one injection during the third week of treatment, and one in the fifth week. The vaccine will then be given every 4 weeks until 21 weeks have passed.
* Treatment will be monitored with frequent blood tests and imaging studies.

Detailed description:
Background:

* Androgen deprivation therapy (ADT) and surveillance are standard therapy options for prostate cancer patients with biochemical progression after localized therapy (or nonmetastatic castration sensitive prostate cancer; nmCSPC also known as D0 Prostate Cancer). These patients cannot be cured of prostate cancer and the primary therapeutic goal is to contain the disease with anti-androgen therapy.
* ADT can be administered intermittently consisting of multiple short courses or continuously with similar long-term clinical outcomes.
* Previous studies with high dose bicalutamide (androgen receptor antagonist, ARA) have shown significant biochemical control in nmCSPC.
* Enzalutamide is a modern ARA with greater androgen receptor affinity than bicalutamide and further impairs downstream effects of androgen receptor activation. This agent is FDA approved for the treatment of chemotherapy refractory metastatic castration resistant prostate cancer.
* Given its favorable side effect profile, there is strong interest in using enzalutamide to treat patients with earlier stages of prostate cancer including nmCSPC.
* PSA-TRICOM (Prostvac; developed by the National Cancer Institute \[NCI\] and licensed to Bavarian Nordic, Mountain View, California (CA)) is a novel candidate prostate cancer immunotherapy for the treatment of prostate cancer. It is a viral vector based therapeutic cancer vaccine that is administered via subcutaneous injections. In a randomized controlled Phase 2 trial, PSA-TRICOM therapy was associated with a prolongation of survival in men with metastatic castrate-resistant prostate cancer. A phase III trial is currently enrolling patients in this same population.
* There is also rationale to use therapeutic cancer vaccines such as PSA-TRICOM in earlier stage prostate cancer patients to maximize the potential therapeutic effect of immune stimulating therapy.
* An ongoing NCI clinical trial that combined PSA-TRICOM with flutamide (an older Food and Drug Administration (FDA) approved ARA) in nonmetastatic castration resistant prostate cancer has demonstrated safety and suggested the potential to improve time to progression.
* Analysis of previous trials using therapeutic cancer vaccines alone and in combination suggests that such therapies may alter tumor growth rate. If this hypothesis is correct, a therapeutic cancer vaccine may alter tumor regrowth rate/recovery after a cytoreductive therapy such as enzalutamide is discontinued.
* If PSA-TRICOM with enzalutamide can result in a reduced tumor regrowth rate as measured by PSA after a short course of enzalutamide therapy, it would provide an important proof of concept and potentially define it more clear role for therapeutic cancer vaccines in prostate cancer and potentially other cancers.
* To prospectively evaluate this hypothesis, all patients will be treated with enzalutamide in a manner similar to how short course ADT is used in common clinical practice. Half the patients will also be given PSA-TRICOM and PSA recovery after enzalutamide therapy will be compared between patients who received vaccine and those who did not.
* Preliminary data from the first cohort of randomized patients suggests that enzalutamide alone can induce an immunologic response. A second cohort of 15 patients will explore a lower dose of enzalutamide at 80 mg to determine if similar immunologic responses can also be seen at a lower dose, where toxicity is less likely.

Objectives:

Primary Endpoint:

-Determine if PSA-TRICOM combined with the novel androgen receptor antagonist enzalutamide will result in a decrease in PSA growth kinetics (tumor re-growth rate) after enzalutamide discontinuation in patients with non-metastatic, castration sensitive prostate cancer (i.e. patients with normal testosterone).

Eligibility:

* Patients with nonmetastatic castration sensitive prostate cancer and a PSA over 2.0 ng/ml
* Patients with normal testosterone levels.
* Histologically confirmed adenocarcinoma.
* Patients with a PSA doubling time of 12 months or less.
* Eastern Cooperative Oncology Group (ECOG) 0-1.

Design:

* Randomized pilot study
* Cohort 1:
* Thirty-four patients to be enrolled and randomized 1:1 to

  * Arm A: Enzalutamide for 3 months.
  * Arm B: Enzalutamide 3 months + PSA-TRICOM on weeks 1, 3,5,9,13,17 and 21.

Cohort 1:

* Arm A: Enzalutamide (n=17)
* Arm B: Enzalutamide + PSA-TRICOM (n=17)

  * Enzalutamide will be given at the standard dose of 160 mg daily for 3 months. PSATRICOM (Prostvac-V/F) will consist of a single subcutaneous (sc) immunization of Prostvac-V in Week 1, followed by 6 Prostvac-F immunizations administered in Weeks 3, 5, 9, 13, 17, and 21. Patients will be retreated with a 3-month course of enzalutamide after PSA has returned to baseline values at study entry or higher. Patients will have had to be on study for at least 7 months or longer in order to be retreated with an additional course of enzalutamide therapy. Patients will be followed for PSA recovery after enzalutamide has been discontinued. Patients who do not develop a 25% decline in PSA after 3 months will not be evaluated for tumor re-growth and additional patients will be enrolled to evaluate for that endpoint. Patients will be stratified based on a doubling time of greater than or less than 6 months.

Arms: arm 1: Enzalutamide for 3 months arm 2: Enzalutamide 3 months + PSA-TRICOM (Prostvac-V/F) on weeks 1, 3, 5, 9,13,17 and 21
Interventions: intervention 1: PROSTVAC-F (Fowlpox)/TRICOM intervention 2: PROSTVAC-V (Vaccinia)/TRICOM intervention 3: Enzalutamide (Xtandi)
Intervention descriptions: intervention 1: A recombinant fowlpox virus vector vaccine containing the genes for human prostate specific antigen (PSA) and three co-stimulatory molecules. intervention 2: A recombinant vaccinia virus vector vaccine containing the genes for human prostate specific antigen (PSA) and three co-stimulatory molecules. intervention 3: An androgen receptor inhibitor.

Protocol documents:
Prot_SAP_000.pdf: 
10 Center Drive RM 13N240B Bethesda, MD 20892 
Abbreviated Title: Enzalutamide in non-met CSPC
CC Protocol #:
13-C-0153
NCT #: 
NCT01875250
OSP #:
IBC #: 
1301-1205
RD-13-I-12
Amendment:
J
A Phase II Trial of Enzalutamide in Combination with PSA-TRICOM in Patients with 
Non-Metastatic Castration Sensitive Prostate Cancer
NCI Principal Investigator:
Ravi Madan, M.D. A, B, C, D, E, F
Genitourinary Malignancies Branch, CCR, NCI
10 Center Drive
Building 10, Room 13N240
Bethesda, MD 20892
Phone: (301) 480-7168
Email: madanr@mail.nih.gov
Statistician:
Seth Steinberg, Ph.D., OCD, CCR, NCI E, F
NIH Associate Investigators:
James Gulley, M.D., PhD, GMB, CCR, NCI A, B, C, D, E, F
William Dahut, M.D., GMB, CCR, NCI A, B, C, D, E, F
Marijo Bilusic, M.D., PhD, GMB, CCR, NCI A, B, C, D, E, F
Anna Couvillon, CRNP, GMB, CCR, NCI A, B, C, D, E, F
Amy Hankin, P.A., GMB, CCR, NCI A, B, C, D, E, F
Myrna Rauckhorst, R.N., OCD, CCR, NCI A, B, C, E, F
Sheri McMahon, R.N., OCD, CCR, NCI A, B, C, E, F
Jennifer Marte, M.D., GMB, CCR, NCI E, F
Fatima Karzai, M.D., GMB, CCR, NCI A, B, C, D, E, F
Julius Strauss, M.D., LTIB, CCR, NCI A, B, C, D, E, F
Guinevere Chun, R.N., OCD, CCR, NCI A, B, C, E, F
Helen Owens, R.N., OCD, CCR, NCI A, B, C, E, F
Referral Contact:
Study Coordinator: 
Anna Couvillon, C.R.N.P.
Helen Owens, R.N., OCD, CCR, NCI
10 Center Drive, 13N244
Bethesda, MD 20892
Phone: 240-760-6068
Email: helen.owens@nih.gov
Non-NIH Associate Investigators:
Philip M. Arlen, M.D. [V], GMB, CCR, NCI A, B, E, F


Version Date: 12/5/17
Abbreviated Title: Enzalutamide in non-met CSPC
2
Collaborators: 
Nima Sharifi, M.D.F,G
Cleveland Clinic Foundation
Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
sharifn@ccf.org
Roles: 
A. Obtain information by intervening or interacting 
with living individuals for research purposes
B. Obtaining identifiable private information about 
living individuals
C. Obtaining the voluntary informed consent of 
individuals to be subjects
D. Makes decisions about subject eligibility
E. Studying, interpreting, or analyzing identifiable 
private information or data/specimens for 
research purposes
F. Studying, interpreting, or analyzing de-identified 
data or specimens for research purposes
G. Some/all research activities performed outside 
NIH
Investigational Agents:    
Drug Name:
Enzalutamide
PROSTVAC-V/F
IND Number:
15455
15455
Sponsor:
Center for Cancer Research, NCI
Center for Cancer Research, 
NCI
Manufacturer:
Medivation and Astellas, Inc.
Bavarian Nordic, Inc.
Supplier
Medivation and Astellas, Inc.
Bavarian Nordic, Inc.


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Abbreviated Title: Enzalutamide in non-met CSPC
3
PRÉCIS
Background
x
Androgen deprivation therapy (ADT) and surveillance are standard therapy options for 
prostate cancer patients with biochemical progression after localized therapy (or non-
metastatic castration sensitive prostate cancer; nmCSPC also known as D0 Prostate 
Cancer). These patients cannot be cured of prostate cancer and the primary therapeutic 
goal is to contain the disease with anti-androgen therapy.
x
ADT can be administered intermittently consisting of multiple short courses or 
continuously with similar long-term clinical outcomes.
x
Previous studies with high dose bicalutamide (androgen receptor antagonist, ARA) have
shown significant biochemical control in nmCSPC.
x
Enzalutamide is a modern ARA with greater androgen receptor affinity than bicalutamide 
and further impairs downstream effects of androgen receptor activation. This agent is 
FDA approved for the treatment of chemotherapy refractory metastatic castration 
resistant prostate cancer.
x
Given its favorable side effect profile, there is strong interest in using enzalutamide to 
treat patients with earlier stages of prostate cancer including nmCSPC.
x
PSA-TRICOM (Prostvac™; developed by the National Cancer Institute [NCI] and 
licensed to Bavarian Nordic, Mountain View, CA) is a novel candidate prostate cancer 
immunotherapy for the treatment of prostate cancer. It is a viral vector based therapeutic 
cancer vaccine that is administered via subcutaneous injections. In a randomized 
controlled Phase 2 trial, PSA-TRICOM therapy was associated with a prolongation of 
survival in men with metastatic castrate-resistant prostate cancer. A phase III trial is 
currently enrolling patients in this same population.
x
There is also rationale to use therapeutic cancer vaccines such as PSA-TRICOM in 
earlier stage prostate cancer patients to maximize the potential therapeutic effect of 
immune stimulating therapy.
x
An ongoing NCI clinical trial that combined PSA-TRICOM with flutamide (an older 
FDA approved ARA) in nonmetastatic castration resistant prostate cancer has 
demonstrated safety and suggested the potential to improve time to progression.
x
Analysis of previous trials using therapeutic cancer vaccines alone and in combination 
suggests that such therapies may alter tumor growth rate. If this hypothesis is correct, a 
therapeutic cancer vaccine may alter tumor regrowth rate/recovery after a cytoreductive 
therapy such as enzalutamide is discontinued.
x
If PSA-TRICOM with enzalutamide can result in a reduced tumor regrowth rate as 
measured by PSA after a short course of enzalutamide therapy, it would provide an 
important proof of concept and potentially define it more clear role for therapeutic cancer 
vaccines in prostate cancer and potentially other cancers.
x
To prospectively evaluate this hypothesis, all patients will be treated with enzalutamide in 
a manner similar to how short course ADT is used in common clinical practice. Half the 
patients will also be given PSA-TRICOM and PSA recovery after enzalutamide therapy 
will be compared between patients who received vaccine and those who did not.
x
Preliminary data from the first cohort of randomized patients suggests that enzalutamide 
alone can induce an immunologic response.  A second cohort of 15 patients will explore a 


Version Date: 12/5/17
Abbreviated Title: Enzalutamide in non-met CSPC
4
lower dose of enzalutamide at 80 mg to determine if similar immunologic responses can 
also be seen at a lower dose, where toxicity is less likely.
Objectives
Primary Endpoint:
x
Determine if PSA-TRICOM combined with the novel androgen receptor antagonist 
enzalutamide will result in a decrease in PSA growth kinestics (tumor re-growth rate)
after enzalutamide discontinuation in patients with non-metastatic, castration sensitive 
prostate cancer (i.e. patients with normal testosterone).
Eligibility
x
Patients with nonmetastatic castration sensitive prostate cancer and a PSA over 2.0 ng/ml
x
Patients with normal testosterone levels.  
x
Histologically confirmed adenocarcinoma.    
x
Patients with a PSA doubling time of 12 months or less. 
x
ECOG 0-1.
Design
x
Randomized pilot study
x
Cohort 1:
Thirty-four patients to be enrolled and randomized 1:1 to 
o
Arm A: Enzalutamide for 3 months.
o
Arm B: Enzalutamide 3 months + PSA-TRICOM on weeks 1, 3,5,9,13,17 and 21. 


Version Date: 12/5/17
Abbreviated Title: Enzalutamide in non-met CSPC
5
x
Enzalutamide will be given at the standard dose of 160 mg daily for 3 months.  PSA-
TRICOM (Prostvac-V/F) will consist of a single subcutaneous (sc) immunization of 
Prostvac-V in Week 1, followed by 6 Prostvac-F immunizations administered in Weeks 3, 5, 
9, 13, 17, and 21. Patients will be retreated with a 3-month course of enzalutamide after PSA 
has returned to baseline values at study entry or higher.  Patients will have had to be on study 
for at least 7 months or longer in order to be retreated with an additional course of 
enzalutamide therapy.  Patients will be followed for PSA recovery after enzalutamide has 
been discontinued. Patients who do not develop a 25% decline in PSA after 3 months will not 
be evaluated for tumor re-growth and additional patients will be enrolled to evaluate for that 
endpoint. Patients will be stratified based on a doubling time of greater than or less than 6 
months.  
R
A
N
D
O
M
I
Z
E
Arm A: Enzalutamide (n=17)
Arm B: Enzalutamide + PSA-TRICOM (n=17)
Cohort 1
Arm A: Enzalutamide (n=17)
Arm B: Enzalutamide + PSA-TRICOM (n=17)


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6
TABLE OF CONTENTS
SUMMARY OF CHANGES.........................................................Error! Bookmark not defined.
PRÉCIS............................................................................................................................................3
TABLE OF CONTENTS.................................................................................................................6
1
INTRODUCTION .............................................................................................................11
1.1
Study Objectives ....................................................................................................11
1.1.1
Primary.......................................................................................................11
1.1.2
Secondary...................................................................................................11
1.2
Background and Rationale.....................................................................................11
1.2.1
Enzalutamide..............................................................................................11
1.2.2
Therapeutic Cancer Vaccines in Prostate Cancer ......................................13
1.2.3
PSA-TRICOM ...........................................................................................14
1.2.4
Rationale for Combining Enzalutamide with PSA-TRICOM ...................15
1.2.5
Combining Androgen Receptor Antagonists with PSA-TRICOM, 
clinical evidence.........................................................................................16
 
................................................16
1.2.6
Enzalutamide’s Immune Effects in Preclinical Models.............................16
1.2.7
Rationale for conducting the study in nmCSPC patients...........................18
1.2.8
The Importance of Evaluating the Immunologic Response.......................18
1.2.9
Change in regrowth rate as endpoint .........................................................19
1.2.10 Tumor Growth Kinetics .............................................................................21
1.2.11 Rationale for Re-Treatment of Patients with a Second Course of 
Enzalutamide..............................................................................................22
1.2.12 Rationale for Evaluating Changes in Testosterone and Related 
Hormone Levels.........................................................................................22
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT....................................................23
2.1
Eligibility Criteria..................................................................................................23
2.1.1
Inclusion Criteria .......................................................................................23
2.1.2
Exclusion Criteria ......................................................................................24
2.1.3
Recruitment Strategies...............................................................................26
2.2
Screening Evaluation .............................................................................................26
2.3
Registration Procedures .........................................................................................26
2.4
Treatment Assignment and Randomization/Stratification Procedures..................26
2.5
Baseline Evaluation ...............................................................................................27


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3 
STUDY IMPLEMENTATION .........................................................................................27 
3.1 
Study Design..........................................................................................................27 
3.1.1 Protocol Stopping Rules ............................................................................28 
3.2 
Drug Administration..............................................................................................29 
3.3 
Treatment Modifications........................................................................................29 
3.3.1 Vaccine ......................................................................................................29 
3.3.2 Enzalutamide..............................................................................................30 
3.4 
Protocol Evaluation (see Appendix C ) .................................................................30 
3.4.1 All patients who are deemed eligible and who sign an informed 
consent will be enrolled in this trial...........................................................30 
3.4.2 A complete history and physical examination, including ECOG 
performance status, will be done within 16 days before enrollment. ........30 
3.4.3 Laboratory Studies.....................................................................................30 
3.4.4 Radiographic assessment ...........................................................................31 
3.4.5 Assessment for PSA-TRICOM administration (Arm B)...........................31 
3.5 
Concurrent Therapies.............................................................................................31 
3.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria....................31 
3.6.1 Criteria for removal from protocol therapy ...............................................31 
3.6.2 Off-Study Criteria......................................................................................32 
3.6.3 Off Protocol Therapy and Off-Study Procedure........................................32 
3.7 
Post-Study Evaluation (Follow-Up) ......................................................................32 
4 
BIOSPECIMEN COLLECTION.......................................................................................32 
4.1 
Correlative Studies for Research ...........................................................................32 
4.1.1 Immunologic Parameters ...........................................................................32 
4.1.2 Collection of Research (Immunologic) Blood Samples ............................33 
4.1.3 Immunologic Assays..................................................................................34 
4.1.4 Additional Assays ......................................................................................35 
4.1.5 Plasma VEGF levels ..................................................................................36 
4.1.6 Serum Analysis ..........................................................................................36 
4.2 
Storage and Tracking of Collected Blood Samples ...............................................37 
4.2.1 Protocol Completion/Sample Destruction .................................................38 
5 
SUPPORTIVE CARE........................................................................................................38 
5.1 
Excluded medications............................................................................................39 
5.2 
Treatment of vaccinia vaccination complication...................................................39 
5.2.1 Vaccinia Immune Globulin:.......................................................................39 
5.2.2 Cidofovir (Vistide®, Gilead Sciences):.....................................................40 
6 
DATA COLLECTION AND EVALUATION..................................................................40 
6.1 
Data Collection ......................................................................................................40 
6.1.1 Eligible patients must be confirmed and checklist completed. 
Consent form must be signed prior to registration with Central 
Registration Information Services. ............................................................40 
6.1.2 Data will be secured in NCI C3D database.  Data will be collected 
using protocol-specific case report forms, and verified for accuracy 


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8
and completeness.  Hard copies of data will be stored in locked 
secured areas and data will be entered onto a secured electronic 
data base. The following protocol-specific study forms will be 
complete and stored: eligibility checklist (developed by Central 
Registration Office, CRO). A copy of all serious AE forms will be 
kept in the research record.........................................................................40 
6.1.3 Treatment is given according to protocol (dated notes about doses 
given, complications, and clinical outcomes)............................................40 
6.1.4 Toxicity is assessed according to protocol (laboratory report slips, 
etc.).............................................................................................................40 
6.1.5 Response is assessed according to protocol (X-ray, scan, lab 
reports, and date noted on clinical assessment, as appropriate).................40 
6.1.6 Drug Accountability Records are kept for each patient.............................40 
6.1.7 We will not report Grade 1 adverse events................................................40 
6.2 
Response Criteria...................................................................................................41 
6.2.1 Disease Progression ...................................................................................41 
6.3 
Toxicity Criteria.....................................................................................................42 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY 
MONITORING PLAN ......................................................................................................42 
7.1 
Definitions..............................................................................................................42 
7.1.1 Adverse Event............................................................................................42 
7.1.2 Suspected adverse reaction ........................................................................42 
7.1.3 Unexpected adverse reaction .....................................................................42 
7.1.4 Serious........................................................................................................43 
7.1.5 Serious Adverse Event...............................................................................43 
7.1.6 Disability....................................................................................................43 
7.1.7 Life-threatening adverse drug experience..................................................43 
7.1.8 Protocol Deviation (NIH Definition).........................................................43 
7.1.9 Non-compliance (NIH Definition).............................................................43 
7.1.10 Unanticipated Problem...............................................................................43 
7.2 
NCI-IRB and Clinical Director Reporting.............................................................44 
7.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated 
Problems and Deaths..................................................................................44 
7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review..............44 
7.2.3 NCI-IRB Reporting of IND Safety Reports...............................................44 
7.3 
IND Sponsor Reporting Criteria............................................................................45 
7.3.1 Reporting Pregnancy..................................................................................45 
7.4 
Safety Reporting Criteria to the Pharmaceutical Collaborators.............................45 
7.4.1 Reporting to Astellas..................................................................................45 
7.4.2 Reporting to Bavarian Nordic, Inc.............................................................46 
7.5 
Institutional Biosafety Committee (IBC) Reporting Criteria.................................46 
7.5.1 Serious Adverse Event Reports to OSP/IBC .............................................46 
7.5.2 Annual Reports to IBC...............................................................................46 
7.6 
Data and Safety Monitoring Plan...........................................................................47 
7.6.1 Principal Investigator/Research Team .......................................................47 


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9
7.6.2 Sponsor Monitoring Plan...........................................................................48 
8 
STATISTICAL CONSIDERATIONS...............................................................................48 
8.1.1 Cohort 1 .....................................................................................................48 
8.1.2 Halting Rules .............................................................................................49 
8.1.3 The regression-growth equation ................................................................49 
8.1.4 Data Analysis.............................................................................................49 
9 
COLLABORATIVE AGREEMENTS..............................................................................50 
9.1 
Agreement Type.....................................................................................................50 
9.1.1 Cooperative Research and Development Agreement (CRADA)...............50 
9.1.2 Material Transfer Agreement (MTA)........................................................50 
10 
HUMAN SUBJECT PROTECTIONS ..............................................................................51 
10.1 
Rationale for Subject Selection..............................................................................51 
10.1.1 Selection Based on Gender, Ethnicity, and Race.......................................51 
10.1.2 Strategies/Procedures for Recruitment ......................................................51 
10.1.3 Justification for Exclusions........................................................................51 
10.2 
Participation of Children........................................................................................51 
10.3 
Participation of NIH Subjects Unable to Give Consent.........................................51 
10.4 
Evaluation of Benefits/Risks/Discomforts.............................................................52 
10.4.1 Alternative Approaches or Treatments ......................................................52 
10.4.2 Procedures to Eliminate or Minimize Potential Risks...............................52 
10.4.3 Provisions for Monitoring Data Collection to Ensure Subject 
Safety 52 
10.5 
Risks/Benefits Analysis .........................................................................................52 
10.6 
Consent and Assent Process and Documentation..................................................53 
10.6.1 Telephone Re-Consent Procedure..............................................................53 
10.6.2 Informed Consent of Non-English Speaking Subjects ..............................53 
11 
PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION...........54 
11.1 
Recombinant Fowlpox-PSA(L155)/TRICOM...................................................54 
11.1.1 How Supplied.............................................................................................54 
11.1.2 Preparation.................................................................................................55 
11.1.3 Storage .......................................................................................................55 
11.1.4 Stability......................................................................................................55 
11.1.5 Route of Administration ............................................................................55 
11.1.6 Special Handling........................................................................................55 
11.2 
Recombinant Vaccinia-PSA(L155)/TRICOM...................................................57 
11.2.1 How Supplied.............................................................................................58 
11.2.2 Preparation.................................................................................................58 
11.2.3 Storage .......................................................................................................58 
11.2.4 Stability......................................................................................................58 
11.2.5 Route of Administration ............................................................................58 
11.2.6 Special Handling and Precautions .............................................................58 
11.3 
Cidofovir (Vistide®, Gilead Sciences)..................................................................68 


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10
11.4 
Enzalutamide..........................................................................................................68 
11.4.1 Description and formulation ......................................................................68 
11.4.2 Source 68 
11.4.3 Storage .......................................................................................................68 
11.4.4 Stability......................................................................................................68 
11.4.5 Dosage and Administration........................................................................69 
11.4.6 Adverse Effects..........................................................................................69 
11.4.7 Drug Interactions .......................................................................................70 
12 
REFERENCES ..................................................................................................................71 
13 
Appendix A: Performance Status Criteria .........................................................................76 
14 
Appendix B: Vaccinia-PSA(L155)/TRICOM Patient Instruction Sheet...........................77 
15 
Appendix C : On Study and Follow-Up Evaluations.........................................................80 
16 
Appendix D: Instructions for Pre-Study and Follow-Up Blood Tests...............................88 


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11
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary
1.1.1.1
Determine if PROSTVAC-V/F combined with the novel ARA enzalutamide will result
in a decrease in PSA growth kinetics after enzalutamide discontinuation in patients with 
non-metastatic, castration sensitive prostate cancer (i.e. patients with normal 
testosterone).
1.1.2
Secondary 
1.1.2.1
Determine the impact of enzalutamide on PSA as a single agent in patients with normal 
testosterone and non-metastatic, castration sensitive prostate cancer
1.1.2.2
Evaluate the immune response in patients treated with both the combination of PSA-
TRICOM and enzalutamide compared to enzalutamide alone. Immune response 
evaluation will include CD4 cells, CD 8 cells, PSA-specific T-cells, natural killer cells, 
Regulatory T-cells, cytokines, anti-glycan antibodies and naïve thymic emigrants.
1.1.2.3
Associate immunologic outcomes with PSA responses. 
1.1.2.4
Evaluate the toxicity of enzalutamide and PSA-TRICOM combination in Arm B and 
compare to enzalutamide alone in Arm A.
1.1.2.5
Evaluate PSA responses to a second 3-month course of enzalutamide in patients eligible 
for re-treatment based on the protocol.
1.1.2.6
Evaluate changes in testosterone and related hormone levels and each follow up visit, 
and pre-Enzalutamide administration, and 1 hour post, 24 hours post, 48 hours post, and 
72 hours post administration, when logistically feasible. 
1.1.2.7
Evaluate plasma VEGF levels at the start and end of each patient’s second 12-week 
course of Enzalutamide.
1.1.2.8
Evaluate the immune response in patients treated with enzalutamide at 80 mg/day.
Immune response evaluation will include CD4 cells, CD 8 cells, PSA-specific T-cells, 
natural killer cells, Regulatory T-cells, cytokines, anti-glycan antibodies and naïve 
thymic emigrants.
1.2
BACKGROUND AND RATIONALE
1.2.1
Enzalutamide
Enzalutamide is a modern update of the original androgen receptor antagonists (ARAs),
the last of which was developed over 2 decades ago. Since then, the prevailing focus shifted to 
chemotherapy and chemotherapy combinations (1). In addition to binding to the androgen 
receptor with greater affinity than standard ARAs, enzalutamide prevents downstream effects 
including nuclear translocation, DNA binding, and signaling to co-activators (2). Furthermore, 
enzalutamide has not demonstrated any agonist properties unlike previous ARAs which showed 
agonist properties in approximately 15%-20% of patients (3, 4). (Figure 1). Another important 


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characteristic is that unlike the modern androgen-biosynthesis inhibitor abiraterone, 
enzalutamide does not require daily prednisone.  (Long-term prednisone could have additional 
side effects and could impact the immune response.) The U.S. Food and Drug Administration 
(FDA) approved enzalutamide for metastatic prostate cancer in docetaxel-refractory patients in 
August, 2012 (5).
Figure 1
A Phase I/II study of enzalutamide demonstrated safety and suggested efficacy in both 
chemotherapy-naïve and chemotherapy-treated castration-resistant prostate cancer (CRPC) 
patients, the vast majority of whom had metastatic disease (6).  Two phase III studies were then 
launched in metastatic CRPC (mCRPC). One study enrolled chemotherapy-naïve patients; the 
other (AFFIRM) evaluated patients who had progressive disease on docetaxel.  AFFIRM 
enrolled 1199 patients with progressive mCRPC on docetaxel and randomized them 2:1 to 
enzalutamide 160 mg/day (n=800) or placebo (n=399).  The overall survival favored patients 
randomized to the enzalutamide arm 18.4 to 13.6 months.  This 4.8 months improvement in 
survival represented a 37% risk reduction in death (hazard ratio 0.63; 95% CI: 0.53 to 0.75; 
P<0.001) the largest relative and absolute improvement in overall survival in an appropriately 
powered phase III study in prostate cancer.  Median TTP based on radiographic findings was 8.3 
vs. 2.9 months; HR: 0.40; P<0.001). (Figure 2)   Modest increases in fatigue, hot flashes, 
diarrhea, musculoskeletal pain, and headaches reported in the enzalutamide group, but this was 
possibly related to the substantially longer monitoring time for patients on this treatment 
compared to the placebo group.  Therefore, there were no significant concerns about the side 
effect profile of enzalutamide compared to placebo (7). The U.S. FDA approved enzalutamide 
for chemotherapy-refractory mCRPC patients in August of 2012 (5). The second phase III trial in 
chemotherapy naïve patients is ongoing.


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Figure 2.  Enzalutamide demonstrates improved overall survival in
mCRPC patients previously treated with docetaxel (7).
The ultimate role of enzalutamide in the treatment of prostate cancer will likely be in 
earlier-stage disease. The minimal side effects of enzalutamide in patients with advanced disease 
will create strong interest in providing this therapy for chemotherapy- naïve mCRPC and even 
patients with non-metastatic disease, thus supplanting the use of older ARAs such as 
bicalutamide which are commonly used in non-metastatic patients (8).  Also, unlike the modern 
androgen-biosynthesis inhibitor abiraterone, enzalutamide does not require daily prednisone. 
Enzalutamide therapy will thus avoid prednisone’s potential long-term side effects in earlier 
stage disease, an important consideration for future treatment strategies in this population.   
Combination with immune based therapies is attractive because unlike abiraterone, this treatment 
does not require prednisone which can be immunosuppressive.  In addition, given the data which 
suggest that hormonal therapies can enhance immune response, it would be valuable to gain a 
better understanding of the immune impact of enzalutamide given the emerging role of 
immunotherapy in prostate cancer (9). 
At this time, there is no data for the role of enzalutamide in non-metastatic, castration-
sensitive prostate cancer (nmCSPC) patients with normal testosterone.  (Hereafter in this 
document, nmCSPC will also refer to patients with a normal testosterone and thus presumed 
sensitivity to castration.)  Previously, the first-generation ARA, bicalutamide, has been evaluated 
in the nmCSPC setting as patients and clinicians seek ways to avoid/delay the symptoms 
associated with ADT.  Forty-one patients with nmCSPC were treated with high-dose (150 mg) 
bicalutamide, with a secondary addition of finasteride but no androgen suppression therapy. 
Thirty-four of 36 evaluable patients reached a PSA nadir that represented a decline of PSA by 
95.5%.  The median time to treatment failure was 21.3 months (10).  This time frame was 
consistent with other trials that evaluated high dose bicalutamide in castration-sensitive 
metastatic disease (11).  Based on these findings, the use of single agent enzalutamide in this 
population would be interesting to evaluate given the limited favorable side effect profile and the 
possibility that enzalutamide is more efficacious than bicalutamide.
1.2.2
Therapeutic Cancer Vaccines in Prostate Cancer
The goal of therapeutic cancer vaccines is to generate a targeted immune response leading to 
immune-mediated anti-tumor activity.  Sipuleucel-T is a therapeutic cancer vaccine generated 
from peripheral blood mononuclear cells obtained from individual patients via leukapheresis. 
This vaccine is generated after a patient’s peripheral immune cells are collected via 


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leukapheresis, transported to a regional processing center where they are exposed in vitro to a 
PAP/GM-CSF fusion protein. At the end of this process, the activated cellular product is re-
infused into the patient. A full course of therapy repeats this process 3 times every 2 weeks for 1 
month (12, 13).  A phase III trial (n = 512) demonstrated an overall survival benefit for the 
vaccine (25.8 months vs. 21.7 months; P = 0.032) (14). Based on these overall survival findings, 
the FDA approved sipuleucel-T for the treatment of asymptomatic or minimally symptomatic 
mCRPC, making it the first FDA-approved therapeutic cancer vaccine for the treatment of any 
malignancy. 
1.2.3
PSA-TRICOM
PSA-TRICOM (Prostvac™; developed by the National Cancer Institute [NCI] and licensed to 
Bavarian Nordic, Mountain View, CA), an off-the-shelf therapeutic cancer vaccine, offers an 
alternative strategy (15, 16).  (The LTIB and Bavarian Nordichave an ongoing CRADA for the 
preclinical and clinical development of PSA-TRICOM.)  To target prostate-specific antigen (PSA), 
PSA-TRICOM vaccine employs genetically altered poxviruses to deliver targeting information to 
immune cells and generate an immune response. Administered subcutaneously, the poxviruses deliver 
the transgenes for the tumor associated antigens (PSA) to antigen presenting cells through cellular 
infection. Once these pox viruses are within the cellular cytoplasm, the transgenes are processed. The 
end result is an antigen presenting cell expressing a PSA peptide within the major histocompatibility
complex, resulting in PSA-specific cytolytic T lymphocytes activation (17, 18). (Figure 4) This 
approach does not require expensive, labor-intensive ex vivo preparation of patients’ peripheral blood.
PSA-TRICOM is thus potentially more logistically and financially feasible over the long-term than 
sipuleucel-T (19).
PSA-TRICOM has been investigated in 2 phase II trials in mCRPC, both of which 
administered the vaccine at monthly intervals until disease progression. An industry-sponsored, 
placebo-controlled, multicenter trial in 125 mCRPC patients randomized them 2:1 in favor of 
PSA-TRICOM; the placebo was an empty poxviral vector containing no transgenes. As was seen 
in the sipuleucel-T studies, patients receiving vaccine showed no change in TTP, yet had an 
overall survival benefit (25.1 months with PSA-TRICOM vs. 16.6 months with placebo; P =
0.0061) (20).  (Figure 3) A second phase II study of PSA-TRICOM of 32 mCRPC patients at the 
NCI demonstrated that the vaccine was able to generate a T-cell specific immune response and 
patients with the greatest magnitude of this response had superior outcomes (21). Based on the 
findings in these trials, a phase III trial of PSA-TRICOM in mCRPC is currently underway (22).


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Figure 3. Poxviral vaccine strategy: Modified poxvirus 
contains transgenes for the tumor-associated antigen PSA 
and 3 T-cell costimulatory molecules (16)
Figure 4. PSA-TRICOM improved survival in mCRPC patients in 
a randomized multi center phase II. (20)
Like enzalutamide, PSA-TRICOM is very well-tolerated, with common side effects of grade 1 
injection-site reactions or flu-like symptoms (20, 21). Also like enzalutamide, favorable side 
effect profile and the potential ability to induce a sustained antitumor immune response, clinical 
trials are ongoing evaluating strategies to use PSA-TRICOM in earlier disease patients.
A phase III trial (NCT01322490) of Prostvac monotherapy, however, was reported to have not 
met its primary endpoint of overall survival in September, 2017. Nonetheless, the combination 
of Prostvac and enzalutamide remains scientifically rational and this trial will continue.  
Furthermore, at this point neither this trial nor the phase III trial have suggested a safety concern 
for Prostvac.
1.2.4
Rationale for Combining Enzalutamide with PSA-TRICOM
Accumulating data demonstrate that androgen-deprivation therapy (ADT) affects not 
only prostate cancer growth, but also the immune system and suggest that ADT in prostate 
cancer can augment the immune response by increasing T-cell infiltration into the prostate (9).
The impact of this T-cell trafficking would be even greater if T cells were primed by a vaccine 
prior to ADT (23).  Furthermore, ADT has been shown to decrease immune tolerance of self 
antigens that are over-expressed in many cancers, increase the production of new T-cells from 


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the thymus (Table 1), and enhance the Cytotoxic T-cell repertoire (9, 24-26).   Of the two 
modern anti-androgen therapies for prostate cancer that have emerged in the last few years, 
enzalutamide is preferred over abiraterone, because abiraterone requires prednisone which may 
influence the immune response in a vaccine-based combination regimen.
Baseline
After ADT
Naïve CD4 cells
3.25%            
of CD3+ cells
3.95%            
of CD3+ cells
p = 0.0060
T-Cell Receptor 
Excision Circles
93               
per 100,000 cells
147              
per 100,000 cells
p = 0.0025
Table 1. ADT Increases Naïve T-cell Emigrants from the Thymus. A previous NCI trial 
(NCT00514072) evaluated naïve T-cell emigrants from the thymus after 3 months of ADT.
T-cell receptor excision circles are detectable byproducts of thymic generation of new T-cells and 
provide a way to quantify such cells.  Naïve CD4 cells are defined by flow cytometry as 
described in the correlative studies section below.  By both measures there was a significant 
increase in the number of naïve T-cells which potentially can be activated by vaccine. 
(unpublished)
1.2.5
Combining Androgen Receptor Antagonists with PSA-TRICOM, clinical evidence
An ongoing clinical trial at the NCI is combining PSA-TRICOM with flutamide, an FDA 
approved ARA, in men with non-metastatic CRPC (NCT00450463) .  Patients are randomized to 
either PSA-TRICOM with flutamide or flutamide alone.  The primary endpoint is TTP as 
determined by PSA (Bubley criteria) or development of metastatic disease (28). An interim
analysis with about half the patients accrued demonstrated that these 2 agents can be safely 
combined with minimal toxicity. The interim TTP analysis favored the combination of PSA-
TRICOM and flutamide compared to flutamide alone (192 days vs. 108 days) (29). (Figure 5) The 
study is completing accrual at the NCI and the Cancer Institute of New Jersey, but the interim 
analysis provides a preliminary clinical rationale for the combination of PSA-TRICOM with a 
modern ARA in chemotherapy-naïve patients with mCRPC. The proposed trial in mCRPC will 
use metastatic progression as an endpoint, which is a more established therapeutic measure than 
criteria currently established for nonmetastatic disease (30).
1.2.6
Enzalutamide’s Immune Effects in Preclinical 
Figure 5. Patient Population: “Biochemical 
Recurrence” or Rising PSA after surgery or RT 
with normal testosterone (nmCSPC)


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Models
Enzalutamide has been evaluated preclinically by Dr. James Hodge of the Laboratory of 
Tumor Immunology and Biology (LTIB) at the NCI.  The first objective was to determine the 
appropriate dose to use in evaluation of the male C57BL/6 mice.  Doses at 1, 10, 50 and 100 
mg/day were evaluated and the 10 mg/day dose was found to be most appropriate given that it 
achieved a serum concentration of 20 ug/ml, consistent with serum levels in humans. Therefore,
that was the dose evaluated in male C57BL/6 mice. (Figure 6A) It was confirmed that 
enzalutamide at 10 mg/day had a significant decrease in the weight of the genitourinary organs 
after 14 days of dosing, demonstrating the physiologic effects of enzalutamide at 10 mg/day dose 
level. Figure 6B)
Figure 6. Enzalutamide mediates a reduction in 
genitourinary (GU) weight. (A) Concentration of 
Enzalutamide in plasma of mice on Enzalutamide daily diet.  
Male C57BL/6 mice (n=3) were treated with Enzalutamide at 
different calculated target daily doses (0, 1, 10, 50, and 100mg) 
for 14 days.  On day 15, blood was collected and Enzalutamide
concentration in the plasma was determined. (B) Exposure to 
Enzalutamide causes reduction of GU weight.  Male C57BL/6 
mice (n=7) were not treated (open circles) or treated with 
Enzalutamide (closed circles) for 14 days.  On day 15, mice 
were sacrificed and their GU and were harvested and weighed. 
All experiments were done three times with similar results.  Statistical analyses were done by Student’s t-test
From an immunologic standpoint, complete blood counts and Fluorescence-activated cell sorting 
analysis of immune cell subpopulations were found to be unchanged.  Furthermore, functional 
analysis based on mixed lymphocyte response and CD3-induced proliferation assays of CD4 
cells demonstrated no significant differences.  In addition, similar to previous studies with 
hormonal therapies, enzalutamide treatment was associated with increased thymic weights and 
increased T-cell excision circles, consistent with the production of new T-cells from the thymus. 
(Figure 7) This series of experiments (publication pending) provides evidence that enzalutamide
likely will not diminish the quantity or functionality of immune cells and may even enhance 
thymic production of naïve T-cells, allowing for potential immune stimulation by a therapeutic 
cancer vaccine such as PSA-TRICOM. 
Figure 7. A. Enzalutamide mediates an enlargement of 
thymus and an increase in T-cell Receptor Excision Circles 
(TREC) levels.  (A). Male C57BL/6 mice (n=7) were not 
treated (open circles) or treated with Enzalutamide (closed 
circles) for 14 days.  On day 15, mice were sacrificed, and 
their thymi harvested and weighed.  (B).
Enzalutamide
significantly increases T-cell Excision Circle (TREC) 
levels in male mice.  Male C57BL/6 mice (n=7) were not 
treated (open circles) or treated with Enzalutamide (closed 
circles) for 14 days.  On day 15, 100ng of DNA from blood 
was collected and TREC levels were quantified by RT-PCR 
in triplicate.  Results were normalized against the constant gene segment of TCRA, which serves as endogenous 
reference gene.  All experiments were done three times with similar results.  Statistical analyses were done by 
Student’s t-test


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1.2.7
Rationale for conducting the study in nmCSPC patients
The standard of care for patients with nmCSPC includes ADT and active surveillance.  
Generally, these patients can be followed without therapy until their PSA doubling time escalates 
at which time ADT is often started.  All patients in the proposed trial will receive enzalutamide.  
Based on previous trials with high dose bicalutamide, 34 of 36 evaluable patients had PSA 
declines by a median of 96.5% and these nadirs were achieved within the first 4 weeks of 
treatment (10). We would expect similar if not better results with enzalutamide.  Therefore, a
clinical trial in this population is ethical and appropriate.  The NCI has conducted several trials in 
this population previously.  
This population will also offer unique opportunity to evaluate the independent impact (in 
the absence of ADT) of enzalutamide on both PSA as well as the immune system.  Much like 
previous studies with high-dose bicalutamide in this population, similar trials are likely to be 
done to see if disease control with enzalutamide is possible in nmCSPC, with less side effects 
relative to ADT (10).
Given the previous experience with high dose bicalutamide in this population, a study 
with time to progression as an end point with continuous enzalutamide would be expected to take 
well over 2 years (10).  We feel that using a short course of enzalutamide therapy of 3 months we 
can assess the immunologic impact and determine the impact of vaccine on tumor re-growth 
rates.  Therefore, for practical considerations (number of patients required and length of time to 
conduct the trial with a clinical progression endpoint) this trial will be conducted over a
minimum of 6-12 months, including a 3 month course of therapy of enzalutamide.
This proposed brief 3 month enzalutamide course of therapy is consistent with a standard 
approach of intermittent ADT (36, 37).  In the intermittent ADT approach in nmCSPC, one or 
two doses of ADT are given and then PSA is followed for recovery at which time subsequent 
ADT dosing is considered.  The same intermittent strategy will be done in this trial, substituting 
enzalutamide for ADT.  Furthermore, this population allows for the unique opportunity to follow 
PSA/tumor re-growth rate/recovery once a standard therapy is discontinued.  Consistent with 
common clinical practice no immediate re-treatment will be required in the months following 
discontinuation of enzalutamide.  Patients would be started on ADT as clinically appropriate, as 
suggested by their PSA doubling time.  
1.2.8
The Importance of Evaluating the Immunologic Response
Our group at in the LTIB has previously evaluated immunologic parameters in clinical 
trials with PSA-TRICOM among several immunotherapy studies.  A previous trial in mCRPC 
patients with PSA-TRICOM alone suggested that patients with greatest magnitude of T-cell-
specific response against PSA had favorable clinical outcomes (21).  That same trial also 
suggested that changes in regulatory T-cell function were also associated with improved clinical 
outcomes (38).  While the these findings are not surrogate markers of response, they have 
improved our knowledge of a vaccine-generated immune response and provided a better 
understanding of what factors are potentially important in mounting a sufficient anti-tumor 
immune response that could be associated with improved clinical outcomes.  These and other 
data have allowed us to optimize vaccines in subsequent clinical trials.
Similarly, immunologic parameters will be valuable in understanding the benefits of 
PSA-TRICOM with enzalutamide.  Are the same associations seen or other changes in natural 
killer cells or cytokines of greater importance in this combination?  Furthermore, baseline 


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immune characteristics will be evaluated to determine if they have the potential to predict 
responders or likely non-responders to immune combinations.  While this hypothesis generating 
data would have to be prospectively evaluated in future clinical trials, it may improve our 
understanding about how best to deploy vaccines in combination with enzalutamide and other 
forms of hormonal therapy.  If enzalutamide increases naïve T-cell production from the thymus 
as suggested by the pre-clinical data, this may have important ramifications in the timing of 
vaccine in future clinical trials. This and other data may also provide information early on in the 
therapeutic regimen about which patients would benefit from continued vaccine in combination 
with enzalutamide. 
It will also be of great importance to understand what the immunologic impact is of 
enzalutamide alone.  New data from commonly used cytotoxic agents has suggested that some 
chemotherapy agents can enhance anti-tumor immune responses (34, 39).  With this new 
understanding, clinical trials are being design to exploit this aspect of these respective therapies.  
Enzalutamide and other modern androgen receptor-targeting agents will be the mainstay of 
prostate cancer therapy for the foreseeable future.  Future trials are likely to evaluate 
enzalutamide monotherapy in men with nmCSPC and this trial will be able to evaluate the 
specific immunologic impact of enzalutamide in men with normal testosterone levels.  With 
sipuleucel-T already approved and ipilimumab and PSA-TRICOM in phase III testing, it is likely 
that immunologic optimization will be important in the future treatments of prostate cancer.  Few 
groups are as well positioned and have the experience as the LTIB to conduct this rigorous 
immune testing from clinical samples of patients treated with enzalutamide to gain a better 
understanding about its immune properties. 
1.2.9
Change in regrowth rate as endpoint
Although vaccines have improved overall survival in mCRPC, they have not been shown 
to change short term TTP when used as monotherapy.  Interestingly, similar findings were also 
seen with ipilumimab in melanoma (40).  Although this is not what is customarily seen with 
cancer treatments, it may be a characteristic of modern immune therapeutics (41).  An emerging 
mechanism to evaluate tumor growth rates using mathematical models may provide additional 
insight into this phenomenon(42, 43).    In a recent review of 5 NCI mCRPC trials including a 
vaccine trial, there appeared to be a sustained decrease in tumor growth rate in vaccine patients 
as compared to those treated with chemotherapy, who had transient reductions in tumor size, but 
then growth rate resumed at the same pre-treatment rate once cytotoxic therapy was 
discontinued. (44) This data suggests that a vaccine induced immune response may not decrease 
tumor size (or change TTP) but may lead to altered tumor growth rates which could have more 
substantial impact on overall survival (41). (See Figure 9)


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Figure 8. PSA-TRICOM can affect growth rate in 80 days.  An analysis of the ECOG trial 9802, 
which treated castration-sensitive non-metastatic prostate cancer patients (n=29) suggests PSA-
TRICOM alters tumor growth rate, as measured by PSA (log g (growth rate) +/- SE (standard 
error)), within 80 to100 days.(45) This retrospective analysis used the tumor growth rate equation 
(44) determined that by day 80 after PSA-TRICOM therapy was initiated a statistically significant 
change in tumor growth rate was detectable compared to baseline.  This altered growth rate was 
sustained at day 100 as well.  These data supports the hypothesis that vaccines exert their therapeutic 
effect not by reducing tumor burden, but by altering tumor growth rate. 
Furthermore, unpublished data from an ECOG PSA-TRICOM trial in non-metastatic 
prostate cancer demonstrated a reduced growth rate within 100 days of vaccine initiation (45).
(Figure 8) Similarly, Sipuleucel-T has significantly prolonged PSA doubling time (another way 
to measure growth rate) after initial hormonal therapy in the same patient population (46).
Together, these data suggest that vaccine can impact growth rate in the nmCSPC population 
within 80 to 100 days.  Furthermore, for patients getting combination therapy, disease can be 
controlled by standard therapies in the short term, while vaccines may impact tumor re-growth 
rates in the long term, ultimately resulting in prolonged TTP compared to standard therapy alone, 
(Figure 10).
This trial will provide an opportunity to prospectively define the mechanism by which 
vaccines in combination with standard therapies can result in TTP benefit compared to that same 
standard therapy alone.  By discontinuing the enzalutamide after 3 months and allowing PSA 
values to recover to baseline, we will have the opportunity to determine if a vaccine-mediated 
immune response can alter that tumor re-growth rate.  As demonstrated by Drs. Fojo and Stein 
previously, 80-100 days is sufficient time to calculate a meaningful change in growth rate in 
patients with nmCSPC. (Figure 8)
If this study can prospectively demonstrate a difference, measured by one standard 
deviation in tumor re-growth rate, it would provide an important proof of concept for the 
mechanism by which vaccines may improve standard therapies.  Furthermore, it would better 
define the potential role of vaccines (as part of a therapeutic combination) in the treatment of 
prostate cancer and other malignancies.


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1.2.10 Tumor Growth Kinetics
1.2.10.1 The regression-growth equation
Drs. Stein and Fojo at the NCI have developed an equation based on the assumption that 
the change of a tumor's quantity during therapy results from 2 independent component processes: 
an exponential (first-order kinetics) decrease/regression and an exponential regrowth of the tumor. 
(44)
The equation is f(t) = exp(-d * t)+exp(g * t) - 1 (A) where exp is the base of the natural 
logarithm, e = 2.7182, and f(t) is the tumor (or in MTC calcitonin) measurement at time t in days, 
normalized to (divided by) the tumor measurement at day 0, the time at which treatment is 
commenced. Rate constant d (decay, in daysí) represents the exponential decrease/regression of 
the serum tumor marker (i.e. PSA) signal during therapy. Rate constant g (growth, also in daysí)
represents the exponential growth/regrowth of the tumor during treatment. These rate constants 
may be expressed in terms of half-lives and doubling times. Thus, d equals ln2 (0.693) divided by 
the time it takes for the regressing part to shrink by half, whereas g equals ln2 divided by the time 
for the growing component to double. (44)
Two earlier papers depict theoretical curves depicting the separate components of Equation 
(A) and how these combine together to give the time dependence of the tumor size,  f. (44)
When the data showed a continuous decrease from the time of treatment start, so that only the 
regression parameter d was found to differ significantly from zero with P < 0.05, Equation (A) 
was replaced by the following reduced form, with the growth rate constant eliminated: f(t) = 
exp(-d * t) (B) When tumor measurements showed a continuous increase, so that only the growth 
parameter g was found to differ significantly from zero with P < 0.05, Equation (A) was replaced 
by the following reduced form, with the decay constant eliminated: f(t) = exp(g *t) .
1.2.10.2 Data Analysis  
For each patient an attempt to fit Equation (A) to each data set for which more than one 
data point is available. Curve fitting will be performed using Sigmaplot (Systat Software), or by 
using the Solver routine in an Excel spreadsheet. We will extract parameters g and d with their 
associated Student's t and P values. (44)
Data will be analyzed in Excel (Microsoft) and in 
Sigmaplot 9.0. Linear regressions to evaluate the relationship between the growth rate constant, g,
or other parameters will be implemented using the polynomial linear routine of Sigmaplot 9.0. 
Sample comparisons were performed by Student's t-test, using SigmaStat 3.5 (Systat Software), 
with P set at 0.05 for significance. (44)
Figure 9.  Enhanced Efficacy with Enzalutamide.  
Enzalutamide has greater androgen receptor (AR) binding 
affinity and a greater negative impact on AR nuclear 
import than bicalutamide with Dihydrotestosterone (DHT) 
as a control.  In addition with enzalutamide there is no AR 
binding with the DNA and coactivatior receruitment.  (2)


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1.2.11 Rationale for Re-Treatment of Patients with a Second Course of Enzalutamide
As previously stated, there is no standard of care for patients with nmCSPC.   Given that 20-40% 
of patients diagnosed each year with prostate cancer (over 250,000 men in the US alone) have 
recurrent disease after definitive therapy, this makes up a large population of patients.  The 
standard of care for patients with nmCSPC includes ADT and active surveillance.  Generally,
these patients can be followed without therapy until their PSA doubling time escalates at which 
time ADT is often started.  ADT can be given continuously or intermittently, i.e. 2-3 doses of 
ADT to suppress PSA, and then allow for PSA recovery.  Once PSA has recovered ADT can be 
resumed for an intermittent basis based on PSA metrics and continued castration sensitive 
disease.  A large study of intermittent vs. continuous ADT in this population of patients has 
demonstrated that intermittent ADT was non-inferior to continuous ADT in terms of overall 
survival.  Also there were improvements in quality of life factors in patients treated with 
intermittent ADT. 49
Given that this trial will explore the short term benefits of a brief course of enzalutamide for 3 
months, it may be prudent to evaluate if this treatment could be given for a second course and 
induce a second, sustained PSA decline.  From a broad prostate cancer perspective, this would be 
valuable information moving forward if future larger trials would be considered to evaluate
enzalutamide as possible alternative form of intermittent anti-androgen therapy.  Such a therapy 
may be preferred over (intermittent) ADT from a quality of life perspective. 
1.2.12 Rationale for Evaluating Changes in Testosterone and Related Hormone Levels
Enzalutamide, an androgen receptor inhibitor, differs from traditional androgen deprivation 
therapy in its ability to inhibit the androgen receptor without lowering testosterone and is 
associated with an overall increase in testosterone levels. Consequently, enzalutamide and other 
non-steroidal antiandrogens have a different side effect profile. A recent European study 
evaluated Enzalutamide monotherapy in hormone-naïve prostate cancer, and examined a series 
of hormone levels at various time points in administration to determine changes in testosterone 
and testosterone related hormones.50 While they found increased levels of testosterone, estradiol, 
and luteinizing hormone, levels were checked until the 25 week time point and only once 
thereafter. 
We seek to further elucidate this mechanism of action by obtaining hormone levels at each 
follow up visit, as well as pre-Enzalutamide, 1 hour post, 24 hours post, 48 hours post, and 72 
hours post administration, when logistically feasible.  Dr. Doug Figg’s lab is currently evaluating 
a murine model to demonstrate the presence of androgen receptors in the hypothalamus which 
may influence the levels of testosterone and related hormones in the serum. This pre-clinical data 
can also be correlated with clinical informatics that will be obtained with these serial hormonal 
levels.
1.2.12.1 Evaluating Immunologic Effects of Low Dose Enzalutamide
Patients from the arm receiving enzalutamide alone (160 mg daily for 84 days, without ADT) 
have been assessed for immunologic impact from cohort 1. Peripheral blood mononuclear cells 


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23
(PBMCs) collected from 12 patients pre and post enzalutamide (days 14, 28, 84, and 100) were
analyzed by flow cytometry to identify 123 immune cell subsets, including 9 standard subsets 
(CD4+ and CD8+ T cells, T-regulatory cells (Treg), B cells, conventional and plasmacytoid 
dendritic cells (cDC, pDC), natural killer cells (NK), natural killer T cells (NKT), and myeloid 
derived suppressor cell (MDSC)), and 114 subsets relating to maturation and function. PBMCs 
were also assessed for TREC to identify recent thymic emigrants, and by microarray to 
determine changes in global gene expression.  
Treatment with enzalutamide induced several notable alterations in peripheral immune cells, 
suggesting that it has potential immune activating properties. These changes occurred early 
following treatment, and included an increase of NK cells, decreased frequencies of MDSCs 
with a suppressive phenotype (e.g. PD-L1+ MDSC, gMDSC, and CD16+ MDSC), and decreased 
frequencies of both CD4+ and CD8+ T-lymphocytes expressing the immune inhibitory 
checkpoint molecule CTLA4. 
Additionally, treatment with enzalutamide increased TREC levels by >75% in 7 out of 12 
patients compared to pre-therapy levels (p=0.012); naïve CD4+and CD8+ T-lymphocytes were 
also elevated by >25% in those patients demonstrating the greatest increase in TREC. Gene
expression analysis of PBMCs corroborated these findings, showing that enzalutamide increased 
activation of interferon-gamma signalingand related immune activating pathways.
These preliminary findings demonstrate that short-course enzalutamide has immune activating 
properties in cancer patients, and support the combination of enzalutamide with immunotherapy.
Since the immunologic effects are likely separate from just blocking AR (based on preclinical 
data serving as the rationale for this study) it would be prudent to explore the immunologic 
impact of lower doses of enzalutamide (i.e. 80 mg) to determine if the immune impact is 
preserved, while also limiting the toxicity seen with enzalutamide alone at 160 mg/day.  
Although enzalutamide is well tolerated, fatigue and breast tenderness in men were frequently 
seen and could limit its use (independent of ADT) as an immune adjuvant.  It is likely these side 
effects can be minimized at a lower dose.  If this can be accomplished at a lower dose, it is more 
likely to lead to the use of enzalutamide as a possible immunologic adjuvant in other diseases 
where immune therapies are now approved including lung cancer, bladder cancer, melanoma, 
and renal cancer.
We planned a study to explore the immunologic effects in biochemically recurrent prostate 
cancer of enzalutamide 80 mg/day for 3 months.  The data were to have been compared against 
the existing immune data described above with enzalutamide at 160 mg/day for 3 months,
however this cohort was closed before enrollment due to lack of patient interest in participation
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
A. Histopathological documentation of prostate cancer confirmed in the 
Laboratory of Pathology at the National Institutes of Health (NIH) Clinical 


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24
Center, or Walter Reed National Military Medical Center prior to enrollment. 
If no pathologic specimen is available, patients may enroll with a pathologist’s 
report showing a histologic diagnosis of prostate cancer and a clinical course 
consistent with the disease. 
B.  Biochemical progression defined as follows:
x
For patients following definitive radiation therapy: DULVHLQ36$RI
ng/mL above the nadir (per RTOG-ASTRO consensus criteria). 
x
For patients following radical prostatectomy: rising PSA after surgical 
procedure. (Patients must have a PSA >2ng/ml)
C.  ECOG performance status of 0–1 (Karnofsky >80%, see Appendix A).
D. Patients must have a PSA doubling time of 12 months or less.
E.  Patients must have a rising PSA as confirmed by 3 values done at least 1 week 
apart and over no less than 1 month.
F.  Recovery from acute toxicity related to prior therapy, including surgery and 
UDGLDWLRQRUQRWR[LFLW\JUDGH
G. Negative CT scan/MRI and bone scan for metastatic prostate cancer.
H. Hematological eligibility parameters (within 16 days before starting therapy; 
see Appendix D):
x
*UDQXORF\WHFRXQW000/mm3
x
3ODWHOHWFRXQWPP3
x
+JEg/dL
I. Biochemical eligibility parameters (within 16 days before starting therapy):
x
+HSDWLFIXQFWLRQELOLUXELQPJG/25LQSDWLHQWVZLWK
*LOEHUW¶VV\QGURPHDWRWDOELOLUXELQ$67DQG$/7
times upper limit of normal.
J.
No other active malignancies within the past 36 months (with the exception of 
nonmelanoma skin cancers or carcinoma in situ of the bladder) or life-
threatening illnesses
K.   Willing to travel to the NIH for follow-up visits.
L. 18 years of age or older. 
M. Able to understand and sign informed consent.
N. %DVHOLQHWHVWRVWHURQHORZHUOLPLWRIQRUPDO.
O. 36$QJP/
P. The effects of enzalutamide, PSA-TRICOM or the combination on the 
developing human fetus are unknown. For this reason, men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry and for the duration of study participation.  Should a woman 
become pregnant or suspect she is pregnant while her partner is participating in 
this study, she should inform her treating physician immediately.
2.1.2
Exclusion Criteria
A. Immunocompromised status due to:
x
Human immunodeficiency virus (HIV) positivity.


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25
x
Active autoimmune diseases such as Addison's disease, Hashimoto's 
thyroiditis, systemic lupus erythematosus, Sjogren syndrome, scleroderma, 
myasthenia gravis, Goodpasture syndrome or active Grave's disease. 
Patients with a history of autoimmunity that has not required systemic 
immunosuppressive therapy or does not threaten vital organ function 
including CNS, heart, lungs, kidneys, skin, and GI tract will be allowed.
x
Other immunodeficiency diseases
B. Chronic administration (defined as daily or every other day for continued use 
> 14 days) of corticosteroids deemed systemic by investigator within 28 days 
before the first planned dose of PSA-TRICOM. Use of inhaled steroids, nasal 
sprays, and topical creams for small body areas is allowed.
C. Serious intercurrent medical illness that, in the judgment of the investigator,
would interfere with patient’s ability to carry out the treatment program.
D. History of seizure, including any febrile seizure, loss of consciousness, or 
transient ischemic attack, or any condition that may pre-dispose to seizure 
(e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of 
consciousness requiring hospitalization).
E. Other medications used for urinary symptoms including 5-alpha reductase 
inhibitors (finasteride and dutasteride) and alternative medications known to 
alter PSA (eg phytoestrogens and saw palmetto)
F. History of prior chemotherapy 
G. History of prior immunotherapy within the last 3 years
H. Major surgery within 4 weeks prior to enrollment (Day 1 visit).
I.
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to enzalutamide or poxviral vaccines (e.g., vaccinia 
vaccine)
J.
Known allergy to eggs, egg products, aminoglycoside antibiotics (for 
example, gentamicin or tobramycin).
K. History of atopic dermatitis or active skin condition (acute, chronic, 
exfoliative) that disrupts the epidermis
L. Previous serious adverse reactions to smallpox vaccination
M. Unable to avoid close contact or household contact with the following high-
ULVNLQGLYLGXDOVIRUWKUHHZHHNVDIWHUWKH'D\YDFFLQDWLRQDFKLOGUHQ
years of age, (b) pregnant or nursing women, (c) individuals with prior or 
concurrent extensive eczema or other eczemoid skin disorders, or (d) 
immunocompromised individuals, such as those with HIV.
N. Receipt of an investigational agent within 30 days (or 60 days for an antibody-
based therapy) before the first planned dose of study drugs.
O. Patients who test positive for HBV or HCV
P. Use of herbal products that may decrease PSA levels (e.g. saw palmetto)  
Q. Any gastrointestinal disease that could hinder the absorption of enzalutamide
R. Uncontrolled hypertension (SBP>170/ DBP>105)


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26
2.1.3
Recruitment Strategies
This study will be listed on available websites (www.clinicaltrials.gov,
https://ccr.cancer.gov/clinical-trials-search-start ) and participants will be recruited from the 
current patient population at NIH.
2.2
SCREENING EVALUATION
A. Pathological confirmation of diagnosis by the Laboratory of Pathology, CC, NIH, or 
Walter Reed National Military Medical Center (if specimen is available) may be 
obtained anytime prior to enrollment.
B. The following parameters will be obtained within 8 weeks prior to start of enrollment:
1. HIV test
2. Hepatitis B and C
3. Tc-99 whole-body scintigraphy
4. CT (or MRI may be substituted at investigator’s discretion) of chest, abdomen 
and pelvis
2.3
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of receiving a signed consent. A registration Eligibility Checklist from the web 
site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents. When relevant, treatment assignment is conveyed to the Pharmacy at the 
same time. Verification of Registration will be forwarded electronically via e-mail to the 
research team. A recorder is available during non-working hours.
2.4
TREATMENT ASSIGNMENT AND RANDOMIZATION/STRATIFICATION PROCEDURES
Cohorts
Number
Name
Description
1
Cohort 1
Patients with nonmetastatic castration sensitive prostate cancer 
Arms
Letter
Name
Description
A
Standard dose enzalutamide 
alone
Enzalutamide alone administered at the standard dose (160 mg 
daily)
B
Enzalutamide with PSA-
TRICOM
Standard dose enzalutamide with concomitant vaccinia-PSA-
TRICOM and then fowlpox-vaccine
Stratifications


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27
Name
Distinct Options
Notes
PSA doubling time less 
than 6 months 
Yes
No
Randomization and Arm Assignment 
After confirmation of eligibility at Central Registration Office (CRO), patients in cohort 1 will be 
randomized on a 1:1 basis between arms A and B, stratifying for PSA doubling time using a
computerized randomization process.
CRO staff will send a secured e-mail to Principal Investigator and research nurse with the 
Verification of Registration of the patient and treatment arm patient is randomized. This process 
will be completed within 15–30 minutes of faxing the eligibility checklist. CRO will keep track of 
all randomization data in Clinical Data Registry (CDR) of CRO. 
2.5
BASELINE EVALUATION
A. Baseline electrocardiogram (EKG) on all patients, and appropriate cardiologic 
evaluation, as clinically indicated, to provide baseline function and identify any 
patients who should be monitored closely for cardiac risks associated with vaccinia 
vaccination
B. Apheresis (cohort 1 only)
C. The following parameters will be obtained within 16 days prior to start of treatment:
1. Clinical evaluation
x
History and physical examination 
x
ECOG performance status (see Appendix A )
x
Height, weight
2. Laboratory studies
x
Serum PSA 
x
CBC/differential, with platelet count
x
Serum testosterone level
x
Serum chemistries (Na+, K+, Cl-, CO2, glucose, BUN, creatinine, 
albumin, calcium, magnesium, phosphorus, alkaline phosphatase, 
ALT, AST, total bilirubin, LDH, CK, uric acid, total protein)
x
Lymphocyte phenotyping CD3/CD4/CD8
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN 
x
This is a randomized Pilot trial of enzalutamide vs. enzalutamide and PSA-TRICOM in 
patients with nmCSPC prostate cancer. Thirty-four patients will be enrolled.  
x
Enzalutamide will be given at the standard dose of 160 mg daily for 3 months (7).  
PSA-TRICOM will be administered identical to the Phase III dosing with vaccine 
given week 1 (vaccinia-PSA-TRICOM, 2x108 infectious units subcutaneously) and 
then fowlpox-vaccine (1x109 infectious units subcutaneously) on weeks 3 and 5


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28
followed by monthly fowlpox-vaccine (1x109 infectious units subcutaneously) for a 
total of 5 months (including vaccinia, vaccine is administered over 6 months).
x
Patients will be followed for PSA recovery after enzalutamide has been discontinued.  
Patients who do not develop a 25% decline in PSA after 3 months will not be evaluated 
for tumor re-growth and additional patients will be enrolled to evaluate for that 
endpoint.
x
Patients who have been on study for at least 7 months without PSA equaling or 
exceeding the value at study entry, and whose PSA subsequently (beyond 7 months) 
returns to or exceeds the value at study entry, may be retreated with a 3-month course 
of Enzalutamide. 
x
Patients who continue to be followed for rising PSA after completing either one or 2 
courses of enzalutamide but have not required ADT may be followed after treatment.  
Such visits may occur at 4 week intervals based on logistics and clinical parameters 
(i.e. PSA velocity) once patients have exceeded their baseline PSA value. This 
approach is consistent with the clinical management of such non-metastatic patients 
(rising PSA and not on ADT.)
x
The primary endpoint of this trial will be a comparison of the tumor re-growth rates at 
7 months. This time frame should be sufficient to evaluate immune effect on the re-
growth rate given that the ECOG 9802 analysis demonstrated a significant change in 
tumor growth rate after starting PSA-TRICOM.
Secondary endpoints include growth rate at points other than 7 months, toxicity, 
immunologic responses to vaccine with enzalutamide and to enzalutamide alone in 
men with normal testosterone, and response to second course of enzalutamide.  When 
possible, patients will be followed for TTP. End of study period will be 12 months in 
each arm (24 months if patients are eligible and elect to receive a 2nd course of 
enzalutamide).
x
Preliminary data from the first cohort of randomized patients suggests that enzalutamide 
alone can induce an immunologic response.  A second cohort of 15 patients will explore a 
lower dose of enzalutamide at 80 mg to determine if similar immunologic responses can 
also be seen at a lower dose, where toxicity is less likely.
3.1.1
Protocol Stopping Rules
This study will utilize the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 for grading systemic toxicity (see section 6.3).
x
One occurrence of grade 5 toxicity by the NCI-CTCAE version 4.0 attributable to 
the treatment regimen.
x
Two occurrences of grade 4 toxicity by the NCI-CTCAE version 4.0 attributable to 
the treatment regimen.
If either of the above occurs, the Principal Investigator will halt accrual to the trial and will 
discuss with the NCI Institutional Review Board (IRB) and Medivation and Astellas Inc. whether 
any changes need to be made to the protocol.


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29
All patients will receive vaccine treatments at the NIH Clinical Center, patients will receive 
enzalutamide primarily in the NCI outpatient setting.
We estimate an accrual of approximately 2 patients per month, with full accrual of 34 patients 
within 18 months.
3.2
DRUG ADMINISTRATION
All patients in cohort 1 (n=34) will receive enzalutamide 160 mg daily orally for 3 months. 
Patients randomized to vaccine arm (Arm B) will receive PSA-TRICOM identical to Phase III 
dosing, which consists of a single immunization of PROSTVAC-V (vaccinia-PSA-TRICOM, 
2x108 infectious units subcutaneously) in Week 1, followed by immunizations of PROSTVAC-F
(fowlpox-PSA-TRICOM 1x109 infectious units subcutaneously) administered in Weeks 3, 5, 9,
13, 17, and 21.  
3.3
TREATMENT MODIFICATIONS
3.3.1
Vaccine
3.3.1.1
Dosing delay
x
3DWLHQWVPXVWKDYHUHFRYHUHGWRJUDGHWR[LFLW\UHODWHGWRYDFFLQHIRUWKH
parameters used to assess levels of organ function required for eligibility (see 
Section 2.1.1) after each vaccination in order to receive a subsequent 
vaccination.  
x
3DWLHQWVZLWKJUDGHWR[LFLW\QRWUHODWHGWRYDFFLQHWUHDWPHQWLHattributed to 
enzalutamide) will remain eligible to receive vaccine.  
x
Patients that recover from > grade 2 toxicity unrelated to vaccine treatment (i.e. 
related to enzalutamide) may remain eligible for the vaccine.  
x
,IJUDGHQRQDXWRLPPXQHWR[LFLW\DWWULEXWDEOHWRWKHYDFFLQHSHUVLVWVIRU!42
days, the patient will not receive further vaccine inoculations and will be 
removed from the protocol treatment and followed for resolution of toxicity and 
immune endpoints.  
x
Patients who develop grade 3 injection site reactions will have their vaccine held 
until injection site reaction resolves to grade 2 or less.
x
3DWLHQWVZKRGHYHORSDJUDGHDOOHUJLFRUDXWRLPPXQe disease that threatens 
YLWDORUJDQIXQFWLRQRUDQ\JUDGHDXWRLPPXQLW\QRWUHODWHGWRDWKHUDSHXWLF
response, will be removed from the protocol treatment and followed for 
resolution of toxicity and immune endpoints.  
x
Patients who develop any grade 4 toxicity attributable to the study drug(s) will be 
removed from the protocol treatment and followed for resolution of toxicity and 
immune endpoints.
x
If a scheduled vaccine dose is missed due to scheduling or logistical issues, the 
vaccine may be given within 7 days of the appointed time
3.3.1.2
Dose modifications
No dose modifications are allowed with this vaccine.


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30
3.3.2
Enzalutamide
,IDSDWLHQWH[SHULHQFHVD*UDGHQRQ-hematologic toxicity attributable to enzalutamide or an 
intolerable side effect attributable to enzalutamide, withhold dosing for one week or until 
V\PSWRPVLPSURYHWR*UDGHWKHQUHVXPHDWWKHVDPHGRVHLIFOLQically appropriate.  If 
toxicity recurs enzaluatmide will be held again using the above parameters or discontinued at the 
discretion of the investigator.
Patients who develop any grade 4 toxicity attributable to the study drug(s) will be removed from 
the protocol treatment and followed for resolution of toxicity and immune endpoints.
3.4
PROTOCOL EVALUATION (SEE APPENDIX C )
3.4.1
All patients who are deemed eligible and who sign an informed consent will be enrolled 
in this trial.
3.4.2
A complete history and physical examination, including ECOG performance status, will 
be done within 16 days before enrollment.  
3.4.3
Laboratory Studies 
(See also Appendix C )
x
Serum PSA 
x
CBC/differential with platelet count
x
Serum testosterone level
x
Serum chemistries (Na+, K+, Cl-, CO2, glucose, BUN, creatinine, albumin, calcium, 
magnesium, phosphorus, alkaline phosphatase, ALT, AST, total bilirubin, LDH, CK, 
uric acid, total protein)
x
HIV/Hepatitis B/Hepatitis C tests (within 8 weeks prior to start of enrollment)
x
Lymphocyte phenotyping CD3/CD4/CD8
x
PAP (prostatic acid phosphatase)
x
The following serum hormone levels will be drawn at each follow up visit after 
enrollment and pre-Enzalutamide administration, and 1 hour post, 24 hours post, 48 
hours post, and 72 hours post administration, when logistically feasible.
o
testosterone 
o
dihydrotestosterone (DHT)
o
sex hormone-binding globulin (SHBG)
o
dehydroepiandrosterone (DHEA)
o
luteinizing hormone (LH)
o
follicle-stimulating hormone (FSH)
o
androstenedione
o
prolactin 
o
estradiol 
x
Plasma VEGF levels will be drawn at the start and at the end of each patient’s second 
12-week course of Enzalutamide. 


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31
3.4.4
Radiographic assessment 
Patients will not undergo scheduled radiographic assessment for metastatic disease unless 
clinically indicated for increasing PSA or symptoms. Radiologic studies consisting of bone scan, 
CT scan of chest, and CT scan of abdomen/pelvis will be performed at baseline. MRI may be 
substituted for CT scan at the discretion of the investigator.
Patients will undergo a radiographic assessment with CT scan of chest, abdomen, and pelvis and 
bone scan once PSA returns to baseline at study entry or higher.  These scans will be obtained 
prior to retreatment with a 3-month course of enzalutamide. 
For patients who are eligible and elect to receive a second course of enzalutamide therapy for 3 
months, re-staging CT scan of chest, abdomen, and pelvis and bone scan will again be done 
when PSA reaches baseline.
3.4.5
Assessment for PSA-TRICOM administration (Arm B)
Dosing and administration of PSA-TRICOM will be performed in the Day Hospital.  Patients 
will be monitored with vital signs (blood pressure, heart rate, respiratory rate, temperature) prior 
to and within 1 hour after the initial vaccine treatment. On subsequent visits (where rF-PSA-
TRICOM is administered) patients will have vital signs checked prior to vaccine and then be 
monitored for 30 minutes after vaccine treatments.  (Post-vaccine vital signs will not be required 
except for the first vaccination.) Documentation of any patient reported symptoms occurring 
between dosing will be included in the assessment.  Laboratory assessments will be conducted as 
per Appendix C : On Study and Follow-Up Evaluations .
3.5
CONCURRENT THERAPIES 
Concurrent hormonal therapy not otherwise stipulated in the protocol will not be allowed. 
Concurrent anticancer treatment with chemotherapy, systemic glucocorticoids (topical and 
inhaled steroids allowed), radiation therapy, major surgical procedures for prostate cancer, and 
nonprotocol-related immunotherapy will not be permitted.
3.6
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy.
3.6.1
Criteria for removal from protocol therapy
Patients will be removed from treatment for the following:
x
Clinical or radiographic progression of disease.
x
Grade 3 or greater toxicity attributed to treatment that does not resolve to grade 1 within 
42 days from time of scheduled treatment.
x
Grade 3 or greater toxicity not related to treatment that does not resolve to grade 2 within 
42 days from time of scheduled treatment.
x
Grade 2 or greater autoimmune disease that threatens vitals organs.


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32
x
Any Grade 4 toxicity that is possibly, probably or definitely related to the protocol 
treatment will require a patient to be off-treatment
x
Intercurrent illness or medical circumstances. If at any time the constraints of this 
protocol are detrimental to the patient’s health, the patient may be removed from protocol 
therapy and reasons for withdrawal will be documented.
x
Any grade of seizure will require a patient to be off-treatment.
x
Requirement for androgen deprivation therapy
x
Completion of protocol therapy 
3.6.2
Off-Study Criteria
x
Patient is off-treatment and has agreed to be followed on a long term therapy protocol as 
outlined in section 3.7
x
Patient requests to be taken off study. Reasons for withdrawal will be documented.
x
Noncompliance with protocol guidelines (patient removed at discretion of Principal 
Investigator).
x
Death
3.6.3
Off Protocol Therapy and Off-Study Procedure
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off
protocol therapy and when a subject is taken off study. A Participant Status Update Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov.
3.7
POST-STUDY EVALUATION (FOLLOW-UP)
The Biologic Response Modifiers Advisory Committee has recommended that long-term follow-
up extend over a period of 15 years. Information regarding the findings will be reported to the 
FDA. Patients randomized to receive PSA-TRICOM will be offered enrollment in the 04-C-0274
“Follow-Up Study of Subjects Previously Enrolled in Immunotherapy Studies Utilizing Gene 
Transfer or other immunotherapeutic agents” once off study.
4
BIOSPECIMEN COLLECTION
4.1
CORRELATIVE STUDIES FOR RESEARCH
4.1.1
Immunologic Parameters
x
IFN-gamma ELISPOT assay for PSA-specific T lymphocytes (HLA-A2 patients 
only)
x
Antibodies to PSA, vaccinia, fowlpox may be tested
x
Leukocyte CD3, CD4, CD8 subsets; CD4:CD8 ratio will be drawn at baseline and 
monthly prior to vaccination while the patient remains on trial.
x
The results of the HIV antibody need to be available before treatment to determine 
eligibility


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33
x
HLA class I expression (HLA typing) with A2 subtyping (obtain anytime prior to 
enrollment).  Patients may refuse or test may be omitted for logistical purposes 
at the discretion of the investigator.
x
Additional studies will include but are not limited to quantitative and qualitative 
assessments of regulatory T-cells, Natural Killers cells, Myeloid Derived 
Suppressor Cells, anti-glycan antibodies and Naïve T-cell/new thymic 
emigrants. 
x
Assessment of levels of cytokines.
x
Immunologic studies will be repeated more frequently if clinically indicated, and 
any abnormalities potentially related to treatment will be followed until they 
have resolved, or have been determined not to be treatment-related.
4.1.2
Collection of Research (Immunologic) Blood Samples
Immunologic blood samples will be obtained via apheresis when logistically feasible at Baseline
(prior to treatment), after 3 months and after 6 months in all HLA-A2 patients. (Additional 
apheresis could be considered at the discretion of the investigator and with the consent of the 
patient.)  We plan to examine the immune response in selected patients (HLA-A2 positive) when 
feasible and if patients consent. (The HLA-A2 requirement is based on the ability to assess 
immune response in these patients using immunologic response techniques (ELISPOT).  This 
analysis is not limited to these patients due to any reason to believe that non-HLA-A2 will not 
have an immune response, but rather those immune responses can not be detected by our current 
ELISPOT methods.)
In all patients undergoing apheresis, 5 x 108 to 2 x 109 mononuclear cells will be obtained by a 
single-access (single venipuncture) mononuclear cell procedure on the Haemonetics V-50
instrument, during which 2.0 liters of whole blood would be process at a flow rate of about 70-80
ml/min.  The total duration of the procedure is 90 min to 2 hours.  Patients will be required to 
have a minimum HCT of 28% and a platelet count of at least 75,000 to undergo a Haemonetics 
procedure. 
Apheresis will allow us to obtain sufficient PBMC samples from patients to be able to perform 
not only the standard Elispot using the PSA-3 peptide, but to also look at other epitopes that may 
be important in evaluating an antigen cascade effect from the therapy administered. This will 
allow us to gain important immunologic information to determine if patients are not only 
mounting immune responses to the antigens in the vaccine, but to also immune responses to 
other antigens present on the tumor cells. At the time points when apheresis is not obtained, we 
will obtain 6 green top (10ml) tubes. These will be used for ELISPOT assays (as described in
Appendix D ). In addition, 2 SST (tiger) top tubes will be drawn for antibody testing (as 
described in Appendix D). If apheresis is not done, research samples will be obtained per
Appendix C
Blood samples may be used for other research studies which may include phenotypic and 
functional analysis of immune cell subsets, and analysis for cytokines, chemokines, antibodies, 
tumor-associated antigens and / or other markers.


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Immunologic blood samples will be processed at:
Clinical Services Program
NCI Frederick Cancer Research and Development Center
PO Box B
Frederick MD 21702
301-846-1707
On days samples are drawn, Jennifer Bangh at CSP should be notified (phone: [301] 
846-5893; fax [301] 846-6222). She will arrange courier delivery of the specimens to 
the processing lab.
The weekly patient lists of samples drawn will be emailed to Jen Bangh at 
banghj@mail.nih.gov and Theresa Burks burkst@mail.nih.gov.
4.1.3
Immunologic Assays
4.1.3.1
IFN-gamma ELISPOT
We plan to examine the immune response in selected patients (HLA-A2-positive). Lymphocytes 
will be separated from heparinized blood using density gradient centrifugation. The lymphocytes 
will then be placed in human AB serum with 10% DMSO and stored in liquid nitrogen. When 
samples are available from pre- and post-treatment, the ELISPOT assay will be performed. The 
ELISPOT assay, measuring IFN-gamma production, is used to determine CTL precursor 
frequency to peptides from PSA, PSMA, MUC-1, PSCA, CEA, and PAP in both pre- and post-
vaccination peripheral blood mononuclear cells, as previously described (39-40). Briefly, 96-
well mL HA plates (Millipore Corporation, Bedford, MA) are coated with 100 Pl/well of capture 
MAb against human IFN-gamma at a concentration of 10 Pg/mL for 12h at RT. Plates are 
blocked for 30 min with RPMI 1640 plus 10% human Ab serum 2 x 105 PBMC are added to each 
well. PSA-3A pulsed C1R-A2 cells are added into each well as antigen-presenting cells (APC) at 
an effector:APC ratio of 1:1. Unpulsed C1R-A2 cells are used as a negative control. HLA-A2 
binding flu matrix peptide 59-66 is used as a positive peptide control (41). We also perform each 
sample with 6 replicates to control for variability. In addition, each sample is run with a flu 
peptide control (pre- and post-vaccine) as well as samples from a “normal” control HLA-A2-
positive individual with previously determined levels of flu-specific T-cell precursors. Cells are 
incubated for 24 h and lysed with phosphate-buffered saline (PBS)-Tween (.05%). Biotinylated 
anti IFN-gamma antibody diluted to 2 Pg/mL in PBS-Tween containing 1% bovine serum 
albumin (BSA) is added and incubated overnight in 5% CO2 at 37qC. Plates are washed 3 times 
and developed with avidin alkaline phosphatase (GIBCO/BRL, Grand Island, NY) for 45 min. 
After washing the plates 3 times, each well is examined for positive dots. This assay will be 
performed in the Laboratory of Tumor Immunology and Biology, NCI, NIH. The number of dots 
in each well will be counted by 2 separate investigators in a blinded manner, and the frequency 
of responding cells will be determined.  
4.1.3.2
CD4 T Cell Proliferation Assay
It is planned that all patients will undergo exploratory analysis of the ability to detect CD4-
positive responses using a whole-protein PSA assay, as well as a peptide mix with 63 different 
15-mer peptides by ELISPOT and/or ELISA. 


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4.1.3.3
Sera Antibody Analysis
Serum will be stored at -80 degrees Celsius and there will be planned analysis for generation of 
antibodies to PSA, BCG, PAP, PSMA, PSCA, and/or MUC-1.
4.1.3.4
Flow cytometry analysis of thymic emigrant
To determine recent thymic emigrants, flow cytometry analysis will be performed on peripheral 
blood mononuclear cells. Cells will be resuspended in staining buffer (phosphate-buffered saline 
containing 3% fetal bovine serum) and stained for 30 minutes at 4°C with the combination of 
following antibodies: APC-H7-conjugated anti-CD4, PE-CY7-conjugated anti-CD3; FITC-
conjugated CD45RA, PE-conjugated CD31, PerCP-CY5.5-conjugated Ki-67, AF-700-
conjugated-CD197, V450-conjugated CD8, APC-conjugated CD103, V500-conjugated CD27 all 
purchased from BD Pharmingen, San Diego, CA). After that, FoxP3 intra-cellular staining will 
be performed on the cells stained with anti-CD4 and anti-CD25. They will be fixed and 
permeabilyzed using a fix/perm kit (eBioscience, San Diego, CA) according to the 
manufacturer’s manual, and will be labeled with FITC-conjugated anti-Foxp3 antibody 
(236A/E7 clone) or its isotype control antibody (eBioscience). Flow cytometry will be performed 
on a Becton Dickinson LSRII (BD Biosciences) device.
4.1.3.5
Natural Killer (NK) CELLS
The number and phenotype of NK cells will be determined by phenotypic analysis of PMBCs 
stained for CD56, CD3, CD8, and CD16 by flow cytometry.
4.1.3.6
Regulatory T Cells
Regulatory T cells have been shown to inhibit the activation and function of T cells that 
participate in antigen-specific immune responses.  Higher levels of regulatory T-cells have been 
reported in the peripheral blood mononuclear cells of patients with several types of tumors.  The 
number and phenotype of regulatory T-cells in peripheral blood mononuclear cells from patients 
in this study will be determined by 7-color flow cytometry analysis.  Cells will be resuspended in 
staining buffer (phosphate-buffered saline containing 3% fetal bovine serum) and stained for 
CD4, CD25, CD127, FoxP3, CTLA-4, CD45RA, and CD8.  The ratios between regulatory T-
cells and CD4 effector cells and the ratios between regulatory T-cells and CD8 Effector cells will 
also be analyzed.
4.1.4
Additional Assays
Blood samples may be used for additional research studies, which may include phenotypic and 
functional analysis of immune-cell subsets and analyses for cytokines (IFN-Ȗ,/-10, IL-12, IL-2,
IL-4, etc.), chemokines, antibodies, tumor associated antigens, and/or other markers
All samples will be labeled with the following identifier system.  
x
Patient’s enrollment #
x
Trial number
x
Patient’s initials
Example: 01-ABC


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These labels are used only to send the samples from the NIH Clinical Center to the NCI
Frederick Central Repository.  The NCI Repository will process all samples, appropriately
discard the label on the blood tube, and then store the samples with unique identifiers, to which 
only NCI study personnel will have the code to link to patient specific clinical information.
Samples will be tracked according to Section 4.2.
If there are inadequate samples for analysis because of loss or destruction of those samples, the 
PI will report this to the IRB.
4.1.5
Plasma VEGF levels
Serum samples will be collected to measure vascular endothelial growth factor (VEGF) levels.  
For this purpose, one 6mL EDTA tube will be obtained at baseline (prior to treatment), 1 month, 
3 months, 3.5 months, 4 months, and 6 months.  The analysis will be done with assays developed 
on electrochemiluminescence platform that provides ultra-high sensitivity and very large signal 
dynamic range. These studies will be done by the Molecular Pharmacology Program, under the 
direction of Dr. Doug Figg. 
Write the collection time on the vacutainer tube and place the sample on wet ice immediately 
after collection. The sample should be picked up within 1 hour of collection. 
Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at 
least 24 hours before transporting samples (the Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044.
4.1.6
Serum Analysis 
Of the sample collected in 4.1.2, de-identified serum may be sent for analysis of pre-treatment, 
on-treatment, on progression and post-treatment absolute concentrations of steroids and ratios of 
11BHSD substrates and products with presence of treatment and the nature of the clinical 
response to enzalutamide.  The serum samples may be sent under an MTA to the laboratory of 
Dr. Nima Sharifi, of the Cleveland Clinic Foundation, at the following address:
Michael P. Berk
Cleveland Clinic Foundation
Lerner Research Institute
Cancer Biology, NB4-15
2111 East 96th Street
Cleveland, OH 44106
Tel. = 216.445.9752
Email = berkm@ccf.org


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4.2
STORAGE AND TRACKING OF COLLECTED BLOOD SAMPLES
All data associated with the patient samples is protected by using a secure database. All samples 
drawn at the NIH Clinical Center will be transported to the NCI Frederick Central Repository by 
couriers.
Samples will be tracked and managed by Central Repository database. All samples will be stored 
in either a -Û&RU-Û&IUHH]HU7KHVHIUHH]HUVDUHORFDWHGDW1&,)UHGHULFN&HQWUDO
Repository in Frederick, Maryland.
American Type Culture Collection (ATCC) manages the NCI Frederick Central Repositories 
under subcontract to Leidos Biomedical Research, Inc., Frederick, Inc. NCI Frederick Central 
Repositories store, among other things, biological specimens in support of NIH clinical studies. 
All specimens are stored in secure, limited-access facilities with sufficient security, backup, and 
emergency support capability and monitoring to ensure long-term integrity of the specimens for 
research. 
ATCC’s role is limited to clinical research databases and repositories containing patient 
specimens. ATCC does not conduct or have any vested interest in research on human subjects, 
but does provide services and support the efforts of its customers, many of which are involved in 
research on human subjects. 
It is the intent and purpose of ATCC to accept only de-identified samples and sample 
information. To the limit of our ability, every effort will be made to ensure that protected 
information is not sent electronically or by hard copy or on vial labels. 
Sample data is stored in the BioSpecimen Inventory System II (BSI). This inventory tracking 
system is used to manage the storage and retrieval of specimens, as well as to maintain specimen 
data. BSI is designed for controlled, concurrent access. It provides a real-time, multi-user 
environment for tracking millions of specimens. The system controls how and in what order 
database updates and searches are performed. This control prevents deadlocks and race 
conditions. For security, BSI has user password access, 3 types of user access levels, and 36 user 
permissions (levels of access) that can be set to control access to the system functions. BSI 
provides audit tracking for processes that are done to specimens including shipping, returning to 
inventory, aliquoting, thawing, additives, and other processes. BSI tracks the ancestry of 
specimens as they are aliquoted, as well as discrepancies and discrepancy resolution for 
specimens received by the repository. If a specimen goes out of the inventory, the system 
maintains data associated with the withdraw request. Vials are labeled with a unique BSI ID 
which is printed in both eye-readable and bar-coded format. No patient-specific information is 
encoded in this ID. 
Investigators are granted view, input, and withdraw authority only for their specimens. They may 
not view specimen data or access specimens for which they have not been authorized. Access to 
specimen storage is confined to repository staff. Visitors to the repositories are escorted by 
repository staff at all times.
Samples will be used for research analysis, including immunologic monitoring as outlined in
section 4.1.3. All specimens for analysis will be requested from Leidos Biomedical Research,


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Inc. and will be delivered by Leidos Biomedical Research, Inc. couriers to the Laboratory of 
Tumor Immunology and Biology.
4.2.1
Protocol Completion/Sample Destruction
Once primary research objectives for the protocol are achieved, intramural researchers can 
request access to remaining samples, provided they have an IRB-approved protocol and patient 
consent.
Samples and associated data will be stored permanently unless the patient withdraws consent. If
the patient withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved. The PI will report destroyed samples to the IRB if samples become unsalvageable or 
destroyed by environmental conditions (ex. broken freezer or lack of dry ice in shipping 
container) or if a patient chooses to withdraw his/her consent. Samples will also be reported as 
lost if they are lost in transit or misplaced by a researcher. Freezer problems, lost samples or 
other problems associated with samples will also be reported to the IRB, the NCI Clinical 
Director, and the office of the CCR, NCI.
5
SUPPORTIVE CARE
For both the administration of PSA-TRICOM and enzalutamide, antiemetics, stool softeners and 
antidiarrheal agents may be administered as required, but are not anticipated to be needed and 
should not be used prophylactically on the first cycle. The selection of the specific antiemetic 
regimen is at the discretion of the treating physician. Antiemetic regimens will not include 
steroids.
Other supportive care with blood components, antibiotics, analgesics, general medical therapy, 
etc., will be delivered as required. Any patients taking antibiotics for any reason must complete 
that course of therapy and be free of evidence of further infection before receiving any dose of 
vaccine.
Symptomatic anemia should be treated with appropriate red blood cell or erythropoietin support.
Thrombocytopenia should be treated conservatively. In the absence of bleeding or a planned 
invasive procedure, platelet transfusions should be given for a platelet count below 10,000/mm3.
If invasive procedures are planned or the patient develops bleeding, platelet transfusions should 
be administered in accordance with the standard of practice, usually maintaining a platelet count 
of > 50,000/mm3.
Any evidence of disseminated intravascular coagulation (DIC), hemolytic uremic syndrome 
(HUS), or thrombotic thrombocytopenic purpura (TTP) including thrombocytopenia, hemolytic 
anemia, renal failure, fever or neurologic changes should be thoroughly evaluated and closely 
monitored and supported as clinically indicated.


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5.1
EXCLUDED MEDICATIONS
While patients on protocol treatment, all medications required for the health of the patient are 
allowed with the following exceptions:
x
Concurrent chemotherapy
x
Concurrent radiation therapy
x
Concurrent immunotherapy
x
Concurrent anti-cancer radionuclides
x
Concurrent systemic corticosteroid use (daily or every other day for continued use >
14 days; See section 2.1.2)
x
Concomitant use of secondary hormonal treatments
5.2
TREATMENT OF VACCINIA VACCINATION COMPLICATION
5.2.1
Vaccinia Immune Globulin:
First-line treatment of some of the complications of vaccinia caused by dissemination of vaccinia
virus (severe cases of inadvertent inoculation involving extensive lesions or if comorbid
conditions exist, severe cases of generalized vaccinia in patients that are systemically ill and
whose condition might be toxic or who have serious underlying immunosuppressive illnesses,
eczema vaccinatum, and progressive vaccinia) is with VIG.
VIG is contraindicated, however, for the treatment of isolated vaccinial keratitis. VIG is a sterile
solution of the immunoglobulin fraction of pooled plasma from individuals inoculated with
vaccinia vaccine. VIG is an investigational agent available through the CDC’s Strategic National
Pharmaceutical Stockpile under an IND protocol by contacting the CDC’s Smallpox Vaccine
Adverse Events Clinician Information Line at 1-877-554-4625. Upon receipt of a call from a
patient or upon direct observation of a patient or contact who manifests signs and symptoms of
any of the above conditions, the investigator should place a call to the CDC as soon as possible:
1) to initiate review of the clinical case, 
2) to seek consultation on the appropriateness of VIG therapy, 
3) to determine the appropriate VIG dose and dosing method for administration, if VIG
therapy is required, and 
4) to determine how to access and have the appropriate doses of VIG delivered.
Early institution of VIG therapy is advised following recognition of clinical symptoms
compatible with some vaccinia complications (eczema vaccinatum, severe generalized vaccinia,
progressive vaccinia, and some cases of inadvertent inoculation). The effectiveness of VIG
therapy appears to be time dependent. VIG has not proven to be of benefit in the treatment of
post-vaccinial encephalitis, and is contraindicated for treatment of isolated vaccinial keratitis due
to the increased risk of corneal scarring.
A new intravenous formulation of VIG is available through the CDC, which has a lower level of
aggregated protein, allowing it to be used by either the IM or IV route. This formulation will
most likely be preferred for administration and investigators will be instructed by the CDC
regarding appropriate dosing and method of administration based on formulation and
availability. There is no guarantee that VIG will successfully treat complications. At present,
there are no other anti-viral therapies of proven benefit for the treatment of vaccinia-related
complications.


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5.2.2
Cidofovir (Vistide®, Gilead Sciences):
Cidofovir is an FDA-approved antiviral drug for the treatment of CMV retinitis among patients
with AIDS. Cell-based in vitro studies and animal model studies have demonstrated antiviral
activity of this agent against certain orthopoxviruses. Currently, efficacy in the treatment of
vaccinia-related complications in humans is unknown. According to the CDC, “VIG is
recommended as first line of therapy. Cidofovir may be considered as a secondary treatment, and 
will only be released by the CDC after all inventories of VIG have been exhausted, after a patient 
fails to improve with VIG treatment, or as a last effort for a patient who is otherwise near death.” 
[Medical Management of Smallpox (Vaccinia) Vaccine Adverse Reactions: Vaccinia
Immune Globulin and Cidofovir. Last updated February 11, 2003. Available at:
http://www.bt.cdc.gov/agent/smallpox/vaccination/mgmt-adv-reactions.asp].
6
DATA COLLECTION AND EVALUATION
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be
attributed to an individual human subject participant.
6.1.1
Eligible patients must be confirmed and checklist completed. Consent form must be 
signed prior to registration with Central Registration Information Services.
6.1.2
Data will be secured in NCI C3D database. Data will be collected using protocol-specific 
case report forms, and verified for accuracy and completeness. Hard copies of data will 
be stored in locked secured areas and data will be entered onto a secured electronic data 
base. The following protocol-specific study forms will be complete and stored: eligibility 
checklist (developed by Central Registration Office, CRO). A copy of all serious AE 
forms will be kept in the research record.
6.1.3
Treatment is given according to protocol (dated notes about doses given, complications, 
and clinical outcomes).
6.1.4
Toxicity is assessed according to protocol (laboratory report slips, etc.)
6.1.5
Response is assessed according to protocol (X-ray, scan, lab reports, and date noted on 
clinical assessment, as appropriate).
6.1.6
Drug Accountability Records are kept for each patient.
6.1.7
We will not report Grade 1 adverse events.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for a minimum of 30 days after removal from study treatment 
or until off-study, whichever comes first.


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An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following:
x
Results in discontinuation from the study
x
Is associated with clinical signs or symptoms 
x
Requires treatment or any other therapeutic intervention
x
Is associated with death or another serious adverse event, including hospitalization. 
x
Is judged by the Investigator to be of significant clinical impact
x
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 
6.2
RESPONSE CRITERIA
Patients will not undergo scheduled radiographic assessment for metastatic disease unless 
clinically indicated for increasing PSA or symptoms.
6.2.1
Disease Progression 
6.2.1.1
PSA will not be used to measure progression of disease given the intermittent use of 
enzalutamide.  It is expected that PSA will rise after a 3 month course of enzalutamide 
is completed and the treatment is discontinued.  Patients will be offered androgen 
deprivation therapy (ADT) as clinically indicated or a second course of enzalutamide as 
indicated in the protocol.  Starting ADT will be done at the discretion of the 
investigator, although this will result in treatment termination and removal from the 
clinical trial.  (Conventionally this is when PSA has a doubling time of less than 3 
months, but patients may refuse treatment in favor of surveillance which is also 
clinically appropriate.  Conversely, patients may go on ADT at any time, although this 


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may result in removal from the trial.) PSA will be used to calculate PSA kinetics/tumor 
growth kinetics.
6.2.1.2
Development of a new bone lesion.
6.2.1.3
Development of a soft tissue mass, identified on CT scan or physical exam, consistent 
with metastatic prostate cancer. If identified on physical exam, the lesion may be 
biopsied to confirm the presence of prostate cancer.
6.2.1.4
Development of urethral, ureteral, or spinal cord obstruction secondary to tumor.
6.2.1.5
Development of cytologically positive pleural effusion or lymphangitic spread in the 
lungs.
6.2.1.6
Symptoms which in the opinion of the investigator are consistent with clinical 
progression.
6.3
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). 
7
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN
7.1
DEFINITIONS
7.1.1
Adverse Event
Any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in research, whether or not considered related to the 
subject’s participation in the research.
7.1.2
Suspected adverse reaction
Suspected adverse reaction means 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’ means 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 adverse reaction, which means any adverse event caused by a drug.
7.1.3
Unexpected adverse reaction
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure 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. 


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"Unexpected”, 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.
7.1.4
Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others.
7.1.5
Serious Adverse Event
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
x
Death,
x
A life-threatening adverse drug experience
x
Inpatient hospitalization or prolongation of existing hospitalization
x
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
x
A congenital anomaly/birth defect.
x
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience 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.
7.1.6
Disability
A substantial disruption of a person’s ability to conduct normal life functions.
7.1.7
Life-threatening adverse drug experience
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death.
7.1.8
Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the IRB-approved research protocol.  
7.1.9
Non-compliance (NIH Definition)
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects.
7.1.10 Unanticipated Problem
Any incident, experience, or outcome that:
x
Is unexpected in terms of nature, severity, or frequency in relation to 


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44
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND
x
Is related or possibly related to participation in the research; AND
x
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.
7.2
NCI-IRB AND CLINICAL DIRECTOR REPORTING
7.2.1
NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director:
x
All deaths, except deaths due to progressive disease 
x
All Protocol Deviations
x
All Unanticipated Problems
x
All non-compliance
Reports must be received within 7 days of PI awareness via iRIS.
7.2.2
NCI-IRB Requirements for PI Reporting at Continuing Review
The protocol PI will report to the NCI-IRB: 
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action.
2. A summary of any instances of non-compliance
3. A tabular summary of the following adverse events:
x
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research; 
x
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research; 
x
All Grade 5 events regardless of attribution; 
x
All Serious Events regardless of attribution. 
NOTE: Grade 1 events are not required to be reported. 
7.2.3
NCI-IRB Reporting of IND Safety Reports
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB.


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7.3
IND SPONSOR REPORTING CRITERIA 
During the first 30 days after the subject receives investigational agent/intervention, the
investigator must immediately report to the sponsor, using the mandatory MedWatch form 
3500a, any serious adverse event, whether or not considered drug related, including those listed 
in the protocol or investigator brochure and must include an assessment of whether there is a 
reasonable possibility that the drug caused the event. For serious adverse events that occur more 
than 30 days after the last administration of investigational agent/intervention, only report those 
that have an attribution of at least possibly related to the agent/intervention.
Required timing for reporting per the above guideline:
x
Deaths (except death due to progressive disease) must be reported via email within 
24 hours.  A complete report must be submitted within one business day. 
x
Other serious adverse events as well as deaths due to progressive disease must be 
reported within one business day
Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov,
and to the CCR PI and study coordinator.
7.3.1
Reporting Pregnancy 
7.3.1.1
Paternal exposure
Male patients should refrain from fathering a child or donating sperm during the study and for 3 
months after the last dose of study treatment.  Pregnancy of the patient’s partner is not considered 
to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date 
of the first dose until 3 months after the last dose should, if possible, be followed up and 
documented.
7.4
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
All events listed below must be reported in the defined timelines to CCRsafety@mail.nih.gov.
The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described 
below.
7.4.1
Reporting to Astellas
The Investigator should complete and submit an SAE Medwatch 3500 Form, containing all 
information that is required by the Regulatory Authorities, to Astellas by either e-mail or fax 
within 24 hours of awareness whether or not related to the study drug. If submission of this SAE 
by email or fax or is not possible within 24 hours, the local drug safety contact (IRB, 
Investigator, etc.) should be informed by phone.
The SAE documentation, including the Medwatch 3500 Form and available source records, 
should be emailed or faxed to:
Astellas Pharma Global Development – United States


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Email: Safety-us@us.astellas.com
Fax number: (847) 317-1241
The following minimum information is required:
xStudy number/IIT regulatory identifier
xSubject number, sex and age
xThe date of report
xA description of the SAE (event, seriousness of the event)
xCausal relationship to the study drug
Follow-up information for the event should be sent within 7 days as necessary.
7.4.2
Reporting to Bavarian Nordic, Inc.
The investigator should also submit all safety reports that are sent to the FDA using the 
Medwatch 3500 Form to:
Bavarian Nordic, Inc. 
Email: pharmacovigilance@bavarian-nordic.com;
Fax number for pharmacovigilance at BN: 888-465-1219
Attention: Karen Latina
7.5
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA
7.5.1
Serious Adverse Event Reports to OSP/IBC
The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-
threatening experience associated with the use of PSA-TRICOM Vaccine as soon as possible but 
in no event later than 7 calendar days of initial receipt of the information.  Serious adverse events 
that are unexpected and associated with the use of the PSA-TRICOM Vaccine, but are not fatal 
or life-threatening, much be reported to the NIH IBC as soon as possible, but not later than 15 
calendar days after the investigator’s initial receipt of the information.  Adverse events may be 
reported by using the FDA Form 3500a.
7.5.2
Annual Reports to IBC
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the Principal 
Investigator (or delegate) shall submit the information described below.  Alternatively, the IRB 
continuing review report can be sent to the IBC in lieu of a separate report.  Please include the 
IBC protocol number on the report.
7.5.2.1
Clinical Trial Information 
A brief summary of the status of the trial in progress or completed during the previous year. The 
summary is required to include the following information: 


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x
the title and purpose of the trial 
x
clinical site
x
the Principal Investigator
x
clinical protocol identifiers; 
x
participant population (such as disease indication and general age group, e.g., adult or 
pediatric); 
x
the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons 
x
the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
or fully completed, 
x
if the trial has been completed, a brief description of any study results. 
7.5.2.2
Progress Report and Data Analysis
Information obtained during the previous year's clinical and non-clinical investigations, 
including: 
x
a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system
x
a summary of all serious adverse events submitted during the past year
x
a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications
x
if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death
x
a brief description of any information obtained that is pertinent to an understanding of the 
gene transfer product’s actions, including, for example, information about dose-response, 
information from controlled trials, and information about bioavailability. 
7.6
DATA AND SAFETY MONITORING PLAN
7.6.1
Principal Investigator/Research Team 
The Principal Investigator, lead associate investigator and the research nurse will meet weekly at 
each clinic to review all adverse events for each subject in this trial and to determine dose 
limiting toxicities and escalation rules.  Unexpected adverse events and/or serious adverse events 
will be reported to the NCI’s Institutional Review Board (IRB) and sponsor/FDA as outlined 
above.  If trends are noted and/or risks warrant it, accrual will be interrupted, dose levels 
expanded and/or the protocol and/or consent will be modified accordingly.
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 


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new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS and to the Sponsor. 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
7.6.2
Sponsor Monitoring Plan
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and 
SOPs; and human subjects protection. This is done through independent verification of study 
data with source documentation focusing on:
x
Informed consent process
x
Eligibility confirmation
x
Drug administration and accountability
x
Adverse events monitoring
x
Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center.
This trial will be monitored by personnel employed by an NCI contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. Safety Monitoring Committee 
(SMC)
This protocol will require oversight from the Safety Monitoring Committee (SMC).  Initial 
review will occur as soon as possible after the annual NCI-IRB continuing review date.   
Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting 
schedule permits or more frequently as may be required by the SMC.   For initial and subsequent 
reviews, protocols will not be reviewed if there is no accrual within the review period. Written 
outcome letters will be generated in response to the monitoring activities and submitted to the 
Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
8
STATISTICAL CONSIDERATIONS
8.1.1
Cohort 1
The primary objective of this study is to compare the change in the growth rate in the two arms 
from the time of discontinuation of enzalutamide (3 months after enrollment) to 4 months after 
completing enzalutamide therapy +/- PSA-TRICOM (7 months after enrollment). With growth 
rate changes obtained on all patients on both arms, and if the growth rate changes in the two 
arms had the same standard deviation, with 17 patients per arm, there would be 80% power to 
detect a difference between the arms equal to 1 SD of the difference from baseline to 7 months 
with a two-tailed 0.05 significance level two-group t-test. Thus, a total of 34 evaluable patients 


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are required for analysis. To allow for a small number of patients who do not develop a 25% 
decline in PSA after 3 months, additional patients will be randomized if necessary to obtain a 
minimum of 17 evaluable patients on each arm. In order to allow for a small number of such 
patients, the accrual ceiling will be 38.
Patients will be stratified based a doubling time of greater than or less than 6 months.  
Secondary endpoints will be compared between the two arms using appropriate non-parametric 
tests, such as a Wilcoxon rank sum test.  Results will be presented without formal adjustment for 
multiple comparisons but reported in the context of secondary evaluation of a potentially large 
number of endpoints. The significance of paired hormone level results within arms will be 
determined by a paired t-test or Wilcoxon signed rank test as appropriate.
8.1.2
Halting Rules
The study will be halted for review of changes to the protocol and consent if either of the
following is met:
x
One occurrence of grade 5 toxicity attributed to the treatment regimen.
x
Two occurrences of grade 4 toxicity attributed to the treatment regimen.
8.1.3
The regression-growth equation
The equation is f(t) = exp(-d * t)+exp(g * t) - 1 (A) where exp is the base of the natural 
logarithm, e = 2.7182, and f(t) is the tumor (or in MTC calcitonin) measurement at time t in days, 
normalized to (divided by) the tumor measurement at day 0, the time at which treatment is 
commenced. Rate constant d (decay, in daysí) represents the exponential decrease/regression of 
the a serum tumor marker (i.e. PSA) signal during therapy. Rate constant g (growth, also in 
daysí) represents the exponential growth/regrowth of the tumor during treatment. These rate 
constants may be expressed in terms of half-lives and doubling times. Thus, d equals ln2 (0.693) 
divided by the time it takes for the regressing part to shrink by half, whereas g equals ln2 divided 
by the time for the growing component to double. (44)
Two earlier papers depict theoretical curves depicting the separate components of Equation (A) 
and how these combine together to give the time dependence of the tumor size,  f. (44) When the 
data showed a continuous decrease from the time of treatment start, so that only the regression 
parameter d was found to differ significantly from zero with P < 0.05, Equation (A) was replaced 
by the following reduced form, with the growth rate constant eliminated: f(t) = exp(-d * t) (B)
When tumor measurements showed a continuous increase, so that only the growth parameter g
was found to differ significantly from zero with P < 0.05, Equation (A) was replaced by the 
following reduced form, with the decay constant eliminated: f(t) = exp(g *t) .
8.1.4
Data Analysis 
For each patient an attempt to fit Equation (A) to each data set for which more than one data 
point is available. Curve fittingbo will be performed using Sigmaplot (Systat Software), or by 


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using the Solver routine in an Excel spreadsheet. We will extract parameters g and d with their 
associated Student's t and P values. (44) Data will be analyzed in Excel (Microsoft) and in 
Sigmaplot 9.0. Linear regressions to evaluate the relationship between the growth rate constant,
g, or other parameters will be implemented using the polynomial linear routine of Sigmaplot 9.0. 
Sample comparisons were performed by Student's t-test, using SigmaStat 3.5 (Systat Software), 
with P set at 0.05 for significance. (44)
9
COLLABORATIVE AGREEMENTS 
9.1
AGREEMENT TYPE
9.1.1
Cooperative Research and Development Agreement (CRADA)
x
A CRADA (#02859) is in place with Medivation and Astellas to provide 
enzalutamide.
x
A CRADA (#02377) is in place with Bavarian Nordic to provide PSA-TRICOM.
9.1.2
Material Transfer Agreement (MTA) 
x
A MTA is in place with The Cleveland Clinic Foundation for the studies discussed in 
section 4.1.6 (MTA#4122006).


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10 HUMAN SUBJECT PROTECTIONS 
10.1 RATIONALE FOR SUBJECT SELECTION
10.1.1 Selection Based on Gender, Ethnicity, and Race 
Subjects from all racial/ethnic groups are eligible for this study if they meet the eligibility criteria. 
To date, there is no information that suggests that differences in drug metabolism or disease 
response would be expected in one group compared with another. Efforts will be made to extend 
accrual to a representative population, but in this preliminary study, a balance must be struck 
between patient safety considerations and limitations on the number of individuals exposed to 
potentially toxic and/or ineffective treatments on one hand and the need to explore ethnic aspects 
of clinical research on the other hand. If differences in outcome that correlate with ethnic identity 
are noted, accrual may be expanded or a follow-up study may be written to investigate those 
differences more fully. Women are not eligible for this study as this diease occurs only in men.
10.1.2 Strategies/Procedures for Recruitment
Patient accrual for this protocol will be facilitated by Web-based recruitment strategies. This 
protocol will be listed on www.clinicaltrials.gov.
10.1.3 Justification for Exclusions
Due to impaired cellular immunity with the concomitant increased risk of serious side effects from 
vaccinations with infectious agents, the Centers for Disease Control and Prevention recommends that 
HIV infected patients be excluded, in addition, patients with chronic hepatitis infection, including B 
and C, because of potential immune impairment.
10.2 PARTICIPATION OF CHILDREN
Men under the age of 18 will not be eligible for participation in this study based on the fact that 
patients under 18 are unlikely to have this disease and there are unknown toxicities in pediatric 
patients.
10.3 PARTICIPATION OF NIH SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 7.5), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed.


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10.4 EVALUATION OF BENEFITS/RISKS/DISCOMFORTS
There is no standard therapy for patients with prostate cancer and rising PSA following local 
definitive therapy. Potential risks of vaccine and enzalutamide therapy in this patient population 
include the range of side effects outlined in section 9. Both drugs have been well tolerated in 
previous large trials and there are no anticipated overlapping toxicities for patients getting both 
drugs.
10.4.1 Alternative Approaches or Treatments
Patients will be advised verbally and in writing regarding the risks and benefits of this trial, 
treatment requirements, and alternative approaches to entering the trial. Written consents will be 
obtained.
10.4.2 Procedures to Eliminate or Minimize Potential Risks
This study may involve unforeseeable risks for patients, such as side effects whose exact nature 
and severity are unpredictable. Scrupulous care will be taken to minimize such side effects. All 
patients will be given blood tests, physical examinations, and scans, as described in the 
monitoring schedule (Appendix C), and must have a local physician to provide long-term care 
and monitoring for complications. Immediate medical treatment is available at the Clinical 
Center, NCI, Bethesda, Maryland, for any patients who suffer physical injury as a result of 
participation in this study. No compensation is available, but any injury will be evaluated and 
treated in keeping with the benefits or care to which patients are entitled under applicable 
regulations.
10.4.3 Provisions for Monitoring Data Collection to Ensure Subject Safety 
As information is gathered from this trial, clinical results will be shared with patients.  
Laboratory and clinical data will be frequently gathered and any new significant finding(s) found 
during the course of the research, which may affect a patient’s willingness to participate further, 
will be explained.
Confidentiality of information concerning participants will be maintained, including in all 
publications and presentations resulting from this study.  Names of participants or material 
identifying participants will not be released without permission, except as such release is 
required by law.  Records at the National Cancer Institute are maintained according to current 
legal requirements, and are made available for review, as required by the Food and Drug 
Administration or other authorized users, only under the guidelines established by the Federal 
Privacy Act.
10.5 RISKS/BENEFITS ANALYSIS
This study involves clinical research with an experimental vaccine designed to generate an 
immune response against antigens found in prostate cancer. Patients will undergo multiple 
vaccinations. Side effects of the vaccine are outlined elsewhere (see section 11).  Whether the 
vaccine will have any clinical effect is unknown; therefore, benefit cannot be promised, nor the 
chance of benefit accurately predicted.  Enzalutamide is an FDA-approved therapy with a known 
and minimal toxicity profile (section 11). Participation in this study is voluntary, and refusal will 
not result in penalty or loss of benefit to which the patient is otherwise entitled.   


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The standard of care for patients with nmCSPC includes ADT and active surveillance.  
Generally, these patients can be followed without therapy until their PSA doubling time escalates 
at which time ADT is often started.  All patients in the proposed trial will receive enzalutamide.  
Based on previous trials with high dose bicalutamide, 34 of 36 evaluable patients had PSA 
declines by a median of 96.5% and these nadirs were achieved within the first 4 weeks of 
treatment (10). We would expect similar if not better results with enzalutamide.  Therefore, a
clinical trial in this population is ethical and appropriate.  The NCI has conducted several trials in 
this population previously.  
Participation may be discontinued at any time without penalty, and the patient will be 
encouraged to discuss any concerns or questions.
10.6 CONSENT AND ASSENT PROCESS AND DOCUMENTATION
The investigational nature and objectives of this trial, the procedures involved, and their 
attendant risks and discomforts, potential benefits, and potential alternative therapies will be 
explained to the patient and a signed informed consent obtained. Any experimental invasive 
procedure will require a separate consent form. All Associate Investigators listed in this protocol 
who have clinical privileges are permitted to obtain informed consent. For the apheresis for 
research in the protocol, the patient will consent at the time of the procedures.  If the patient 
refuses the apheresis at that time, the refusal will be documented in the medical record and in the 
research record.
10.6.1 Telephone Re-Consent Procedure
Re-consent on this study may be obtained via telephone according to the following procedure: 
the informed consent document will be sent to the subject. An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form. 
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent.  The original informed consent document will be sent back to the 
consenting investigator who will sign and date the consent form with the date the consent was 
obtained via telephone. A fully executed copy will be returned via mail for the subject’s records.  
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record.
10.6.2 Informed Consent of Non-English Speaking Subjects
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OSHRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2).  The 
summary that will be used is the English version of the extant IRB approved consent document.  
Signed copies of both the English version of the consent and the translated short form will be 


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given to the subject or their legally authorized representative and the signed original will be filed 
in the medical record.
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation (using either the long translated form or the short form). Preferably 
someone who is independent of the subject (i.e., not a family member) will assist in presenting 
information and obtaining consent. Whenever possible, interpreters will be provided copies of 
the relevant consent documents well before the consent conversation with the subject (24 to 48 
hours if possible). 
We request prospective IRB approval of the use of the short form process for non-English 
speaking subjects and will notify the IRB at the time of continuing review of the frequency of the 
use of the Short Form.
11 PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION
11.1RECOMBINANT FOWLPOX-PSA(L155)/TRICOM
Other Names: PROSTVAC-F/TRICOM; PROSTVAC-F
Classification: Recombinant fowlpox virus vector vaccine of the genus Avipoxvirus.
Product Description:
Recombinant Fowlpox-PSA(L155)/TRICOM is a recombinant 
fowlpox virus vector vaccine containing the genes for human PSA and three co-stimulatory 
molecules (designated TRICOM): B7.1, ICAM-1 (intercellular adhesion molecule-1), and 
LFA-3 (leukocyte function-associated antigen-3). The PSA gene coding sequence is modified to 
code for a single amino acid substitution [isoleucine to leucine at amino acid position 155 of the 
PSA antigen (designated L155)], which is designed to enhance immunogenicity. This modification 
occurs in a 10-mer, HLA-A2-restricted, immunodominant epitope of the antigen [designated PSA-
3 (amino acids 154-163)]. An attenuated, live, plaque-purified isolate from the POXVAC-TC 
strain of fowlpox virus was used as the parental virus for this recombinant vaccine. A plasmid 
vector containing the modified PSA gene and the genes for the three co-stimulatory molecules 
is used for in vivo recombination between the plasmid vector and parental fowlpox virus genome. 
The recombinant vaccine is manufactured by infection of primary chicken embryo dermal (CED) 
cells with the recombinant fowlpox virus. Fowlpox virus can infect mammalian cells and express 
the inserted transgenes to stimulate both humoral and cellular immunity, but cannot replicate in 
non-avian species, making systemic infections unlikely. 
11.1.1 How Supplied 
Recombinant Fowlpox-PSA(L155)/TRICOM is supplied in vials containing 0.75 mL of the 
vaccine at a final viral concentration titer of 2 x 109 infectious units/mL formulated in phosphate-
buffered saline containing 10% glycerol.


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11.1.2 Preparation 
Thaw vials completely at room temperature. Ensure the thawed contents are at the bottom of the 
upright vial and vortex vigorously at high power for at least ten seconds prior to dose preparation. 
Withdraw 0.5 mL (1 x 109 infectious units) into a 1 mL syringe for administration by subcutaneous 
injection.
11.1.3 Storage 
Store intact vials of Recombinant Fowlpox-PSA(L155)/TRICOM at –70oC or colder. 
11.1.4 Stability
Shelf-life stability studies of the intact vials are ongoing. Once the intact vials are thawed, the vaccines 
maintain their potency for up to 4 days when stored at 2-8oC. Do not re-freeze thawed vials. Vials of 
Recombinant Fowlpox-PSA(L155)/TRICOM are for single-use only and do not contain a 
preservative. Administer prepared doses as soon as possible following preparation (i.e., within one 
hour). If necessary, store prepared doses at 2-8oC for up to 4 hours following preparation.
11.1.5 Route of Administration 
Recombinant Fowlpox-PSA(L155)/TRICOM is administered by subcutaneous injection. 
11.1.6 Special Handling
Fowlpox virus is classified as a Biosafety Level 1 agent.  These agents are not known to cause 
disease in healthy human adults and are of minimal potential hazard to personnel and the 
environment under ordinary conditions of use. Clinicians can use techniques generally acceptable 
for nonpathogenic material. The recombinant vaccine is a preparation of a live virus (infectious 
for birds) containing DNA sequences derived from the human genome. Handle the recombinant 
vaccine as a hazardous biological substance and dispose of waste materials as hazardous biological 
waste, with incineration according to local institutional policy and according to local, state, and 
federal regulations. Healthcare workers handling the recombinant fowlpox vaccine should avoid 
direct contact with pet birds for at least 72 hours after working with the agent. 
Preparation, Handling and Disposal Recommendations 
1. Strictly adhere to standard microbiological practices and techniques.
2. Limit/restrict access to preparation areas while dose preparation is in progress. 
3. Use appropriate infection control measures (e.g., thorough hand washing) after handling any 
materials.
4. Institute and follow policies for safe handling of sharps.
5. Perform all dose preparations in a certified Class II biological safety cabinet, generally using 
procedures, guidelines and personal protective apparel used during preparation of 
antineoplastic agents [e.g., minimizing creation of aerosols; no eating, drinking, handling 
contact lenses or applying cosmetics in the work area; using appropriate personal protective 
apparel - gowns, sterile latex gloves (double-gloving is recommended), respirator masks, 
protective eye wear, hair cover]. 


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6. Decontaminate the biological safety cabinet prior to dose preparation with sterile gauze soaked 
in 10% bleach solution (0.52% sodium hypochlorite solution), or other appropriate disinfectant 
suitable for decontamination, rinsing, then wiping down with sterile gauze soaked in 70%
alcohol. Consult specific manufacturer’s recommendations with respect to disinfectant 
concentration, contact time and method of application. 
7. Have all necessary supplies on-hand before beginning the preparation procedure. Develop a 
detailed worksheet outlining all supplies, dose calculations, and preparation procedures, and 
keep it available.
8. Place an empty biohazard sharps container lined with a leak-proof biohazard bag in or near the 
biosafety cabinet to dispose of all waste generated.
9. Transport the agent from the freezer to the work area in leak proof bag. 
10. Wipe or spray items used for dose preparation with 70% alcohol before placing in the 
biological safety cabinet. Disinfectants should remain in contact with the surfaces for at least 
five minutes prior to dose preparation. Avoid exposing the virus to disinfectants.
11. Wipe the syringe containing the prepared dose with 70% alcohol before removing it from the 
biological safety cabinet; transport it in a leak proof bag or container labeled with a biohazard 
symbol.
12. Place all waste into the sharps container lined with the leak proof biohazard bag and 
decontaminate the biological safety cabinet again by wiping down all surfaces with sterile 
gauze soaked in 10% bleach solution, or other appropriate disinfectant, rinsing, then wiping 
down with sterile gauze soaked in 70% alcohol. Following decontamination, dispose of 
personal protective apparel in the biohazard safety bag.
13. Incinerate waste according to institutional policy and according to local, state, and federal 
regulations.
14. Handle accidental spills similarly to antineoplastic spills and/or according to institutional 
policy:
x
Prevent others from entering the area and allow aerosols time to settle (approximately 10 
minutes). 
x
Use protective apparel, eyewear, mask, and gloves. 
x
Cover spills with disposable absorbent towels. 
x
Decontaminate the area with 10% bleach solution, or other appropriate disinfectant suitable 
for decontamination, allowing approximately a 20-minute contact time. 
x
Dispose of all waste as biohazardous waste and incinerate according to institutional policy 
and according to local, state, and federal regulations. 
15. Immediately report spills and accidents resulting in overt exposure to recombinant DNA 
molecules to the Institutional Biosafety Committee and NIH/OSP (Office of Science Policy). 
Send reports to the Office of Science Policy, National Institutes of Health, 6705 Rockledge 
Drive, Suite 750, MSC 7985, Bethesda, MD 20892-7985. Phone (301) 496-9838. Provide 
medical evaluation, surveillance, and treatment as appropriate and maintain written records of 
the event.
For more information about biohazard risk group classification and biohazard safety 
levels see:
x
NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH 
Guidelines). See current version at:
http://osp.od.nih.gov/sites/default/files/NIH_Guidelines.html


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x
Biosafety in Microbiological and Biomedical Laboratories; U. S. Department of 
Health and Human Services Centers for Disease Control and Prevention and 
National Institutes of Health. See current edition at:
http://www.cdc.gov/biosafety/publications/index.htm
Patient Care Implications and Contraindications 
Cover vaccination sites with a sterile dry dressing (e.g., Telfa pad). Once the injection site is 
healed, no further barrier is necessary. As a precaution, protect injection sites that are 
exhibiting evidence of weeping, oozing or ulceration with a sterile dry dressing. In these 
circumstances, instruct patients to avoid direct contact of the injection site with susceptible 
individuals (e.g.; those who may be immunocompromised by disease or therapy). Instruct
patients to avoid fathering a child for at least 4 months following therapy completion with the 
recombinant vaccine. Instruct patients receiving fowlpox vaccines to avoid direct contact with 
pet birds for at least 72 hours after vaccination or while there are any visible lesions at the 
injection site.
Due to the method of manufacturing (virus grown in primary chicken embryo dermal 
cells), patients with a history of allergy to eggs or egg products should not receive the 
vaccine.
11.2 RECOMBINANT VACCINIA-PSA(L155)/TRICOM
Other Names: PROSTVAC-V/TRICOM; PROSTVAC-V
Classification: Recombinant vaccinia virus vector vaccine of the genus Orthopoxvirus.
Product Description: Recombinant Vaccinia-PSA(L155)/TRICOM is a recombinant vaccinia 
virus vector vaccine containing the genes for human PSA and three co-stimulatory molecules
(designated TRICOM): B7.1, ICAM-1 (intercellular adhesion molecule-1), and LFA-3
(leukocyte function-associated antigen-3). The PSA gene coding sequence is modified to code for 
a single amino acid substitution [isoleucine to leucine at amino acid position 155 of the PSA antigen 
(designated L155)], which is designed to enhance immunogenicity. This modification occurs in a 
10-mer, HLA-A2-restricted, immunodominant epitope of the antigen [designated PSA-3 (amino acids 
154-163)]. An attenuated, live, derivative of the Wyeth (New York City Board of Health) strain of 
vaccinia virus is used as the parental virus for the recombinant vaccine. A plasmid vector 
containing the modified PSA gene and the genes for the three co-stimulatory molecules is used for 
in vivo recombination between the plasmid vector and parental vaccinia virus genome. The 
recombinant vaccine is manufactured by infection of primary chicken embryo dermal (CED) cells 
with the recombinant vaccinia virus. Vaccinia virus can infect mammalian cells and express the 
inserted transgenes, and is a potent immune stimulator, eliciting both a strong humoral and cellular 
immune response. Vaccinia virus is replication competent in mammalian cells, making systemic 
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11.2.1 How Supplied 
Recombinant Vaccinia-PSA(L155)/TRICOM is supplied in vials containing 0.75 mL of the 
vaccine at a final viral concentration titer of 4 x 108 infectious units/mL formulated in phosphate-
buffered saline containing 10% glycerol. 
11.2.2 Preparation 
Thaw vials completely at room temperature. Ensure the thawed contents are at the bottom of the 
upright vial and vortex vigorously at high power for at least ten seconds prior to dose preparation. 
Withdraw 0.5 mL (2 x 108 infectious units) into a 1 mL syringe for administration by subcutaneous 
injection.
11.2.3 Storage 
Store intact vials of Recombinant Vaccinia-PSA(L155)/TRICOM at –70oC or colder.
11.2.4 Stability
Shelf-life studies of the intact vials are ongoing. Once the intact vials are thawed, the vaccines 
maintain their potency for up to 4 days when stored at 2-8oC. Do not re-freeze thawed vials. Vials of 
Recombinant Vaccinia-PSA(L155)/TRICOM are for single-use only and do not contain a 
preservative. Administer prepared doses as soon as possible following preparation (i.e., within one 
hour). If necessary, store prepared doses at 2-8oC for up to 4 hours following preparation.
11.2.5 Route of Administration 
Recombinant Vaccinia-PSA(L155)/TRICOM is administered by subcutaneous injection. 
11.2.6 Special Handling and Precautions
Vaccinia virus is classified as a Biosafety Level 2 agent. These agents are associated with human 
disease and are of moderate potential hazard to personnel and the environment. The recombinant 
vaccine is a preparation of a live virus affecting humans and contains DNA sequences derived 
from the human genome. Handle the recombinant vaccine as an infectious hazardous biological 
substance and dispose of waste materials as infectious hazardous biological waste, with 
incineration according to local institutional policies and according to local, state, and federal 
regulations. 
Preparation, Handling and Disposal Recommendations 
1. Prepare a biosafety manual which advises personnel of special hazards and specific 
instructions on practices and procedures.
2. Post warning hazard signs on access doors, identifying the agents, the biosafety level, the name 
and phone number of the Principal Investigator or other responsible person, and any special 
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3. Establish policies and procedures allowing only personnel who are knowledgeable of the 
potential hazards and meet specific entry requirements (e.g., immunization) into agent 
preparation or storage areas.
4. Strictly adhere to standard microbiological practices and techniques.
5. Limit/restrict access to preparation areas while dose preparation is in progress.
6. Use appropriate infection control measures (e.g., thorough hand washing) after handling any 
materials.
7. Institute and follow policies for safe handling of sharps. Use only needle-lock syringes and 
needles for dose preparation. Use extreme caution to prevent autoinoculation. Do not bend, 
shear, or replace the needle guard from the syringe following use. Promptly place used needles 
and syringes in puncture-resistant containers for disposal.
8. Perform all dose preparations in a certified Class II biological safety cabinet, generally using 
procedures, guidelines and personal protective apparel used during preparation of 
antineoplastic agents [e.g., minimizing creation of aerosols; no eating, drinking, handling 
contact lenses or applying cosmetics in the work area; using appropriate personal protective 
apparel - gowns, sterile latex gloves (double-gloving is recommended), respirator masks, 
protective eyewear, hair cover]. 
9. Perform all procedures carefully to minimize aerosol creation.
10. Decontaminate the biological safety cabinet prior to dose preparation with sterile gauze soaked 
in 10% bleach solution (0.52% sodium hypochlorite solution), or other appropriate disinfectant 
suitable for decontamination, rinsing, then wiping down with sterile gauze soaked in 70% 
alcohol. Consult specific manufacturer’s recommendations with respect to disinfectant 
concentration, contact time and method of application. 
11. Have all necessary supplies on-hand before beginning the preparation procedure. Develop a 
detailed worksheet outlining all supplies, dose calculations, and preparation procedures, and 
keep it available.
12. Place an empty biohazard sharps container in the biosafety cabinet to dispose of all waste 
generated.
13. Transport the agent from the freezer to the work area in leak proof bag. 
14. Wipe or spray items used for dose preparation with 70% alcohol before placing in the 
biological safety cabinet. Disinfectants should remain in contact with the surfaces for at least 
five minutes prior to dose preparation. Avoid exposing the virus to disinfectants.
15. Wipe the syringe containing the prepared dose with 70% alcohol before removing it from the 
biological safety cabinet; transport it in a leak proof bag or container labeled with a biohazard 
symbol.
16. Place all waste into a sharps container lined with the leak proof biohazard bag and 
decontaminate the biological safety cabinet again by wiping down all surfaces with sterile 
gauze soaked in 10% bleach solution, or other appropriate disinfectant, rinsing, then wiping 
down with sterile gauze soaked in 70% alcohol. Following decontamination, dispose of 
personal protective apparel in the biohazard safety bag.
17. Place all waste and protective apparel in a leak proof biohazard bag, and place the bag inside 
a biohazard sharps container for incineration according to institutional policy and according to 
local, state, and federal regulations.
18. Handle accidental spills similarly to antineoplastic spills and/or according to institutional 
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a.
Prevent others from entering the area and allow aerosols time to settle (approximately 10 
minutes). 
b. Use protective apparel, eyewear, mask, and gloves. 
c.
Cover spills with disposable absorbent towels. 
d. Decontaminate the area with 10% bleach solution, or other appropriate disinfectant suitable 
for decontamination, allowing approximately a 20-minute contact time. 
e.
Dispose of all waste and protective apparel as infectious biohazardous waste and incinerate 
according to institutional policy and according to local, state, and federal regulations. 
19. Immediately report spills and accidents resulting in overt exposure to recombinant DNA 
molecules to the Institutional Biosafety Committee and NIH/OSP (Office of Science Policy). 
Send reports to the Office of Science Policy, National Institutes of Health, 6705 Rockledge 
Drive, Suite 750, MSC 7985, Bethesda, MD 20892-7985. Phone (301) 496-9838. Provide 
medical evaluation, surveillance, and treatment as appropriate and maintain written records of 
the event.
For more information about biohazard risk group classification and biohazard safety levels: 
x
NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH 
Guidelines). See current version at: 
http://osp.od.nih.gov/sites/default/files/NIH_Guidelines.html
x
Biosafety in Microbiological and Biomedical Laboratories; U. S. Department of 
Health and Human Services Centers for Disease Control and Prevention and 
National Institutes of Health. See current edition at: 
http://www.cdc.gov/biosafety/publications/index.htm
Precautions for Healthcare Workers
Recombinant vaccinia virus transmission risk to exposed healthcare workers is unknown. To date, 
no reports of transmission to healthcare personnel from vaccine recipients have been published. If 
appropriate infection control precautions are observed (such as covering the vaccination site and 
washing hands after contact with the vaccination site or bandages), healthcare workers are 
probably at less risk of infection than laboratory workers because of the smaller volume and lower 
titers of virus in clinical specimens as compared with laboratory material. However, because of 
the potential risk for transmission, healthcare personnel who prepare or administer doses of 
recombinant vaccinia vaccine or have direct contact with contaminated dressings or other 
infectious material from participants in clinical studies must adhere to appropriate infection control 
measures and should be offered vaccination with the licensed vaccinia vaccine. Do not administer 
routine, non-emergency vaccination with the licensed vaccinia vaccine to healthcare workers, if 
they, or for at least three weeks after vaccination, their close household contacts (close household 
contacts are those who share housing or have close physical contact): 
x
have active eczema or a history of eczema or atopic dermatitis, or Darier’s disease.
x
have other acute, chronic, or exfoliative skin conditions (e.g., burns, impetigo, varicella zoster, 
severe acne, or other open rashes or wounds), until the condition resolves.
x
are pregnant or intend to become pregnant within 4 weeks of vaccination or are breast-feeding.
x
are immunodeficient or immunocompromised (by disease or therapy), including HIV 
infection.


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Additionally, do not administer routine, non-emergency vaccination with the licensed vaccinia 
vaccine to healthcare workers if the vaccinee:  
x
has a moderate or severe acute illness, until the illness resolves.
x
is less than 18 years of age, unless specifically indicated.
x
is undergoing topical steroid therapy for inflammatory eye diseases or undergoing therapy with 
systemic steroids; potential immune suppression increases risk for vaccinia-related 
complications. 
x
has a history of allergy or serious reaction to prior vaccinia vaccination or any of the vaccine’s 
components.
x
As a precaution, the CDC recommends that individuals with known cardiac disease (e.g., 
previous MI, angina, CHF, cardiomyopathy, stroke or TIA) or who have > 3 known risk factors 
for cardiac disease (e.g., hypertension, hypercholesterolemia, diabetes, first degree relative 
with onset of cardiac complications prior to age 50, smoker), not receive routine, non-
emergency, prophylactic vaccination with the licensed vaccinia vaccine while a possible causal 
relationship between vaccination and cardiac events is being evaluated.
Avoid exposure to the recombinant vaccinia vaccine, any contaminated dressings, or other 
infectious materials from patients, or the patient’s inoculation site if you are pregnant or breast-
feeding; have a history or presence of active eczema or atopic dermatitis; have acute, chronic or 
exfoliative skin conditions; or, are immunocompromised. More information on vaccinia 
precautions for healthcare workers can be obtained from 
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5010a1.htm#tab2 and 
http://www.cdc.gov/mmwr/PDF/rr/rr5207.pdf.
The CDC is the only source of the licensed vaccinia vaccine. The CDC will provide vaccinia 
vaccine to protect laboratory and other healthcare personnel, whose occupations place them at risk 
of exposure to vaccinia and other closely related orthopoxviruses, including vaccinia 
recombinants. The vaccine should be administered under the supervision of a physician selected 
by the study institution. Revaccination is recommended every 10 years. For instructions on 
obtaining the licensed vaccinia vaccine, contact Drug Services, National Center for Infectious 
Diseases, CDC at (404) 639-3670.
Recombinant Vaccinia Vaccine Patient Care Implications, Contraindications and Potential 
Complications 
Patient Care Implications and Contraindications
Cover vaccination sites with a sterile dry dressing (e.g., Telfa pad). Instruct patients on proper hand-
hygiene, sterile dressing care, bathing, laundering of clothing, etc. Treat patient bandages or dressings 
removed from the vaccination site as infectious waste and dispose in appropriate biohazard containers. 
Do not administer the recombinant vaccinia vaccine if the recipient, or for at least three weeks after 
vaccination, their close household contacts (close household contacts are those who share housing 
or have close physical contact): 
x
have active eczema or a history of eczema or atopic dermatitis, or Darier’s disease.
x
have other acute, chronic, or exfoliative skin conditions (e.g., burns, impetigo, varicella zoster, 
severe acne, contact dermatitis, psoriasis, herpes or other open rashes or wounds), until the 
condition resolves.


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x
are pregnant or intend to become pregnant (due to the potential risk of fetal vaccinia); or are 
breast-feeding (due to the potential risk of contact transmission and inadvertent inoculation). 
It is currently unknown if vaccinia virus or antibodies are excreted in breast milk. Patients 
(i.e., vaccinees) should avoid fathering a child for at least 4 months following completion of 
therapy with the recombinant vaccine.
x
are in close contact with children less than 3 years of age (due to the potential risk of contact 
transmission and inadvertent inoculation).
x
are immunodeficient or immunocompromised (by disease or therapy), including individuals 
with HIV infection.
Additionally, do not administer the recombinant vaccinia vaccine if the vaccinee:
x
has a moderate or severe acute illness, until the illness resolves.
x
is undergoing topical steroid therapy for inflammatory eye diseases, or undergoing therapy 
with systemic steroids; potential immune suppression increases risk for vaccinia-related 
complications.
x
At this time, until a more definitive causal relationship is determined, it is recommended that 
patients with known CHF or clinically significant cardiomyopathy, not be vaccinated with 
recombinant vaccinia-based vaccines, due to the potential for development of myocarditis 
and/or pericarditis. 
Although the CDC believes that there is no evidence to conclude that the licensed vaccinia 
vaccine used in the Smallpox Vaccination Program causes angina or heart attacks, it 
acknowledges a possible causal relationship between the vaccination and heart inflammation.  
The CDC continues to study the relationship, but in the meantime, recommends excluding 
individuals with underlying heart disease from participation in the current Smallpox 
Vaccination Program. Patients are being immunized with recombinant vaccinia vaccines with 
therapeutic intent and will be evaluated for cardiovascular risk factors and recent or 
symptomatic cardiac events per protocol eligibility criteria. Patients will be encouraged to 
minimize cardiovascular disease risks and encouraged to follow risk reduction according to 
standard medical practice. 
Due to the method of manufacturing (virus grown in primary chicken embryo dermal cells), 
do not administer the recombinant vaccinia vaccine to patients with a history of allergy to 
eggs or egg products. Do not administer the recombinant vaccinia vaccine to patients with a 
history of allergy or serious reaction to prior vaccinia vaccination (e.g., smallpox 
vaccination).
Potential Complications Associated With Recombinant Vaccinia Vaccination
When vaccinia vaccine is administered by scarification for vaccination against smallpox, expected 
local reactions in individuals that have not previously been vaccinated with vaccinia include the 
appearance of a red papule in 3-4 days, followed by vesiculation in 5-6 days, and then the 
formation of a pustule on days 8-9. A large area of erythema may surround the vesicle and pustule. 
A crusted scab usually forms by the second week and sloughs by the third week, leaving a well-
formed scar. Maximal viral shedding occurs from days 4-14, but can continue until the scab is shed 
from the skin. Other normal local reactions can include development of local satellite lesions, 
regional lymphadenopathy that can persist for weeks following healing of the skin lesion, 
considerable local edema, and intense inflammation from the vaccination (i.e., viral cellulites), 
which may be confused with bacterial cellulites. Systemic symptoms typically occur between 8-


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10 days post-vaccination and include fever, malaise, headache, chills, nausea, myalgia, local 
lymphadenopathy, soreness and intense erythema surrounding the vaccination site.
When administered by scarification in individuals that have previously been vaccinated with 
vaccinia, expected local reactions include the appearance of a clear cut pustule 6-8 days following 
vaccination or the development of an area of definite induration around a central lesion that may 
be an ulcer or scab 6-8 days following vaccination. The response to re-vaccination depends on the 
degree of residual immunity following previous vaccination. Similar systemic symptoms may 
occur, but typically at a lower frequency. 
When recombinant vaccinia vaccines are administered by intradermal, intralesional, subcutaneous 
or intramuscular routes of injection, milder local reactions are expected, but similar systemic 
symptoms may occur.
There have been a number of complications reported in the literature associated with vaccinia 
vaccination for smallpox. Reported complications from vaccinia vaccine when given by 
scarification include: a) auto-inoculation of other sites with vaccinia, b) generalized vaccinia, c) 
eczema vaccinatum, d) progressive vaccinia (vaccinia necrosum), or e) post-vaccinial 
encephalitis.  In a 1968 ten-state survey, cases of these complications per million vaccinations in 
adult recipients (> 20 years of age) of vaccinia primary vaccination and revaccination were:
Primary Vaccination
Revaccination
auto-inoculation
606.1
25
generalized vaccinia
212.1
9.1
eczema vaccinatum
30.3
4.5
progressive vaccinia
none reported
6.8
postvaccinial encephalitis
none reported
4.5
Based on a 1968 national survey, the number of deaths in primary vaccinees was approximately 1 
per million and the number of deaths in recipients of revaccination was approximately 0.25 per 
million. Deaths were most often the result of postvaccinial encephalitis or progressive vaccinia.
Information has been reported by the US Department of Defense (DoD) during the post-
vaccination surveillance assessment of adverse events in military personnel following 
implementation of a Smallpox Vaccination Program from the period of December 13, 2002 
through May 28, 2003. Although not directly comparable to historical numbers, due to
differences in multiple population variables, estimated cases (number of cases per million 
vaccinations based on vaccination of 450,293 personnel, with a median age of 26 years and 
70.5% as primary vaccinees) of these same complications per million vaccinations were:
auto-inoculation
107
generalized vaccinia
80
eczema vaccinatum
none reported
progressive vaccinia
none reported
postvaccinial encephalitis
2.2


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Generally, self-limited adverse reactions that can be serious, but not life-threatening include 
autoinoculation, erythematous and urticarial rashes, and generalized vaccinia. More serious 
life-threatening complications include progressive vaccinia, eczema vaccinatum, and post-
vaccinial encephalitis/encephalomyelitis. The complications of vaccinia vaccination may 
involve a number of different reactions:
1. Non-specific erythematous or urticarial rashes: These rashes can appear approximately 
10 days after vaccination and may sometimes be confused with generalized vaccinia, but 
are generally self-limiting. Patients are usually afebrile and these benign rashes usually 
resolve spontaneously within 2-4 days. Erythema multiforme can present as different types 
of lesions, including macules, papules, urticaria, and bull’s eye lesions (dark papule or 
vesicle surrounded by a pale zone and an area of erythema). These lesions may be 
extremely pruritic, lasting up to four weeks. Rarely, more serious bullous erythema 
multiforme (Stevens-Johnson syndrome) may occur, requiring hospitalization. Vaccinia 
Immune Globulin (VIG) therapy is not indicated to treat these rashes. Supportive care 
measures are warranted since these rashes are likely manifestations of an immune response 
or hypersensitivity reaction to the vaccine and are not likely to contain vaccinia virus.
2. Bacterial Infection: Vaccination site infection, most likely due to staphylococcus and 
streptococcus normal skin flora, is rare. Onset is approximately 5 days post-vaccination 
and is more common in children. Appropriate antibiotic therapy is required.
3. Inadvertent Inoculation: This can occur in the vaccinee (autoinoculation) as well as in 
close contacts (contact transmission). Accidental infection is the most common 
complication of vaccinia vaccination, accounting for approximately 50% of all 
complications associated with vaccination and revaccination. This usually results from 
autoinoculation of vaccinia virus transferred from the site of the vaccination. Sites typically 
involved include the face, eyelids, nose, mouth, genitalia, or rectum, but can also involve 
the arms, legs, and trunk. Contact transmission of vaccinia, with accompanying toxicities, 
may occur when a recently vaccinated individual has contact with a susceptible individual.  
In a 1968 ten-state survey, contact transmissions were reported to occur at a rate of 27 
infections per million vaccinations.  The age group in which contact transmission occurred 
most commonly was in children d 5 years. Eczema vaccinatum as a result of contact 
transmission may result in a more severe syndrome than that seen in vaccinees, perhaps 
because of multiple simultaneous inoculations. About 30% of eczema vaccinatum cases 
reported in the 1968 ten-state survey were a result of contact transmission. It is possible 
that the number of cases of contact transmission would be greater in today’s population, 
due to a largely unvaccinated patient population against smallpox. Contact transmission 
rarely results in postvaccinial encephalitis or progressive vaccinia. Most cases of 
inadvertent inoculation usually resolve without specific therapy and resolution of lesions 
follow the same course as the vaccination site in immunocompetent individuals. VIG can 
be used for severe cases involving extensive lesions or if comorbid conditions exist. VIG 
is contraindicated in the presence of isolated keratitis due to the risk of increased corneal 
scarring. VIG use can be considered in cases of ocular implantation, with keratitis, if 
vision-threatening or if other life-threatening vaccinia-related complications exist that 
require VIG therapy.  
4. Generalized vaccinia: Generalized vaccinia (GV) is characterized by a disseminated 
maculopapular or vesicular rash of varying extent on any part of the body and typically 


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develops 6-9 days after vaccination. The lesions follow the same course as the vaccination 
site lesion. The lesions are hematogenously spread and may contain vaccinia virus. In 
immunocompetent individuals, the rash is generally self-limiting and requires supportive 
care therapy. VIG treatment can be used in severe cases for patients who are systemically 
ill and whose condition might be toxic or who have serious underlying immunosuppressive 
illnesses.
The differential diagnosis of GV includes eczema vaccinatum, erythema multiforme, 
inadvertent inoculation at multiple sites, and uncommonly, early stages of progressive 
vaccinia or other vesicular diseases (e.g., severe chickenpox or disseminated herpes). 
Several publications have investigated the reporting of GV among those individuals who 
received smallpox vaccinations during 2003.  Out of 38,440 vaccine recipients, 29 reports 
of possible GV during January 2003–December 2003 were identified but only 2 reports
met the case definition. More than 75% of the reports received a final diagnosis of 
hypersensitivity reaction or nonspecific rash after review by dermatologists or because 
laboratory results were negative for vaccinia and other orthopoxviruses.  Of 74 cases 
investigated in 753,226 smallpox vaccinations administered in December 2002 to 
December 2004, 50 (67.6%) met the case definition of possible GV.  Cases occurred more 
frequently in primary vaccinees (rate, 81 per 1 million vaccinees) than in those 
revaccinated (rate, 32 per 1 million vaccinees).  However, none met the case definition of 
probable or confirmed GV, including 15 with virologically negative laboratory evaluations 
(e.g., culture, polymerase chain reaction, or skin biopsy).  Twenty-one reports of postscab 
lesions were made between January and August 2003 among 37,542 smallpox vaccinees.  
The lesions (scab and/or fluid) of seven patients were tested for vaccinia virus by use of 
polymerase chain reaction and/or immunohistochemistry; all were found to be negative.  
In addition, the postscab lesions of four of the patients were biopsied.  The results from 
two of the biopsies suggested an allergic contact dermatitis, and results of one each 
demonstrated chronic dermatitis and squamous cell carcinoma.  None of the four biopsied 
lesions had histologic evidence of viropathic changes and no evidence supported smallpox 
vaccination as a cause for any of the lesions.  
5. Eczema vaccinatum: Eczema vaccinatum is a serious complication in persons with 
eczema and other types of chronic or exfoliative skin conditions. It can also occur among 
eczematous contacts of recently vaccinated persons. Vaccinial lesions (generalized 
papular, vesicular or pustular lesions) develop on areas of the skin that are, or had at one 
time been, eczematous. These areas become highly inflamed and lesions may spread to 
healthy skin. The rash is often accompanied by fever and individuals are systemically ill. 
The fatality rate for untreated cases (prior to availability of VIG) has been reported from 
30-40%. Following availability of VIG, mortality was reduced to approximately 7%. Early 
diagnosis and prompt treatment with VIG is necessary to reduce mortality. 
6. Progressive vaccinia: Progressive vaccinia is the most serious cutaneous complication,
occurring when the local vaccination lesion fails to heal and develops progressive necrosis, 
with destruction of large areas of skin, subcutaneous tissue, and underlying structures. 
Progressive lesions may spread to other skin surfaces and to bone and viscera.   Progressive 
vaccinia is associated with a high mortality rate. This complication has been seen in 
patients with a compromised immune system due to a congenital deficiency, 
lymphoproliferative 
disease, 
immunosuppressive 
treatment, 
or 
HIV 
infection.
Management should include aggressive VIG therapy.


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7. Post-Vaccinial Encephalitis/Encephalomyelitis: Vaccinial complications affecting the 
CNS are unpredictable. Post-vaccinial encephalitis typically affects children < 2 years of 
age and is characterized by an onset of symptoms 6-10 days following vaccination, which 
include seizures, hemiplegia, aphasia, and transient amnesia. Histopathological changes 
include generalized cerebral edema, mild lymphocytic meningeal infiltration, ganglion 
degenerative changes and perivascular hemorrhages. Older children and adults can develop 
encephalitis or encephalomyelitis characterized by an onset of symptoms 11-15 days 
following vaccination, which include fever, vomiting, headache, malaise, and anorexia, 
progressing to loss of consciousness, amnesia, confusion, disorientation, restlessness, 
delirium, drowsiness, seizures and coma. Histopathological changes include demyelination 
with lymphocytic infiltration, but limited cerebral edema. Mortality rates have ranged from 
15-25%, with 25% of patients who recover being left with varying degrees and types of 
neurological deficits. VIG has not been shown to be effective in treating CNS disease and 
is not recommended. Post-vaccinial encephalitis/encephalomyelitis are diagnoses of 
exclusion and are not believed to be a result of replicating vaccinia virus.  Although no 
specific therapy exists, supportive care, anticonvulsants, and intensive care might be 
required. A review of vaccinia-related deaths (68) during a 9-year period (1959–1966 and 
1968) revealed that among first-time vaccines, 36 (52%) patients died as a result of post-
vaccinial encephalitis.  
8. Fetal Vaccinia: Fetal vaccinia is a rare, but serious complication following vaccinia 
vaccination during pregnancy or shortly before conception (e.g., within four weeks).  To 
date, fewer than 50 cases have been reported and often result in fetal or neonatal death. 
Efficacy of VIG therapy in a viable infant or used prophylactically in women during 
pregnancy is unknown. The CDC has established a National Smallpox Vaccine in 
Pregnancy Registry. This registry will follow women during their pregnancies and their 
babies, after they are born, to determine the outcome of such pregnancies. The CDC can 
be contacted at (404) 639-8253.
9. Myocarditis/Pericarditis: The CDC has recommended a temporary medical deferral to 
the voluntary Smallpox Vaccination Program for persons with heart disease or 
cardiovascular risk factors (March 25, 2003) and issued “interim supplementary 
information” regarding evidence that smallpox vaccination may cause myocarditis and/or 
pericarditis (March 31, 2003) in people recently vaccinated with the smallpox vaccine. The 
cardiac events reported include myocardial infarction, angina, myocarditis, pericarditis, 
and myopericarditis. Although the CDC believes that there is no evidence to conclude that 
the licensed vaccinia vaccine causes angina or heart attacks, it acknowledges a possible 
causal relationship between the vaccination and heart inflammation.  The CDC continues 
to study the relationship, but in the meantime, recommends that individuals with 
underlying heart disease be excluded from participation in the current Smallpox 
Vaccination Program. While it is currently not possible to fully evaluate the risk of cardiac 
events or the risk of myocarditis, pericarditis, or myopericarditis associated with vaccinia 
vaccination, it is reasonable to inform patients participating in studies using recombinant 
vaccinia virus of these reports and provide relevant guidance for evaluating these events. 
Further investigation from the ongoing vaccine program may provide additional data 
regarding an association or lack of association with cardiovascular disease. Patients are 
being immunized with recombinant vaccinia vaccines with therapeutic intent and will be 
evaluated for cardiovascular risk factors and recent or symptomatic cardiac events per 


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protocol eligibility criteria. Patients will be encouraged to minimize cardiovascular disease 
risks and encouraged to follow risk reduction according to standard medical practice. At 
this time the evidence for an association with myocarditis, pericarditis, or myopericarditis 
seems plausible, but a rare event.  If not otherwise excluded, patients with known CHF or 
clinically significant cardiomyopathy requiring treatment should be excluded from 
protocol eligibility.      
Out of a total of 540,824 military personnel vaccinated with a New York City Board of 
Health strain of vaccinia from December 2002 through December 2003, 67 developed 
symptomatic myopericarditis.  In the 61 ECGs that were reviewed, an identifiable 
abnormality was evident in 46 (75.4%).  The most common abnormalities included ST-
segment changes observed evident in 40 patients (65.6%); 5 patients (8.2%) had normal 
variant early repolarization, and T-wave abnormalities were noted in 11 patients (18.0%).  
In addition, cardiac enzymes were elevated in 60 of 61 (98.4%) patients evaluated with this 
assay.  On follow-up of 64 patients, all patients had objective normalization of 
electrocardiography, echocardiography, graded exercise testing, laboratory testing, and 
functional status; 8 (13%) reported atypical, non-limiting persistent chest discomfort.  
Among 37,901 health care workers vaccinated with the identical strain, 21 myo/pericarditis 
cases were identified; 18 (86%) were revacinees. Twelve met criteria for either myocarditis 
or myopericarditis, and 9 met criteria for pericarditis only (6 suspected and 3 probable).  
The severity of myo/pericarditis was mild, with no fatalities, although 9 patients (43%) 
were hospitalized.
Treatment of Vaccinia Vaccination Complications
Vaccinia Immune Globulin (VIG): First-line treatment of some of the complications of vaccinia 
caused by dissemination of vaccinia virus (severe cases of inadvertent inoculation involving 
extensive lesions or if comorbid conditions exist, severe cases of generalized vaccinia in patients
that are systemically ill and whose condition might be toxic or who have serious underlying 
immunosuppressive illnesses, eczema vaccinatum, and progressive vaccinia) is with VIG.  VIG is 
contraindicated, however, for the treatment of isolated vaccinial keratitis.  VIG is a sterile solution 
of the immunoglobulin fraction of pooled plasma from individuals inoculated with vaccinia 
vaccine.  VIG is only available through the CDC’s Strategic National Pharmaceutical Stockpile by 
contacting the CDC’s Clinician Information Line at 1-877-554-4625 or the Director's Emergency 
Operations Center (DEOC) at 770-488-7100. Upon receipt of a call from a patient or upon direct 
observation of a patient or contact who manifests signs and symptoms of any of the above 
conditions, the investigator should place a call to the CDC as soon as possible: 1) to initiate review 
of the clinical case, 2) to seek consultation on the appropriateness of VIG therapy, 3) to determine 
the appropriate VIG dose and dosing method for administration, if VIG therapy is required, and 4) 
to determine how to access and have the appropriate doses of VIG delivered.  Early institution of 
VIG therapy is advised following recognition of clinical symptoms compatible with some vaccinia 
complications (eczema vaccinatum, severe generalized vaccinia, progressive vaccinia, and some 
cases of inadvertent inoculation).  The effectiveness of VIG therapy appears to be time dependent. 
VIG has not proven to be of benefit in the treatment of post-vaccinial encephalitis, and is 
contraindicated for treatment of isolated vaccinial keratitis due to the increased risk of corneal 
scarring.  A new IV formulation of VIG that has a lower level of aggregated protein allowing it to 


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be used by either the IM or IV route is available through the CDC.  This formulation will most 
likely be preferred for administration and the CDC will instruct investigators regarding appropriate 
dosing and method of administration based on the formulation and availability.  There is no 
guarantee that VIG will successfully treat complications.  At present, there are no other anti-viral 
therapies of proven benefit for the treatment of vaccinia-related complications.
11.3 CIDOFOVIR (VISTIDE®, GILEAD SCIENCES)
Cidofovir is an FDA-approved antiviral drug for the treatment of CMV retinitis among patients 
with AIDS. Cell-based in vitro studies and animal model studies have demonstrated this agent’s 
antiviral activity against certain orthopoxviruses.  Currently, its efficacy in the treatment of 
vaccinia-related complications in humans is unknown.  According to the CDC, VIG is 
recommended as first line of therapy.  Cidofovir may be considered as a secondary treatment, 
and will only be used when VIG therapy is not effective [Medical Management of Smallpox 
(Vaccinia) Vaccine Adverse Reactions: Vaccinia Immune Globulin and Cidofovir. Last updated 
September 28, 2009.  Available at:  http://www.bt.cdc.gov/agent/smallpox/vaccination/mgmt-
adv-reactions.asp]. 
11.4 ENZALUTAMIDE 
Please see FDA-approved packet insert for Enzalutamide for complete agent information.
11.4.1 Description and formulation
Enzalutamide (XTANDI ©) is an androgen receptor inhibitor. The chemical name is 4-{3-[4-
cyano-3-(trifluoromethyl)phenyl]-5,5- dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-
fluoro-N-methylbenzamide. Enzalutamide is a white crystalline non-hygroscopic solid. It is 
practically insoluble in water. XTANDI is provided as liquid-filled soft gelatin capsules for oral 
administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl 
polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated 
hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified 
water, titanium dioxide, and black iron oxide.
11.4.2 Source
Medivation and Astellas Inc. have reviewed the proposed clinical trial design and have agreed to 
provide enzalutamide for the trial. 
11.4.3 Storage
Store enzalutamide capsules at 20°C to 25°C (68°F to 77°F) in a dry place and keep the 
container tightly closed. Excursions permitted from 15°C to 30°C (59°F to 86°F).
11.4.4 Stability
The company providing the IND drug will also provide the expiration date for each lot allocated 
to this study.


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11.4.5 Dosage and Administration
Enzalutamide 160 mg (four 40 mg capsules) administered orally once daily.
Swallow capsules whole. Enzalutamide can be taken with or without food.
11.4.6 Adverse Effects
Seizure
In the randomized clinical trial, 7 of 800 (0.9%) patients treated with enzalutamide 160 mg once 
daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures 
occurred from 31 to 603 days after initiation of enzalutamide. Patients experiencing seizure were 
permanently discontinued from therapy and all seizures resolved. There is no clinical trial 
experience re-administering enzalutamide to patients who experienced seizures. The safety of 
enzalutamide in patients with predisposing factors for seizure is not known because these 
patients were excluded from the trial. These exclusion criteria included a history of seizure, 
underlying brain injury with loss of consciousness, transient ischemic attack within the past 12
months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use 
of concomitant medications that may lower the seizure threshold. Because of the risk of seizure 
associated with enzalutamide use, patients should be advised of the risk of engaging in any
activity where sudden loss of consciousness could cause serious harm to themselves or others.
Other adverse events 
7KHPRVWFRPPRQDGYHUVHGUXJUHDFWLRQVUHSRUWHGLQSDWLHQWVUHFHLYLQJHQ]DOXWDPLGHLQ
the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, 
peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular 
weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and
cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher 
adverse reactions were reported among 47% of enzalutamide-treated patients and 53% of 
placebo-treated patients. Discontinuations due to adverse events were reported for 16% of 
enzalutamide-treated patients and 18% of placebo-treated patients. The most common adverse 
reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the 
enzalutamide-treated patients compared to none (0%) of the placebo-treated patients.
Laboratory Abnormalities
In the randomized clinical trial, Grade 1-4 neutropenia occurred in 15% of patients on 
enzalutamide (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of 
Grade 1-4 thrombocytopenia was similar in both arms; 0.5% of patients on enzalutamide and 1% 
on placebo experienced Grade 3-4 thrombocytopenia. Grade 1-4 elevations in ALT occurred in 
10% of patients on enzalutamide (0.3% Grade 3-4) and 18% of patients on placebo (0.5% Grade 
3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients on enzalutamide and 2% of 
patients on placebo.
Infections
In the randomized clinical trial, 1.0% of patients treated with enzalutamide compared to 0.3% of 
patients on placebo died from infections or sepsis. Infection-related serious adverse events were 
reported in approximately 6% of the patients on both treatment arms.


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Falls and Fall-related Injuries
In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients 
treated with enzalutamide compared to 1.3% of patients on placebo. Falls were not associated 
with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated 
with enzalutamide and included non-pathologic fractures, joint injuries, and hematomas.
Hallucinations
In the randomized clinical trial, 1.6% of patients treated with enzalutamide were reported to have 
Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with 
hallucinations, the majority were on opioid-containing medications at the time of the event. 
Hallucinations were visual, tactile, or undefined.
11.4.7 Drug Interactions
Drugs that Inhibit or Induce CYP2C8
Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area 
under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl 
enzalutamide in healthy volunteers. Co-administration of enzalutamide with strong CYP2C8 
inhibitors should be avoided if possible. If co-administration of enzalutamide with a strong
CYP2C8 inhibitor cannot be avoided, reduce the dose of enzalutamide.
The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been 
evaluated in vivo.
Co-administration of enzalutamide with strong or moderate CYP2C8 inducers (e.g., rifampin) 
may alter the plasma exposure of enzalutamide and should be avoided if possible. Selection of a 
concomitant medication with no or minimal CYP2C8 induction potential is recommended.
Drugs that Inhibit or Induce CYP3A4
Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of 
enzalutamide plus Ndesmethyl enzalutamide by 1.3 fold in healthy volunteers 
The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been 
evaluated in vivo.
Co-administration of enzalutamide with strong CYP3A4 inducers (e.g., carbamazepine, 
phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of 
enzalutamide and should be avoided if possible. Selection of a concomitant medication with no 
or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., 
bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the 
plasma exposure of enzalutamide and should be avoided if possible.
Effect of Enzalutamide on Drug Metabolizing Enzymes
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in 
humans. At steady state, enzalutamide reduced the plasma exposure to midazolam (CYP3A4 
substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant 
use of enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus 


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and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., proton pump inhibitors 
(lansoprazole, omeprazole, pantoprazole, rabeprazole) and clopidogrel.) should be avoided, as 
enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, 
conduct additional INR monitoring.
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13 APPENDIX A: PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Descriptions
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
100
Normal, no complaints, no evidence 
of disease.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out light or sedentary 
work (e.g., light housework, office 
work).
80
Normal activity with effort; some 
signs or symptoms of disease.
70
Cares for self, unable to carry on 
normal activity or to do active 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 
> 50% of waking hours.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
50
Requires considerable assistance and 
frequent medical care.
3
In bed > 50% of the time. Capable 
of only limited self-care, confined 
to bed or chair > 50% of waking 
hours.
40
Disabled, requires special care and 
assistance.
30
Severely disabled, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any self-
care.  Totally confined to bed or 
chair.
20
Very sick, hospitalization indicated. 
Death not imminent.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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14 APPENDIX B: VACCINIA-PSA(L155)/TRICOM PATIENT INSTRUCTION SHEET
1.
What vaccination site reactions can you expect?
2.
How should you care for the vaccination site? 
3.
Are there any activities I should avoid?
4.
What about contact with other people?
5.
Who do I contact when I have a question?
1.
What vaccination site reactions can you expect?
A typical reaction in a patient who has been previously vaccinated with vaccinia includes the 
appearance of a small swelling in 2-3 days that may enlarge to 1-2 inches across, a small blister or 
pustule after 5-7 days, and healing with little scarring within 2-3 weeks. Some patients may have 
very little skin reaction.   Often the leg that received the vaccine may become swollen. Swollen or 
tender lymph nodes (“glands”) in the groin may be felt. A fever to 100-101qF may occur on the 
second or third day.  You may notice that you feel tired for 3 or 4 days. The vaccination site may 
itch for about 2 weeks while the scab is forming. You can take acetaminophen ("Tylenol") if you 
have any aches or fever but should avoid aspirin.  If fever continues for more than a day or two, 
you should call to speak to the clinic nurse or the research nurse. 
In patients who have never received vaccinia or in some who received it a very long time ago, a 
red swelling is followed by a blisters on day 5 to 6 and then formation of a pustule (or "boil") 1-2
inches in diameter on day 9 to 11.  A large area of redness may surround this area.  A crusted scab 
usually forms by the second week and falls off by the third week leaving a scar roughly 1/2 inch in 
diameter.  Fever and malaise (the "blahs") may occur during the blister and pustular phases. 
Swollen and tender lymph nodes may persist for months. Many of the local toxicities described 
(e.g., pustule and scab formation) are typical of reactions seen when vaccinia is administered via 
scarification or intradermal administration. These reactions may be seen, but are usually not seen 
when administered via subcutaneous injection.
2.
How should you care for the vaccination site?
Live vaccinia virus is in skin cells at the vaccination site during the 1-2 weeks until healing has 
occurred.  Maximal viral "shedding" from the vaccination site occurs from days 4-14, but can 
continue until the scab falls off from the skin. After that there is no vaccinia virus in your body.  
You can spread the virus to other parts of your body or to other people by touching the vaccination 
site and then touching your eyes, mouth, a cut or some other break in the skin. You do not pass 
vaccinia virus by coughing or sneezing or by sharing food or cups and dishes.
In general, frequent careful hand washing by you and by any persons in physical contact with you 
is the best way to prevent transmission of virus.  You should also use two types of barriers over 
your vaccination site at all times until the scab is gone.  These barriers are (1) the bandage and (2) 
clothing (pants or elbow length sleeves depending on the site of vaccination).  These barriers 
should remain in place until the scab has fallen off.


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For dressing care you will have a bag with some no-stick "First-Aid" or "Telfa" pads, disposable 
gloves, and zip-lock plastic bags.  If you run out of supplies between visits, you can use a dry 
sterile bandage (gauze or "First-Aid" or "Telfa") from the drug store.
The no-stick pad ("First-Aid" or "Telfa" pad) dressing should be worn until the site has healed.  If 
it remains clean and dry and is not coming off, you do not need to change it.  If the dressing gets 
wet either from drainage from the vaccination or from water when you are showering or if it starts 
coming off, you should remove it and put on a clean bandage.  Wear the gloves when handling the 
old dressings.  Put the old dressing and the gloves in the zip-lock bag, then wash your hands, put 
on the new bandage, and wash your hands again.  You do not need to wear gloves for the new 
bandage.  You do not need to wash the vaccination site, but while the dressing is off, you may 
wash it lightly with a cloth, soap, and water.  If you do wash, blot the site dry with a towel (don't 
rub), then put the wash cloth and the towel in the laundry.  Do not let the shower run on the 
unbandaged site because live virus could be washed onto other areas on your body. Do not put any 
steroid cream, medicated creams, or other ointments on the vaccination site.
Before you throw away the zip-lock bag with the old dressing and gloves in it, pour a little bleach 
(about a quarter cup) in the bag to help kill any virus.
Wash your hands after each step.
3. Are there any activities I should avoid or take special care?
You should not go swimming until the vaccination site has healed and you no longer need to wear 
a bandage on it. 
If you wear contact lenses, have removable dentures, have a colostomy or any other "open" area on 
your body that needs daily care, always wash your hands very well before handling your contact 
lenses, dentures, dressings, etc.  Take care of all of these procedures before changing your 
vaccination dressing.
4.
What about contact with other people?
Remember, frequent careful hand washing by you and by any persons with whom you have 
physical contact is the best way to prevent transmission of virus.  During the time you need to wear 
a bandage (for 7-14 days after vaccination) there are several kinds of people with whom you 
should avoid close contact.  "Close contact" means that you sleep in the same bed with the person, 
give the person baths, and/or touch their bare skin to change their clothes (or diapers), apply 
ointments, or change their bandages. 
The individuals you should avoid include children < 3years of age; pregnant women or nursing 
women; individuals with eczema, history of eczema or other skin conditions such as active cases 
of extensive psoriasis, severe rashes, generalized itching, infections, burns, chicken pox, or skin 
trauma; and/or immune suppressed individuals such as individuals with leukemia or lymphoma, 
with AIDS, or those receiving immunosuppressive treatment (for example, after organ transplant).  


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5.
Who do I contact when I have a question?
If you have any questions at any time, please call.  A nurse or a physician is available 24 hours a 
day by telephone.  To speak with your main doctor or with a clinic nurse, call the 
Hematology/Oncology Clinic between 8 AM and 4:30 PM Monday to Friday.  To speak with the 
research nurses, call the research nurse office during the day; during nights, weekends, and 
sometimes during the day, when the research office is empty, you may leave a message for the 
research nurse on the answering machine.  You can call Dr. Ravi Madan or Dr. James Gulley any 
time during weekday hours.  In an emergency on weekends, evenings, or holidays, you can always 
get in touch with the MEDICAL ONCOLOGY DOCTOR ON CALL (listed below) The on call 
doctor will call you back.   If you have to go to an emergency room near your home, go to the 
hospital first, and then have the doctors there call for more information.
PHONE NUMBERS
3 South East
(301) 451-1152
12th floor Oncology Clinic
(301) 496-4026*
Ravi Madan, MD
(301) 480-7168*
James Gulley, MD, PhD
(301) 480-7164*
*after clinic hours the NCI 
Medical Oncology physician 
On call through NIH page
operator
(301) 496-1211


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15 APPENDIX C : ON STUDY AND FOLLOW-UP EVALUATIONS
COHORT 1
Arm A (Enzalutamide 
only)
Arm B (Enzalutamide + PSA-
TRICOM)
Prior to Enrollment
Screening for eligibility, 
Informed consent, NIH 
Advanced Directives Form1
Screening for eligibility, Informed 
consent, NIH Advanced Directives 
form1
Within 8 weeks of 
initiating treatment
*Apheresis, Lab work (HIV, 
Hep B and C), baseline scans 
(MRI/CT and bone scans),
EKG
*Apheresis, Lab work (HIV, Hep B 
and C), baseline scans (MRI/CT and 
bone scans), EKG
Within 16 days of 
beginning treatment 
(day -16 to day 1)
Baseline history and physical 
exam, ECOG status, Research 
Blood, CBC, Acute, Hepatic, 
Mineral Panels, LDH, CK, 
Uric Acid, Total Protein, 
TBNK, PSA, testosterone,
PAP (prostatic acid 
phosphatase),
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol 
Randomization
Baseline history and physical exam, 
ECOG status, Research Blood, CBC, 
Acute, Hepatic, Mineral Panels, 
LDH, CK, Uric Acid, Total Protein, 
TBNK, PSA, testosterone, PAP 
(prostatic acid phosphatase),
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol 
Randomization
Day 1
Enzalutamide day 1 month 1
(daily dose of 160 mg)
Enzalutamide day 1 month 1 + 
PSA-TRICOM (Prostvac-V) dose 1
Week 3
Physical examination
Research Blood, CBC, Acute, 
Hepatic, Mineral Panels, LDH, 
CK, Uric Acid, Total Protein,
Physical examination
Research Blood, CBC, Acute, 
Hepatic, Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,


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Arm A (Enzalutamide 
only)
Arm B (Enzalutamide + PSA-
TRICOM)
TBNK, PSA, testosterone,
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol 
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol 
PSA-TRICOM (Prostvac-F) dose 1
Week 5
Physical examination
Research Blood, CBC, Acute, 
Hepatic, Mineral Panels, LDH, 
CK, Uric Acid, Total Protein,
TBNK, PSA, testosterone,
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol 
Enzalutamide day 1 month 2
(daily dose of 160 mg)
Physical examination
Research Blood, CBC, Acute, 
Hepatic, Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol 
Enzalutamide day 1 month 2 + 
PSA-TRICOM (Prostvac-F) dose 2
Week 9
Physical examination
, CBC, Acute, Hepatic, 
Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone,
PAP, dihydrotestosterone 
(DHT), sex hormone-binding 
globulin (SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
Physical examination
, CBC, Acute, Hepatic, Mineral 
Panels, LDH, CK, Uric Acid, Total 
Protein,
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol 


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Arm A (Enzalutamide 
only)
Arm B (Enzalutamide + PSA-
TRICOM)
prolactin, estradiol
Enzalutamide day 1 month 3
(daily dose of 160 mg)
Enzalutamide day 1 month 3 + 
PSA-TRICOM (Prostvac-F) dose 3
Week 13
Physical examination
, CBC, Acute, Hepatic, 
Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone,
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol 
*Apheresis
Enzalutamide therapy is 
discontinued
Physical examination
, CBC, Acute, Hepatic, Mineral 
Panels, LDH, CK, Uric Acid, Total 
Protein,
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol 
*Apheresis
Enzalutamide therapy is 
discontinued
PSA-TRICOM (Prostvac-F) dose 4
Week 15
, CBC, Acute, Hepatic, 
Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone,
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol
, CBC, Acute, Hepatic, Mineral 
Panels, LDH, CK, Uric Acid, Total 
Protein,
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol 


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Arm A (Enzalutamide 
only)
Arm B (Enzalutamide + PSA-
TRICOM)
Week 17
Physical examination
Research Blood, CBC, Acute, 
Hepatic, Mineral Panels, LDH, 
CK, Uric Acid, Total Protein,
TBNK, PSA, testosterone,
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol
Physical examination
Research Blood, CBC, Acute, 
Hepatic, Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol 
PSA-TRICOM (Prostvac-F) dose 5
Week 21
Physical examination
, CBC, Acute, Hepatic, 
Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone,
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol
Physical examination
, CBC, Acute, Hepatic, Mineral 
Panels, LDH, CK, Uric Acid, Total 
Protein,
TBNK, PSA, testosterone, PAP
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol 
PSA-TRICOM (Prostvac-F) dose 6
Week 25
Physical examination
, CBC, Acute, Hepatic, 
Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone,
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
Physical examination
, CBC, Acute, Hepatic, Mineral 
Panels, LDH, CK, Uric Acid, Total 
Protein,
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 


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Arm A (Enzalutamide 
only)
Arm B (Enzalutamide + PSA-
TRICOM)
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol
*Apheresis
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol 
*Apheresis
PSA-TRICOM (Prostvac-F) is 
discontinued
Week 29
Physical examination
, CBC, Acute, Hepatic, 
Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone,
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol
Physical examination
, CBC, Acute, Hepatic, Mineral 
Panels, LDH, CK, Uric Acid, Total 
Protein,
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol
Up to Week 52
Every 4 weeks **
Physical examination
, CBC, Acute, Hepatic, 
Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone, 
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol 
Research Blood (week 52 
only)
Physical examination
, CBC, Acute, Hepatic, Mineral 
Panels, LDH, CK, Uric Acid, Total
Protein,
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol 
Research Blood (week 52 only)


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Arm A (Enzalutamide 
only)
Arm B (Enzalutamide + PSA-
TRICOM)
Beyond Week 52
Every 8 weeks (+/-
7 days)**
Physical examination
, CBC, Acute, Hepatic, 
Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone, 
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol 
Research Blood (every 16 
weeks)
Physical examination
, CBC, Acute, Hepatic, Mineral 
Panels, LDH, CK, Uric Acid, Total 
Protein,
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol 
Research Blood (every 16 weeks)
Once PSA reaches 
baseline value
Restaging Scans (MRI/CT and 
bone scans)
Restaging scans (MRI/CT and bone 
scans)
Course 2, Week 1
Enzalutamide day 1 month 1,
course 2
(daily dose of 160 mg)
Research labs including 
plasma VEGF levels
Enzalutamide day 1 month 1, course 
2
Research labs including plasma 
VEGF levels
Course 2,Week 5
Physical examination
Research Blood, CBC, Acute, 
Hepatic, Mineral Panels, LDH, 
CK, Uric Acid, Total Protein,
TBNK, PSA, testosterone, 
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
Physical examination
Research Blood, CBC, Acute, 
Hepatic, Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH),
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol


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Arm A (Enzalutamide 
only)
Arm B (Enzalutamide + PSA-
TRICOM)
hormone 
(FSH)androstenedione
prolactin, estradiol
Enzalutamide day 1 month 2
course 2
(daily dose of 160 mg)
Enzalutamide day 1 month 2 course 2
Course 2, Week 9
Physical examination
, CBC, Acute, Hepatic, 
Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone, 
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol
Enzalutamide day 1 month 3
course 2
(daily dose of 160 mg)
Physical examination
, CBC, Acute, Hepatic, Mineral 
Panels, LDH, CK, Uric Acid, Total 
Protein,
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol
Enzalutamide day 1 month 3 course 2
Course 2, Week 13
Physical examination
Research Blood, CBC, Acute, 
Hepatic, Mineral Panels, LDH, 
CK, Uric Acid, Total Protein,
TBNK, PSA, testosterone, 
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol
Physical examination
Research Blood, CBC, Acute, 
Hepatic, Mineral Panels, LDH, CK, 
Uric Acid, Total Protein,
TBNK, PSA, testosterone, PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol
Research labs including plasma 
VEGF levels


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Arm A (Enzalutamide 
only)
Arm B (Enzalutamide + PSA-
TRICOM)
Research labs including 
plasma VEGF levels
*Apheresis
Enzalutamide therapy is 
discontinued for course 2
*Apheresis
Enzalutamide therapy is discontinued
for course 2
Every 4 weeks 
thereafter
Physical examination
, CBC, Acute, Hepatic, 
Mineral Panels, LDH, CK, 
Uric Acid, Total Protein, 
TBNK, PSA, testosterone, 
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), 
dehydroepiandrosterone 
(DHEA), luteinizing hormone 
(LH), follicle-stimulating 
hormone (FSH), 
androstenedione
prolactin, estradiol
Research Blood (every 16 
weeks)
Physical examination
, CBC, Acute, Hepatic, Mineral 
Panels, LDH, CK, Uric Acid, Total 
Protein, TBNK, PSA, testosterone, 
PAP,
dihydrotestosterone (DHT),
sex hormone-binding globulin 
(SHBG), dehydroepiandrosterone 
(DHEA), luteinizing hormone (LH), 
follicle-stimulating hormone (FSH), 
androstenedione
prolactin, estradiol
Research Blood (every 16 weeks)
*Apheresis is not mandatory and will be scheduled based on availability 
-Patients may come off study before week 52 as clinically indicated.
-All patient visits can be delayed by 1 week for logistical issues.
** Patients will be followed until PSA reaches baseline.  Patients who continue to be 
followed for rising PSA but have not required ADT may be seen beyond the study period.
The study period ends 52 weeks after enrollment unless patients receive a second course 
of enzalutamide, then study period ends 9 months after the end of the second course.
1 As indicated in section 7.3, all subjects will be offered the opportunity to complete an 
NIH advanced directives form.  This should be done preferably at baseline but can be 
done at any time during the study as long as the capacity to do so is retained.  The 
completion of the form is strongly recommended, but is not required.


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16
APPENDIX D: INSTRUCTIONS FOR PRE-STUDY AND FOLLOW-UP BLOOD 
TESTS
Blood Studies
Blood Tube/Comments
Destination
CBC with differential
1 light lavender tube
CC Department of 
Laboratory Medicine (DLM)
Hepatic Panel, Mineral Panel, 
Acute Care Panel, LDH, CK, 
Uric Acid, Total Protein
1 4 mL SST
CC DLM
Anti-HIV-1/2
1 8 mL SST
CC TTV lab
Testosterone, total 
1 red top tube
CC DLM
Prostate Specific Antigen
4 mL SST
CC DLM
Lymphocyte Phenotyping, 
TBNK
1 light lavender tube
CC DLM
Immunology Assays
6 10 mL Na Heparin tubes
2 7 ml SST tubes
Apheresis Product
NCI-Frederick
1-301-846-5893
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ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
 
 
INSTITUTE:                        National Cancer Institute 
 
STUDY NUMBER:             13-C-0153                                             PRINCIPAL INVESTIGATOR: Ravi Madan, M.D. 
 
 
STUDY TITLE:                   A Phase II Trial of Enzalutamide in Combination with PSA-TRICOM in Patients with Non-   
                                              Metastatic Castration Sensitive Prostate Cancer 
 
 
Continuing Review Approved by the IRB on 10/16/17 
Amendment Approved by the IRB on 12/22/17 (J)                                                   Date posted to web: 01/05/18  
Standard Cohort 1 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary.  
 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
 
Why is this study being done?  
Androgen deprivation therapy (ADT) and close clinical monitoring are standard therapy for 
prostate cancer patients who have biochemical progression (rise in PSA) after local radiation or 
surgery therapy. This group of patients is also referred to as non-metastatic castration sensitive 
prostate cancer (nmCSPC) or as D0 prostate cancer.  These patients cannot be cured of prostate 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 2 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
cancer and the primary therapeutic goal is to control the disease with ADT, which lowers 
testosterone. ADT consists of an injection (shot) of a normally occurring hormone called 
gonadotropin-releasing hormone. The injection is given under the skin of the abdomen once 
every three months.  Alternative approaches include intermittent use of ADT and other hormonal 
therapies called androgen receptor antagonists (ARAs). Enzalutamide is a modern ARA. This 
agent is FDA approved to treat metastatic prostate cancer after chemotherapy.  Enzalutamide 
treatment consists of four pills taken together once a day. 
 
In addition to the direct anti-cancer effect of enzalutamide, there is evidence that hormonal 
therapies like enzalutamide enhance the immune system.  This study will also test a new way of 
potentially treating prostate cancer using a PSA-targeted immunotherapy vaccine product called 
PROSTVAC-V/F in combination with enzalutamide.  This combination may help cells from 
your own body to recognize and kill the cancer cells. The study will test how safe it is to receive 
this vaccine and how well it works in prostate cancer in combination with enzalutamide.    
 
All patients in this study will get enzalutamide.  Half of the patients will receive enzalutamide 
only and half of the patients will receive enzalutamide plus PROSTVAC-V/F vaccine.  Your 
treatment is determined by a randomization process (chosen as if by the flip of a coin).  You 
have an equal chance of being randomized to any of the two groups.   
 
Clinical development of PROSTVAC-V/F is based on the idea that the immune system (group of 
cells and organs in the body that recognize and fight infection) can be taught to find and kill 
certain cancer cells, in this case prostate cancer cells. This is an investigational vaccine regimen, 
which means that it is not yet approved by health authorities and can be used only in a research 
study. In September of 2017, it was reported that a large (phase III) study of PROSTVAC alone 
did not show that this treatment could improve survival in advanced prostate cancer.  However, 
the scientific reasoning to combine PROSTVAC with enzalutamide remains sound, and this 
study will continue. Furthermore, at this point neither this trial or the phase III trial have 
suggested a safety concern for PROSTVAC.  
 
The goal of this study is to determine if the short-term benefits of enzalutamide (lowering of 
PSA/disease control) can be improved when used with PROSTVAC-V/F, resulting in a slower 
PSA rise after enzalutamide. 
 
Patients will be randomly assigned to either one of two main study groups. One group will 
receive only enzalutamide and the other group will receive enzalutamide and PSA-TRICOM 
vaccine. Random assignment will be done with the help of a computer and patients will be 
informed on the day of their start about their respective group.   
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 3 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Why are you being asked to take part in this study? 
You are being asked to participate in this study for three reasons: 1) You had received local 
therapy for prostate cancer and now your PSA is rising 2) You do not have tumor anywhere else 
in the body that can be seen on imaging 3) you have normal levels of testosterone, all of which 
indicate that you have nmCSPC or D0 prostate cancer.  
 
How many people will take part in this study?  
We plan to enroll 38 patients. 
  
Description of Research Study 
What will happen if you take part in this research study?   
Before you begin the study 
Certain standards (criteria) have been established to ensure that you are a medically appropriate 
candidate for this trial. These criteria also make sure that the results of this study can be used to 
help make decisions about treating other patients. We will record your medical history and give 
you a physical examination. You will undergo standard blood tests including a complete blood 
count, chemistry panel, and prostate-specific antigen (PSA) levels, and scans and x-rays as part 
of the NCI Screening Protocol. One test of your immune system will be a blood test that checks 
for the presence of the human immunodeficiency virus (HIV), the cause of acquired 
immunodeficiency syndrome (AIDS). HIV infection may disqualify you from this study. If you 
test positive for HIV, we will tell you what the results mean, how to find care, how to avoid 
infecting others, how we report HIV infection. We will do other blood tests to look for infection 
with hepatitis B and C. If these tests are positive, you will not be eligible to participate in the 
study because of the potential harm the vaccine may cause. Altogether, these tests will require 
about 100 cc (6 to 7 tablespoons) of blood. 
 
During the study 
Once you agree to participate in this study, you will be assigned to 1 of 2 groups: the 
enzalutamide only group or the enzalutamide plus PSA-TRICOM vaccine group 
 
All patients will receive the enzalutamide. You will receive enzalutamide (Arm A and B) at a 
dose of 160 mg daily orally for 3 months.  You may receive a second course of enzalutamide if 
at any time after you have been on the study for 7 months, your PSA level rises higher than what 
it was at the beginning if the study. 
 
For most patients, if you do not receive a second course of enzalutamide, you will be followed 
for up to 1 year total, potentially 9 months after completing enzalutamide therapy.  If you receive 
a second course, you will be followed for 9 months after completing your second course of 
enzalutamide therapy.  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 4 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Patients randomized to receive enzalutamide and vaccine. If you are randomized to enzalutamide 
plus vaccine arm (Arm B), you will receive PSA-TRICOM. It will be administered as a shot 
under the skin on week 1 (vaccinia version of PSA-TRICOM) and then week 3, 5 and then 
monthly (fowl-pox version of the same vaccine) until week 21.  For description of the versions 
of the vaccine and explanation of why there are two versions, see pages 6-8, under Vaccinia 
Virus and Fowlpox Virus. 
 
At each visit, we will give you a physical exam and standard blood tests, and ask you how you 
are feeling. This is standard care you would receive as part of your cancer treatment, whether 
you were participating in a study or not. 
 
Research Tests  
An important part of this study is testing the effects of this treatment on your tumor and immune 
system. The following blood samples and tests will be done while you participate in this study:  
 
Research blood samples  
Research tests will be done on blood obtained by apheresis and on blood taken at various times 
during your participation in this study and for as long as we continue to follow you. If research 
blood needs to be drawn on the same day as apheresis, it will be taken at the same time. Each of 
these blood draws will take about 6 tablespoons of blood. The NIH has set a limit on the 
maximum amount of blood that can be taken for research. This limit is based on your age. For 
adults, no more than 37 tablespoons can be taken over an 8-week period. Specimens obtained 
during your participation in this study may be sent for testing to investigators outside of NCI or the 
NIH. 
 
Scans and x-rays  
As part of this study, we will look for any signs that your cancer is recurring or getting worse:  
1. Your PSA level will be checked at each visit when blood is taken for standard laboratory tests.  
2. Bone scan will be done at baseline and as needed.  
3. CT scan of the chest, abdomen, and pelvis will be done at baseline and as needed.  
 
These tests will be initially done before your treatment begins. The bone and CT scans will be 
repeated if the doctor suspects your cancer has gotten worse. PSA level will be checked 
frequently throughout the study.  
 
When you are finished taking the drugs (treatment) 
You will be followed for a total of 52 weeks from the start of study if you receive one course of 
enzalutamide.  If you receive a second course, the follow up period extends for up to 9 months 
after you have completed the second enzalutamide course. You will finish your first course of 
enzalutamide in 12 weeks and those in Arm B will finish vaccine in 21 weeks. The second 
course of enzalutamide (if given) will be completed 12 weeks after it has begun. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 5 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
However, if you have rising prostate-specific antigen (PSA) but have not required additional 
therapy, you may continue to be seen on this study beyond the treatment period. 
 
What Do I Have To Do?  
It is important that you inform your trial doctor of any changes in your health, whether or not 
you think that it is related to the trial drug.  
 
You must tell your trial doctor about all medications you are currently taking. This includes both 
medications prescribed by your regular doctor and medications you obtain without prescription, 
(e.g., from a pharmacy or health food shop, including herbal medication and vitamin 
supplements). Your trial doctor will inform you whether you can continue taking these. You 
must tell your trial doctor before making changes in to your existing medications or taking any 
new medication. Always follow your trial doctor’s instructions during the trial.  
 
If you are involved in any other clinical trials, you should inform your trial doctor. You cannot 
be involved in another clinical trial during your participation in this trial.  
 
In case you need to contact your trial doctor in an emergency, you will be given a contact card 
with all the relevant contact information. It is important that you follow your trial doctor’s 
instructions throughout the trial. If you have questions or want further information, 
contact your trial doctor. 
 
Gene Therapy Long Term Follow Up  
You will be followed on a separate protocol once you are off study. The Food and Drug 
Administration (FDA) requires that people who receive gene therapy be watched even after they 
complete therapy.  Once you have finished therapy, you will be watched for up to 15 years to see 
how well you are doing.  At least, you will be asked to have a routine physical exam each year 
for five years following your last vaccination.  You will be asked questions about your health 
such as whether you have developed any new cancers or problems with your blood or immune 
system (the organs and cells that defend your body against infections and other diseases).  You 
will also be asked whether you have had a hospital stay for something you did not expect and the 
medicines you are taking. You will be called by telephone for more information about your 
health each year for 15 years following your last treatment. The FDA will have access to this 
information. For this reason, we ask that you continue to provide us with a current address and 
telephone number, even after you complete this research study. 
 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
As with all treatments, there are several side effects or risks from the treatments provided in this 
study. However, doctors don’t know all the side effects that may happen with this combination 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 6 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
of drugs, so it is important to report any changes that you notice, even if your study team does 
not ask specifically about them. Side effects may be mild or severe. Your study team will give 
you medicines to help lessen side effects. Many side effects go away with those medicines and 
others may go away soon after you stop treatment. In some cases, side effects can be serious, 
long-lasting, or may never go away. In very rare instances, they could cause death. 
 
 
Possible side effects of enzalutamide: 
 
Likely 
Less Likely 
Rare but Serious 
• Ankle swelling. 
• Fatigue 
• Headache 
• Hot flashes 
• Diarrhea  
• Low blood counts 
• Back pain 
• Upper respiratory tract 
infection 
• High blood pressure 
• Dizziness, anxiety 
• Dry skin 
• Blood in urine 
• Jaundice 
• Weakness of muscles 
 
• Seizures 
• *Posterior reversible 
encephalopathy 
syndrome (PRES) 
*There have been rare reports of posterior reversible encephalopathy syndrome (PRES), a rare, 
reversible condition involving the brain, in patients treated with enzalutamide. If you have a 
seizure, worsening headache, confusion, blindness or other vision problems, please contact your 
doctor right away. Your doctor will stop enzalutamide if you develop PRES.   
 
Risks to be considered with PSA-TRICOM 
Vaccinia Virus 
The first vaccine injection you will receive will be PSA-TRICOM vaccinia (PROSTVAC-V). It 
is derived from the vaccinia virus. Vaccinia virus has been given to hundreds of millions of 
people worldwide to prevent the disease smallpox. Vaccinia immunization has resulted in the 
worldwide elimination of smallpox. It is a live replicating virus that infects large mammals and 
rodents, and usually causes only a self-limited skin infection in humans. The virus stimulates a 
strong immune response, which results in the body eliminating the virus. However, caution is 
required in its use, in that subjects or their contacts may experience inadvertent spread of 
vaccinia, or worse may experience more severe rare infections. The potential for these risks, and 
the precautions necessary to minimize these risks, are discussed further below. 
 
Importantly, in order to be in this study, you must have been previously vaccinated with vaccinia 
for smallpox (this was probably done when you were a child or possibly as a young adult). 
Immunity induced by vaccinia lasts decades, and the chances for complications are markedly 
reduced. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 7 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
In clinical studies of PSA-TRICOM, the vaccine is given by injection under the skin. Most 
subjects experience some redness and diffuse swelling in the surrounding area, approximately 1-
4 inches (2-10 centimeters) in diameter. This lasts for 7-14 days and may be accompanied by 
itching and soreness. There is typically full healing and no residual scarring from subcutaneous 
administration. On average, vaccinia stays active in your body for approximately 10-14 days. 
Prior to receiving your next vaccine, you will be evaluated for evidence of bacterial infection, 
blisters, vesicles, (lesions seen on your skin at or around your vaccine site) or evidence of 
persistent vaccinia infection. 
 
When vaccinia is given to protect against smallpox, it is usually scratched into the outer layers of 
the skin with a two-pronged needle. A normal reaction after this administration in a person who 
has been previously vaccinated with vaccinia includes appearance of a small bump (papule) in 3 
days, a small blister or cluster of blisters in 5-7 days, and healing with little scarring within 2 to 3 
weeks. Swollen lymph nodes (“swollen glands”) and/or fever are infrequent. 
 
You would receive your investigational vaccine by a shot under the skin rather than by 
scratching it onto the skin the way a traditional smallpox vaccination is given. Therefore, you 
may have less of a skin reaction; however, vaccination with PSA-TRICOM may produce 
reactions similar to those seen with the smallpox vaccine. 
 
A potential problem associated with vaccinia vaccination is accidental spread of the virus to 
another area of your body. This occurs rarely (incidence 1 in 4000 in some reports), however, it 
is very important to protect against. You can transfer the virus to your eye and mucous 
membranes (inner lining) of the nose, mouth or genitals by scratching the vaccination site and 
then rubbing the eye or an open skin area. If you participate in this study you will have to take 
special care of your vaccination site and wash your hands often to prevent spreading of the virus. 
You will be provided with written instructions with details about the vaccination site and how to 
care for it, as well as how to contact the study staff if you have questions or concerns. 
 
Because you may “shed” live virus from the vaccination site after vaccination until the 
vaccination site heals completely, and could spread the virus to others, you must avoid close 
contact with the following people for approximately 3 weeks after the first vaccination only: 
• persons with weak or suppressed immune systems such as individuals with leukemia or 
lymphoma, individuals with AIDS, or those receiving treatment to suppress their immune 
system (for example, after organ transplantation). 
• individuals with eczema or other significant skin rashes, itching infections, burns, chicken 
pox, or skin injury 
• pregnant or breast-feeding women 
• or, children under 3 years of age 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 8 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
“Close contact” means that these people share your house with you, are in physical contact with 
you, come in contact with your bed linens or clothes, and/or you take care of them and touch 
them. 
 
For every 1 million people vaccinated with vaccinia scratched into the outer layer of the skin, the 
vaccinia virus was transmitted to roughly 75 of their contacts (In this study, the investigational 
vaccine will be injected under the skin which minimizes this risk). A dressing will be placed over 
the vaccination site to reduce the risk of accidental spreading. It is very important that you keep 
the vaccination site covered. Hand washing is also necessary. 
 
During the reintroduction of smallpox vaccination in the past decade, several individuals thought 
to be at risk for heart disease experienced inflammation around the heart (myopericarditis). With 
careful monitoring it was noted that approximately 1/2000 subjects, who had not been previously 
vaccinated, developed this condition. The incidence was lower in re-vaccinees. The symptoms of 
myopericarditis were typically mild and transient. If you have poor heart function requiring 
treatment, you will not be able to participate in this study. 
 
Possible adverse reactions can also be related to allergic responses the vaccine itself. An allergic 
reaction to the study vaccine may be development of a rash or hives within 7 to 10 days of 
vaccination, which usually gets better within 2 to 4 days. Rarely, a serious allergic reaction 
requiring hospitalization may occur. 
 
Generalized vaccinia may be characterized by several small blisters around the vaccination site 
or by widely distributed lesions developing 7-12 days after immunization. This is also known as 
a disseminated vaccinia infection. These tend to follow a course of healing similar to that of the 
inoculation site. 
 
Serious side effects from the vaccinia vaccine are most common in young children, subjects with 
disorders of the immune system, and individuals with skin disorders. That is why precautions are 
taken to exclude such individuals from exposure. 
 
Serious reactions such as post-vaccinia encephalomyelitis (“brain inflammation”), which can 
lead to coma and death, or progressive vaccinia which leads to a large unhealing sore and death 
are the most severe complications after vaccination. They occur almost exclusively in very 
young children who are exposed to vaccinia for the first time, or in subjects with impaired 
immunity; such individuals are not eligible for this study and must be avoided after vaccination. 
The death rate for people receiving revaccination with vaccinia for smallpox is about 1 in 10 
million. 
 
These serious reactions have not been seen in any subjects treated with PROSTVAC-V to date. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 9 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Vaccinia Immune Globulin (VIG) has been successful as a therapy for some but not all of these 
complications. VIG is an injectable antibody preparation made from the plasma of people 
vaccinated with the vaccinia vaccine. If symptoms develop suggestive of one of the previously 
described vaccinia complications, or a close contact occurs between a recently vaccinia-
vaccinated subject and a susceptible person with one of the pre-existing medical conditions 
described above, the subject should report the findings immediately to the protocol investigator 
or other established contact, for consideration for VIG therapy, since VIG may work better if 
given early. 
 
There are other anti-viral treatments with activity against vaccinia virus. Cidofovir, FDA 
approved for use in treating cytomegalovirus infections, has antiviral activity against poxviruses. 
However, the drug is only given intravenously under careful monitoring as it has some side 
effects, in particular risk for kidney toxicity. 
 
Fowlpox Virus  
PROSTVAC-F (the second and subsequent doses of PSA-TRICOM) is based on fowlpox virus. 
Fowlpox virus naturally infects birds, not mammals, and has been researched and used in other 
vaccines for at least twenty years. The virus does not grow (replicate) in human cells and is not 
known to cause human disease. Previous studies have indicated that using the fowlpox-based 
vaccine after the vaccinia-based vaccine induces a better clinical response than either virus used 
alone or fowlpox followed by vaccinia. The vaccines including fowlpox virus have been given in 
research studies to both animals and humans for HIV, malaria and cancer. Side effects from 
fowlpox are mild and could include injection site reactions, fever, fatigue, anemia (low red blood 
cell count) and leucopenia (low white blood cell count). With any experimental compound, there 
is the risk of unexpected and serious or deadly complications even if they have not been seen 
previously. 
 
Additional risks and side effects related to the vaccine therapy with PROSTVAC-V/TRICOM 
and PROSVTAC-F/TRICOM 
 
Likely: 
• Injection site reaction (pain, swelling, itching, induration, and redness) 
• Tiredness, weakness 
• Fever 
• Shaking chills 
• Nausea 
• Glands, (lymph node) enlarge and become tender 
 
Less likely: 
• Headache 
• Allergic reaction 
• Sweating 
• Wound complication 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 10 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• Vomiting 
• Confusion and disorientation 
• Loss of appetite 
• Yeast infection 
• Constipation 
• Cough 
• Diarrhea 
• Indigestion 
• Fatigue 
• Facial tingling 
• Muscle ache 
• Nausea 
• Facial numbness 
• Pruritus (itching) 
 
Rare but serious: 
• An uncommon blood condition called thrombotic thrombocytopenic purpura (TTP). One 
patient treated with this vaccine developed TTP. It is not known if this was related to the vaccine 
or from something else. This is a serious disease that is associated with low blood counts (both 
red blood cells that carry oxygen and platelets that help your blood clot), bleeding, fever, 
neurologic symptoms (such as changes in level of alertness including coma, headache, difficulty 
speaking confusion or paralysis) and kidney dysfunction. The symptoms are due to the formation 
of clots that form or spread to many organs. This can usually be treated with exchange 
plasmapheresis, a therapy that removes and replaces plasma the protein containing fluid from a 
patient’s blood. Should you go on this trial, we will follow you closely for any signs or 
symptoms of this disease. 
• Leg weakness 
 
Other Potential Side Effects 
Additional adverse effects could be related to the immune response to the PSA and/or TRICOM 
proteins that are part of the vaccines. Some normal human cells (such as normal prostate cells) 
have these proteins on their surface. If the vaccine causes an immune reaction against these 
normal cells, you could develop swelling or inflammation of these tissues. While unlikely, it is 
also possible that if you develop a very active antibody (immune) reaction after the vaccination, 
you could develop an immune complex disease (or serum sickness) which can cause fevers, 
rashes, joint pains, and less commonly, kidney failure and severe allergic reaction inside blood 
vessels (vasculitis) or any part of your body. None of these symptoms have been observed to 
date in subjects receiving Bavarian Nordic’s vaccines, but the possibility of their occurrence 
exists. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 11 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Risks to an Unborn Child and Sexual Partner 
Birth Control 
Your study doctor will discuss the risks to unborn children for drugs other than PROSTVAC or 
GM-CSF that may be used in this study. The effects of PROSTVAC, if any, on unborn children 
are unknown. If your partner is capable of becoming pregnant and you wish to participate in this 
study, and you have not had your prostate or testicles removed, or you are not receiving 
continuous hormone therapy, then you must use a medically acceptable method of birth control. 
 
You should refrain from fathering a child or donating sperm during the study and for 3 months 
after you finish study treatment. If your partner becomes pregnant during the course of treatment, 
you must inform your doctor immediately. Your doctor will ensure that you and your partner 
receive information about options available to you in relation to pregnancy and that you and your 
partner are fully supported in whichever option you chose. 
 
Acceptable birth control options for you and your partner include: 
• surgical sterilization (you and/or your partner) 
• approved hormonal contraceptives or therapies (such as birth control pills, Depo-Provera, 
or Lupron Depot) 
• barrier methods (such as a condom or diaphragm) used with a spermicide 
• an intrauterine device (IUD) 
 
Other Risks 
The study treatment may involve risks to you that are currently unknown. Your cancer may not 
get better or may become worse while you are in this study. 
 
Risks from X-rays and / or Scans: Radiological testing, such as CT scans, MRIs, X-rays and/or 
radioactive drugs may be used to assess the treatment of your disease at various times during 
therapy. The cumulative radiation exposure from these tests is considered very small and is 
unlikely to adversely affect you or your disease. Because some of these tests require 
administration of contrast you could experience pain, bruising, and/or infection at the site of 
injection, or an allergic reaction to the contrast agent. Please notify the investigator if you know 
or suspect you are allergic to contrast dye. 
 
EKG: There are no significant risks or discomforts associated with an EKG. Some patches will 
be adhered to your skin that may cause some reddening or slight itching. 
 
Blood draws: There may be some side effects associated with the procedures for drawing blood 
in this study, but the person drawing your blood will attempt to minimize this discomfort.  Side 
effects include pain and bruising in the area where the needle is inserted, lightheadedness, and 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 12 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
rarely, fainting. When large amounts of blood are collected, low red blood cell count (anemia) is 
a risk. 
 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if enzalutamide with PROSTVAC vaccine will cause your tumor 
growth rate to decrease as compared to enzalutamide alone.  We do not know if you will receive 
personal, medical benefit from taking part in this study.  These potential benefits could include 
delayed relapse or progression of your tumor.  Because there is not much information about the 
vaccine’s effect on your cancer, we do not know if you will benefit from taking part in this study, 
although the knowledge gained from this study may help others in the future who have cancer.   
 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options:  
• Taking part in another study 
• Getting treatment with standard therapy outside this study. 
• Observation only, where your doctor, depending on his clinical judgment and your 
opinion, follows your PSA and watches you for cancer recurrence.  
Please talk to your doctor about these and other options. 
 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 13 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board 
• The study Sponsor (Center for Cancer Research) or their agent(s)  
• Qualified representatives from Bavarian Nordic and/or Medivation and Astellas, Inc., the 
pharmaceutical companies who produce the study drugs.  
 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  At 
most the Web site will include a summary of the results.  You can search this Web site at any 
time.  
 
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
• will be used for auditing or program evaluation internally by the NIH; or  
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 14 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
 
Stopping Therapy  
How long will I be in the study?  
You will continue to receive therapy and medical follow-up until:  
• The study is completed;  
• You decide that you no longer wish to participate in the study;  
• You experience unacceptable side effects;  
• Your cancer gets worse;  
• You need to start another kind of therapy (called androgen deprivation therapy) for your 
cancer 
• The doctor feels that it is unsafe for you to continue;  
• New information becomes available that suggests another treatment would be better for 
you; or  
• The study is stopped.  
 
You can stop taking part in the study at any time.   However, if you are thinking about dropping 
out of the study, please tell your research team so they can tell you how to end your participation 
safely. 
 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Bavarian Nordic, Inc. 
and/or Medivation and Astellas, Inc. or designated representatives. If you withdraw your consent 
and leave the trial, any samples of yours that have been obtained for the study and stored at the 
NCI can be destroyed upon request. However, any samples and data generated from the samples 
that have already been distributed to other researchers or placed in the research databases cannot 
be recalled and destroyed. 
 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide. You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH. 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 15 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
The National Institutes of Health and the research team for this study are using vaccine 
developed in collaboration with the National Cancer Institute under a Cooperative Research and 
Development Agreement with Bavarian Nordic, Inc. The company also provides financial 
support for this study. 
 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
 
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
 
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 
Apheresis  
You will undergo a procedure called apheresis to collect certain blood cells for immune studies 
to measure your immune response to the vaccine. This test will be of no benefit to you, but is 
part of the experimental portion of this study. Apheresis will be done at several different points 
for each course of enzalutamide treatment: before treatment begins, 13 weeks after treatment the 
treatment course has begun and at about 25 weeks after the treatment course has begun. 
Apheresis is a very common procedure at the Clinical Center and has very few risks. A needle is 
inserted into a vein in your arm to obtain blood that then goes into an apheresis machine. This 
machine divides whole blood into red cells, plasma (serum), and lymphocytes (white cells). The 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:   13-C-0153 
CONTINUATION: page 16 of 18 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
sample cells are taken out and the rest of the blood is returned to you through a second needle in 
your other arm. A total of 2 Liters of blood will undergo this process. 
 
A separate consent form will be provided to you at the time of the apheresis for you to grant 
permission to that procedure if you agree to the apheresis.  You can participate in the study even 
if you decide not to undergo the apheresis procedure.   
 
Risks of Apheresis 
You may have pain or bruising where the needle is inserted. There is a very small chance of 
introducing infection at the needle site. There is a slight chance of blood infections from 
contamination of the apheresis machine, but this has never occurred at the NIH. Some patients 
feel weak or dizzy during apheresis. Some have tingling or numbness in their lips, fingers or 
toes. These symptoms don’t last long, and they often stop when the procedure is slowed down. 
 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  13-C-0153 
CONTINUATION: page 17 of 18 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Ravi Madan, M.D., Building 10, Room 13N240, Telephone:  301-480-
7168. You may also call the Clinical Center Patient Representative at 301-496-2626. If you have 
any questions about the use of your specimens or data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone:  240-760-6070.  
 
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  13-C-0153 
CONTINUATION: page 18 of 18 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM OCTOBER 16, 2017 THROUGH OCTOBER 15, 2018. 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name