Clinical trial NCT02430480
Conditions: Prostate Cancer
Keywords: Multiparametric MRI Prostatectomy Focal Prostate Cancer Normal Testosterone Non-Metastatic
Sponsor: National Cancer Institute (NCI)
Start date: 2015-06-03; Completion date: 2024-06-11
Enrollment: 39 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* There are several ways to treat prostate cancer. Researchers want to see how well a certain kind of imaging helps detect prostate cancer. They also want to see if a particular drug combination used before surgery will benefit people with prostate cancer that hasn't spread in the body (non-metastatic). The combination will be androgen deprivation therapy and enzalutamide.
* The combination of androgen deprivation therapy and enzalutamide has been shown to make patients with advanced (metastatic disease) live longer. The investigators want to see if using it earlier can increase cure rate of surgery and identify genetic or molecular characteristics that are associated with better outcomes.

Objectives:

\- To develop better ways of detecting prostate cancer before and after pre-operative treatment.

Eligibility:

\- Men at least 18 years old with non-metastatic prostate cancer. They must be candidates for a radical prostatectomy.

Design:

* Participants will be screened with medical history, physical exam, and blood tests. They will have scans and X-rays.
* Before starting the study drugs, participants will have:
* Vital signs taken, medical history, and blood tests.
* Electrocardiogram (ECG) heart test, with patches stuck on the skin.
* Small piece of tumor removed (biopsy) using image guidance from magnetic resonance imaging (MRI) and ultrasound.
* 3T multi-parametric magnetic resonance imaging (mpMRI). Participants will lie on a table that slides into a metal cylinder. A probe will be inserted in the rectum. They will be in the scanner for about 60 minutes, lying still. The scanner makes loud knocking sounds. Participants will get earplugs.
* Participants will take the 2 study drugs for 6 months.
* Enzalutamide is taken as 4 pills once a day.
* Androgen deprivation therapy is given by injection 2 times over 6 months.
* During these 6 months, participants will visit the clinic monthly. They will have physical exam, vital signs, and blood drawn.
* After finishing the study drugs, participants will have another 3T mpMRI. Then they will have prostate removal surgery.

Detailed description:
Background:

* Most men diagnosed with prostate cancer will present with intermediate or high-risk disease
* Many develop castrate resistant prostate cancer (CRPC) as curative strategies are often unsuccessful
* Treatment options typically involve radical prostatectomy (RP) or radiation therapy (RT) in combination with androgen deprivation therapy (ADT)
* Even when cancers are initially sensitive to ADT, resistance ultimately emerges either through clonal selection or through a variety of adaptive mechanisms (secondary resistance).
* The recent introduction of novel androgen pathway inhibitors offers an opportunity to potentially improve the cure rate of men with intermediate and high risk localized prostate cancer
* There remains a great need for improved techniques to determine mechanisms of treatment response and resistance.

Objectives:

-To test the feasibility of multi parametric magnetic resonance imaging (mpMRI) for the localization and detection of focal prostate cancer both before and after pre-operative treatment with ADT and enzalutamide.

Eligibility:

* Patients with nonmetastatic castration sensitive prostate cancer with intermediate or high-risk features
* Patients with testosterone levels greater than or equal to 100 ng/dL.
* Eastern Cooperative Oncology Group (ECOG) 0-1.

Design:

* Patients will be treated with ADT and enzalutamide for 6 months
* Two 3T mpMRI endorectal examinations (One at screening and after 6 month of treatment)
* Screening biopsy (magnetic resonance (MR)/ultrasound (US) guided) samples
* Standard of care prostatectomy (RP) following post treatment mpMRI
* All tumor specimens will undergo genomic analysis

Arms: arm 1: Patients will have an multi-parametric magnetic resonance imaging (mpMRI) guided biopsy, then receive enzalutamide and goserelin subcutaneous (SC) treatment for 6 months followed by a second mpMRI examination.
Interventions: intervention 1: Goserelin intervention 2: Enzalutamide intervention 3: mpMRI
Intervention descriptions: intervention 1: 10.8mg administered subcutaneously every 12 weeks (2 doses) intervention 2: 160mg orally, daily for 24 weeks intervention 3: Multiparametric MRI - One at baseline and after 6 months of treatment

Protocol documents:
Prot_SAP_004.pdf: 
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Abbreviated Title: Neoadjuvant ADT & Enzalutamide  
Version Date: 01/25/2024 
 
Abbreviated Title: Neoadjuvant ADT & Enzalutamide  
NIH Protocol #: 15C0124  
Version Date: 01/25/2024 
NCT Number: NCT02430480 
 
 
 
Title: Neoadjuvant Androgen Deprivation and Enzalutamide: Using Multiparametric MRI to 
Evaluate Intraprostatic Tumor Responses and Androgen Resistance Patterns in Newly Diagnosed 
Prostate Cancer 
 
NCI Principal Investigator:    
Fatima Karzai, M.D.  
GMB, CCR, NCI  
10 Center Drive  
10, Room 13N240 
Bethesda, MD 20892 
Phone: 301-480-7174 
E-Mail: fatima.karzai@nih.gov  
 
 
 
 
Commercial Agents:  
Goserelin, Enzalutamide 


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PRÉCIS  
Background: 
• Most men diagnosed with prostate cancer will present with intermediate or high-risk 
disease. 
• Many develop castrate resistant prostate cancer (CRPC) as curative strategies are often 
unsuccessful. 
• Treatment options typically involve radical prostatectomy (RP) or radiation therapy (RT) 
in combination with androgen deprivation therapy (ADT). 
• Even when cancers are initially sensitive to ADT, resistance ultimately emerges either 
through clonal selection or through a variety of adaptive mechanisms (secondary 
resistance). 
• The recent introduction of novel androgen pathway inhibitors offers an opportunity to 
potentially improve the cure rate of men with intermediate and high risk localized 
prostate cancer. 
• There remains a great need for improved techniques to determine mechanisms of 
treatment response and resistance. 
Objectives: 
• To test the feasibility of multi parametric magnetic resonance imaging (mpMRI) for the 
localization and detection of focal prostate cancer both before and after pre-operative 
treatment with ADT and enzalutamide. 
Eligibility: 
• Patients with nonmetastatic castration sensitive prostate cancer with intermediate or high-
risk features 
• Patients with testosterone levels ≥ 100 ng/dL   
• ECOG 0-1 
Design: 
• Patients will be treated with ADT and enzalutamide for 6 months 
• Two 3T mpMRI endorectal examinations (One at screening and after 6 month of 
treatment) 
• Screening biopsy (MR/US guided) samples  
• Standard of care prostatectomy (RP) following post treatment mpMRI 
• All tumor specimens will undergo genomic analysis  
 
 


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TABLE OF CONTENTS  
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
STATEMENT OF COMPLIANCE ................................................................................................ 5 
1 
INTRODUCTION .................................................................................................................. 5 
1.1 
Study Objectives .............................................................................................................. 5 
1.2 
Background and Rationale ............................................................................................... 5 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 10 
2.1 
Eligibility Criteria .......................................................................................................... 10 
2.2 
Screening Evaluation...................................................................................................... 13 
2.3 
Participant Registration and Status Update Procedures ................................................. 13 
2.4 
Treatment Assignment Procedures................................................................................. 14 
2.5 
Baseline Evaluation ........................................................................................................ 14 
3 
STUDY IMPLEMENTATION ............................................................................................ 14 
3.1 
Study Design .................................................................................................................. 14 
3.2 
Drug Administration ...................................................................................................... 15 
3.3 
Dose Modifications ........................................................................................................ 15 
3.4 
Imaging........................................................................................................................... 16 
3.5 
On–Treatment evaluation ............................................................................................... 17 
3.6 
Follow up Procedures ..................................................................................................... 17 
3.7 
Study Calendar ............................................................................................................... 18 
3.8 
Cost and Compensation .................................................................................................. 19 
3.9 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 19 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 19 
5 
CORRELATIVE STUDIES FOR RESEARCH ................................................................... 21 
5.1 
Biospecimen Collection ................................................................................................. 21 
5.2 
Sample Storage, Tracking and Disposition .................................................................... 26 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 27 
6.1 
Data Collection ............................................................................................................... 27 
6.2 
Response Criteria ........................................................................................................... 28 
6.3 
Toxicity Criteria ............................................................................................................. 29 
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN .. 29 


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7.1 
Definitions ...................................................................................................................... 29 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 29 
7.3 
NCI Clinical Director Reporting .................................................................................... 29 
7.4 
NIH Required Data and Safety Monitoring Plan ........................................................... 30 
8 
STATISTICAL CONSIDERATIONS.................................................................................. 30 
9 
HUMAN SUBJECTS PROTECTIONS ............................................................................... 31 
9.1 
Rationale For Subject Selection ..................................................................................... 31 
9.2 
Participation of Children ................................................................................................ 31 
9.3 
Participation of Subjects Unable to Give Consent ......................................................... 31 
9.4 
Evaluation of Benefits and Risks/Discomforts .............................................................. 31 
9.5 
Risks/Benefits Analysis.................................................................................................. 33 
9.6 
Consent Process and Documentation ............................................................................. 33 
10 REGULATORY AND OPERATIONAL CONSIDERATIONS ......................................... 34 
10.1 Study Discontinuation and Closure ................................................................................ 34 
10.2 Quality Assurance and Quality Control ......................................................................... 35 
10.3 Conflict of Interest Policy .............................................................................................. 35 
10.4 Confidentiality and Privacy ............................................................................................ 35 
11 PHARMACEUTICAL INFORMATION ............................................................................. 36 
11.1 Enzalutamide .................................................................................................................. 36 
11.2 Goserelin ........................................................................................................................ 36 
12 REFERENCES ..................................................................................................................... 37 
13 APPENDIX A-Performance Status Criteria ......................................................................... 41 


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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
• To test the feasibility of mpMRI for the localization and detection of focal prostate cancer 
both before and after pre-operative treatment with ADT and enzalutamide. 
1.1.2 Secondary Objectives 
• To perform parallel sequencing of each unique tumor focus in the prostate before and 
after treatment with ADT and enzalutamide to determine the genetic predictors of 
primary resistance. (This will be done both inter-patient and intra-patient.) 
• To determine the quantitative and qualitative mpMRI characteristics of response both 
before and after treatment, to predict resistance to intensive androgen targeted therapies 
and link imaging to genomic characterization of resistance. 
• To evaluate the pathological complete response rate after neoadjuvant treatment with 
ADT and enzalutamide. 
1.2 
BACKGROUND AND RATIONALE 
It is expected that 29, 480 men will die from prostate cancer in the US in 2014.[1] The majority 
of these men will present with intermediate or high risk localized cancer. While some of these 
men are cured, many men (20 – 40% of those diagnosed) will ultimately develop castrate 
resistant prostate cancer (CRPC) and succumb to the disease.[2] Treatment options typically 
involve radical prostatectomy (RP) or radiation therapy (RT) in combination with androgen 
deprivation therapy (ADT). Following RP upwards of 50% of patients with high-risk disease will 
experience a biochemical recurrence at 5 years,[3] and approximately 20% will die of their 
disease in 10-15 years.[4]    


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ADT interferes with androgen production or blocks androgen at the level of the androgen 
receptor (AR).[5] As a consequence prostate cancer growth is suppressed and apoptosis occurs.  
There is great variability in prostate cancers’ sensitivity to ADT and the mechanism of induction 
of apoptosis when it occurs is poorly understood. Some tumors appear to exhibit primary 
resistance, meaning the tumor persists despite ADT.  Even when cancers are initially sensitive to 
ADT, resistance ultimately emerges either through clonal selection or through a variety of 
adaptive mechanisms (secondary resistance).[6] Thus, the duration of long-term response to 
ADT is unpredictable. Due to the lack of in vivo markers of tumor response it has not been 
possible to predict either the inherent cellular properties of resistance (primary resistance) or the 
timing of conversion to castration resistance prostate cancer (secondary resistance).   
The recent introduction of novel androgen pathway inhibitors offers an opportunity to potentially 
improve the cure rate of men with intermediate and high risk localized prostate cancer but has 
also creates a need for improved techniques to determine mechanisms of treatment response and 
resistance. It is this challenge that we seek to address in this clinical trial by linking pathologic 
tumor response to both genomics and imaging to predict androgen resistance. We will examine 
the response of tumors to goserelin and enzalutamide in the preoperative setting.   
1.2.1 Preliminary experience with ADT prior to prostatectomy  
In a previous study, the 17 α-hydroxylase/C17,20 lyase inhibitor abiraterone +ADT prior to 
prostatectomy yielded rapid PSA declines (including near or complete responses), however 
approximately two-thirds of studied patients demonstrated little or no tumor shrinkage.[7] This 
suggests that primary resistance to even modern anti-androgen therapy remains a formidable 
challenge.  Several mechanisms of resistance to ADT have been identified, including persistent 
ligand and androgen receptor mutation.[6, 8] Despite this, the genomic determinants of 
resistance to ADT remain incompletely characterized. The extent to which such mechanisms 
might generalize across ADT regimens (such as ADT + Enzalutamide) or operate in specific 
therapeutic contexts also remains unknown.  
1.2.2 Rationale for Enzalutamide in the Neoadjuvant Setting 
The clinical importance of enzalutamide in the treatment of prostate cancer is likely just 
emerging.  Given its ability to improve survival (in both chemotherapy-naïve patients and 
patients who have already received docetaxel), its relative lack of toxicity, and no requisite 
prednisone, there is increasing interest to use this treatment earlier in the disease process.  One 
possible therapeutic strategy could employ enzalutamide in the neoadjuvant setting.  It would be 
interesting to determine if enzalutamide can induce a complete pathologic response in some 
patients, or significantly shrink tumors (identified via endo-rectal MRI) in other patients.  
Associations with these pathologic and/or radiographic changes and delayed recurrence or cure 
could drive additional studies in the future with clinical endpoints. 
1.2.3 Possible Mechanisms of Resistance in Prostate Cancer 
There are multiple mechanisms of resistance that have been proposed in prostate cancer, but it 
remains unclear which are most prevalent and relevant in newly diagnosed patients.  In treatment 
naïve patients it is most likely that signaling within the androgen receptor pathway drives 
prostate cancer cellular proliferation.  Therefore AR over expression at baseline, via amplified 
gene expression or increased molecular stability, may be one mechanism of resistance.[9, 10] 


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Molecular changes in the AR such as AR splice variants could enhance ligand-independent AR 
signaling and lead to primary drug resistance.[6] Enhanced efficacy of intranuclear steroid 
receptors functioning downstream from the AR could serve as coactivators for transcription, 
promoting treatment resistance. In addition, prostate cancer cells may utilize autocrine- or 
paracrine-mediated cellular growth, producing various androgens to drive these aberrant 
mechanisms through cytochrome P17 (CYP17)–mediated androgen synthesis.[11, 12] Additional 
possible mechanisms include AR signaling cascades that have been associated with cellular 
proliferation and decreased apoptotic activity.[13]  
1.2.4 Understanding Resistance Patterns 
Broadly, several hypotheses may explain genetic resistance to ADT (Table 1):  
I. 
Positive selection for intrinsic clonal or subclonal resistance effectors present within 
heterogeneous tumors, 
II. 
 Acquisition of new resistance effectors as a result of therapy, or  
III. 
Adaptive cellular responses (e.g., feedback mediated up-regulation of bypass pathways). 
 
Table 1. Potential resistance effectors and approaches for discovery. 
Putative 
Resistance 
Mechanism 
Sequencing 
Platform 
Discovery 
Proposed 
Computational 
Solution 
Tumor 
heterogeneity 
Whole genome 
sequencing 
Assess clonal and 
subclonal driver 
alteration selection 
Selection for 
tumor suppressor 
losses or 
oncogene 
amplification 
Whole genome 
Assess for clonal 
and subclonal copy 
gains and losses 
Acquisition of 
new variants 
Whole genome 
sequencing 
Identify acquired 
driver alterations 
Adaptive cellular 
response 
Transcriptome 
Identify 
longitudinal 
alteration and 
expression changes 
A goal of this proposal is to systematically interrogate these potential resistance 
mechanisms by computationally identifying in genomic resistance effectors to ADT in the 
preoperative setting.   Previous studies have utilized massively parallel sequencing technologies 
to define the spectrum of somatic events occurring in primary and metastatic prostate cancer. 


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[14-16] These studies have identified multiple genomic events that may contribute to prostate 
oncogenesis. 
1.2.5 Preliminary studies for prostate Multiparametric 3T prostate magnetic resonance 
imaging guided prostate biopsy 
Recent literature supports the contention that Multiparametric 3T prostate magnetic resonance 
imaging (mpMRI) has high specificity for the detection of focal prostate cancer. [17] Multi-
parametric techniques are a combination of morphologic and functional sequences. These mpMR 
exams include diffusion (DWI), contrast enhanced (DCE) and T2W sequences. This combination 
allows for a detailed assessment of focal cancers, based upon cellularity (DWI), perfusion 
(DCE), neovascularity (DCE) and cell density (T2W).  Many studies have demonstrated the 
increased specificity for in vivo cancer detection, diagnosis, tumor volume and most importantly 
the ability to differentiate aggressive (Gleason 4 or greater) from the indolent (Gleason 3 or less) 
cancer. [17, 18]  Each of the individual sequences T2W, diffusion (DWI) and dynamic contrast 
enhanced (DCE) have been tested and validated both individually and in combination. A recent 
study done here at the NCI reported positive predictive values of 98%, 98% and 100% for whole 
gland, peripheral zone and central gland lesions respectively and like other studies also suggest it 
is more accurate for focal lesions over 0.5 cm and for higher Gleason grade lesions.[17]  As 
Turkbey et al have also shown, using ROC analysis the AUC value for MRI volume estimates of 
tumors over 0.5cm3 is 0.95. [19] 
1.2.6 MR-US prostate Biopsy 
The MR-US “fusion” approach pioneered by Drs. Pinto and Choyke can be used to specifically 
biopsy lesions seen on mpMRI.  Such targeted biopsies will be evaluated in the men prior to 
neoadjuvant anti-androgen therapy. All men will have a 3T MR examination and MR/US fusion 
guided biopsy will utilize custom biopsy probe with the embedded passive electromagnetic (EM) 
tracker that allows real-time tracking of the US image and needle location. 3D reconstructed US 
volume will be registered and fused with the pre-biopsy MRI dataset. Continuous correction of 
rigid motion between the reconstructed reference 3D US volume and real-time 2D US images 
will enable tracking of the target lesions over the course of the biopsy procedure. The technical 
aspects and validation of this approach have been described earlier.[20] Biopsy targets identified 
in the MRI and re-identified in TRUS by means of registration will be sampled under real-time 
US guidance. The EM tracking and fusion technology we plan to use for this procedure has been 
developed and thoroughly validated by the NCI, and has been applied in more than 195 cases. 
[21, 22] 
 


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Custom made patient –specific MR based prostate gland molds: A 3D model of the prostate 
can be created in a novel technique developed and pioneered in the Clinical center (Figure 2), as 
described previously.[23] In brief it is a 3D model based upon MR images, which begins with 
manual segmentation of the MR T2W images.  The prostate is outlined and converted via 
software into a 3D object. This is then imported into SolidWorks (SolidWorks, Dassault 
Systèmes SolidWorks Corp., Concord, MA, USA). There it is subtracted to create an internal 
cavity that precisely shapes the patients’ gland. Slots for slicing the gland at 6mm intervals are 
designed and orientation markings (Superior/Inferior, Right/Left etc.) are added and it is then 
created using a 3D printer.  
 
 
 
The mold approach has also been shown to allow for decision system support development [24] 
that provides a probability map of peripheral zone cancers based upon MRI.  This expertise will 
be critical to the imaging, allowing suspicious lesions to be targeted for biopsy and subsequent 
correlative genetic analyses to be performed on the tissue from the index lesion(s).  This unique 
tool allows for the most accurate alignment of the prostate specimen to MR images that is 
available today. This resource available here at the NCI will be essential for the success of this 
proposal allowing for precise validation of in vivo imaging studies by enabling registration for 
focal lesion core biopsy and whole mount histopathology. 
 
 
Figure 1: Cancer detection rates comparing 
12 core TRUS and MR/US biopsy based 
upon MR suspicion level. 
Figure 2: Customized, patient-specific prostate 
specimen mold. (a)Three-dimensional 
representation of final prostate mold in green, 
shown in two halves with a 3D model of the 
patient’s prostate shown in brown. (b) Mold is 
created using a 3D printer, shown here in two 
halves fit together using small pegs/slots in the 
corners. 


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1.2.7 Summary  
Patients will be treated with goserelin and enzalutamide prior to RP. Learning what molecular 
profile is associated with resistance to intense anti-androgen therapy and linking this to 
predictive information from imaging will provide critical insight into the biology of prostate 
cancer and help develop predictive markers for potentially curative therapy. We will define the 
corresponding roles of imaging and genomics before and after treatment with goserelin and 
enzalutamide in men on this clinical trial 
A complex but central prostate cancer research problem, the unpredictable resistance to ADT in 
high risk prostate cancer, is addressed in this study. There is currently no way to detect early 
resistance to ADT. As the common pathway for lethal prostate cancer is resistance to ADT, 
prediction and visualization of resistance to ADT through imaging and genomic markers would 
be a major advance for all men with this phenotype. It will allow quantification and 
characterization of the residual cancer burden (RCB) and this knowledge if predictive of long-
term tumor response will allow real-time stratification of patients to the most effective therapy. 
The advent of targeted therapies, exemplified by immunotherapy agents, creates new 
complexities in the assessment of response. There is increasing need for imaging modalities 
which can accurately and reproducibly measure not just change in tumor size, but changes in 
relevant metabolic parameters, modulation of relevant signaling pathways, drug delivery to 
tumor, and differentiation of apoptotic cell death from other changes in the tumor volume.  Our 
studies here at the NCI have previously developed three unique contributions to the imaging and 
image guided diagnosis of prostate cancer, namely validated quantitative mpMR, MR-ultrasound 
guided biopsy techniques and mapping of tumor loci from MRI to prostatectomy specimen, by 
custom designed 3D molds.  
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
1.3 
ELIGIBILITY CRITERIA 
1.3.1 Inclusion Criteria 
1.3.1.1 Patients must have histologically or cytologically confirmed prostate cancer confirmed by 
the Laboratory of Pathology, NCI or Pathology Department at Walter Reed Bethesda. 
1.3.1.2 Must have previously untreated (with definitive therapy) prostate cancer with 
intermediate or high risk features defined as: 
Figure 3: Digitized multiparametric MRI 
maps (left) and the corresponding 
digitized whole-mount histopathology 
(right) slice with tumor outlined by a 
prostate cancer pathologist, and used as 
a landmark for lesion confirmation on 
mp 
MRI 
maps 
determine 
lesion 
localization. 


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Intermediate risk: 
-PSA level is between 10 and 20 ng/ml or 
-Gleason score is 7 or 
-Stage T2b or T2c 
High Risk: 
-Gleason 8 and higher OR 
-PSA > 20 at the time of diagnosis OR 
-Seminal vesicle involvement OR 
-Possible (on MRI) Extra-capsular extension (T3 disease) 
1.3.1.3 Patients must be eligible for and must be planning to undergo radical prostatectomy 
1.3.1.4 Patients must have testosterone levels ≥ 100 ng/dL 
1.3.1.5 Men age >18 years.   
Children are excluded because prostate cancer is not common in pediatric populations. 
Women are not eligible because this disease occurs only in men. 
1.3.1.6 ECOG performance status <1 (see APPENDIX A-Performance Status Criteria). 
1.3.1.7 Patients must have normal organ and marrow function as defined below:  
− Hemoglobin  
 
 
 
 
≥ 9 g/dL 
− leukocytes  
 
 
 
 
>3,000/mcL 
− absolute neutrophil count  
>1,500/mcL 
− platelets  
 
 
 
 
 
>150,000/mcL 
− total bilirubin 
 
 
 
 
within normal institutional limits 
− AST(SGOT)/ALT(SGPT)  
<3 X institutional upper limit of normal 
− creatinine 
 
 
 
 
 
within normal institutional limits 
 
OR 
− creatinine clearance  
 
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(calculated via Cockcroft-Gault equation) 
1.3.1.8 The effects of enzalutamide on the developing human fetus are unknown.  For this reason 
and because androgen receptor antagonists as well as other therapeutic agents used in 
this trial are known to be teratogenic, male participants and their female partners of 
child bearing potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence). Male participants should use a condom if having 
intercourse with a pregnant woman. Additionally, a condom plus another effective 
method of birth control is recommended during therapy and for 3 months after 
treatment for male participants having intercourse with a woman of reproductive 
potential.  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. 
1.3.1.9 Ability of subject to understand and the willingness to sign a written informed consent 
document. 


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1.3.1.10 Willingness to undergo biopsy. 
1.3.1.11 Ability to detect lesions within prostate on MRI for biopsy 
1.3.1.12 Willingness to travel to NIH for follow-up visits. 
1.3.2 Exclusion Criteria 
1.3.2.1 Patients who are receiving any other investigational agents (in the past 28 days) or herbal 
medications (within 1 day). 
1.3.2.2 Patients with distant metastatic disease beyond N1 (regional) lymph nodes on 
conventional imaging studies (CT, MRI or Bone Scan). 
1.3.2.3 Patients who have received any prior therapy for prostate cancer with surgery, radiation, 
and/or chemotherapy   
1.3.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to enzalutamide or other agents used in study. 
1.3.2.5 Clinically significant cardiac disease, e.g., New York Heart Association (NYHA) classes 
III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension, 
myocardial infarction in the previous 6 months as confirmed by an electrocardiogram 
(ECG). 
1.3.2.6 Contraindication to biopsy: 
- Bleeding disorders  
- PT/PTT ≥ 1.5 times the upper limit of normal 
- Artificial heart valve 
1.3.2.7  Contraindication to MRI: 
- Patients weighing more than weight limit for the scanner tables 
- Allergy to MR contrast agent 
- Patients with pacemakers, cerebral aneurysm clips, shrapnel injury or implantable 
electronic device 
1.3.2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study 
requirements. 
1.3.2.9 Patients with known HIV are ineligible.  These patients are at increased risk of lethal 
infections when treated with marrow-suppressive therapy.  In addition, if patients are 
receiving combination antiretroviral therapy, there is potential for pharmacokinetic 
interactions with enzalutamide.  Appropriate studies will be undertaken in patients 
receiving combination antiretroviral therapy when indicated. 
1.3.2.10 Patients with known active treatment for Hepatitis B and C infections. 
1.3.2.11 Patients who are taking medications that are strong inhibitors of CYP3A4 or PgP and 
need to remain on these medications. For a current table of Substrates, Inhibitors and 
Inducers 
please 
access 
the 
following 
website: 


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http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Drug
InteractionsLabeling/ucm093664.htm 
1.3.2.12 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). 
1.3.2.13 Other medications used for urinary symptoms including 5-alpha reductase inhibitors 
(finasteride and dutasteride) and alternative medications known to alter PSA (e.g., 
phytoestrogens and saw palmetto) cannot be taken while patients are receiving 
enzalutamide 
1.3.2.14 Patients with a malignancy within the past 3 years for which study drugs or a 
prostatectomy is a contraindication. 
1.3.3 Recruitment Strategies 
This protocol may be abstracted into a plain language announcement posted on NIH websites 
and on NIH social media platforms. 
1.4 
SCREENING EVALUATION 
1.4.1 Screening activities performed after a consent for screening has been signed 
Screening evaluation testing/procedures are conducted under the separate screening protocol, 01-
C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural Research Program 
Clinical Protocols). 
• Pathological confirmation of malignancy by the Laboratory of Pathology, NCI or 
Pathology Department at Walter Reed National Military Medical Center. 
• Within 12 weeks of study entry:  Bone scan, CT and/or MRI scans as appropriate for 
disease evaluation. 
• Within 8 weeks of study entry:  ECG, laboratory tests: CBC with differential and platelet 
count, Creatinine, ALT, AST, total bilirubin, PT/PTT, serum PSA, testosterone level, 
focused history, physical examination with documentation of weight, measurable disease 
and performance status. 
• Within 6 months of study entry: 3T mpMRI and U/S Guided Targeted Biopsy of the 
prostate 
For baseline evaluations, please see Section 2.5.  
1.5 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration 
& 
Status 
Updates 
found 
at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.   


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1.6 
TREATMENT ASSIGNMENT PROCEDURES 
Cohort 
Number Name 
Description 
1 
Cohort 1 
Men ≥18 years old with non-metastatic prostate cancer 
Arm 
Number Name 
Description 
1 
Arm 1 
Patients will have an mpMRI guided biopsy, then 
receive enzalutamide and goserelin treatment for 6 
months followed by a second mpMRI examination. 
1.7 
BASELINE EVALUATION 
• History and physical examination within 17 days of treatment initiation (for medical 
record only). 
• Laboratory and urine studies (Tests completed at screening may be omitted if performed 
within 17 days of treatment initiation): CBC with differential and platelet count, 
PT/PTT, and Acute care panel (Serum sodium, Potassium test, Serum chloride, CO2, 
Creatinine, Glucose test, BUN); Mineral panel (Albumin, Calcium, Magnesium, 
Phosphorus – serum); Hepatic Panel (Alkaline phosphatase, ALT, AST, direct and total 
bilirubin); Gamma-GT, LDH, total cholesterol, total protein, Serum PSA, uric acid, 
urinalysis 
• Baseline ECG (within 17 days of treatment initiation) 
• Vital signs including weight and height. 
STUDY IMPLEMENTATION 
1.8 
STUDY DESIGN 
All men (n=50) enrolled in the trial will undergo two 3T mpMRI endorectal examinations, one at 
screening before treatment and a second after completing 6 months of goserelin and 
enzalutamide just prior to surgery. Radical Prostatectomy will be performed as per standard 
procedures at either the Clinical Center or Walter Reed Bethesda. Screening biopsy (MR/US 
guided) samples and tissue from the prostatectomy specimens will all undergo pathologic and 
genomic analysis.  Genomic analysis will only be performed after obtaining informed consent. 
Genomic analysis will involve parallel sequencing and evaluation of molecular resistance 
mechanisms. We will obtain one or two cores from each index lesion(s)-up to 3 index lesions 
will be identified per patient and record all the needle locations. One core from each index lesion 
will undergo both routine pathologic examination as well as genetic analysis. Patients will be 
treated prior to surgery with standard doses of goserelin and enzalutamide. It is anticipated that 
different patients and conceivably different lesions within a patient may have differential 
responses to treatment by mpMRI. Genomic analysis will be performed from areas of 


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pathologically confirmed and MRI identified unresponsive areas of tumor within the same 
patient. In addition, using a whole-mount prostate mold, the same areas identified as were 
biopsied at screening (e.g., dominant lesion identified on mpMRI) can be directly re-biopsied for 
comparative genomic analysis.  
Figure 4: Study Schema 
After 6 months of goserelin and enzalutamide therapy, all men will have a second mpMRI 
examination. The primary goal being to create the 3D mold prior to prostatectomy and the 
secondary to obtain the post treatment mpMRI data. 
 
1.9 
DRUG ADMINISTRATION 
1.9.1 Enzalutamide 
All patients will receive enzalutamide 160mg orally, daily for 24 weeks. Enzalutamide may be 
administered with or without food. The study drug will be dispensed by the institutional 
pharmacy.  
1.9.2 Goserelin 
Goserelin will be administered SC for a total of 24 weeks. The following are examples of 
acceptable regimens (no dose modifications will be permitted): 
Goserelin 10.8mg administered subcutaneously every 12 weeks (2 doses). 
(Equivalent forms of ADT would also be acceptable including other GnRH agonists/antagonists) 
1.10 DOSE MODIFICATIONS 
1.10.1 Enzalutamide Dose Modification   
If a patient experiences a ≥ Grade 3 non-hematologic toxicity (except hypertension) attributable 
to enzalutamide or an intolerable side effect attributable to enzalutamide, withhold dosing for up 
to 1 month or until symptoms improve to ≤ Grade 2, then resume at the same dose if clinically 
appropriate. If toxicity recurs and or in the judgment of the investigator dose reduction is 
appropriate, lower dose levels (120 mg /DL-1 or 80 mg/DL-2), may be considered. Enzalutamide 
may be discontinued if toxicity recurs and dose modification is no longer clinically appropriate. 
1.10.1.1 Enzalutamide Dose Delay 
Enzalutamide may be started within 7 days if a dose is missed due to scheduling or logistical 
issues (e.g., vacation, weather) during the treatment period.  If more than 7 days have elapsed, 
patients will need to be seen before further doses can be dispensed. 
Enzalutamide 
160mg PO Daily 
+ Goserelin SC 
for 24 weeks  
Intermediate-
High Risk 
Localized 
Prostate Cancer  
N=50 
RP  
MRI 
MRI-
Guided 
Biopsy  


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1.10.2 Enzalutamide Dose Modification for Hypertension 
If a patient experiences hypertension attributable to enzalutamide, patients should be optimally 
managed prior to withholding enzalutamide dose. Clinical judgment should be used in deciding 
whether the new or worsened hypertension emerging during treatment with enzalutamide 
requires immediate therapy. 
 
Grade 2 
≥ 140 mmHg (systolic) and < 160 mmHg  
OR  
≥ 90 mmHg (diastolic) and < 100 mmHg 
 
Maintain dose of enzalutamide 
 
Increase antihypertensive therapy if clinically 
appropriate (consider increase dose of existing 
medications and/or add new antihypertensive 
medications 
Grade 3 
≥ 160 mmHg (systolic)  
OR 
≥ 100 mmHg (diastolic)  
 
Maintain dose of enzalutamide 
 
Increase antihypertensive therapy (increase dose 
of existing medications and/or add new 
antihypertensive medications) 
 
If optimal antihypertensive therapy does not 
result in a clinically significant reduction in 
blood pressure, enzalutamide should be held 
until blood pressure returns to baseline or < 140 
/ 90. 
Grade 4 
 
Discontinue enzalutamide 
1.11 IMAGING 
1.11.1 mpMRI pre and post preoperative goserelin and enzalutamide 
Patients will undergo pre-therapy ecoil MRI at 3T at screening. All MR data sets will be 
reviewed for quality and completeness. DCE PK analysis will be performed using commercially 
available iCAD software (http://www.icadmed.com). Post 6 months of preoperative therapy, a 
second ecoil MRI at 3T will be obtained. At both time points, quantitative T2, ADC values and 
DCE metrics will be extracted and recorded from all foci. DCE metrics to be collected include 
empirical indices such as Area Under the Curve at 90 seconds (AUC90) and Time to Peak (TTP), 
and also the derived indices Ktrans (the forward volume transfer constant of Gadolinium between 
blood plasma and the interstitial space, expressed in units of min-1), and ve, the dimensionless 
fractional volume of interstitial or extracellular space per unit volume of tissue. In addition, 
PiRads data will be collected for both time points. 
1.11.2 Registration of pre- and post-therapy prostate MRIs  
Drs. Choyke, Turkbey, and Harmon will collaborate on evaluation and registration of pre- and 
post-treatment MRIs. We will use non-rigid image registration for establishing correspondence 
between the targets and sub-areas in the baseline and post-therapy MR images. Preoperative 
therapies are known to significantly alter MR signal signatures for both normal and tumor tissue. 
[25, 26] We expect large reduction of the prostate gland from the baseline to post-treatment 
imaging session. These issues undoubtedly make the registration problem very challenging. 
Based on the limited preliminary evidence, intensity-based deformable registration based on 
Mutual information similarity metric pioneered by our group [27] can be used for co-registration 
of pre- and post-treatment prostate MRI. Our early preliminary results show the feasibility of 
such registration for the data collected in preoperative therapy cases (see Figure 5 below). A 


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variety of deformable registration methods based on Mutual Information are available in 3D 
Slicer, [28] and will be applied to this problem.  The transformations derived by the registration 
will be used to map the areas in the pre-treatment scans to the post-treatment gland 
configuration. This information will be used in manufacturing the custom mold that will include 
needle access to the image-registered locations of lesions to collect tissue samples from the ex 
vivo specimen.  
Figure 5:  
 
1.12 ON–TREATMENT EVALUATION 
• Physical examination and vital signs 
• Laboratory studies: CBC with differential, PT/PTT, Acute care panel (Serum sodium, 
Potassium test, Serum chloride, CO2, Creatinine, Glucose test, BUN); Mineral panel 
(Albumin, Calcium, Magnesium, Phosphorus – serum); Hepatic Panel (Alkaline 
phosphatase, ALT, AST, direct and total bilirubin); LDH; Serum PSA; and 
Testosterone 
• Correlative studies (see Section 5.1) 
1.13 FOLLOW UP PROCEDURES 
After patient has completed their post-surgery visit, the patient will be contacted remotely (e.g., 
phone) annually up to five years by the research team to determine their PSA level. PSA levels 
may be obtained at NIH or through a local provider. If PSA recurs at 0.2 ng/mL or higher, the 
patient 
will 
come 
off 
study 
and 
will 
no 
longer 
be 
followed.


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1.14 STUDY CALENDAR 
Procedure 
Screen 
Base
-line 
Day 1a 
Post-Tx 
--------- 
Pre-
Surgery 
Post-
Surgeryc 
Follow 
upf 
Month 
1 
 Month 
2 
Month 
3 
Month 
4 
Month 
5 
Month 
6 
Physical Exam & Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance Score 
X 
X 
 
 
 
 
 
 
 
 
 
Labs (See Sections 2.2 and 2.5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pathologic Confirmation 
X 
 
 
 
 
 
 
 
 
 
 
Biopsy 
Xe 
 
 
 
 
 
 
 
 
 
 
3T mpMRI 
Xe 
 
 
 
 
 
 
 
X 
 
 
Correlative Research Studiesb 
 
X 
 
 
 
X 
 
 
X 
X 
 
Imaging studiesd 
X 
 
 
 
 
 
 
 
X 
 
 
ECG 
X 
X 
 
 
 
 
 
 
X 
 
 
Prostatectomy 
 
 
 
 
 
 
 
 
X 
 
 
Enzalutamide 
 
 
X 
 
X 
 
 
 
ADT 
 
 
X 
 
 
X 
 
 
 
 
 
Adverse Events 
 
X 
 
 
 
 
 
 
X 
 
 
Concomitant Medications 
 
X 
 
 
 
 
 
 
X 
 
 
Telephone call 
 
 
 
 
 
 
 
 
 
 
X 
a Assessments will be performed on day one of each month of treatment ± 7 days 
b See Section 5.1 for information on correlative research 
c Approximately 12 weeks after surgery, may be in combination with urology branch post-surgical visit  
d Imaging studies, if clinically indicated, for disease evaluation within 12 weeks of study entry and pre-prostatectomy 
e Performed within 6 months prior to starting protocol therapy  
f Follow-up will be at least annually and may be done remotely (see Section 3.6).  


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1.15 COST AND COMPENSATION 
1.15.1 Costs 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs if they 
are not covered by insurance company.  Medicines that are not part of the study treatment will 
not be provided or paid for by the NIH Clinical Center. 
1.15.2 Compensation 
Participants will not be compensated on this study. 
1.15.3 Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy. 
1.16 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. 
1.16.1 Criteria for removal from protocol therapy 
• Completion of protocol therapy  
• Participant requests to be withdrawn from active therapy 
• Unacceptable Toxicity (Section 3.3.1).  
• Investigator discretion 
1.16.2 Off-Study Criteria 
• Completed study follow-up period (Follow-up period will be 5 years or until PSA 
recurrence of 0.2 ng/mL whichever is sooner) 
• Initiation of new therapy 
• Participant requests to be withdrawn from study 
• Death 
• Study is cancelled 
CONCOMITANT MEDICATIONS/MEASURES 
Patients may be on concomitant drugs to prevent bone loss, including calcium, vitamin D, 
bisphosphonates and denosumab.  
Other supportive care with blood components, antibiotics, analgesics, general medical therapy, 
etc., will be delivered as required.  


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1.16.3 General Guidelines 
All medications (other than study drug) and significant non-drug therapies (including physical 
therapy and blood transfusions) taken within 28 days of starting study treatment through the 6 to 
10 week safety follow up visit should be reported on the CRF. 
While patients on protocol treatment, all medications required for the health of the patient are 
allowed with the following exceptions: 
• Concurrent chemotherapy 
• Concurrent radiation therapy 
• Concurrent immunotherapy 
• Concurrent anti-cancer radionuclides 
• Concurrent systemic corticosteroid use (daily or every other day for continued use 
>14 days) 
• Concomitant use of secondary hormonal treatments 
• Concomitant use of herbal supplements 
1.16.4 Seizure threshold lowering drugs 
• Concomitant medications that can lower seizure threshold should be excluded during the 
course of this study, e.g., atypical antipsychotic drugs, phenothiazines, bupropion, 
aminophylline/theophylline, tricyclic and tetracyclic antidepressants, lithium, pimozide, 
venlafaxine. 
1.16.5 Cytochrome P450 and P-glycoprotein 
• Co-administration of enzalutamide with strong or moderate CYP2C8 inducers (e.g., 
rifampin) may alter the plasma exposure of enzalutamide. Moderate CYP2C8 inducers 
may be used concomitantly with enzalutamide at the investigator’s discretion. If co-
administration of enzalutamide with a strong CYP2C8 inhibitor cannot be avoided, 
reduce the dose of enzalutamide to 80 mg per day. 
• 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. 
• Concomitant use of enzalutamide with narrow therapeutic index drugs that are 
metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, 
warfarin) should be avoided, as enzalutamide may decrease their exposure.  
• 
Grapefruit, Seville oranges, and starfruit affect P450 and PgP activity. Concomitant use 
should be avoided. 


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CORRELATIVE STUDIES FOR RESEARCH 
1.17 BIOSPECIMEN COLLECTION 
Note: Tubes and media may be substituted based on availability with the permission of the PI or 
laboratory investigator. 
1.17.1 Histopathological Analysis 
After localization by MR of the desired pretreatment and post treatment biopsy sites, one or two 
immediately adjacent tissue cores will be obtained from the lesion.  One core will be placed in 
formalin (FFPE) for processing for histopathology, to confirm tumor diagnosis, Gleason grade 
and extent of tumor. The second core, if obtainable (presumed to be nearly identical in features 
to the first core), will be reserved for molecular analyses detection of androgen receptor variants. 
This analysis will be done only if there is sufficient tissue and after obtaining informed consent.  
 
Table 2: Clinical Protocol Procedures 
At prostatectomy, the fresh prostate gland will be processed.  The custom-made 3D mold, 
created for the individual patient with MRI data, will be used to guide placement of the “post 
treatment biopsy”, which is actually a sampling of the prostatectomy specimen in the exact 
geometric location as the pre-treatment biopsy.  The fresh prostatectomy specimen will be placed 
in the mold and the one or two core samples obtained will be handled as described above. 
Documentation of precise location of the biopsy will be recorded with appropriate coordinates, 
and location will be correlated with the subsequent cutting of tissue cross sections. Then, the 
tissue will be processed by NCI Laboratory of Pathology staff for diagnosis and pathology report 
generation. The cross sections will be labeled and will be cut into halves or quadrants for routine 
histology processing, while documenting which cross section and quadrant (right anterior #1, left 
posterior #1, etc.) from which they originated.  This will serve as a guide to the location of the 
post treatment biopsy, as that location will have been recorded keeping in mind the cross section 
number. After the prostatectomy specimen has been signed out by the Pathology Department 
Clinical protocol steps 
Procedures 
Core pathology analyses 
Pre-treatment (MR 1): 
MRI Index lesion(s) identified 
In vivo Biopsy  
Index lesion(s)  
Optional biopsy  
#1: FFPE (histology) 
#1A FFPE & 1 H&E 
(molecular analyses) 
#2: Fresh frozen (optional) 
ADP Therapy 
Prostatectomy 
 Full pathology report issued 
Post-treatment (MR 2): 
MRI Index lesion(s)  
identified 
(same lesion(s) as above) 
Ex Vivo Biopsy  
Index lesion(s)  
Optional biopsy 
#1: FFPE (histology) 
#1A FFPE & 1 H&E 
(molecular analyses) 
#2: Fresh frozen (optional)  


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with final diagnosis and report issued, correlation between the post treatment biopsy and the 
whole section will occur. The tissue section(s) from which the post treatment biopsy was taken 
will be analyzed morphologically and compared to the biopsy. If indicated, the block or blocks 
of the slides to be compared can be sectioned further for complete morphologic analysis of 
presence/absence of residual tumor, tumor grade, tumor extent, etc. 
MR 2 data will be performed according to the specialized protocol reported previously. [17, 23] 
All tumor foci will be re-identified. The 3D mold will provide target localization and trajectory 
path for post prostatectomy core biopsies. 
Prior to prostatectomy we will use the MRI data and resulting 3D custom built molds of the 
entire prostate gland and foci of tumor within it. [29] Focal tumors and all prior biopsy targets 
will be re-identified where possible and mapped on MR imaging. This allows for image-based 
targets and/or regions registered from baseline MR exam to be re-identified for repeat biopsy. 
This second set of biopsies will be taken after gland removal. The core needle biopsies will be 
taken before specimen fixation and pathological analysis. These cores will be taken from the pre-
defined locations identified on MR and displayed in the 3D mold.  Most importantly this will 
provide tissue samples from the same locations both before and after therapy and allow for 
sampling of sub regions of activity within the lesion based upon the mpMRI appearances. The 
prostate specimen can be whole mount sectioned in a customized mold, allowing geometric 
alignment to magnetic resonance imaging and therefore precise comparison of MRI/pathologic 
response. The prostate specimen, after the core needle biopsy samples have been removed, the 
specimen will be processed in the routine way with full histo-pathological and genomic analysis. 
1.17.2  Immunohistochemistry 
The Laboratory of Pathology and the Warren G. Magnuson Clinical Center will perform 
Immunohistochemistry on biopsied tissue, if the patient elects to have the procedure.  
Immunohistochemistry of these tissue specimens will be obtained for CD4, CD8, and FOX-P3.  
In addition, phenotypic analysis of infiltrating immune cells will be performed. 
Immunohistologic grading schema of the lesions  
Score  
%positive cells of each subtype 
0 
 
0 
1 
 
1-25% 
2 
 
26-50% 
3 
 
>50% 
All staining will be categorized as being membrane or nuclear. 
The 
Laboratory 
of 
Genitourinary 
Cancer 
Pathogenesis 
will 
perform 
H&E 
and 
immunohistochemistry on radical prostatectomy specimens and biopsied tissue for research 
purposes. Immunohistochemistry will be performed on cases with treatment effect or residual 
tumor cells following neoadjuvant enzalutamide treatment to identify potential genes or proteins 
associated with resistance to therapy. Immunohistochemistry targets will include AR, AR-V7, 
PD-L1, PTEN, GR and MYC. Additional targets will be added upon evaluation of sequencing 
results (Section 5.1.3 below). Staining qualitative assessment and (semi-)quantitative 


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measurements will be performed in collaboration with Huihui Ye, M.D. at UCLA and Rosina 
Lis, M.D. at Dana-Farber Cancer Institute using scanned or glass slides. Slides will be coded, 
linked; Drs. Ye and Lis will not have access to PII. 
1.17.3 Next-Generation Sequencing and Genomic Analysis 
Prostate cancer genomics are markedly heterogeneous, even within an individual focus. Genomic 
heterogeneity is associated with therapy resistance in multiple studies, and it is hypothesized that 
existing subclones comprise subclonal resistance effectors. Alternatively, the acquisition of new 
genomic alterations may confer a resistance phenotype to tumor cell clones or subclones. The 
analysis of tumor genomics both before therapy and after completion of neoadjuvant therapy can 
elucidate molecular features of resistant effectors and indicate if they arose through enrichment 
of intrinsic heterogeneity or acquisition of new alterations. Whole genome and/or exome 
sequencing will be performed on DNA isolated from matched core biopsy samples (MR1.1a and 
MR 2.1a). DNA taken from the buffy coat (see section on ctDNA) or benign adjacent prostate 
tissue will be used for a reference sample from which somatic alterations are identified. 
Germline analysis of DNA for inherited alterations reveal valuable insight into mechanisms of 
disease and will only be used for this purpose. Additionally, DNA may be isolated from involved 
tissue in the prostatectomy specimen after completion of clinical diagnostic evaluation by the 
Laboratory of Pathology, as described above. DNA sequencing and genomic analysis will be 
done using approved protocols under the auspices of Drs. Sowalsky in the Laboratory for 
Genitourinary Cancer Pathogenesis, CCR. 
Sample Collection 
Pretreatment screening biopsy samples will be received by Laboratory of Pathology and 
processed in standard fashion using formalin fixation and paraffin embedding. Post-treatment 
biopsy samples will be obtained by Laboratory of Pathology and processed in standard fashion 
using formalin fixation and paraffin embedding, as described above. Biopsy samples and, if 
appropriate, adjacent areas of the prostatectomy specimen, will be used for molecular studies 
after completion of clinical diagnostic evaluation. To enrich for tumor cell purity, it is expected 
tumor specimens will undergo microdissection prior to isolation of DNA and preparation of 
sequencing libraries. 
1.17.4 Circulating Tumor DNA (ctDNA) 
Circulating tumor DNA (ctDNA) is shed into the bloodstream by cells undergoing apoptosis or 
necrosis and in patients a proportion of the fragmented DNA in circulation is derived directly 
from the tumor. In recent years, ctDNA has shown promise as a non-invasive sensitive 
biomarker of tumor burden, and hence has potential as both a prognostic and surrogate response 
biomarker. In a study to detect ctDNA across 14 tumor types that had not yet metastasized or 
released detectable circulating tumor cells, ctDNA was detected at relatively high concentrations 
in the patients with metastatic cancer and at lower but detectable concentrations in those with 
localized cancers.[30]  Together, these findings suggest that ctDNA could be a reliable 
biomarker for early detection as well as for determining optimal treatment, and monitoring 
resistance. ctDNA is abundant and readily detectable in most patients with advanced cancer; in 
cases with lower levels of ctDNA such as in early stage disease or minimal residual disease, 
detection is made possible with the use of advanced genomic methodologies. The analysis of 
ctDNA has considerable potential in the assessment of molecular heterogeneity, for monitoring 


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tumor dynamics, identifying genetic determinants of therapy, and evaluating treatment response; 
as well as detecting acquired resistance and developing potential strategies to circumvent 
this.[31] A recent study found that genomic analysis of ctDNA in plasma of mCRPC patients 
treated with abiraterone and enzalutamide identified key aberrations that may be associated with 
therapeutic resistance.[32]  This data will be for research purposes only and will not be shared 
with patients. 
Sample Collection 
A baseline blood sample will be collected at the start of study and serial blood samples will be 
collected during the course of treatment at q3months, and at the end of study. Blood samples will 
be collected in 2 10-ml Streck Cell-Free DNA tube at room temperature and delivered to Dr. 
Figg’s lab for barcode labeling and/or processing and then Bldg. 37, Rm1066 by Clinical Center 
Messenger Escort Service using a CRIS order. Processing and/or sequencing of plasma for 
ctDNA analysis will be performed by the Laboratory of Genitourinary Cancer Pathogenesis (Dr. 
Sowalsky). 
1.17.5 Androgen Receptor Variants 
Detection of androgen receptor variants in tissue samples will be performed on one-half of one 
core biopsy to isolate total RNA from screening biopsy and radical prostatectomy specimens. 
RNA will be reverse transcribed and full-length androgen receptor (AR with LBD) as well as 
androgen receptor variants 5, 6, 7, 8 (V5-V8) will be detected by droplet digital PCR. This 
analysis will be performed when logistically feasible and only if there is sufficient tissue 
available. 
Sample Collection 
A baseline and post-treatment tumor sample will be collected, if feasible. Notify Jane Trepel’s 
lab in advance of the scheduled procedure by email. At the time of the procedure, please notify 
Ms. Trepel’s lab by phone at 301-496-1547. A member of Ms. Trepel’s lab will be present for 
the procedure to collect the sample, if available. Ms. Trepel’s lab will provide the collection 
media. 
1.17.6 Peripheral Blood microRNA and mRNA 
MicroRNA will be isolated from plasma and analyzed using Exiqon microRNA PCR panels. AR 
full-length (with the LBD) and splice variants will be assayed from CTCs isolated from 
peripheral blood drawn into two 10-ml lavender top tubes and from RNA purified from blood 
collected in one 2.5-ml PAXgene tube. The copy number of splice variants will be quantified 
using droplet digital PCR and a comparison performed between PAXgene and CTC-enriched 
samples. This sample will be collected only when logistically feasible 
Sample Collection 
For microRNA analysis, peripheral blood will be collected in two 10-ml EDTA lavender top 
tubes and one 2.5-ml PAXgene tube at baseline and post-treatment, if feasible. Blood samples 
will be held at room temperature and picked up by Ms. Trepel’s lab. Contact study team for 
PAXgene tube. 


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1.17.7 Tumor Gene Expression 
In addition to acquiring resistance through enrichment or acquisition of genomic alterations, 
resistance may also arise through adaptive cellular responses in the absence of identifiable 
genomic alterations.  This can best be evaluated through evaluation of tumor gene expression. 
Total RNA will be isolated from matched tumor tissue both before and after therapy, reverse 
transcribed, and used for transcriptome analysis.  RNA will be isolated from matched FFPE 
cores (MR 1.1a and MR 2.1a). Additionally, RNA may be isolated from involved tissue in the 
prostatectomy specimen after completion of clinical diagnostic evaluation by the Laboratory of 
Pathology, as described above. Transcriptome sequencing and analysis will be done using 
approved protocols under the auspices of Dr. Sowalsky in the Laboratory for Genitourinary 
Cancer Pathogenesis, CCR. 
Sample Collection 
Pretreatment screening biopsy samples will be received by Laboratory of Pathology and 
processed in standard fashion using formalin fixation and paraffin embedding.  Post-treatment 
biopsy samples will be obtained by Laboratory of Pathology and processed in standard fashion 
using formalin fixation and paraffin embedding, as described above. Biopsy samples and, if 
appropriate, adjacent areas of the prostatectomy specimen, will be used for molecular studies 
after completion of clinical diagnostic evaluation. To enrich for tumor cell purity, it is expected 
tumor specimens will undergo microdissection prior to isolation of RNA and preparation of 
sequencing libraries. 
1.17.8 Management of Results 
The results of molecular studies conducted using specimens collected on this protocol are for 
research purposes only and will not be disclosed to individual subjects.  The exception to this is 
potential incidental findings that are deemed medically significant and actionable. The policy for 
this disclosure is outlined below and in the consent form for this study.  
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
incidental findings that is current at the time of primary analysis. (A list of current guidelines is 
maintained on the CCR intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). 
Inherited 
alterations that may contribute to disease susceptibility in addition to prostate cancer may also be 
uncovered. Subjects will be contacted at this time with a request to provide a blood sample to be 
sent to a CLIA certified laboratory. If the research findings are verified in the CLIA certified lab, 
the subject will be offered the opportunity to come to NIH (at our expense) to have genetic 
education and counseling to explain this result. If the subject does not want to come to NIH, a 
referral to a local genetic healthcare provider will be provided (at their expense). 
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 
Subject’s genetic data may be deposited in a database such as dbGaP. Although there is 
controlled access to such a database, such a submission carries theoretical risks of revealing the 
identity of the subject. This is discussed in the consent. 


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1.17.9 Comparison of pathology to imaging 
The use of a patient-specific mold (as described in Section 1.2.6.) allows the radical 
prostatectomy specimen will be sectioned in the same plane as the MRI scans (see Section 3.4.1 
and 3.4.2), and thus any immunohistochemistry (IHC) performed (see Sections 5.1.1 and 5.1.2) 
may help to inform analysis or interpretation of MRI in the post-treatment setting. There are no 
commercial software packages that specifically address the issue of automated quantification of 
post-treatment IHC and alignment with MRI. Drs. Choyke, Turkbey, and Harmon in the 
Molecular Imaging Program will collaborate with Drs. Sowalsky in the Laboratory of 
Genitourinary Cancer Pathogenesis to identify appropriate programs and tools for assessing 
correlation. As necessary, collaborations with third parties (including academic centers and 
commercial manufacturers of quantitative software) may be sought for finding the optimal 
solution. If a collaboration with an external party is to be sought, a personnel change amendment 
to this protocol will be made. All data shared with third parties will be coded, linked and covered 
under a human-materials MTA written specifically for each collaboration (see Section 9.1). 
1.18 SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
Samples will not be sent outside NIH appropriate approvals and/or agreements, if required.  
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below. 
The study will remain open so long as sample or data analysis continues. Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. The PI will 
record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the 
requirements of Section 7.2. 
1.18.1 Sample Data Collection - Blood Processing Core (BPC)  
Please e-mail NCIBloodcore@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 NCIBloodcore@mail.nih.gov. 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix 
limited to defined Figg lab personnel, who are issued individual user accounts. Installation of 
Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password 
restricted login screen.  
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 


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patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
1.18.2 Sample Storage and Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C 
according to stability requirements. These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed.  The PI will record any loss or unanticipated destruction of samples as 
a deviation. Reporting will be per requirements of Section 7.2.1. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
DATA COLLECTION AND EVALUATION  
1.19 DATA COLLECTION 
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR 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. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant. 
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.  
Document AEs from the first study intervention, Study Day 1, through the end of treatment. 
Beyond 30 days after the last intervention, only adverse events which are serious and related to 
the study intervention need to be recorded.  
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 


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• Results in discontinuation from the study 
• Is associated with clinical signs or symptoms  
• Requires treatment or any other therapeutic intervention 
• Is associated with death or another serious adverse event, including hospitalization.  
• Is judged by the Investigator to be of significant clinical impact 
• 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.  
The NCI investigators will be responsible for the collection, maintenance, and quality control of 
the study data. Clinical data will be entered into a data capture system provided by the NCI CCR 
at least once every two weeks when patients are enrolled on the trial. Protocol-specific eCRFs 
will be developed for this trial. All data will be kept secure. 
Only the following adverse events will be recorded on the Case Report Form: 
– Grade 2 unexpected events that are possibly, probably or definitely related to the 
study drugs;  
– Grade 3 and 4 events;  
– Grade 5 events regardless of attribution;  
– Serious Events regardless of attribution; 
– Surgical side effects will be collected at the post-surgery visit only and not recorded if 
they occur after that time.   
1.20 RESPONSE CRITERIA 
For the purposes of this study, patients will be monitored for response via endorectal MRI for 
research purposes, but there will be no formal radiographic assessment of clinical response.  It is 
anticipated that all patients will have a stable or declining PSA throughout the study (prior to 
surgery) and thus additional response assessments are not required. 
Index lesions identified on mpMRI will be entered into a data capture system provided by the 
NCI CCR. 
In the rare case that patients develop a rising PSA while on this study appropriate imaging 
studies will be performed at the discretion of the treating physician. 
Definitions: 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with enzalutamide. 
Evaluable for objective response: As described in the first paragraph above, patients will be 
followed for PSA and changes on endorectal MRI for research purposes only. 


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1.20.1 Disease Parameters 
All patients will be required to have pathologically proven prostate cancer at enrollment and 
confirmation that they do not have metastatic disease. 
1.21 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). 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN 
1.22 DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
1.23 OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
1.23.1 Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 
Non-Compliance 
Human 
Subjects 
Research 
found 
at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
1.23.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.   
1.24 NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.  
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death. 


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1.25 NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
1.25.1 Principal Investigator/Research Team  
The clinical research team will meet weekly when patients are being actively treated on the trial 
to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable 
will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
Section 7.2.1 will be submitted within the appropriate timelines.  
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.  
STATISTICAL CONSIDERATIONS   
The primary objective of this exploratory trial is to obtain pilot data to assess the utility and role 
of mpMRI in localization and detection of focal prostate cancer both before and after treatment 
with pre-operative ADT and enzalutamide. Secondary objectives include obtaining pilot data to 
guide future studies with respect to determining genetic predictors and correlates of response to 
therapy as well as to link imaging information to genomic information related to resistance. 
Patients who have newly diagnosed prostate cancer will undergo treatment with androgen 
deprivation therapy and enzalutamide and will undergo mpMRI imaging at screening and 6 
months. The imaging will be used to monitor the changes in the individual tumors located within 
the prostate. As these patients will all have multiple tumors within the prostate, it is anticipated 
that approximately 25% of the patients will experience minimal declines in tumor and still have 
significant residual disease, 25% may have complete disappearance of tumor, and the remainder 
will show substantial improvement (disappearance of some lesions, with others being much 
smaller). To guide sample size determination, it is estimated that for an exploratory investigation 
of the association of genomic information and its relationship to response, it would be useful to 
have at least a minimum of 10 patients who still have significant residual disease in order to form 
preliminary assessments of the relationships noted. As such, if 50 total evaluable patients were to 
enroll on the trial and if the probability of being in this category was 25%, there would be 83.6% 
probability of having at least 10 such patients. Thus, this pilot study will plan to enroll 50 total 
evaluable patients who would all undergo primary treatment and mpMRI imaging to assess the 
role of imaging in this setting. The accrual ceiling will be 55 in order to accommodate a small 
number of patients who may be inevaluable.  Successful use of this imaging will lead to analyses 
related to the association with genomic traits at baseline and prostatectomy and whether there is 
disappearance of tumor or not. On this trial, all of these investigations will be performed with 
exploratory, hypothesis generating intent. 


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HUMAN SUBJECTS PROTECTIONS  
1.26 RATIONALE FOR SUBJECT SELECTION 
1.26.1 Selection Based on 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 protocol as this disease 
occurs only in men. 
1.27 PARTICIPATION OF CHILDREN 
Because no dosing or adverse event data are currently available on the use enzalutamide in 
patients <18 years of age and because prostate cancer is uncommon in pediatric populations, 
children are excluded from this study, but may be eligible for future pediatric trials. 
1.28 PARTICIPATION OF 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 9.5), all subjects ≥ age 18 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 (ACAT) for evaluation to assess ongoing capacity of the 
subjects and to identify an LAR, as needed. 
Please see Section 9.6.1 for consent procedure 
1.29 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
1.29.1 Alternative Approaches or Treatments 
Patients will be consented regarding the risks and benefits of this trial, the treatment 
requirements, and alternative approaches to entering on this trial.   
1.29.2 Identified Risks to Study Procedures 
1.29.2.1 Blood Sampling 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.  
1.29.2.2 Urine Collection 


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No physical risks are associated with urine collection. 
1.29.2.3 Electrocardiogram 
Some skin irritation can occur where the ECG/EKG electrodes are placed. The test is completely 
painless, and generally takes less than a minute to perform. 
1.29.2.4 Tumor Biopsy  
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained 
fully during informed consent. The patient will consent at the time of the procedure. 
1.29.2.5 MR Imaging 
The risks of MR imaging are relatively small. 
The US Food and Drug Administration has issued warnings that administration of gadolinium 
(updated September 9, 2010), the MRI contrast imaging agent used in this protocol, has been 
associated with development of a disease called nephrogenic systemic fibrosis (NSF). The 
syndrome is rare (approximately 600 cases reported worldwide as of September 2010, out of 
several million administrations of gadolinium), but disabling and in some cases, fatal. All cases 
to date have occurred in patients with severe renal disease, including patients on dialysis. NSF 
has been nearly eradicated secondary to careful screening of renal function and avoiding use of 
gadolinium in patients with eGFR <30 ml/min/1.73 BSA. Even in patients with end stage renal 
disease, there have been only rare occurrences of NSF because of precautions taken to use more 
stable contrast agents at lower doses. This protocol excludes patients with severe renal 
insufficiency (eGFR <30 ml/min/1.73 BSA). The FDA has issued warnings in 2017 and 2018 
that some gadolinium may be retained in the brain, bone and skin although health risks of 
accumulation have not been reported to date. In accordance with the FDA Drug Safety 
Communication of 05/16/2018, the Medication Guide for gadobutrol (or other macrocyclic 
gadolinium contrast agent if applicable) will be made available to all subjects with scans that will 
involve gadolinium-based contrast agent administration. 
1.29.3 Non-Physical Risks of Genetic Research 
1.29.3.1 Risk related to possibility that information may be released 
This includes the risk that data related to your genetic testing can be released to members of the 
public, insurers, employers, or law enforcement agencies.  
1.29.3.2 Risk of receiving unwanted information 
Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related genetic analysis. Patients will be clearly informed that the data related to genetic 
analysis is coded, investigational and will not be shared with patients, family members or health 
care providers. 
1.29.3.3 Risk to family or relatives 
Family members or relatives may or may not want to be aware of familial tendencies or genetic 
risks of disease which may cause anxiety about possible future health problems. As previously 
noted, patients will be notified of any medically significant and actionable incidental findings. 
Study results will not be shared with patients. 


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1.29.4 Procedure for Protecting Against or Minimizing any Potential Risks 
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity. This study may involve risks to patients, which are currently unforeseeable. All patients 
will have blood tests, examinations and scans as described in the protocol evaluation (Section 
3.7, Study Calendar). Patients will also be required to have a local physician to provide long-
term care and to monitor for complications. If patients suffer any physical injury as a result of the 
participation in this study, immediate medical treatment is available at the Clinical Center, 
National Cancer Institute, Bethesda, Maryland. Although no compensation is available, any 
injury will be evaluated and treated in keeping with the benefits or care to which patients are 
entitled under applicable regulations. 
1.29.5 Provisions for Monitoring Data Collection to Ensure Safety of Subjects 
As information is gathered from this trial, clinical results will be shared with patients as they 
become available. 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 and/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. 
1.30 RISKS/BENEFITS ANALYSIS 
The risks of blood draw, MR imaging, and biopsy are relatively small.  Because prostate biopsy 
is a clinically accepted intervention in patients with no evidence of metastatic disease, the risk of 
this study does not significantly differ from the risk of standard therapy with the exception that 
MR guided prostate biopsies typically involve obtaining a greater number of biopsies than a 
standard. In addition, the drug (dosage and formulation) being used in this study has been 
approved by the FDA for the treatment of prostate cancer. 
1.31 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting.  A designated 
study investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy, including HRPP Policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s).  Whether in person or remote, the privacy 
of the subject will be maintained. Consenting investigators (and participant/consent designee, 
when in person) will be located in a private area (e.g., clinic consult room). When consent is 


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conducted remotely, the participant/consent designee will be informed of the private nature of 
the discussion and will be encouraged to relocate to a more private setting if needed. 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant. 
Manual (non-electronic) signature on electronic document: 
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the following to obtain the required signatures: 
• 
Adobe platform (which is not 21 CFR Part 11 compliant); or,  
• 
iMedConsent platform (which is 21 CFR Part 11 compliant) 
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the same 
screen may be used when in the same location but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse.  
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) 
found 
at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
1.31.1 Consent Process for Adults Who Lack Capacity to Consent to Research 
Participation 
For participants addressed in Section 9.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 9.6. 
REGULATORY AND OPERATIONAL CONSIDERATIONS  
1.32 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants. If the 
study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform study participants and the Institutional Review Board (IRB) and will provide the 
reason(s) for the termination or suspension.  Study participants will be contacted, as applicable, 
and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 


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• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the IRB. 
1.33 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
1.34 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest. 
1.35 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
and their staff. This confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, representatives of the Institutional Review Board (IRB), and/or regulatory 
agencies may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records 
for the participants in this study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB or Institutional policies.. 


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Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by the clinical site(s) and by NCI CCR research staff will be secured and password 
protected. At the end of the study, all study databases will be archived at the NIH. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants. 
PHARMACEUTICAL INFORMATION   
1.36 ENZALUTAMIDE 
Please see FDA-approved packet insert for Enzalutamide for complete agent information. 
1.36.1 Source 
Enzalutamide will be obtained from commercial sources and dispensed by the institutional 
pharmacy. 
1.36.2 Administration Procedures 
Enzalutamide 160 mg (four 40 mg capsules) administered orally once daily. 
Swallow capsules whole. Enzalutamide can be taken with or without food. 
1.37 GOSERELIN 
Please see package insert for complete drug information. 
1.37.1 Source 
Goserelin will be obtained from commercial sources and dispensed by the institutional 
pharmacy. 
1.37.2 Administration Procedures 
See Section 3.2.2 for details. 


37 
Abbreviated Title: Neoadjuvant ADT & Enzalutamide  
Version Date: 01/25/2024 
 
REFERENCES  
1. 
Siegel R, Ma J, Zou Z, Jemal A: Cancer statistics, 2014. CA: a cancer journal for 
clinicians 2014, 64(1):9-29. 
2. 
Zelefsky MJ, Eastham JA, Cronin AM, Fuks Z, Zhang Z, Yamada Y, Vickers A, 
Scardino PT: Metastasis after radical prostatectomy or external beam radiotherapy 
for patients with clinically localized prostate cancer: a comparison of clinical 
cohorts adjusted for case mix. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2010, 28(9):1508-1513. 
3. 
Kane CJ, Presti JC, Jr., Amling CL, Aronson WJ, Terris MK, Freedland SJ, Group SDS: 
Changing nature of high risk patients undergoing radical prostatectomy. The 
Journal of urology 2007, 177(1):113-117. 
4. 
Stephenson AJ, Kattan MW, Eastham JA, Bianco FJ, Jr., Yossepowitch O, Vickers AJ, 
Klein EA, Wood DP, Scardino PT: Prostate cancer-specific mortality after radical 
prostatectomy for patients treated in the prostate-specific antigen era. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2009, 
27(26):4300-4305. 
5. 
Sharifi N, Gulley JL, Dahut WL: Androgen deprivation therapy for prostate cancer. 
JAMA : the journal of the American Medical Association 2005, 294(2):238-244. 
6. 
Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad 
TA, Chen Y, Fedor HL et al: AR-V7 and resistance to enzalutamide and abiraterone 
in prostate cancer. The New England journal of medicine 2014, 371(11):1028-1038. 
7. 
Taplin ME, Montgomery RB, Logothetis C, Bubley GJ, Richie JP: Effect of 
neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, 
pathological complete response (pCR), and near pCR in localized high-risk prostate 
cancer (LHRPC): Results of a randomized phase II study. Journal of Clinical 
Oncology, vol 30, no 15 (May 20 Suppl), p 4521, 2012. 
8. 
Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, Nelson 
PS, Montgomery RB: Resistance to CYP17A1 inhibition with abiraterone in 
castration-resistant prostate cancer: induction of steroidogenesis and androgen 
receptor splice variants. Clinical cancer research : an official journal of the American 
Association for Cancer Research 2011, 17(18):5913-5925. 
9. 
Koivisto P, Kononen J, Palmberg C, Tammela T, Hyytinen E, Isola J, Trapman J, 
Cleutjens K, Noordzij A, Visakorpi T et al: Androgen receptor gene amplification: a 
possible molecular mechanism for androgen deprivation therapy failure in prostate 
cancer. Cancer research 1997, 57(2):314-319. 
10. 
Gregory CW, Johnson RT, Jr., Mohler JL, French FS, Wilson EM: Androgen receptor 
stabilization in recurrent prostate cancer is associated with hypersensitivity to low 
androgen. Cancer research 2001, 61(7):2892-2898. 
11. 
Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG, Balk 
SP: Increased expression of genes converting adrenal androgens to testosterone in 
androgen-independent prostate cancer. Cancer research 2006, 66(5):2815-2825. 


38 
Abbreviated Title: Neoadjuvant ADT & Enzalutamide  
Version Date: 01/25/2024 
 
12. 
Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True 
LD, Nelson PS: Maintenance of intratumoral androgens in metastatic prostate 
cancer: a mechanism for castration-resistant tumor growth. Cancer research 2008, 
68(11):4447-4454. 
13. 
Zhu ML, Kyprianou N: Androgen receptor and growth factor signaling cross-talk in 
prostate cancer cells. Endocrine-related cancer 2008, 15(4):841-849. 
14. 
Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP, White 
TA, Stojanov P, Van Allen E, Stransky N et al: Exome sequencing identifies recurrent 
SPOP, FOXA1 and MED12 mutations in prostate cancer. Nature genetics 2012, 
44(6):685-689. 
15. 
Berger MF, Lawrence MS, Demichelis F, Drier Y, Cibulskis K, Sivachenko AY, Sboner 
A, Esgueva R, Pflueger D, Sougnez C et al: The genomic complexity of primary 
human prostate cancer. Nature 2011, 470(7333):214-220. 
16. 
Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, Quist MJ, Jing 
X, Lonigro RJ, Brenner JC et al: The mutational landscape of lethal castration-
resistant prostate cancer. Nature 2012, 487(7406):239-243. 
17. 
Turkbey B, Mani H, Shah V, Rastinehad AR, Bernardo M, Pohida T, Pang Y, Daar D, 
Benjamin C, McKinney YL et al: Multiparametric 3T prostate magnetic resonance 
imaging to detect cancer: histopathological correlation using prostatectomy 
specimens processed in customized magnetic resonance imaging based molds. The 
Journal of urology 2011, 186(5):1818-1824. 
18. 
Vargas HA, Akin O, Franiel T, Mazaheri Y, Zheng J, Moskowitz C, Udo K, Eastham J, 
Hricak H: Diffusion-weighted endorectal MR imaging at 3 T for prostate cancer: 
tumor detection and assessment of aggressiveness. Radiology 2011, 259(3):775-784. 
19. 
Turkbey B, Mani H, Aras O, Rastinehad AR, Shah V, Bernardo M, Pohida T, Daar D, 
Benjamin C, McKinney YL et al: Correlation of magnetic resonance imaging tumor 
volume with histopathology. The Journal of urology 2012, 188(4):1157-1163. 
20. 
Xu S, Kruecker J, Turkbey B, Glossop N, Singh AK, Choyke P, Pinto P, Wood BJ: Real-
time MRI-TRUS fusion for guidance of targeted prostate biopsies. Computer aided 
surgery : official journal of the International Society for Computer Aided Surgery 2008, 
13(5):255-264. 
21. 
Vourganti S, Rastinehad A, Yerram NK, Nix J, Volkin D, Hoang A, Turkbey B, Gupta 
GN, Kruecker J, Linehan WM et al: Multiparametric magnetic resonance imaging 
and ultrasound fusion biopsy detect prostate cancer in patients with prior negative 
transrectal ultrasound biopsies. The Journal of urology 2012, 188(6):2152-2157. 
22. 
Pinto PA, Chung PH, Rastinehad AR, Baccala AA, Jr., Kruecker J, Benjamin CJ, Xu S, 
Yan P, Kadoury S, Chua C et al: Magnetic resonance imaging/ultrasound fusion 
guided prostate biopsy improves cancer detection following transrectal ultrasound 
biopsy and correlates with multiparametric magnetic resonance imaging. The 
Journal of urology 2011, 186(4):1281-1285. 


39 
Abbreviated Title: Neoadjuvant ADT & Enzalutamide  
Version Date: 01/25/2024 
 
23. 
Trivedi H, Turkbey B, Rastinehad AR, Benjamin CJ, Bernardo M, Pohida T, Shah V, 
Merino MJ, Wood BJ, Linehan WM et al: Use of patient-specific MRI-based prostate 
mold for validation of multiparametric MRI in localization of prostate cancer. 
Urology 2012, 79(1):233-239. 
24. 
Shah V, Turkbey B, Mani H, Pang Y, Pohida T, Merino MJ, Pinto PA, Choyke PL, 
Bernardo M: Decision support system for localizing prostate cancer based on 
multiparametric magnetic resonance imaging. Medical physics 2012, 39(7):4093-
4103. 
25. 
Barrett T, Gill AB, Kataoka MY, Priest AN, Joubert I, McLean MA, Graves MJ, Stearn 
S, Lomas DJ, Griffiths JR et al: DCE and DW MRI in monitoring response to 
androgen deprivation therapy in patients with prostate cancer: a feasibility study. 
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance 
in Medicine / Society of Magnetic Resonance in Medicine 2012, 67(3):778-785. 
26. 
Groenendaal G, van Vulpen M, Pereboom SR, Poelma-Tap D, Korporaal JG, 
Monninkhof E, van der Heide UA: The effect of hormonal treatment on conspicuity of 
prostate cancer: implications for focal boosting radiotherapy. Radiotherapy and 
oncology : journal of the European Society for Therapeutic Radiology and Oncology 
2012, 103(2):233-238. 
27. 
Wells WM, 3rd, Viola P, Atsumi H, Nakajima S, Kikinis R: Multi-modal volume 
registration by maximization of mutual information. Medical image analysis 1996, 
1(1):35-51. 
28. 
Fedorov A, Tuncali K, Fennessy FM, Tokuda J, Hata N, Wells WM, Kikinis R, Tempany 
CM: Image registration for targeted MRI-guided transperineal prostate biopsy. 
Journal of magnetic resonance imaging : JMRI 2012, 36(4):987-992. 
29. 
Turkbey B, Shah VP, Pang Y, Bernardo M, Xu S, Kruecker J, Locklin J, Baccala AA, Jr., 
Rastinehad AR, Merino MJ et al: Is apparent diffusion coefficient associated with 
clinical risk scores for prostate cancers that are visible on 3-T MR images? 
Radiology 2011, 258(2):488-495. 
30. 
Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, 
Luber B, Alani RM et al: Detection of circulating tumor DNA in early- and late-stage 
human malignancies. Science translational medicine 2014, 6(224):224ra224. 
31. 
Diaz LA, Jr., Bardelli A: Liquid biopsies: genotyping circulating tumor DNA. Journal 
of clinical oncology : official journal of the American Society of Clinical Oncology 2014, 
32(6):579-586. 
32. 
Azad A, Lester R, Leibowitz-Amit R, Joshua. A DYCH, Bernhard J. Eigl, Kim N. Chi; 
British Columbia Cancer Agency, Vancouver, BC, Canada; Tom Baker Cancer Centre, 
Calgary, AB, Canada; Division of Medical Oncology, Princess Margaret 
Hospital/University of Toronto, Toronto, ON, Canada; Princess Margaret Hospital, 
University Health Network, Toronto, ON, Canada; Tom Baker Cancer Centre, University 
of Calgary, Calgary, AB, Canada; BC Cancer Agency, Vancouver, BC, Canada; BC 
Cancer Agency, Vancouver Cancer Centre, Vancouver, BC, Canada: Population-based 
analysis of a novel prognostic model for metastatic castration-resistant prostate 


40 
Abbreviated Title: Neoadjuvant ADT & Enzalutamide  
Version Date: 01/25/2024 
 
cancer (mCRPC) patients (pts) treated with abiraterone acetate (AA). Journal of 
Clinical Oncology 2014, 32(5S):abstract 5078. 
 


41 
Abbreviated Title: Neoadjuvant ADT & Enzalutamide  
Version Date: 01/25/2024 
 
APPENDIX A-PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
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 work of a light or 
sedentary nature (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 more than 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 more 
than 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. 
 

ICF_003.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 05/16/2022
Page 1 of 14
CC pre rCR ICF template v. 12.01.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR: Fatima Karzai, M.D.
STUDY TITLE:
Neoadjuvant Androgen Deprivation and Enzalutamide:  
Using Multiparametric MRI to Evaluate Intraprostatic Tumor 
Responses and Androgen Resistance Patterns in Newly 
Diagnosed Prostate Cancer
STUDY SITE:
NIH Clinical Center
Cohort: 
Standard 
Consent Version:  
05/16/2022 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:
Fatima Karzai, M.D.
 
Phone: 301-480-7174
Email: fatima.karzai@nih.gov
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
The remaining document will now describe the research study in more detail.  This information 
should be considered before you make your choice. Members of the study team will talk with you 
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research interventions in which they would want to 
participate. Take the time you need to ask any questions and discuss this study with NIH staff, and 
with your family, friends, and personal health care providers.
If the individual being asked to participate in this research study is not able to give consent for 
themselves, you, as the Legally Authorized Representative, will be their decision-maker and you 
are being asked to give permission for this person to be in this study. For the remainder of this 
document, the term “you” refers to you as the decision-maker and/or the individual being asked to 
participate in this research. 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
This study is being done to develop improved techniques for the detection of prostate cancer both 
before and after pre-operative treatment.  In this study we will be testing whether we can use a 
IRB NUMBER: 15C0124
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PATIENT IDENTIFICATION
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technique called multi parametric magnetic resonance imaging (mpMRI) for localizing and 
detecting prostate cancer.  We also want to determine if two drugs used in combination prior to 
surgery will provide any benefit to people who have non-metastatic prostate cancer (cancer that 
has not spread to other parts of the body).  There are several therapies available to treat prostate 
cancer.  This study will utilize a combination of androgen deprivation therapy (example goserelin 
or leuprolide) and enzalutamide followed by surgery.  Goserelin and enzalutamide are both 
approved by the Food and Drug Administration (FDA) to treat prostate cancer.  However, less is 
known about the effect of using these drugs in combination before surgery.
Why are you being asked to take part in this study?
You are being asked to take part in this study because you have been recently diagnosed with 
prostate cancer that is non-metastatic and you are a candidate for a radical prostatectomy following 
treatment.  After considering all treatment options discussed with you, including possible radiation 
therapy options, you have decided to undergo a radical prostatectomy as part of the standard care 
for your cancer. 
How many people will take part in this study? 
About 55 people at NIH will take part in this study.
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. 
During the study
If you are found to be eligible for this trial, you will be asked to complete the following tests and 
procedures:

Physical Exam and vital signs monthly

Provide samples of blood and urine for standard and research testing.  The total amount of 
blood we will draw for research in this study is about 75ml (5 tablespoons). 

ECG before treatment and surgery

3T mpMRI after 6 months of treatment
You will be offered the opportunity to fill in your 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 your medical care in the event 
that you lose the ability to provide on-going consent during the course of the study.
3T mpMRI
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PATIENT IDENTIFICATION
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During the procedure, you will be asked to lie down on the MRI platform and turn on your side 
with your back to the nurse or technician. A brief digital exam will be performed to assess the anus 
for safe probe insertion and then an endorectal probe will be inserted.  Then, you will need to turn 
on your back so that you can be positioned within the bore of the scanner. You will also be given 
earphones or earplugs to help block out noise from the MRI scanner. 
While inside the MRI bore and during the course of the scan, you, doctors, and technologists may 
communicate via a microphone and room loudspeaker system.  In order for us to obtain the best 
images and data, you will need to remain motionless and relaxed during the entire exam, which 
lasts about 60 minutes. 
Upon completion of the exam, you will be moved outside of the MRI bore and the endorectal 
probe will be removed. 
Following these tests and procedures you will take the two study medications for 6 months.  
Enzalutamide is given by mouth.  You will take 4 pills one time per day.  Goserelin is given by 
injection once every 3 months for 6 months (2 doses in 6 months).  If Goserelin is not available 
another form of androgen deprivation therapy may be prescribed.  The doses and how you take 
these alternate medications may be different.  If an alternate medication is prescribed, the study 
staff will let you know how much medication and how often you will need to take it.
You will be asked to return to the clinic once each month for safety tests which will include a 
physical exam, having your vital signs taken and standard blood tests.  
If your PSA rises during the study, other treatment options may be available to you including new 
imaging studies, re-biopsy and possibly earlier surgery.  The study doctor will discuss all these 
options with you and you will have the opportunity to decide which is best for your care.
Research Studies
Tumor samples that have been collected during surgery will be analyzed by the pathologist and 
the results will be discussed with you.
All of your samples collected for research purposes on this study (such as your tumor,  urine and 
blood) may be used to look for specific changes in the DNA of genes that may cause prostate 
cancer or other types of cancer. DNA (also called deoxyribonucleic acid) in the cells carries genetic 
information and passes it from one generation of cells to the next – like an instruction manual. 
Normal tissue contains the DNA (instructions) that you were born with, DNA in tumor cells has 
changed – or mutated – and we think that change in the DNA is what causes tumors to form and 
to grow. 
To look at your DNA, we may use do what is called “whole genome sequencing.”  This is where 
we will do special tests in the lab to look at the entire sequence, or order, of how your DNA is put 
together.  This is what makes you unique.  
To determine which parts of the DNA have mutated, we will compare the DNA in your tumor cells 
to DNA from your normal cells. We will then analyze the results from similar tumors to see if 
there are any changes in the DNA that are common to a particular type of tumor. To examine your 
tissue we may use several different techniques depending on the type of tissue we collect. These 
could include growing cell lines (cells which keep dividing and growing in the laboratory, 
sometimes for years allowing us to continually study those cells), xenograft studies (placing or 
IRB NUMBER: 15C0124
IRB APPROVAL DATE: 05/18/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 05/16/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
growing cells in another animal, such as mice), and looking in detail at the parts of the genes that 
produce specific proteins.
However, you should know that the analyses that we perform in our laboratory are for research 
purposes only; they are not nearly as sensitive as the tests that are performed in a laboratory that 
is certified to perform genetic testing or testing for routine clinical care. For these reasons, we will 
not give you the results of the research tests done on your research samples in most cases.  There 
may be exceptions to what we share with you and this is described in the next section, “Return of 
research results.”
Return of research results
When we are examining your DNA, it is possible that we could identify possible changes in other 
parts of your DNA that are not related to this research.  These are known as “incidental medical 
findings”.
These include: 

Changes in genes that are related to diseases other than cancer 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that 
we do not know if they could cause or contribute to a disease or if they are normal 
variations. 
Since the analyses that we perform in our laboratory are not nearly as sensitive as the tests that are 
performed in a laboratory that is certified to perform genetic testing, the genetic changes that we 
find may or may not be valid.  Therefore, we do not plan to inform you of all of the genetic results 
of testing on your tissue and blood that is performed in our research lab.  However, in the unlikely 
event that we discover a finding believed to be clinically important based on medical standards at 
the time we first analyze your results, we will contact you.  This could be many years in the future. 
We will ask you to have an additional tube of blood drawn to verify the findings we have seen in 
our lab. If the results are verified, you will be re-contacted and offered a referral to a genetic 
healthcare provider to discuss the results. 
Note: In order for us to contact you about genetic variants as described above, we must maintain 
your up to date contact information. This will allow us to contact you at the time findings are 
discovered. 
When you are finished taking the drugs 
After you have completed the study medications, you will be asked to undergo another 3T mpMRI, 
blood tests and then you will have surgery to remove your prostate.  This surgery may be performed 
at either the Clinical Center or Walter Reed Bethesda.  After the surgery you will return for a 
follow up visit about 6-10 weeks after your prostate is removed and then we will call you yearly 
for the next five years to check your PSA level. PSA levels may be obtained at NIH or through a 
local provider.   
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PATIENT IDENTIFICATION
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Standard of Care Treatment
Treatments covered under this study include a combination of medications and surgery to treat 
your cancer. These treatments will not be experimental. Your doctors will describe your treatment 
plan to you in detail before asking you to sign this consent form. You may be asked to sign a 
separate consent form for any treatment procedures not outlined in this consent.
Birth Control
If you are the partner of a woman who can become pregnant, you and your partner will need to 
practice an effective form of birth control before starting study treatment, during study treatment, 
and for 3 months after you finish study treatment.  If you think that your partner is pregnant, you 
should tell your study doctor or nurse at once.  
Effective forms of birth control include:

abstinence 

intrauterine device (IUD)

hormonal [birth control pills, injections, or implants]

tubal ligation

vasectomy
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 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

Nipple tenderness

High blood pressure

Dizziness, anxiety

Dry skin

Blood in urine

Jaundice

Weakness of muscles

Seizures
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PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Possible Side effects of goserelin:
Likely (greater than 5%)
Less Likely (1%–5%)
Rare but Serious
Hot flashes
Generalized pain or pain in 
the pelvis or bone
Enlarged breasts
Weakness
Pain in abdomen and/or 
back
Flu-like symptoms
Headache
Cardiac problems (chest 
pain, clots, varicose veins)
Diarrhea
Vomiting blood
Sugar in blood
Low red cells (anemia)
Swelling in hands or feet
Dizziness
Numbness or tingling
Frequent urination, unable 
to void, unable to hold 
urine, urinary infection, 
blood in urine
Impotence
Itchy skin
Herpesvirus of the skin
Infection in blood
Heart failure
Stroke
Clot that may travel to 
lungs or brain
Other Risks
ECG
There are no significant risks or discomforts associated with an ECG. 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 rarely, fainting. When 
large amounts of blood are collected, low red blood cell count (anemia) is a risk.
Urine collection
There are no risks associated with urine collection.
Risks of mpMRI
Magnetic resonance imaging (MRI) uses a strong magnetic field and radio waves to take pictures 
of the body.  We will obtain pictures of your chest, abdomen and pelvis for this study. The MRI 
scanner is a metal cylinder surrounded by a strong magnetic field.  People are at risk for injury 
from the MRI magnet if they have some kinds of metal in their body.  It may be unsafe for you to 
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have an MRI scan if you have pacemakers or other implanted electrical devices, brain stimulators, 
some types of dental implants, aneurysm clips (metal clips on the wall of a large artery), metal 
prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent 
eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. Welders and metal workers 
may have small metal fragments in the eye. You will be screened for these conditions before 
having any MRI scan.  If you have a question about metal in your body, you should inform the 
staff. You will be asked to complete an MRI screening form before each MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone 
having a research MRI scan will be fitted with hearing protection. If the hearing protection comes 
loose during the scan, you should let us know right away.
There are no known long-term risks of MRI scans.
Risks of gadolinium
During part of the MRI you will receive gadolinium, a contrast agent, through an intravenous (IV) 
catheter (small tube). It will be done for both research and medical purposes. 
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, hives, 
and lowering of blood pressure. You should not receive gadolinium if you previously had an 
allergic reaction to it.  You will be asked about such allergic reactions before gadolinium is given.   
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF)”. This condition always involves the skin and can also 
involve the muscles, joints, and internal organs. NSF has resulted in a very small number of deaths. 
A blood test of your kidney function may be done within the month before an MRI scan with 
gadolinium contrast. You will not receive gadolinium for a research MRI scan if your kidney 
function is below the safe level. 
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA has issued a 
safety alert that indicates small amounts of gadolinium may remain in the body for months to years.  
The effects of the retained gadolinium are not clear. At this time, retained gadolinium has not been 
linked to health risks in people whose kidneys work well.  Some types of gadolinium contrast 
drugs are less likely to remain in the body than others. In this study, we will use the gadolinium 
contrast drugs that are less likely to remain in the body.
Risks of Biopsy
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A hollow needle is used to withdraw small cylinders (or cores) of tissue from your tumor using a 
MRI scan or ultrasound for guidance. The needle is put in 3 to 6 times to get the samples, or cores. 
This procedure usually causes only brief discomfort at the site from which the biopsy is taken and 
you will be offered medication to help numb the pain. Biopsy collection may cause bruising and 
bleeding, but usually does not leave scars. Rarely infection may occur at the needle site.
Psychological or Social Risks Associated with Loss of Privacy 
The following general points are indirectly related to your participation in the research study:
1. Unanticipated medical information: During the course of this investigation, it is possible 
(although not likely) that we will obtain unanticipated information about your health or 
genetic background.  
2. Release of genetic information:

Your privacy is very important to us and we will use many safety measures to protect your 
privacy. However, in spite of all of the safety measures that we will use, we cannot 
guarantee that your identity will never become known. Although your genetic information 
is unique to you, you do share some genetic information with your children, parents, 
brothers, sisters, and other blood relatives. Consequently, it may be possible that genetic 
information from them could be used to help identify you. Similarly, it may be possible 
that genetic information from you could be used to help identify them. 

Patterns of genetic variation also can be used by law enforcement agencies to identify a 
person or his/her blood relatives. Therefore, your genetic information potentially could be 
used in ways that could cause you or your family distress, such as by revealing that you (or 
a blood relative) carry a genetic disease. 

It is possible also that someone could get unauthorized access or break into the system that 
stores information about you.  Every precaution will be taken to minimize this risk.  

There also may be other privacy risks that we have not foreseen.
Protections against misuse of genetic information
This study involves genetic testing on samples. Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component. 
Potential Benefits of Participation
Are there benefits to taking part in this study? 
The primary aim of this study is to see if mpMRI imaging is a good method to localize and detect 
prostate cancer.  During the study we will also administer 2 drugs in combination. Although these 
drugs are already approved for treating prostate cancer, less is known about how they work 
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together and what effect they have when given before surgery.  It is possible that you will receive 
some additional personal medical benefit from participating in this trial, but we cannot be certain.  
These potential benefits could include shrinking of your tumor or lessening of your symptoms, 
such as pain, that are caused by the cancer.  We hope that the knowledge gained from this study 
may help to detect prostate cancer. We also hope that that you will receive direct benefit to your 
cancer but because we do not have enough information about how these drugs work together, it is 
also possible that you may receive no benefit.  However, the information gained during this trial 
may help others with cancer in the future.
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:

Getting treatment or care for your cancer without being in a study

Taking part in another study

Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible.
Please talk to your doctor about these and other options.
Stopping Therapy
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
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 Astellas Pharma US 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 Conflict of Interest (COI) Guide.  You may ask your 
research team for a copy of the COI Guide or for more information.  Members of the research team 
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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.
No NIH investigator involved in this study receives payments or other benefits from any company 
whose drug, product or device is being tested.
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.
Genomic Data Sharing
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we cannot 
offer you a choice of whether your data will be shared.  If you do not wish to have your data placed 
in a repository, you should not enroll in this study.
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IRB APPROVAL DATE: 05/18/2022


PATIENT IDENTIFICATION
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PAYMENT
Will you receive any type of payment for taking part in this study?
You will not receive any payment for taking part in this study. 
REIMBURSEMENT
Will you receive reimbursement or direct payment by NIH as part of your participation?
On this study, the NCI will reimburse the cost for some of your expenses such as those for hotel, 
travel, meals. Some of these costs may be paid directly by the NIH and some may be reimbursed 
after you have paid. The amount and form of these payments are determined by the NCI Travel 
and Lodging Reimbursement Policy. You will be given a summary of the policy which provides 
more information.
If your travel to the NIH Clinical Center (e.g. flight, hotel) is arranged and paid for by the NIH, 
the agency making the reservations and their representatives will have access to your identifiable 
information.
COSTS
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center.

You will receive study treatment at no charge to you. This may include surgery, medicines, 
laboratory testing, 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.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
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.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
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:
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PATIENT IDENTIFICATION
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.    
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court. 
The Certificate does not protect your information when it: 
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA);
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act. In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality. For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
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federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH 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 NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
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, Fatima Karzai, 
fatima.karzai@nih.gov, at 301-480-7174. You may also call the NIH Clinical Center Patient 
Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you 
have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
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Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either : 
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 15C0124
IRB APPROVAL DATE: 05/18/2022