Clinical trial NCT02064582
Conditions: Prostate Cancer
Keywords: prostate cancer, enzalutamide, radiation, hormone therapy
Sponsor: University of Texas Southwestern Medical Center
Start date: 2014-05-01; Completion date: 2018-06-09
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study is being done to find out whether combining two FDA approved drugs along with radiation therapy for the treatment of high risk localized prostate cancer is safe and well tolerated.

Detailed description:
* this pilot study will assess the safety and tolerability of combining enzalutamide with an gonadotropin-releasing hormone agonist (GnRH) and external beam radiation
* Correlative imaging and tissue biopsy analysis will be performed to assess the radiographic response to enzalutamide plus gonadotropin-releasing hormone agonist (GnRH) therapy as well as intratumoral androgen signaling

Arms: arm 1: Single arm Enzalutamide 160 mg daily for 6 months Leuprolide acetate 22.5mg every 3 months or 45mg every 6 months Radiation therapy as standard of care
Interventions: intervention 1: Enzalutamide intervention 2: Leuprolide acetate intervention 3: radiation
Intervention descriptions: intervention 1: 160mg by mouth each day intervention 2: 22.5 mg intramuscular every 3 months or 45mg intramuscular every 6 months intervention 3: External beam radiation will be delivered as per standard radiation therapy protocol

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
Phase II study of enzalutamide (MDV3100) and gonadotropin-releasing hormone (GnRH) 
agonist before, during, and after radiation therapy in treatment of patients with high-risk 
localized prostate cancer 
 
 
NCT02064582 
 
Date Approved: 12/29/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
PROTOCOL NUMBER 
Phase II study of enzalutamide (MDV3100) and gonadotropin-releasing hormone 
(GnRH) agonist before, during, and after radiation therapy in treatment of patients 
with high-risk localized prostate cancer 
 
Principal Investigator:  
Kevin Courtney, MD, PhD 
 
 
 
Assistant Professor 
 
 
 
UT Southwestern Medical Center 
 
 
 
Division of Hematology/Oncology 
 
 
 
5323 Harry Hines Boulevard 
 
 
 
Dallas, TX  75390-8852 
 
 
 
Telephone: 214/648-4180 (academic office)  
 
 
 
Telephone: 214/648-1948 (direct extension) 
  
 
 
Fax: 214/648-1955 
 
Co-Investigators: 
 
Yull Arriaga, MD 
 
 
 
 
Raquibul Hannan, MD, PhD 
 
 
 
 
 
 
 
 
 
 
 
Yi Yin, MD, PhD 
 
 
 
 
Michael Folkert, MD 
 
 
 
 
Aaron Laine, MD 
 
 
 
 
Neil Desai, MD 
 
Biostatistician: 
 
Chul Ahn, PhD 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Boulevard, Dallas, TX  75390-9066 
 
 
 
 
(Phone) 214-648-9148 
 
 
 
 
Email chul.ahn@utsouthwestern.edu 
 
Study Drug: 
 
 
Enzalutamide (Xtandi) 
 
IND Number: 
 
 
N/A. 
 
IND Holder Name: 
 
N/A. 
 
Funding Source:  
Astellas Pharma U.S., Inc.; Medivation, Inc 
 
Initial version:  
 
28 Aug 2013 
 
Amended:                       
27 Sep 2013 
 
 
 
            26 Dec 2014 
 
 
 
 
10 Apr 2015 
 
 
 
 
29 Jun 2015 
 
 
 
 
            18 Feb 2016 
 
 
 
 
06Jun 2016 
 
 
 
 
29 Dec 2016 
 
 
 
 
UT Southwestern Medical Center at Dallas 
Harold C. Simmons Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 


 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:_____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 


________________________________________________________________________ 
i 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS............................................................................................................. 1 
STUDY SCHEMA ............................................................................................................................ 3 
STUDY SUMMARY ......................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE ...................................................................................... 5 
1.1 
Disease Background........................................................................................................ 5 
1.2 
Study Agent(s) Background and Associated Known Toxicities ....................................... 5 
1.3 
Other Agents .................................................................................................................. 10 
1.4 
Rationale ........................................................................................................................ 10 
1.5 
Correlative Studies ........................................................................................................ 12 
2.0 
STUDY OBJECTIVES ......................................................................................................... 12 
2.1 
Primary Objectives ......................................................................................................... 12 
2.2 
Secondary Objectives .................................................................................................... 12 
2.3 
Exploratory Objectives ................................................................................................... 13 
2.4 
Endpoints ....................................................................................................................... 13 
3.0 
PATIENT ELIGIBILITY ........................................................................................................ 13 
3.1 
Inclusion Criteria ............................................................................................................ 13 
3.2 
Exclusion Criteria ........................................................................................................... 15 
4.0 
TREATMENT PLAN ............................................................................................................ 16 
4.1 
Treatment Dosage and Administration .......................................................................... 16 
4.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 17 
4.3 
Concomitant Medications/Treatments ........................................................................... 18 
4.4 
Other Modalities or Procedures ..................................................................................... 19 
4.5 
Duration of Therapy ....................................................................................................... 25 
4.6 
Duration of Follow Up .................................................................................................... 25 


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ii 
4.7 
Removal of Patients from Protocol Therapy .................................................................. 25 
4.8 
Patient Replacement ..................................................................................................... 25 
5.0 
STUDY PROCEDURES ....................................................................................................... 25 
5.1 
Screening/Baseline Procedures .................................................................................... 25 
5.2 
Procedures During Treatment ....................................................................................... 27 
5.3 
Follow-up Procedures .................................................................................................... 27 
5.4 
Time and Events Table .................................................................................................. 28 
5.5 
Removal of Subjects from Study ................................................................................... 28 
6.0 
MEASUREMENT OF EFFECT ............................................................................................ 29 
6.1 
Antitumor Effect- Solid Tumors ...................................................................................... 29 
6.2 
Safety/Tolerability .......................................................................................................... 30 
7.0 
ADVERSE EVENTS ............................................................................................................. 31 
7.1 
Experimental Therapy.................................................................................................... 31 
7.2 
Adverse Event Monitoring ............................................................................................. 32 
7.3 
Definitions ...................................................................................................................... 33 
7.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 36 
7.5 
Reporting Requirements for Adverse Events ................................................................ 36 
7.6 
Unblinding Procedures .................................................................................................. 37 
7.7 
Stopping Rules .............................................................................................................. 37 
8.0 
DRUG INFORMATION ........................................................................................................ 37 
8.1 
Enzalutamide ................................................................................................................. 37 
9.0 
CORRELATIVES/SPECIAL STUDIES ................................................................................ 38 
9.1 
Sample Collection Guidelines ........................................................................................ 38 
9.2 
Assay Methodology ....................................................................................................... 39 
9.3 
Specimen Banking ......................................................................................................... 39 
10.0 
STATISTICAL CONSIDERATIONS .................................................................................. 40 


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iii 
10.1 
Study Design/Study Endpoints ...................................................................................... 40 
10.2 
Sample Size and Accrual .............................................................................................. 40 
10.3 
Data Analyses Plans...................................................................................................... 41 
11.0 
STUDY MANAGEMENT .................................................................................................... 41 
11.1 
Conflict of Interest .......................................................................................................... 41 
11.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 41 
11.3 
Data Management and Monitoring/Auditing .................................................................. 42 
11.4 
Adherence to the Protocol ............................................................................................. 42 
11.5 
Amendments to the Protocol ......................................................................................... 43 
11.6 
Record Retention ........................................................................................................... 43 
11.7 
Obligations of Investigators ........................................................................................... 43 
12.0 
REFERENCES ................................................................................................................... 43 
13.0 
APPENDICES .................................................................................................................... 45 


________________________________________________________________________ 
1 
LIST OF ABBREVIATIONS 
 
Examples Include: 
 
 
3D-CRT 
Three Dimensional Conformal Radiation Therapy 
ADC 
Apparent Diffusion Coefficient 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AR 
Androgen Receptor 
AST 
Aspartate Aminotransferase 
AUC 
Area Under Curve 
BUN 
Blood Urea Nitrogen 
CaP 
Prostatic Adenocarcinoma 
CBC 
Complete Blood Count 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Comprehensive Metabolic Panel 
CRPC 
Castrate-Resistant Prostate Cancer 
CT 
Computed Tomography 
CTV 
Clinical Target Volume 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DHEA 
Dehydroepiandrosterone 
DHT 
Dihydrotestosterone 
DSMB 
Data and Safety Monitoring Board 
EBRT 
External Beam Radiation Therapy 
 
 
ECOG 
Eastern Cooperative Oncology Group 
eGFR 
Estimated Glomerular Filtration Rate 
EORTC 
European Organization for Research and Treatment of Cancer 
FDA 
Federal Drug Administration 
GnRH 
Gonadotropin Releasing Hormone 
GTV 
Gross Tumor Volume 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IC50 
Inhibitory Concentration 50% 
IMRT 
Intensity-Modulated Radiation Therapy 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
kV 
Kilovoltage 
LDH 
Lactate Dehydrogenase 
MG (or mg) 
Milligram 


________________________________________________________________________ 
2 
ML (or mL) 
Milliliter 
MRI 
Magnetic Resonance Imaging 
MV 
Megavoltage 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NG (or ng) 
Nanogram 
PK 
Pharmacokinetics 
PSA 
Prostate Specific Antigen 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
p.o. 
peros/by mouth/orally 
PR 
Partial Response 
PTV 
Planning Target Volume 
qRT-PCR 
Quantitative Reverse Transcription Polymerase Chain Reaction 
RTOG- 
ASTRO 
Radiation Therapy Oncology Group – American Society for Therapeutic 
Radiology and Oncology 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
T1/2 (or t1/2) 
Half-life 
TRUS 
Transrectal Ultrasound 
WBC 
White Blood Cells 
 
 
 
 
 
 
 


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3 
STUDY SCHEMA 
 
 
STUDY SUMMARY 
Title 
Phase II pilot study of enzalutamide (MDV3100) and gonadotropin-
releasing hormone (GnRH) agonist before, during, and after radiation 
therapy in treatment of patients with high-risk localized prostate cancer 
Short Title 
Phase II trial of radiation with enzalutamide (MDV3100) and androgen 
deprivation 
Protocol Number 
The standard protocol number used to identify this study 
Phase 
2 
Methodology 
Open label 
Study Duration 
5 years 
Study Center(s) 
Single-center  
Objectives 
This is a single institution phase II trial studying the safety and efficacy of 
combined enzalutamide and GnRH agonist therapy administered with 
EBRT for high-risk and locally advanced prostate cancer.  
Number of Subjects 
7 
 


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4 
Diagnosis and Main 
Inclusion Criteria 
- 
Patients must be candidates for long-term androgen 
deprivation in combination with EBRT for the treatment of 
high-risk or locally-advanced prostate cancer by the following 
criteria: 
o 
High risk disease: T3a or Gleason 8-10 or serum 
PSA > 20 ng/mL 
 
Gleason 7 also allowed if > 50% of cores 
positive for cancer or PSA velocity > 2 
ng/mL/year in preceding 12 months 
o 
Locally advanced (very high risk) disease: T3b-T4 
- 
  
- 
Patients may have radiographic evidence of metastasis in 
regional lymph nodes (N1 disease as defined by the National 
Comprehensive Cancer Network Prostate Cancer Guideline 
Verson 3.2012) at the discretion of the treating physicians, if 
regional lymph nodes can be included in the planned 
radiation field. 
 
Study Product(s), Dose, 
Route, Regimen 
Enzalutamide (MDV3100) (Xtandi), 4 x 40 mgcapsules (160 mg total) by 
mouth daily 
Duration of administration 
6 months 
Reference therapy 
N/A 
Statistical Methodology 
Descriptive statistics will be used in the analysis of safety and tolerability 
and the outlined imaging and biological correlates. 
 
 
 


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5 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Androgens fuel the growth of prostate cancer cells. Interfering with androgen signaling 
impairs prostate cancer growth. External beam radiation therapy (EBRT) employs x-rays 
to kill tumor cells and is an effective treatment for localized prostate cancer. Previous 
clinical trials have demonstrated that combining EBRT with inhibitors of androgen 
signaling improves overall survival in patients with high-risk and locally-advanced 
prostate cancer.1-9 D’Amico and colleagues reported that 6 months of combined 
androgen suppression therapy by administration of a GnRH agonist and an anti-
androgen before, during, and after EBRT improved survival compared to EBRT alone in 
patients with intermediate-risk or high-risk prostate cancer.4 RTOG 9202 was a 
randomized study of 1521 patients treated with radiation therapy plus 4 months of the 
GnRH agonist goserelin with the anti-androgen flutamide before and during radiation 
therapy, followed by 0 vs 24 months of goserelin.5 The study showed an improvement in 
disease free survival at 10 years. Overall survival showed no statistically significant 
difference between the two arms, but subgroup analysis showed an overall survival 
benefit for patients with prostatic adenocarcinoma of Gleason score 8-10.5 In the phase 
III randomized trial EORTC 22961, Bolla and colleagues subsequently reported that 3 
years of androgen suppression therapy (comprised of 6 months of combined GnRH 
agonist and androgen receptor antagonist treatment followed by 30 months of GnRH 
agonist therapy) before, during, and after EBRT lead to improved overall survival 
compared to 6 months of combined androgen suppression therapy plus EBRT in patients 
with high-risk prostate cancer.2 Taken together, these data provide category 1 evidence 
for treatment of high-risk and locally advanced prostate cancer with EBRT plus long-term 
neoadjuvant / concomitant / adjuvant androgen suppression therapy for 2-3 years as a 
standard of care (www.nccn.org). However, a substantial proportion of these patients will 
develop metastatic prostate cancer and die as a result of their metastatic disease. We 
propose that enzalutamide plus GnRH agonist treatment in combination with EBRT 
should be safe and well tolerated for the treatment of prostate cancer. We propose to 
carry out a pilot phase II study to assess the safety and tolerability of this combination, 
along with imaging and biologic correlates to assess response to enzalutamide plus 
GnRH treatment prior to initiation of EBRT. We hypothesize that enzalutamide plus 
GnRH agonist combined with EBRT may improve survival compared to standard 
treatment with GnRH agonist plus first-generation anti-androgens combined with EBRT.  
1.2 
Study Agent(s) Background and Associated Known Toxicities 
Enzalutamide (MDV3100, Xtandi) is an androgen receptor inhibitor. In August 2012, 
enzalutamide received US FDA approval for the treatment of patients with metastatic 
castration-resistant prostate cancer who have previously received docetaxel. The 
approved dose of enzalutamide is 160 mg (four 40 mg capsules) by mouth once daily. 
 
Although the primary endpoint of this study is to assess the safety and tolerability of 
enzalutamide plus GnRH agonist combined with EBRT, there is no reason a priori to 
believe that this combination of therapy will increase the known potential risks associated 
with enzalutamide. There may be unexpected risks from this combination, and this 
possibility will be evaluated in the clinical study.  
 
We believe that this study meets criteria for exemption from application for an 
Investigational New Drug (IND) based on the following criteria as enumerated in the 
Code of Federal Regulations (CFR 312.2) and copied directly below: 
 


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6 
“Exemptions. (1) The clinical investigation of a drug product that is lawfully marketed in 
the United States is exempt from the requirements of this part if all the following apply: 
 
(i) The investigation is not intended to be reported to FDA as a well-controlled study in 
support of a new indication for use nor intended to be used to support any other 
significant change in the labeling for the drug; 
 
(ii) If the drug that is undergoing investigation is lawfully marketed as a prescription drug 
product, the investigation is not intended to support a significant change in the advertising 
for the product; 
 
(iii) The investigation does not involve a route of administration or dosage level or use in 
a patient population or other factor that significantly increases the risks (or decreases the 
acceptability of the risks) associated with the use of the drug product; 
 
(iv) The investigation is conducted in compliance with the requirements for institutional 
review set forth in part 56 and with the requirements for informed consent set forth in part 
50; and 
 
(v) The investigation is conducted in compliance with the requirements of 312.7.” 
(http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.2) 
  
 
The presented background information about the study agent enzalutamide (MDV3100, 
Xtandi) is taken directly from the Enzalutamide Investigators Brochure provided by 
Astaellas Pharma U.S., Inc.: Medivation, Inc. MDV3100 Investigator's Brochure 
23 MAR 2012 - v5.0 FINAL. More information is provided in the Investigator’s Brochure. 
 
1.2.1 Summary of Pre-Clinical Studies of enzalutamide (MDV3100): 
 
Enzalutamide (MDV3100) is an androgen receptor (AR) signaling inhibitor rationally 
designed to block multiple steps in the AR signaling pathway and to be devoid of agonist 
activity. MDV3100 inhibits androgen-induced receptor activation (binding of androgens to 
ARs in the cytosol), inhibits nuclear translocation of activated ARs, and inhibits the 
association of the activated AR with chromatin, even in the setting of AR overexpression 
and in prostate cancer cells resistant to anti-androgens such as bicalutamide. The 
consequence of MDV3100 AR signaling inhibition is decreased growth of prostate cancer 
cells, induction of cancer cell death, and tumor regression. 
 
Safety pharmacology studies in mice, rats, and dogs were performed with MDV3100 to 
assess any acute effects on central nervous system, respiratory, and cardiovascular 
parameters. No MDV3100-related effects were noted in the central nervous system study 
assessing a functional observation battery and in a respiratory study in rats. MDV3100 
inhibits the human ether-a-go-go-related gene (hERG) channel; however, the highest free 
concentrations of MDV3100 expected in patient plasma at a steady-state dose of 160 
mg/day are well below the hERG inhibitory concentration 50% (IC50) value. No 
MDV3100-related effects on cardiac electrophysiology were noted in a safety 
pharmacology study in conscious, telemetered dogs. 
 
As MDV3100 inhibits the gamma amino butyric acid (GABA)-gated chloride channel, 
convulsion potential was assessed in single- and multiple-dose studies in mice.5 Oral 
MDV3100 daily for 7 days was associated with convulsions in a dose-dependent manner 
with doses ≥ 200 mg/kg being active. When administered as a single dose of 400 mg/kg 
MDV3100 treatment was also associated with convulsions. At the highest dose at which 
no convulsions occurred (single dose, 100 mg/kg), the maximum plasma concentration 


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7 
(Cmax) and area under the curve at 24 hours after dosing (AUC24) were at least 2.5-
times higher than those in patients receiving 160 mg/day. 
 
MDV3100 is metabolized primarily to 2 metabolites, M1 (a carboxylic acid derivative) and 
M2 (N-desmethyl MDV3100). The metabolite M2 has a pharmacology profile similar to 
that of the parent molecule and may contribute to the therapeutic effects of MDV3100 in 
patients. M2 also binds to and inhibits the GABA-gated chloride channel with potency 
similar to that of the parent molecule and may contribute to convulsion risk. Metabolite 
M1 does not have significant pharmacological actions and probably does not contribute 
to the therapeutic effects of MDV3100. 
 
Nonclinical Pharmacokinetics and Metabolism 
Following oral administration, MDV3100 has a half-life (t1/2) of approximately 0.25 to 
3 days in mice, rats, dogs, and monkeys. The t1/2 does not appear to be affected by the 
dose size; however, the bioavailability in animals appears to decrease with increasing 
dose size. 
In vitro studies show the following: 
 MDV3100 is metabolized by human recombinant cytochrome P450 (CYP) isoenzymes 
CYP2C8 and CYP3A4/5; 
 MDV3100 and/or its major human metabolites are potential inhibitors of CYP2C8 and 
CYP2C19 with lesser potential for inhibitory effects on CYP2B6 and CYP2C9; 
 MDV3100 is a potential inducer of CYP3A4; 
 MDV3100 is a potential inhibitor, but not a substrate, of the efflux transporter 
permeability glycoprotein (P-gp); 
 The protein binding of MDV3100 in human plasma is 97% to 98% and is similar in 
mice,rats, rabbits, and dogs; 
 The protein binding of metabolites M1 and M2 in human plasma was 98% and 95%, 
respectively, and was comparable across species. The extent of binding for both 
metabolites was constant over a wide range of concentrations (0.5 to 25 μg/mL). 
 
Toxicology 
MDV3100 has been evaluated in nonclinical toxicity studies from single doses up to 
26 weeks of daily dosing, in mice, rats, dogs, and cynomolgus monkeys. Rats and dogs 
were the species chosen for the majority of the toxicity studies. The key findings from the 
MDV3100 toxicity studies were as follows: 
 MDV3100 was well tolerated in rats at doses up to 100 mg/kg/day for 26 weeks and in 
dogs at doses up to 20 mg/kg/day for 13 weeks. 
 MDV3100 was well tolerated in cynomolgus monkeys at the highest dose tested, 
100 mg/kg as a single oral dose. 
 Treatment-related mortality occurred in mice given ≥ 400 mg/kg as a single dose 
or ≥ 100 mg/kg/day for 7 days. In repeat-dose studies in rats, mortality was attributed to 
gavage error or accidental aspiration of the Labrasol formulation; however, no 
treatment-related mortality was observed at doses up to 200 mg/kg/day. In dogs, 
mortality at 100/60 mg/kg/day was attributed to accidental aspiration of Labrasol, but in 
some cases was of uncertain relationship to MDV3100. 
 The main findings in repeat-dose oral studies in rats and dogs were MDV3100-related 
macroscopic findings, microscopic findings, and organ weight changes in reproductive 
and hormone-sensitive tissues. All of these tissues changes were consistent with the 
pharmacological activity of MDV3100. The organs affected, depending on the species or 
duration of dosing, were prostate glands, seminal vesicles, testes, and/or epididymides, 
mammary glands, pituitary glands and adrenal glands. Full or partial reversibility was 
noted after treatment-free periods ranging from 4 to 21 weeks. 
 Clinical signs such as salivation (rats and dogs), vomiting, fecal changes (dogs and 
monkeys), and audible respiration (rats and mice) were attributed to the vehicle Labrasol. 
 Central nervous system effects, including decreased motor activity, ataxia, clonic 
convulsions, and/or tremors, occurred in dose range finding toxicokinetic studies in mice 


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8 
given ≥ 400 mg/kg as a single dose or 200 mg/kg/day for 7 days. One instance each of 
convulsions was noted in 1 dog and 1 rat in the good laboratory practice (GLP) toxicity 
studies. 
 There were no treatment-related adverse clinical pathology findings. Mild changes, 
possibly attributable to the pharmacological activity of MDV3100 were noted, including 
increases in glucose and cholesterol, and decreases in hematology parameters (red 
blood cell counts, hemoglobin, and hematocrit). 
 Toxicokinetic evaluations in rats and dogs showed that systemic exposure to MDV3100 
generally increased with increasing dose size, but the increases were less than dose 
proportional. With daily oral administration, the mean accumulation index was 
approximately 1 to 3 in rats and 1 to 4 in dogs. The magnitude of accumulation did not 
appear to increase with the dose. 
 The 2 major human metabolites M1 and M2 were detected in all toxicology species. 
 MDV3100 was non-mutagenic in bacteria, non-clastogenic in mammalian cells, and 
non-genotoxic in vivo in mice. 
 MDV3100 did not induce phototoxicity in cultured mammalian cells. 
Consistent with the expected pharmacology of MDV3100 to inhibit the AR signaling 
pathway, the most salient effects of MDV3100 in rats and dogs were on male sex organs. 
Reductions in prostate, epididymis, and/or seminal vesicle weight were observed, and 
these were associated with corresponding histopathological findings of prostatic and 
seminal vesicle secretory depletion and/or atrophy, and with epididymal atrophy in dogs 
only. Hypospermatogenesis and degeneration of seminiferous tubules in testes were 
observed in dogs, but not in rats. Females were included in each toxicity study, except 
the 13-week toxicity study in dogs. 
 
Specifically in regards to effects in females, enlarged uteri were noted in 4- and 26-week 
repeat-dose studies in rats only, and were considered related to MDV3100. Enlargement 
of the uterine lumen, observed microscopically, correlated with this finding and was 
reversible. Mammary glands of both male and female rats were affected histologically by 
MDV3100 in the 26-week study, though with qualitatively different results. Mild 
glandular/lumen dilationand mild lobular hyperplasia were observed in females, whereas 
mammary gland atrophy was observed in males. The mammary gland changes persisted 
after an 8-week recovery period in male and female rats. Mammary gland and uterine 
changes noted in female rats were not seen in female dogs in the 4-week dog study, the 
longest dosing duration studied in female dogs. Histopathological changes definitively 
related to MDV3100 treatment of dogs have been confined to changes in male sex 
organs. 
 
Overall, MDV3100 was generally well tolerated in pivotal nonclinical studies with rats and 
dogs with the most prominent effects occurring in reproductive and hormone-sensitive 
tissues. 
 
1.2.2 Summary of human experience with enzalutamide (MDV3100) 
 
The pharmacokinetics (PK), tolerability, and antitumor activity of MDV3100 were first 
studied in a multi-center, open-label, first-in-human, dose-escalation study of MDV3100 
in 140 patients with castration-resistant prostate cancer (S-3100-1-01).10 Patients who 
were chemotherapy-naïve or who had previously failed docetaxel-based chemotherapy 
were treated with MDV3100 at doses of 30 to 600 mg/day until disease progression or 
intolerable side effects developed.  
 
MDV3100 was absorbed rapidly after oral administration, with the time to maximum 
plasma concentration (tmax) after a single dose typically occurring at 1 hour postdose. 
No major deviations from dose proportionality were observed over the dose range 30 to 
600 mg. Due to the long t1/2 (~ 5.8 days), it took approximately 1 month to reach steady 
state. With daily oral administration MDV3100 accumulation was observed at steady 


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9 
state with an 8.3-fold higher exposure (steady-state area under the curve [AUC]) relative 
to a single dose. Based on the mean peak-to-trough ratio, the average difference 
between the peak (Cmax) and trough (minimum plasma concentration [Cmin]) 
concentrations was ≤ 25%. As a result of the low daily fluctuations, plasma profiles at 
steady-state resembled a constant infusion. The Cmin values in individual patients 
remained constant beyond Day 28 of chronic therapy, suggesting time-linear PK once 
steady state was achieved.  
 
The maximum tolerated dose was determined to be 240 mg daily. MDV3100 
demonstrated antitumor activity across endpoints in patients both with and without 
previous exposure to chemotherapy. The antitumor activity endpoints included prostate-
specific antigen (PSA) reduction from baseline, median time to PSA progression, 
responses on imaging, and circulating tumor cell conversion from unfavorable to 
favorable counts. Three potential MDV3100-associated toxicities were identified in this 
study: fatigue, rash, and seizure.Three seizures (2 witnessed, 1 unwitnessed) occurred in 
this study at doses of 360, 480, and600 mg/day, and were reported between 26 and 48 
days after initiation of MDV3100. After review of all data available from the S-3100-1-01 
study, the optimal dose of MDV3100 for evaluation in Phase 3 clinical trials was 
determined to be 160 mg/day. A Phase 3, randomized, double-blind, placebo-controlled 
efficacy and safety study of oral MDV3100 (160 mg daily) in patients with progressive 
castration-resistant prostate cancer previously treated with docetaxel-based 
chemotherapy (CRPC2, also known as AFFIRM) was conducted in 1199 men, 800 of 
whom received treatment with MDV3100.11  
 
A formal interim analysis of overall survival was performed at 520 events (80% of the 650 
targeted number of events for final analysis) and demonstrated a statistically-significant 
increase in the duration of survival among patients treated with MDV3100 compared with 
patients treated with placebo (hazard ratio = 0.631 [95% CI: 0.529, 0.752], p < 0.0001). 
Median survival was 18.4 months in the MDV3100 arm and 13.6 months in the placebo 
arm (Δ = 4.8 months). The survival benefit was seen in all pre-specified patient 
subgroups defined by age, geographic region, Eastern Cooperative Oncology Group 
(ECOG) performance status, pain score, Gleason score, number of prior chemotherapy 
regimens, type of disease progression at study entry, baseline level of PSA, baseline 
level of hemoglobin, and baseline level of lactate dehydrogenase (LDH). There were also 
statistically-significant increases in time to PSA progression; radiographic progression-
free survival (assessed by computed tomography [CT] or magnetic resonance imaging 
[MRI] and by bone scan); time to first skeletal-related event; PSA response, and overall 
objective soft tissue radiographic response among patients treated with MDV3100 
compared to placebo. In addition, statistically-significant differences favoring MDV3100 
over placebo in pain palliation and pain progression rate at Week 13 were also 
observed.11 
 
Of the MDV3100-treated patients, 98.1% reported at least 1 treatment-emergent adverse 
event as compared to 97.7% of placebo patients as of the data cutoff date of 25 
September 2011. Serious adverse events were reported in 33.5% of MDV3100-treated 
patients as compared with 38.6% of placebo-treated patients. Of the MDV3100-treated 
patients, 7.6% discontinued study drug due to adverse events as compared with 9.8% of 
placebo patients.  
 
Adverse events reported by those treated with MDV3100 with an incidence at least 2% 
greater than that among those who received placebo included fatigue, diarrhea, hot flush, 
musculoskeletal pain, headache, insomnia, anxiety, hypertension, nasopharyngitis, 
pollakiuria, fall, pruritus, dry skin, and musculoskeletal stiffness. Serious adverse events 
reported with an incidence of at least 0.5% and more frequently by MDV3100-treated 
patients compared to placebo patients were spinal cord compression, general physical 
health deterioration, hematuria, pneumonia, bone pain, metastatic pain, pathologic 


________________________________________________________________________ 
10 
fracture, urinary tract obstruction, cauda equina syndrome, pain, metastases to central 
nervous system, and urosepsis. The most common adverse events leading to treatment 
discontinuation among those receiving MDV3100 were fatigue, dysphagia, vomiting, 
nausea, and cerebrovascular accident, and were reported with incidence between 0.4% 
to 0.6%. 
 
As an inhibitor of the GABA-gated chloride channel, MDV3100 has the potential to cause 
seizures.5 A dose-dependent relationship between MDV3100 exposure and seizure 
incidence was seen in both a nonclinical mouse study and the Phase 1 S-3100-1-01 
study in which seizures were reported at supra-clinical doses in 3 patients (all with other 
seizure risk factors such as use of concomitant medication that may lower seizure 
threshold). Seizures have also been reported at the 160 mg dose; however, there were 
confounding factors that may have contributed to the occurrence of seizures in the 
majority of these cases. In the Phase 3 CRPC2 study, seizures were reported in 5 (0.6%) 
patients treated with MDV3100 (160 mg daily) and no placebo patients as of the data 
cutoff date of 25 September 2011. Two of these patients had brain metastases, 1 had 
inadvertently received an intravenous lidocaine overdose, 1 had recently initiated 
haloperidol in the context of heavy alcohol use with brain atrophy, and 1 had cortical 
atrophy with microvascular disease. These observations suggest that MDV3100 may 
lower the seizure threshold at the clinical dose of 160 mg daily. Overall, MDV3100 (160 
mg daily) was well-tolerated in the CRPC2 study. 
 
1.3 
Other Agents 
Synthetic peptide analogs of gonadotropin releasing hormone (GnRH) are FDA approved 
for palliative treatment of advanced prostate cancer. In addition, there is category 1 
evidence to support the use of GnRH agonists in combination with an antiandrogen and 
radiation therapy for the treatment of patients with high-risk localized or locally advanced 
prostate cancer (NCCN Guidelines Version 1.2013). GnRH agonist treatment is a form of 
androgen deprivation therapy (ADT). In the current study, subjects will receive treatment 
with an approved GnRH agonist, leuprorelin acetate (administered as an intramuscular). 
Planned treatment duration will be for 2 - 3 years, at the discretion of the treating 
physician and the patient. Adverse effects associated with GnRH agonist treatment 
include diminished libido, hot flashes, hot flushes, gynecomastia, osteoporosis, increased 
incidence of fracture, obesity, alterations in serum lipid levels, insulin resistance, 
increased risk for development of diabetes mellitus, and increased risk for cardiovascular 
disease (NCCN Guidelines Version 1.2013).  
 
1.4 
Rationale 
Prostate cancer is the leading cause of non-skin cancer in the United States, with an 
estimated 241,740 new cases diagnosed in 2012.12 It is the number two cause of 
prostate cancer mortality among men in the US, accounting for 28,170 deaths.12 The 
majority of these deaths are attributed to metastatic prostate cancer that is resistant to 
castration. Castration, defined as a serum testosterone level < 50 ng/dL, has been the 
mainstay of intervention for metastatic prostate cancer for decades. Castrate-levels of 
testosterone are achieved surgically through bilateral orchiectomy, or alternatively 
through treatment with administration of GnRH agonists or antagonists. Castrate-
resistant prostate cancer (CRPC) often continues to rely on signaling through the 
androgen receptor that can be maintained even at very low (castrate) levels of circulating 
androgens. The androgen receptor signaling inhibitor enzalutamide has demonstrated 
activity against prostate cancer cells that overexpress the androgen receptor and are 
resistant to earlier generation anti-androgens such as bicalutamide.13,14 Enzalutamide is 
well-tolerated and is FDA-approved for use in combination with castration therapy for the 


________________________________________________________________________ 
11 
treatment of patients with metastatic CRPC who have experienced disease progression 
despite docetaxel chemotherapy.11  
 
Several predictors enable us to identify patients with localized prostate cancer who are at 
highest risk to develop metastatic CRPC. These include serum prostate specific antigen 
(PSA), Gleason score, and clinical tumor (T) stage on physical examination. Patients with 
high-risk localized, or locally advanced (those with radiographic or biopsy-demonstrated 
evidence of pelvic lymph node involvement) prostate cancer are routinely treated with a 
combination of GnRH agonist, first-generation anti-androgen, and EBRT. Androgen 
deprivation therapy (ADT) combined with radiation therapy has demonstrated superior 
survival outcomes when compared to either ADT or EBRT alone.1-9 Standard of care 
treatment of men with high-risk localized or locally-advanced prostate cancer who receive 
external beam radiation therapy is 2-3 years of androgen deprivation therapy with a 
GnRH agonist, with concurrent treatment with a first-generation anti-androgen for the 
initial 4-6 months. EORTC 22961 demonstrated an improvement in 5 year overall survival 
for men with locally advanced prostate cancer treated with EBRT plus 6 months of GnRH 
agonist therapy plus a first-generation anti-androgen, followed by 30 months of GnRH 
agonist treatment alone, compared to this treatment without the additional 30 months of 
GnRH agonist therapy.2 However, since many of these high-risk patients will go on to 
develop metastatic prostate cancer, there remains a significant need to improve upon the 
current treatment. No trial to date has tested the combination of enzalutamide with GnRH 
agonist therapy and external beam radiation therapy (EBRT) for patients with high-risk 
localized or locally-advanced prostate cancer. We hypothesize that this combination will 
be safe and well-tolerated. Once the safety profile has been established, we hypothesize 
that this combination may provide superior androgen signaling suppression and prostate 
cancer cell cytotoxicity compared to a first-generation anti-androgen plus GnRH agonist 
and improve clinical outcomes. 
 
This pilot study will assess the safety and tolerability of combining enzalutamide with 
GnRH agonist treatment and EBRT. We hypothesize that administration of enzalutamide 
plus a GnRH agonist for 6 months in combination with EBRT, followed by treatment with 
a GnRH agonist alone for 18 - 30 months, will be a safe and well-tolerated treatment for 
patients with high-risk localized or locally advanced prostate cancer. We will perform 
correlative imaging and tumor tissue biopsy analysis to assess the radiographic response 
to enzalutamide plus GnRH therapy as well as intratumoral androgen signaling.  
 
The primary endpoint is to determine the safety and tolerability of combining enzlutamide 
plus a GnRH agonist with EBRT up to 12 months following initiation of treatment with 
enzalutamide plus GnRH agonist. Primary endpoint measures are frequency of AEs with 
monitoring for  
1. 
Expected toxicities specific to the combination of enzalutamide plus GnRH 
agonist based on the clinical experience with this FDA-approved combination for the 
treatment of metastatic castration-resistant prostate cancer as annotated in section 1.2.2 
2. 
Expected radiation-related toxicities as annotated in section 4.4.1.8 
3. Unexpected severe AEs due to combination of enzalutamide plus GnRH agonist with 
EBRT. 
 
Secondary endpoints will include  
 
1. Molecular markers of androgen signaling and cell proliferation in prostate biopsy 
samples 
a. Inhibition of androgen-regulated gene expression (potential  targets to 
include NDRG1, FKBP5, TMPRSS2, and PSA) by qRT-PCR  
b. Inhibition of androgen receptor (AR) nuclear localization and prostate 
cancer cell proliferation measured by immunohistochemistry (IHC) 
c. Androgen metabolism in prostate biopsy samples 


________________________________________________________________________ 
12 
2. Serum PSA and testosterone following combination therapy with enzalutamide plus 
GnRH agonist therapy prior to initiation of radiation therapy 
3. Changes in prostate tumor volume and activity following 2 months of combined 
enzalutamide plus GnRH therapy compared to baseline as measured by multi-
parametric magnetic resonance imaging (MRI) 
 
 
 
These results will lay the groundwork for subsequent randomized trials to compare this 
treatment combination with the current standard of care in patients with high-risk 
localized and locally-advanced prostate cancer. 
 
1.5 
Correlative Studies 
In pre-clinical studies, enzalutamide was shown to inhibit androgen receptor signaling 
through multiple mechanisms.13,14 Enzalutamide inhibits androgen-induced receptor 
activation (binding of androgens to ARs in the cytosol), inhibits nuclear translocation of 
activated ARs, and inhibits the association of the activated AR with chromatin, even in 
the setting of AR overexpression and in prostate cancer cells resistant to anti-androgens 
such as bicalutamide. However, inhibition of AR signaling by enzalutamide has not been 
reported directly in primary patient tumor samples. We hypothesize that enzalutamide will 
impair AR nuclear localization and expression of AR-regulated genes in human tumors 
when administered in combination with GnRH agonist treatment. We hypothesize that 
this treatment combination will also result in a measurable anti-tumor response by muli-
parametric magnetic resonance imaging (MRI). 
 
To test these hypotheses, we will obtain prostate cancer tumor biopsies at the time of 
study enrollment and following two months of treatment with enzalutamide plus GnRH 
agonist. MRI of the pelvis, protocolled to assess the prostate, will be performed prior to 
the initial biopsy and again prior to the subsequent biopsies obtained following two 
months of treatment. 
 
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
 
2.1.1 
To determine the safety and tolerability of combining enzalutamide 160 mg by 
mouth daily with a GnRH and EBRT. Enzalutamide and GnRH agonist will be 
administered in combination for 6 months, beginning two months prior to the start 
of EBRT. Enzalutamide and GnRH agonist treatment will continue for the 
duration of EBRT and for approximately two months after completion of EBRT, 
for a total of 6 months of combined enzalutamide plus GnRH treatment. Patients 
will subsequently receive an additional 18 - 30 months of GnRH agonist therapy 
for a total of two - three years of GnRH agonist treatment. Safety and tolerability 
will be assessed by frequency and severity of adverse events with monthly 
monitoring for 12 months following initiation of enzalutamide plus GnRH therapy. 
Secondary Objectives 
 
2.1.2 
To determine whether enzalutamide combined with GnRH agonist treatment 
inhibits intra-tumoral androgen-regulated gene expression (potential  targets to 
include NDRG1, FKBP5, TMPRSS2, and PSA) as measured by qRT-PCR 
 


________________________________________________________________________ 
13 
2.1.3 
To determine whether enzalutamide combined with GnRH agonist treatment 
impairs androgen receptor nuclear localization and cancer cell proliferation in 
targeted prostate cancer biopsy samples. 
 
2.1.4 
To determine the impact of enzalutamide combined with GnRH agonist on 
androgen metabolism in prostate biopsy samples. 
 
2.1.5 
To determine the impact of enzalutamide plus GnRH agonist therapy on serum 
prostate specific antigen (PSA) and testosterone following two months of 
treatment. 
 
2.1.6 
To describe any preliminary evidence of anti-tumor activity by assessment of 
objective response as determined by multiparametric MRI in patients with high-
risk localized or locally-advanced prostate cancer. 
2.2 
Exploratory Objectives 
Exploratory objectives are those defined above as secondary objectives 2.1.2 – 2.1.4. 
2.3 
Endpoints 
2.1.1  
Safety and tolerability will be assessed based on the rate of drug-related grade 1-
5 adverse events experienced within the first 12 months of study treatment. These will be 
assessed via NCI’s CTCAE v4.0 toxicity criteria.  
 
2.1.2 
Molecular markers of androgen-regulated gene expression in tumor biopsy 
samples will be assessed by qRT-PCR at the time of study initiation and following two 
months of combined treatment with enzalutamide plus GnRH agonist.  
 
2.1.3 
Androgen receptor nuclear localization and cancer cell proliferation (using Ki-67) 
will be analyzed by immunohistochemical analysis of tumor biopsy samples at the time of 
study initiation and following two months of combined treatment with enzalutamide plus 
GnRH agonist. 
 
2.1.4 
Enzymes of androgen metabolism will be assessed from prostate tumor biopsy 
specimens by qRT-PCR 
 
2.1.5 
Serum levels of prostate specific antigen (PSA) and testosterone will be 
measured at study initiation and following two months of treatment with enzalutamide 
combined with GnRH agonist. 
 
2.1.6 
Changes in prostate tumor volume and tumor activity will be measured by 
magnetic resonance imaging (MRI) at the time of study initiation prior to the initial study 
biopsy and again following two months of combined enzalutamide plus GnRH agonist 
treatment just prior to the second study biopsy to be performed at the time of fiducial 
marker placement.  
 
3.0 
Subject  ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered. 
3.1 
Inclusion Criteria 
 
3.1.1 
Histologically proven adenocarcinoma of the prostate obtained within 6 months of 
screening. Patients in whom a diagnosis of high-risk localized or locally-
advanced prostatic adenocarcinoma is suspected based on a serum PSA > 20 


________________________________________________________________________ 
14 
ng/mL or clinical T3 disease by digital rectal examination, but who have not yet 
undergone diagnostic prostate biopsy, will be eligible for screening and initial 
MRI and targeted prostate cancer biopsies which will be obtained at the same 
time as diagnostic biopsies. Those patients in whom the diagnostic biopsies 
confirm prostatic adenocarcinoma will be permitted to continue with study 
treatment if they meet all additional eligibility criteria. 
 
3.1.2 
Age ≥ 18 years. 
 
3.1.3 
Eastern Cooperative Oncology Group (ECOG) performance status < 2 
 
3.1.4 
Adequate organ and marrow function as defined below: 
- leukocytes 
 
≥ 3,000/mcL 
- absolute neutrophil count ≥ 1,500/mcL 
- platelets  
 
≥ 100,000/mcl 
- hemoglobin 
 
> 10 g/dL 
- total bilirubin 
 
< 1.5 X institutional upper limit of normal (except 
for patients with documented Gilbert’s disease) 
- AST(SGOT)/ALT(SPGT) ≤ 2.5 X institutional upper limit of normal 
- creatinine 
< 1.5 X institutional upper limit of normal or 
estimated glomerular filtration rate < 45 
mL/min/1.73m2, given the risk of nephrogenic 
systemic fibrosis when using gadolinium-based 
intravenous contrast agents in these subjects. 
- serum testosterone 
> 100 ng/dL 
 
 
3.1.5 
Men who are sexually active with female partners of child-bearing potential must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and for 90 
days following completion of therapy. Should a woman become pregnant or 
suspect she is pregnant following intercourse with a study participant during his 
participation in this study, she should inform her treating physician immediately, 
and the study principal investigator should be informed immediately. 
 
3.1.6.1 A female of child-bearing potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria: 
 
 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
 
3.1.6 
Patients must be candidates for long-term androgen deprivation in combination 
with EBRT for the treatment of high-risk or locally-advanced prostate cancer by 
the following criteria: 
 
High risk disease: T3a or Gleason 8-10 or serum PSA > 20 ng/mL 
 
Gleason 7 also allowed if > 50% of cores positive for cancer or PSA velocity 
> 2 ng/mL/year in preceding 12 months 
 
Locally advanced (very high risk) disease: T3b-T4 
 
3.1.7 
Patients may have radiographic evidence of metastasis in regional lymph nodes (N1 
disease as defined by the National Comprehensive Cancer Network Prostate Cancer 
Guideline Version 3.2012) at the discretion of the treating physicians, if regional 
lymph nodes can be included in the planned radiation field. 


________________________________________________________________________ 
15 
3.1.8 
Participants in the study must permit targeted prostate biopsy prior to initiation of 
study treatment and at the time of fiducial marker placement 
3.1.9 
Able and willing to provide written authorization for use and release of health and 
research study information 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent. 
3.2 
Exclusion Criteria 
 
3.2.1 
Prior treatment with the following agents known to have endocrine effects on 
prostate cancer: GnRH agonist, GnRH antagonist, anti-androgen (bicalutamide, 
nilutamide, flutamide), ketoconazole, diethylstilbestrol, estrogen, abiraterone 
acetate. Concurrent use of 5-reductase inhibitors finasteride or dutasteride is 
permitted for patients who have been already receiving either of these treatments 
for at least 1 month at the time of study enrollment. Baseline PSA must have 
been obtained in such patients after at least 1 month on 5-reductase treatment. 
Initiation of treatment with 5-reductase inhibitors is not permitted within the first 
12 months of study participation.  
 
3.2.2 
Concomitant treatment with agents thought to have endocrine effects on prostate 
cancer: PC-SPES, saw palmetto 
3.2.3 
Treatment with corticosteroids within 4 weeks prior to enrollment. 
3.2.4 
Treatment with androgens within 6 months prior to study enrollment. 
3.2.5 
Subjects may not be receiving any other investigational agents. Concurrent 
enrollment in another clinical investigational drug or device study is prohibited. 
3.2.6 
Prostate cancer metastases to the bones, viscera, or non-regional lymph nodes 
(lymph nodes other than pelvic lymph nodes within the radiation treatment field) 
3.2.7 
Serum PSA > 160 ng/dL 
3.2.8 
History of malignancy (other than non-melanoma skin cancer) within 5 years of 
enrollment 
3.2.9 
Patients with histologic evidence of small cell carcinoma of the prostate will not 
be eligible.  
 
3.2.10 Treatment for malignancy with anticancer therapy, including cytotoxic agents, 
hormonal agents, or immunotherapy, within 5 years of enrollment 
 
3.2.11 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to enzalutamide or other agents used in this study. 
 
3.2.12 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure (> NYHA class II hear failure), 
unstable angina pectoris, cardiac arrhythmia, chronic active hepatitis, acute 
hepatitis, uncontrolled diabetes mellitus, or psychiatric illness/social situations 
that would limit compliance with study requirements. 
3.2.13 Patients with any of the following within 6 months of enrollment: deep vein 
thrombosis, pulmonary embolus, myocardial infarction, cerebrovascular accident, 
unexplained loss of consciousness. 


________________________________________________________________________ 
16 
3.2.14 Patients with any history of seizure or seizure disorder. 
3.2.15 Patients with medical conditions which, in the opinion of the investigators, would 
pose undue risk to the patient 
 
3.2.16 Subjects unwilling to use contraceptives if they have sexual intercourse with a 
female partner of child-bearing potential while receiving treatment on this study. 
3.2.17 Standard contraindications to MRI: For example, MRI non-compatile cardiac 
pacemakers, intracranial clips, foreign metal objects in the body and others as 
defined in the UT Southwestern Institutional MRI Safety Policy) 
3.2.18 The following medications are prohibited during the study:  
 
Substrates of CYP2B6, CYP2C8, CYP2C9, and CYP2C19 with a narrow 
therapeutic index, including paclitaxel, phenytoin, warfarin, omeprazole  
 
Substrates of CYP3A4 with a narrow therapeutic index, including alfentanil, 
cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus 
 
Strong CYP2C8 inhibitors, including gemfibrozil 
 
Strong CYP3A4/5 inhibitors, including clarithromycin, itraconazole, 
ketoconazole 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
4.1.1 
We propose a single-institution, single-arm study of neo-adjuvant, concomitant, 
and adjuvant enzalutamide plus GnRH agonist with external beam radiation 
therapy for the treatment of patients with high-risk and locally-advanced prostate 
cancer.  
 
4.1.2 
Eligible study participants will receive treatment with enzalutamide 160 mg daily 
for 6 months in combination with GnRH agonist treatment. Following the initial 
two months of treatment with enzalutamide and GnRH agonist, radiation therapy 
will be administered as detailed below. GnRH agonist treatment will be continued 
for a total treatment duration of 24 - 36 months at the discretion of the treating 
physician in concert with the patient. Treatment will be administered on an 
outpatient basis. 
 
 
 
Table 4.1 
Agent 
 
Dose 
 
Route 
 
Schedule 
Enzalutamide 
160 mg daily (four 40 
mg capsules) 
p.o.  
Daily for 6 months 
Leuprolide acetate 
22.5 mg every 3 months 
 
or 
 
45 mg every 6 months 
IM  
Every 3 or 6 months 
(depending on dosage 
form used) for a total 
treatment duration of 
24-36 months 
 
 


________________________________________________________________________ 
17 
A study medication diary will be provided to each subject in which daily oral self-
administration of enzalutamide will be documented. If a dose is missed, enzalutamide 
should be resumed the next day at the established daily dose of 160 mg. A vomited dose 
should not be replaced. 
 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
table (Table 5.4). Toxicity will be assessed according to the NCI Common Toxicity 
Criteria for Adverse Events (CTCAE), version 4.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity.  
 
Enzalutamide (Xtandi, MDV3100) has been shown to be well-tolerated when used in 
combination with androgen deprivation (in the form of GnRH agonists or castration by 
orchiectomy) in completed phase I, II, and III clinical trials.  
 
Table 4.2.1 Hematological Toxicity Dose Reductions for Enzalutamide 
ANC 
Platelets 
Action 
≥ 1,500/L 
100,000/L 
None. 
 
1000-1499/L 
 
75,000-99,000/L 
-1st Occurrence:Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 100,000/L. Do not 
replace missed doses. Restart next treatment at 
120 mg dose.  
-2nd Occurrence:Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 100,000/L. Do not 
replace missed doses. Restart next treatment at 
80 mg dose.  
-3rd Occurrence: Discontinue protocol therapy. 
 
500-999/L 
 
50,000-74,000/L 
-1st Occurrence:Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 100,000/L. Do not 
replace missed doses. Restart next treatment at 
120 mg dose.  
-2nd Occurrence: Discontinue protocol therapy. 
 
<500/L 
 
<50,000/L 
 
-1st Occurrence: Discontinue protocol therapy.  
 
 
Table 4.2.2. Non-hematological Toxicity Dose Reductions 
NCI CTC Grade 
Enzalutamide 
0-2 
No change from original starting dose (with the exception of seizure) 
3-4 
Hold until resolved to <Grade 2, then reduce to 120 mg dose 
Second episode of 
grade 3 or 4 toxicity 
Hold until resolved to <Grade 2, then reduce to 80 mg dose 
Third episode of 
grade 3 or 4 toxicity 
Remove subject from trial 


________________________________________________________________________ 
18 
 
In the randomized clinical trial of patients with docetaxel-refractory metastatic CRPC, 7 of 800 patients 
(0.9%) treated with enzalutamide 160 mg daily experienced a seizure. No seizures occurred in patients 
treated with placebo. Patients experiencing seizures were permanently discontinued from therapy and all 
seizures resolved. There is no clinical trial experience re-administering enzalutamide to patients who 
experienced seizures. Therefore, should a subject experience any seizure, enzalutamide will be 
discontinued and the subject removed from the trial. 
 
4.3 
Concomitant Medications/Treatments 
In vitro studies show that enzalutamide and/or metabolite M2 are potential inhibitors of 
CYP2C8 and CYP2C19 with lesser potential for inhibitory effects on CYP2B6 and 
CYP2C9. Enzalutamide is a moderate CYP2C9 and CYP2C19 inducer in humans. For 
this study, substrates of CYP2B6, CYP2C8, CYP2C9, and CYP2C19 that have a narrow 
therapeutic index (e.g., paclitaxel, phenytoin, warfarin, omeprazole) are prohibited.  
 
In vitro studies show that enzalutamide is an inducer of CYP3A4. Induction of CYP3A 
occurs via activation of the nuclear pregnane X receptor (PXR), which is expected to 
result in co-induction of CYP2C. Co-administration of enzalutamide with CYP3A or 
CYP2C substrates may reduce oral bioavailability and/or accelerate elimination of these 
substrates. Enzalutamide is a strong CYP3A4 inducer in humans. For this study, 
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) is prohibited. 
 
In vitro studies show that enzalutamide is metabolized by CYP2C8 and CYP3A4/5. 
Strong inhibitors or inducers of these enzymes may affect enzalutamide exposures. Co-
administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area 
under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl 
enzalutamide in healthy volunteers. For this study, co-administration of enzalutamide and 
strong CYP2C8 inhibitors (e.g., gemfibrozil) is prohibited. Co-administration of a strong 
CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-
desmethyl enzalutamide by 1.3 fold in healthy volunteers. For this study, strong inhibitors 
of CYP3A4/5 (e.g., clarithromycin, itraconazole, ketoconazole) are prohibited during 
enzalutamide treatment. 
 
Use caution when co-administering strong inducers of CYP2C8 (e.g., rifampin) or 
CYP3A4/5 (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) during 
enzalutamide treatment, as enzalutamide concentrations may decrease. 
 
In vitro studies show that enzalutamide and metabolite M2 are potential inhibitors of the 
efflux transporter P-gp. Co-administration of enzalutamide with P-gp substrates may 
increase the plasma concentrations of the P-gp substrate. Use caution when co-
administering sensitive P-gp substrates (e.g., colchicine, dabigatran etexilate, digoxin) 
during enzalutamide treatment. 
 
Food has no clinically significant effect on the extent of absorption. Enzalutamide may be 
taken with or without food. 
 
Osteoporosis is a potential adverse effect of GnRH agonist therapy. As per the NCCN 
Prostate Cancer Guidelines Version 1.2013, screening and treatment for osteoporosis 
are recommended according to guidelines for the general population provided by the 
National Osteoporosis Foundation (www.nof.org). It is advised that subjects enrolled in 
this study be treated for osteoporosis at the discretion of the investigator according to 
NOF guidelines. These recommendations include treatment with supplemental calcium 
(1200 mg daily) and vitamin D3 (800-1000 IU daily) for all men > 50 years of age and 


________________________________________________________________________ 
19 
additional treatment for men with a 10 year probability of hip fracture > 3% or 10 year 
probability of a major osteoporosis-related fracture > 20% as assessed using the FRAX 
algorithm established by the World Health Organization. Using the FRAX algorithm, 
GnRH agonist treatment should be considered a secondary osteoporosis risk factor. 
Osteoporosis reatment options permitted in conjunction with this study for appropriate 
patients include denosumab 60 mg SQ every 6 months x 6 doses, zoledronic acid 5 mg 
iv annually, or alendronate 70 mg PO weekly. 
 
Medications known to lower the seizure threshold include but are not limited to: 
 
Aminophylline/theophylline; 
 
Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone); 
 
Bupropion; 
 
Lithium; 
 
Pethidine (meperidine); 
 
Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine); 
 
Tricyclic and tetracylic antidepressents (e.g., amitriptyline, desipramine, doxepin, 
imipramine, maprotiline, mirtazapine). 
 
4.4 
Other Modalities or Procedures 
4.4.1 
RADIATION THERAPY  
Radiotherapy should begin within 8-10 weeks(+/- 7 days) after the date of the GnRH and 
enzalutamide administration.injection. Radiotherapy will be administered as standard of care 
treatment.  
 
4.4.1.1. Plan 1: Whole pelvis including prostate and seminal vesicles 
Acceptable Treatment Modalities: 
3D-CRT or IMRT. For patients with N1 disease, only IMRT plan will be allowed. 
 
Prescription Dose (See Table 4.4.1.1): 
45 Gy to cover 98% (+/- 3%) of PTV 
 Minimum dose within PTV – 95% (+/- 5%) of prescribed dose and for a volume that is 0.03 cc 
 Maximum dose within the PTV – 107% (+/- 3%) of prescribed dose and for a volume that is 
0.03 cc 
 
In patients with N1 disease, PTV-N will be defined: 
Prescription dose (See table 4.4.1.2) 
55 Gy to cover 95 % (+/- 5%) of PTV-N 
 
Minimum dose within PTV – 93% (+/- 3%) of prescribed dose and for a volume that is 0.03 cc 
 
Maximum dose within the PTV – 105% (+/- 5%) of prescribed dose and for a volume that is 
0.03 cc 
 
Table 4.4.1.1: Radiation Therapy Dose Objectives for Plan 1 – Pelvic and Prostate Radiation 
PTV dose 
(encompassin
g 98% PTV 
(+/- 3%)) 
Minimu
m PTV 
dose for 
a point 
with a 
volume 
of .03cc 
Maximu
m PTV 
dose for a 
point 
with a 
volume 
of .03cc 
Maximum 
PTV dose 
to a 
volume of 
.03 cc of 
PTV 
(variation 
acceptable
) 
Maximum 
PTV dose to 
a volume of 
.03 cc of 
PTV  
(Deviation 
unacceptabl
e 
45 Gy 
42.8 Gy 
48.2 Gy 
> 48.2-
49.5 Gy 
>49.5 Gy 
 


________________________________________________________________________ 
20 
*Maximum dose must not be within an organ at risk (OAR) such as the rectum, bladder. 
 
Table 4.4.1.2: Radiation Therapy Dose Objectives for Plan 1 – PTV-N 
PTV-N dose 
(encompassin
g 95% PTV 
(+/- 3%)) 
Minimu
m PTV-
N dose 
for a 
point 
with a 
volume 
of .03cc 
Maximu
m PTV-N 
dose for a 
point 
with a 
volume 
of .03cc 
Maximum 
PTV-N 
dose to a 
volume of 
.03 cc of 
PTV 
(variation 
acceptable
) 
Maximum 
PTV-N dose 
to a volume 
of .03 cc of 
PTV  
(Deviation 
unacceptabl
e 
55 Gy 
50.06 
Gy* 
60.05 Gy 
> 57.75-
60.05 Gy 
>60.05 Gy 
*if PTV-N is adjacent to small bowel, minimum acceptable PTV-N dose will be dose that can be 
achieved while meeting absolute small bowel dose constraints. 
 
4.4.1.2. Plan 2: Reduce volume cone down boost plan to the prostate and (proximal) seminal 
vesicles 
Acceptable Treatment Modalities: 
IMRT or 3DCRT 
 
Table 4.4.2 : Radiation Therapy Dose Objectives for Plan 2 – Prostate and Seminal Vesicle Boost 
PTV dose 
(encompassin
g 98% PTV 
(+/- 3%)) 
Minimu
m PTV 
dose for 
a point 
with a 
volume 
of .03cc 
Maximu
m PTV 
dose for a 
point 
with a 
volume 
of .03cc 
Maximum 
PTV dose 
to a 
volume of 
.03 cc of 
PTV 
(variation 
acceptable
) 
Maximum 
PTV dose to 
a volume of 
.03 cc of 
PTV  
(Deviation 
unacceptabl
e 
34.2 Gy 
32.49 Gy 
37.62 Gy 
> 36.6-
37.6 Gy 
>37.6 Gy 
Maximum dose must not be within an OAR such as rectum, or bladder. 
 
4.4.1.3 Technical Factors 
Either 3DCRT or IMRT may be used for treatment. For 3DCRT treating the whole pelvis (WPRT), 
a minimum of 4-fields should be used and a 4 field plan is recommended. For IMRT, no specific 
field arrangement is required. RT will be delivered with megavoltage equipment at energies ≥ 6 
MV. Typically, except for VMAT techniques, 5 to 9 gantry angles are employed for the IMRT 
treatments.  When using IMRT, preference will be given to using photon energies <=10MV, but 
higher energies will be permitted if necessary for production of a more optimal plan due to 
anatomic constraints. 
4.4.1.4 EBRT Localization, Simulation, and Immobilization 
Simulation will be CT-based in all cases. A urethrogram or MRI is recommended, but not 
required, to be used for target delineation. Rectal contrast is discouraged because it may distend 
the rectum and artificially displace the prostate in the anterior direction. Intravenous contrast is 
permitted but not required to assist in identifying the pelvic vessels. Patients will be positioned 
supine or prone on a flat tabletop with a customized thermoplastic immobilization cast or a 
molded foam cradle or similar immobilization for stabilization and setup reproducibility. The 
degree of bladder fullness should be made to duplicate the degree of fullness anticipated for daily 
treatment, i.e., if the patient is instructed to maintain a full bladder for treatment, he should be 
simulated as such (especially for cases in which image guidance is not implemented). The rectum 
should be kept as empty as possible; recommendation is for an enema 1-2 hours prior to 
simulation. CT images should be acquired at a slice thickness of ≤3 mm from L3/L4 vertebral 


________________________________________________________________________ 
21 
body to the perineum inferiorly. If Calypso beacons are used, slice thickness of 1.5-2 mm will be 
recommended. Target volumes and normal critical structures (as defined in section 4.4.1.5.3)  will 
be defined in the slices in which they are visualized. The 3DCRT cases must utilize “beam’s eye 
view” representations to define final beam aperture. 
 
4.4.1.5 Treatment Planning/Target Volumes 
4.4.1.5.1 Patients must have a composite treatment plan generated at the beginning of Plan 1 so 
that the final EBRT dose to critical structures is evaluated before any dose delivery has begun. 
Dose for initial treatment (CTV1/PTV1) will be 45.0 Gy at 1.8 Gy per fraction.  If patient has N1 
disease, CTV-N/PTV-N will be defined, and will received 55 Gy at 2.2 Gy per fraction during plan 
1of the treatment course using simultaneous integrated boost technique (SIB).  All patients with 
N1 disease will be treated with IMRT, and 3DCRT will not be permitted. Once this portion is 
completed, a cone down boost to the prostate and (proximal) seminal vesicles will be delivered  
by either IMRT or 3DCRT.  Brachytherapy boost is not permitted on this study. For the boost, the 
dose to the CTV2/PTV2 will be 34.2 Gy at 1.8 Gy per fraction, for a total prostate dose of 79.2 
Gy.  For pelvic 3D-CRT, a 4-field technique, using opposed anterior-posterior and opposed lateral 
fields, is recommended. All fields should conform to the beam’s-eye-view of the target. No 
specific field arrangement is required for IMRT, although typically 5-9 fields are used for fixed 
gantry treatment. Tomotherapy and VMAT/rapid arc/ smart arc IMRT technologies) also are 
allowed for IMRT treatment on this protocol. 
4.4.1.5.2. The definition of GTV, CTV and PTV will be in accordance with the ICRU Report #50: 
Prescribing, Recording, and Reporting Photon Beam Therapy. 
 
4.4.1.5.2.1 Plan 1 Pelvis, including prostate and seminal vesicles 
Gross Target Volume (GTV1 and GTV-N) 
The GTV1 is defined by the physician as all known disease as defined by the planning CT, 
urethrogram, MRI, and clinical information. If a urethrogram is used, the GTV will encompass a 
volume inferiorly 5 mm superior to the tip of the dye and no less than the entire prostate. Prostate 
dimensions should be defined as visualized on CT scan. If MRI is performed, fusion of planning 
CT with the MRI will be performed on the treatment planning system, and MRI will be utilized to 
help further refine and delineate the GTV.   
 
GTV-N will be defined as all positive pelvic nodal disease > 1.5 cm in short axis diameter seen on 
CT scan or MRI before initiation of hormone therapy.  Nodal disease will be contoured based on 
the pre-hormone therapy imaging studies.  If necessary, a CT simulation can be performed prior 
to initiation of hormone therapy as a baseline study that can be used for treatment planning 
purposes.   At the discretion of the treating physician, nodal disease >=1cm will also be 
considered for GTV-N, particularly if there are multiple gross nodal disease present. 
 
Clinical Target Volume (CTV1) 
The CTV1 will include the prostate and entire seminal vesicles (SV), the obturator, external iliac, 
proximal internal iliac and distal common iliac nodes, using the vascular structures, up to a level 
corresponding to the top of L5-S1. At the treatment team’s discretion, coverage can be increased 
to include common iliac nodes up to L4/L5 level. One can refer to the pelvic nodal atlas at the 
RTOG Web site (Pelvic Lymph Node Volumes for Prostate Cancer Atlas; 
http://www.rtog.org/CoreLab/ContouringAtlases/ProstatePelvicLymphNodes.aspx). 
The presacral nodes from L5-S1 to S3 may be included if desired depending on whether the dose 
constraints to the rectum are achievable (see Table 4.4.3).  The CTV1 will include a 7 mm margin 
in 3-dimensions to the contoured iliac vessels, but not extend outside of the true pelvis, into the 
pelvic musculature nor into adjacent identifiable organs, such as the bladder, rectum or other 
bowel. Extension of the CTV into adjacent bone may be carved out.  Anatomical boundaries to 
consider if 3DCRT is used include superiorly from L5-S1 to 0.5 cm below the tip of the urethral 
contrast dye inferiorly to ensure that the entire prostate gland is included (MRI can also be used 
to help define the apex). Lateral borders will be at least 1 cm from the pelvic brim. In the lateral 
fields, the external and internal iliac lymph nodes below the SI joints, and the posterior extension 
of the seminal vesicles should be covered. The usual posterior border is approximately S2-3, but 


________________________________________________________________________ 
22 
CT anatomy should take precedence. The inferior extent of the external iliac lymph nodes is at 
the top of the femoral heads. The inferior extent of the obturator lymph nodes is at the top of the 
symphysis pubis. 
 
If there are grossly involved nodes seen in the pelvis, this can be treated to a higher dose using a 
simultaneous integrated boost technique (see section 4.4.1.1 and Table 4.4.1.2).  For these 
patients, a GTV-N will be defined as the grossly evident node based on imaging studies (> 1.5 cm 
for solitary, and > 1 cm for multiple nodes at the discretion of treating physician) (see section 
4.4.1.5.2.1).  Imaging studies prior to hormone therapy can be used to guide in the delineation of 
GTV-N. Alternatively for node positive patients, a CT simulation in the treatment position can be 
performed prior to hormone therapy to be used in fusion with CT simulation to be performed at a 
later date to help define the nodal volume.  CTV-N will be defined as being GTV-N + 7mm margin 
in 3-dimensions.  As always careful consideration will be made in defining CTV to carve disease 
out of the bowel.   
 
Planning Target Volume 
The PTV1 margins should be a minimum of 0.5 cm and a maximum of 1.5 cm in all dimensions. 
 
4.4.1.5.2.2 Plan 2 Prostate and Proximal Seminal Vesicles Boost with IMRT  
Gross Target Volume (GTV 2) 
See Section 4.4.1.5.2.1 above for GTV1. 
 
Clinical Target Volume (CTV2) 
The CTV2 is the GTV2 plus areas considered to contain microscopic disease, delineated by the 
treating physician. The CTV2 includes the GTV (prostate) plus areas at risk for microscopic 
disease extension plus the proximal bilateral seminal vesicles. Typically, only the proximal 1.0 cm 
of seminal vesicle tissue adjacent to the prostate shall be included in the clinical target volume. 
This 1.0 cm of seminal vesicles refers to both radial (in plane) and superior (out of plane) extent. 
If both prostate and seminal vesicle are visualized in the same CT slice, this seminal vesicle 
tissue will contribute to the 1.0 cm of tissue as seen on the CT simulation scan. For patients with 
clinical biopsy proven involvement of the seminal vesicles, or with imaging evidence of seminal 
vesicle involvement, or with clinical suspicion at the discretion of treating physician, treatment of > 
1 cm of the proximal seminal vesicles (up to entire seminal vesicle), is acceptable as long as it 
does interfere with the ability to achieve dose constraints to the critical normal structures (see 
section 4.4.1.5.3). 
 
Planning Target Volume (PTV2) 
The PTV2 will provide a margin around the CTV2 to compensate for the variability of treatment 
set up and internal organ motion. A range of 5-10 mm around the CTV is required to define each 
respective PTV. Individual selection of a PTV margin should be based on the institution’s level of 
confidence in patient set-up and the availability of image guidance. Superior and inferior margins 
(capping) should be 5-10 mm depending on the thickness and 
spacing of the planning CT scan. Careful consideration should be made when defining the 5- 10 
mm margin in 3 dimensions. 
 
4.4.1.5.3 Normal Critical Structures and Dose Constraints 
Normal critical structures to be defined on the treatment planning CT scan will include the 
following: bladder, rectum (from its origin at the rectosigmoid flexure superiorly or the bottom of 
the SI joints, whichever is more inferior to the inferior-most extent of the ischial tuberosities), 
sigmoid colon (to the level of superior border of PTV1),  bilateral femora (to the level of ischial 
tuberosity), penile bulb, and skin. Any small bowel within the primary beam aperture should be 
defined as well. The normal tissues will be contoured and considered as solid organs. The 
bladder should be contoured from its base to the dome, and the rectum from the anus (at the 
level of the ischial tuberosities) for a length of 15 cm or to the rectosigmoid flexure. This generally 
is below the bottom of the sacroiliac joints. If IMRT is being used to treat the pelvic nodes, the 
potential bowel space (not just individual loops of bowel) where the small and large bowel may 


________________________________________________________________________ 
23 
fall should be outlined. The borders are the abdominal wall anteriorly, pelvic sidewalls laterally 
(excluding the pelvic lymph node regions), superiorly to one cut above the last axial CT image on 
which the lymph nodes are outlined and inferiorly from the level of the top of PTV1 (outlining 
around the sides of the bladder near the top of the bladder to encompass the bowel that may fall 
into these regions). See the ITC web site (http://atc.wustl.edu) to view examples of target and 
normal tissue contours. 
The following table summarizes the dose constraints for the critical structures. 
 
Table 4.4.3 Organs at Risk, and Dosimetric Constraints 
 
 
≤ 15% 
≤ 20% 
≤ 35% 
≤ 50% 
Rectum/Sigmoid 
75 Gy 
70 Gy 
65 Gy 
40 Gy 
 
10 cc < 75.6 Gy  
20 cc < 70 Gy 
Bladder 
80 Gy 
75 Gy 
70 Gy 
50 Gy 
 
90 cc < 70 Gy  
150 cc < 65 Gy 
Potential Bowel 
Space 
0.03 cc < 50.4 Gy* 
50 cc < 45 Gy* 
L and R Femur 
≤ 5% receives 50 Gy 
Penile bulb 
Mean dose ≤ 52.5 Gy 
 
 
While every effort should be made to deliver prescription doses to the PTV as specified while 
adhering to these constraints, it is recognized that certain anatomical factors may prevent this. 
Prescription dose reduction to a level of 77.4 Gy or 75.6 Gy is permitted if constraints cannot be 
met at a prescription dose of 79.2 Gy. For purposes of compliance, up to a 5% absolute increase 
in the volume of critical structure receiving greater than the specified dose will be considered 
”variation acceptable,” e.g. up to 20% of the rectum may receive a dose of > 75.6 Gy without a 
protocol deviation. Any increase in critical structure volume greater than 5% receiving more than 
the specified dose will be considered a ”deviation unacceptable.” It is at this point that a dose 
reduction to 77.4 Gy or 75.6 Gy should be implemented. The prescription dose should be the 
maximum deliverable up to 79.2 Gy while respecting the critical normal structure constraints. Of 
note, the penile bulb constraint is to be regarded as a guideline, and adherence to this should not, 
in any way, result in a reduction of the prescription dose or compromised dose coverage of the 
target volume.  In the event that PTV-N is in close proximity to the small bowel, absolute small 
bowel constraints will be prioritized over PTV-N coverage. * variation will be noted if > 50 cc to 
150 cc of potential small bowel space receives ≥ 45 Gy. A secondary variation will be noted if > 
150 cc receives >45 Gy. However, at the discretion of the treating physician, will consider max 
point dose up to 55 Gy.   
 
4.4.1.6 Treatment Verification 
4.4.1.6.1  For 3DCRT: First day port films or portal images of each field along with orthogonal 
isocenter verification films (or images) must be obtained. If modifications are made in field 
shaping or design, a port film/image of each modified field along with orthogonal isocenter 
verification films (or images) is required on the first day’s treatment of that field. Thereafter, 
weekly verification films or images of orthogonal isocenter views (anterior to posterior and lateral 
projection) are required. 
 
For IMRT:  the intensity profiles of each beam must be independently verified and compared to 
the planned field intensity. Portal films/images are required for IMRT but orthogonal verification 
films/images are required, just as for 3DCRT. Real-time ultrasound localization and on-line cone 
beam CT image guidance are important complements to conventional port films or portal imaging 
and should be used when available. Weekly port filming/imaging is required in this study. 
 


________________________________________________________________________ 
24 
4.4.1.6.2 Daily on-line target localization (kV or MV imaging with fiducials, kV or MV ConeBeam 
CT, trans-abdominal ultrasound, or other) or off-line adaptive approaches to account for 
interfraction organ motion and setup variability are permitted on this study.  Fiducials (gold seeds) 
will be placed by the UT Southwestern Urology department at least 10-14 days prior to the 
intiation of radiation therapy date and details for this process are outlined in 4.4.2.  Calypso 
Beacons are permitted to be used in place of gold seed fiducial markers, if monitoring 
intrafractional motion is desired at the discretion of the treatment team. 
 
4.4.1.7 Quality Assurance 
4.4.1.7.1 Compliance Criteria for Cases Treated with EBRT 
Cases that are treated entirely with external beam radiation therapy must meet the criteria 
as stated in Sections 4.4.1.1 and 4.4.1.2 (see also Tables 4.4.1.1, 4.4.1.2, and 4.4.2). Both the 
Plan 1 and 2 requirements must be met.  In addition, the critical structure dose constraints of 
Section 4.4.1.5.3 and Table 4.4.3 must be met.  
4.4.1.7.1.1 Acceptable dose heterogeneity for external beam treatment is summarized in Tables 
5.1 and 5.2. The treating physician must carefully consider the tolerance dose/volume to each 
critical normal structure and unspecified tissue. 
4.4.1.7.2 Radiation Quality Assurance Review 
The study’s radiation PI or his designees will perform an RT Quality Assurance remote review 
after complete data for the first 4 of the cases enrolled has been made available. The study PI or 
his designees will perform the next remote review after complete data for the next 3 cases have 
been enrolled. The final cases will be reviewed within 3 months after this study has reached the 
target accrual or as soon as complete data for all cases enrolled has been made available, 
whichever occurs first. These reviews will be ongoing and performed remotely. 
 
4.4.1.8. Radiation Therapy Adverse Events 
All patients will be seen weekly by their treating radiation oncologist while undergoing EBRT. Any 
observations with respect to the following symptoms/side effects will be recorded: Bowel/rectal 
irritation manifesting as cramping, diarrhea, urgency, proctitis, or hematochezia, urinary 
frequency, urgency, dysuria, hematuria, urinary tract infection, or incontinence. CTCAE 4.0 will be 
used to grade all toxicities. 
 
4.4.1.8.1. Clinical discretion may be used in managing radiotherapy-related side effects. 
Diarrhea/rectal frequency/urgency may be managed with diphenoxylate or loperamide. Bladder 
irritation may be mitigated with phenazopyridine. Urinary frequency/urgency can be managed with 
anticholinergic agents or alpha-blockers such as tamulosin.  Erectile dysfunction can be managed 
with phosphodiesterase (PDE) inhibitors such as sildenafil.   
 
4.4.1.9. Quality of Life Outcomes Related to Radiation Treatment 
All patients will be given quality of life and symptom monitoring questionnaires including AUA 
symptom score sheet and the SHIM score sheet.  The  questionnaries will be given at the 
radiation consult visit and at follow up visits as part of the standard of care treatment. 
 
4.4.2 
SURGICAL PROCEDURES 
4.4.2.1 Gold fiducial marker placement.  
Gold seeds will be placed under ultrasound guidance in the prostate of patients as fiducial 
markers for radiation therapy prior to commencement of EBRT. Fiducial marker placement is 
standard of care for patients undergoing EBRT and will be performed following standard 
techniques. 
 
4.4.2.2. Prostate biopsies. 
Standard 12-core biopsies for diagnosis will be performed under transrectal ultrasound (TRUS) 
guidance at study entry on subjects who have not yet undergone diagnostic biopsy for prostate 
cancer. At the same time, up to 6 additional targeted core biopsy research samples will be 
obtained for purposes of the correlative studies described in Section 9.0. Subjects who have 
already undergone diagnostic prostate biopsies at the time of screening will undergo repeat 


________________________________________________________________________ 
25 
TRUS-guided biopsy to obtain up to 6 core biopsy samples for correlative studies at the time of 
study enrollment. TRUS-guided biopsy is performed as standard of care for the diagnosis and 
risk-stratification of patients with prostate cancer. A second set of up to -6 targeted research 
biopsy samples will be obtained under TRUS-guidance at the time of gold seed fiducial marker 
placement in all subjects enrolled in the study. 
 
Biopsies will be formed using the Koelis Urostation with PROMAP-MR software. This approved, 
commercially available imaging and biopsy technology permits 3-dimensional transrectal 
ultrasound and MRI fusion to target tumor tissue within the prostate for biopsy, and will permit 
repeat biopsy of the same sites. The Urostation is a mobile software platform which can improve 
the prostate biopsy procedure with 3D imaging and image fusion capabilities. The Urostation 
connects to an ultrasound scanner equipped with a 3D transrectal probe. It receives stores and 
processes 3D Dicom images of the prostate as the physician performs the biopsy procedure.  
Organ-Based Tracking is an automatic 3DTRUS/3DTRUS registration based on the organ 
position within the image. This registration is robust to prostate and patient motion.  The 
MRI/3DTRUS fusion is elastic since prostate deformation is corrected for optimal precision using 
a morphological contouring method.  One significant advantage of this system is allowing 
mapping of biopsies as the Urostation guides and records each biopsy.  It also allows real-time 
feedback on the targeted prostate region with an overlay of prior biopsy locations so a rebiopsy 
can be performed accurately of the region of interest.  
 
4.5 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for up 
to 36 months or until: 
 
Disease progression 
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Subject  decides to withdraw from the study, OR 
 
General or specific changes in the patient’s condition render the subject  
unacceptable for further treatment in the judgment of the investigator”. 
4.6 
Duration of Follow Up 
Subjects will be followed for 12 months after initiation of treatment with enzalutamide 
plus GnRH agonist or until death, whichever occurs first. Subjects removed from 
treatment for unacceptable adverse events will be followed until resolution or stabilization 
of the adverse event. Subjects will be followed at monthly (every 28 +/- 3 days) visits for 
12 months from the time of initiation of treatment with enzalutamide plus GnRH agonist. 
Total treatment will be for up to 36 months. The frequency of the follow up visits will be at 
the discretion of the investigator up to 36 months.The duration of treatment with the study 
agent enazalutamide will be for the initial 6 months, and follow up on study will continue 
for an additional 6 months following completion of enzalutamide.  
4.7 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
Notify the Principal Investigator, and document the reason for study removal and the date 
the subject was removed in the Case Report Form. The subject should be followed-up 
per protocol.  
4.8 
Subject Replacement 
If a subject is withdrawn from the study prior to the initiation of radiation therapy for 
reasons other than AEs as outlined in tables 4.2.1 and 4.2.2, an additional subject may 
be added to the study.  


________________________________________________________________________ 
26 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures  with the exception of a bone scan, must be performed 
within - 56 days prior to registration unless otherwise stated. A bone scan must be 
performed within – 90 days prior to registration. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical and surgical history, history of infections 
5.1.3 Demographics 
Age, gender, race, ethnicity 
5.1.4 Review subject eligibility criteria 
5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.7 Performance status 
Performance status evaluated prior to study entry . 
5.1.8 Adverse event assessment 
Baseline adverse events will be assessed. See section 6 for Adverse Event 
monitoring and reporting. 
 
5.1.9 Hematology 
5.1.10 
Blood draw for baseline blood counts, serum chemistries, PSA, and 
 
testosterone: 
Complete blood count with automated or manual differential. Comprehensive 
metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT/SGPT, 
AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, 
bicarbonate), glucose, and total bilirubin. PSA. Serum total testosterone. 
5.1.11 
Tumor assessment and imaging 
5.1.12.1 
For patients with prostatic adenocarcinoma histologically 
confirmed prostatic adenocarcinoma, imaging assessment will include CT of the 
abdomen and pelvis OR pelvic MRI; PA/lateral chest x-ray OR chest CT; and 
bone scan. CT, MRI, and CXR must be performed within 56 days of enrollment. 
Bone scan must be performed within 90 days of enrollment. At enrollment, these 
subjects will undergo a research MRI of the prostate with TRUS-guided targeted 
prostate tumor biopsies. For patients who have not yet undergone CT 
abdomen/pelvis or MRI of the pelvis but are otherwise eligible for the trial, the 


________________________________________________________________________ 
27 
mandated research sequences from the prostate MRI may be obtained 
concurrently with the required standard of care MRI.  
5.1.12.2 
For subjects who have not yet undergone diagnostic prostate 
biopsies to confirm the presence of prostatic adenocarcinoma at the time of study 
enrollment, but who otherwise meet eligibility criteria (as defined in section 3.1.1: 
serum PSA > 20 ng/dL and/or clinical T3 disease by digital rectal exam), 
standard of care diagnostic and research biopsies of the prostate will be 
performed simultaneously under ultrasound guidance. Subjects will undergo MRI 
of the pelvis, bone scan, and CXR (PA and lateral)or chest CT at enrollment. MRI 
of the pelvis must be performed prior to prostate biopsy. 
 
 
 
5.2 
Procedures During Treatment 
Subjects will receive treatment in the following phases:  
o 
Neo-adjuvant: Subjects will receive treatment with enzalutamide plus GnRH agonist 
for 8-10 weeks prior to the initiation of EBRT 
o 
Concurrent: Subjects will continue to receive treatment with enzalutamide plus GnRH 
agonist for the duration of EBRT (8-10 weeks) 
o 
Adjuvant: Subjects will receive treatment with enzalutamide plus GnRH agonist 
following completion of EBRT until a total duration of 24 weeks of enzalutamide plus 
GnRH agonist treatment has been completed 
o 
Maintenance: Subjects will continue to receive GnRH agonist therapy following 
completion of treatment with enzalutamide to achieve a total of 24 - 36 months of 
GnRH agonist treatment. 
o 
During the neo-adjuvant, concurrent, and adjuvant phases, subjects will receive 
treatment with enzalutamide plus GnRH agonist therapy for six 28 day cycles for a 
total duration of 24 weeks. 
5.2.1 
Prior to Each Treatment Cycle During Neo-Adjuvant, Concurrent, and 
Adjuvant phases (weeks 1-24): 
 Physical exam, vital signs 
 Hematology 
 Serum chemistries 
 Toxicity evaluation 
5.2.2 
Day – 56 to – 14: 
 Procedure: 
o 
MRI pelvis  
o 
TRUS-guided prostate biopsies  
5.2.3 
Weeks 7-11 
 MRI pelvis 
 Fiducial marker placement and TRUS-guided targeted prostate biopsies 
5.2.4 
Every 4 weeks during weeks 28-48 of Maintenance Phase:  
 Physical exam, vital signs 
 Hematology 
 Chemistries 
 Toxicity evaluation 
5.2.5 
Every 8 weeks during weeks 1-48:  
 PSA, testosterone 


________________________________________________________________________ 
28 
5.3 
Follow-up Procedures 
Subjects will be followed every 4 weeks(+/- 3 days)  after completion of (or early 
withdrawal from) study treatment until 48 weeks (12 months) after initiation of 
enzalutamide plus GnRH agonist. Following completion of the study, subjects will 
continue with maintenance therapy with GnRH agonist for up to 36 months total 
treatment time as standard of care and will be monitored at the discretion of the treating 
provider according to standard of care. 
5.4 
Time and Events Table 
 
 
 
Pre-study 
Days -56 
to - 14 
Day 1 
Every 4 
weeks 
(weeks 4-
48)  
Every 8 
Weeks 
(weeks 
8-48) 
Weeks 8-
10 
End of 
study visit  
Assessment 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
History and PE 
X 
X 
X 
 
 
X 
Performance 
Status 
X 
X 
X 
 
 
X 
Toxicity 
Evaluations 
 
X 
X 
 
 
X 
CBC 
X 
X* 
X 
 
 
 
CMP 
X 
X* 
X 
 
 
 
PSA, 
testosterone 
X 
X* 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CXR PA/lateral or 
CT chest 
X 
 
 
 
 
 
Bone scan 
X# 
 
 
 
 
 
CT abd and 
pelvis 
x 
 
 
 
 
 
MRI pelvis 
X 
 
 
 
X 
 
TRUS-guided 
prostate biopsy 
X 
 
 
 
X 
 
 *These tests will be repeated at day 1 if the pre-screening tests were done greater than 28 days 
before Day 1. 
 
# Bone scan will be performed during pre-study days – 90 to – 14. 
5.5 
Removal of Subjects from Study 
Subjects  can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Subject voluntarily withdraws from treatment (follow-up permitted); 
5.5.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.5.3 
Subject is unable to comply with protocol requirements; 
5.5.4 
Subject demonstrates disease progression (unless continued treatment with 
study drug is deemed appropriate at the discretion of the investigator); 


________________________________________________________________________ 
29 
5.5.5 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.5.6 
Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.5.8 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.5.9 
Lost to follow-up. If a research subject cannot be located to document survival 
after a period of 12 months, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the 12 months must be documented and 
approved by the Data Monitoring Committee. 
6.0 
Measurement of Effect 
6.1 
Antitumor Effect- Solid Tumors 
 
Patients with high-risk localized or locally-advanced prostate cancer are eligible for 
enrollment in this study. Patients with high-risk localized prostate cancer by definition will 
not have measurable disease by RECIST. Patients also may have radiographic evidence 
of metastasis in regional lymph nodes (N1 disease as defined by the National 
Comprehensive Cancer Network Prostate Cancer Guideline Verson 3.2012) at the 
discretion of the treating physicians, if regional lymph nodes can be included in the 
planned radiation field. RECIST will not be used to monitor these regional lymph nodes 
for treatment response. Rather, in all patients, treatment response will be monitored by 
serum prostate specific antigen (PSA). The PSA nadir with EBRT combined with 
androgen deprivation therapy is known to vary. Following RTOG-ASTRO Phoenix 
Consensus, a PSA rise by 2 ng/mL or more above the nadir PSA is the standard 
definition for biochemical failure after EBRT with or without ADT. As the primary endpoint 
of this study is safety and tolerability as measured up to 12 months following initiation of 
combined enzalutamide and GnRH agonist therapy, it is expected that subjects will 
remain under treatment with maintenance GnRH agonist therapy at the completion of 
their time on study. Consequently, it is anticipated that subjects will not experience a PSA 
rise suggestive of disease progression as defined by RTOG-ASTRO Phoenix Consensus 
during the study enrollment period. Should subjects experience any PSA rise on 2 or 
more consecutive measurements while enrolled in the study, this will be considered 
evidence of disease progression. Subjects will undergo research MRI of the pelvis to 
quantify local response following 8 weeks of combined enzalutamide plus GnRH agonist 
treatment for research purposes.  
 
6.1.1 
Definitions 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of 
their first treatment with study drug. 
 
6.1.2 
Methods for Evaluation of Measurable Disease: Magnetic Resonance 
Imaging (MRI) of the prostate and pelvis 
6.1.2.1 Patient preparation 
The participants will undergo prostate MRI following the standard institutional 
procedure. If patients have had prostate biopsies, a minimum of 3 weeks is 
recommended between the date of the MRI exam and the previous biopsy to 
reduce the influence of post-biopsy changes in diagnostic accuracy.15 Patients 
will be asked to refrain from ejaculation for 3 days preceding the examination to 
maximize distention of the seminal vesicle.16 


________________________________________________________________________ 
30 
 
6.1.2.2 Image acquisition 
Patients will undergo an MR examination with our routine clinical protocol using a 
3T MRI system (Philips Medical Systems, Cleveland, OH) and a pelvic phased-
array coil. Endorectal coil will not be used. The patient is imaged in the supine 
position and artifacts due to bowel peristalsis are minimized with sublingual 
administration of 0.250 mg of hyoscyamine sulfate (Levsin). Our protocol 
includes T2-weighted fast spin-echo images in the transverse, sagittal, and 
coronal planes; axial diffusion-weighted transverse single shot echo planar image 
(with ADC map); T1-weighted gradient-echo images acquired before, during, and 
following the intravenous injection of a single dose of a gadolinium-based 
contrast as it is done for our clinical prostate MRI protocol. Additional pulse 
sequences such as arterial spin labeling (ASL), blood oxygen level dependent 
(BOLD), and others might be incorporated into the MRI protocol for additional 
research purposes; the total examination time will not exceed 1.5 hours and the 
amount of intravenous contrast administered will be similar to the dose given for 
clinical prostate MRI examinations. If at any point during the study the participant 
indicates a desire to withdraw, the exam will be interrupted. 
 
6.1.2.3 Potential risks associated with MRI 
Patients will be screened for MRI contraindications and these will be exclusion 
criteria for this study. Safety rules will be strictly enforced and followed by the 
research study team, MRI technologists, and the study subjects themselves. 
During the MRI scanning process, the study team is in constant two-way 
communication with the participant and can remove him from the magnet 
immediately as needed. The MRI personnel are trained to respond to emergency 
situations, further supported by an institutional Rapid Response Team should an 
adverse event arise during the study visit. Standard radiofrequency coils 
provided by manufacturers of MRI machines will be used in this study. The risks 
associated with the use of these coils are minimal.  However, with any RF coil, 
there is a small risk of skin burns if the coil is used improperly or is 
malfunctioning.  The MRI staff at UT Southwestern Medical Center is fully trained 
in the proper use of these devices. 
 
Subjects will be screened for renal impairment prior to administration of 
gadolinium-based contrast agents as it is routinely done in the Radiology 
Department at UT Southwestern. A serum creatinine determination within 30 
days prior to the research MRI examination must be available to calculate an 
estimated glomerular filtration rate (eGFR). An eGFR calculation may be 
repeated closer to the MRI appointment if the patient’s medical condition has 
changed. An eGFR ≥45 mL/min/1.73m2 is considered acceptable for 
administration of a standard weight-based dose of intravenous contrast for 
research purposes.17  
 
We do not anticipate significant psychological stress related to this study 
procedure.  Patients will be able to refuse to answer any of the questions, take a 
break or stop their participation in this study at any time. 
 
6.1.2.4 Image interpretation 
MR images will be interpreted by a single radiologist. The following criteria for 
tumor identification are widely accepted in the literature and are used in routine 
clinical practice: round or ill-defined, low-signal-intensity focus in the peripheral 
zone; or homogeneous signal mass with indistinct margins in the transition zone 
on T2-weighted imaging; high signal intensity on DWI and low ADC values when 
compared to the remainder of the prostate tissue.18 In addition, dynamic contrast-
enhanced images will be analyzed using a FDA-approved software for 


________________________________________________________________________ 
31 
pharmacokinetic evaluation (VividLook with Versavue Enterprise, iCAD, Nashua, 
NH). Suspicious areas for tumor are defined as those with increased relative 
peak enhancement and subsequent decrease in signal intensity—“rapid wash-in 
and wash-out pattern”). Color-coded map will be generated to highlight areas 
with high microvascular permeability and low to medium extracellular volume 
fraction.19  
 
6.1.2.5 MRI-US image fusion 
Anatomic co-registration of biopsy samples and MRI findings are essential in this 
proposal. Transrectal ultrasound images will be fused with initial MRI performed 
prior to therapy using a specialized device (UroStation; Koelis, Grenoble, 
France). This technology allows 3-dimensional anatomic co-registration of 
volumetric transrectal ultrasound (TRUS) and MRI acquisitions. Once the TRUS 
and MRI volumes are co-registered, the urologist can use the real-time fusion 
dataset to perform routine sextant biopsies and also target biopsies directly to the 
suspicious areas on MRI. Furthermore, this system allows for saving a 3D map of 
the prostate with the biopsy tracts of the needle biopsies and data from 
pathologic analysis, once it becomes available, can be loaded into the system for 
further analysis. Because these 3D maps can be loaded into the biopsy US unit 
prior to performing the follow-up biopsy after treatment, we will use this capability 
to facilitate the anatomic coregistration of the initial pre-treatment biopsies and 
the repeat biopsy performed after treatment.20  
 
6.1.2.6 Evaluation of changes in tumor volume and tumor activity 
Tumor volume will be assessed using a planimetric approach.21 On each MRI 
prostate section the outline of suspicious areas will be traced on the computer 
screen and the surface area will be calculated. After counting the number of 
separate foci and defining the most representative site of origin, tumor foci 
volume will be calculated by multiplying the sum of the suspicious surface areas 
by the slice thickness (usually 2-3 mm). 
 
Tumor activity will be assessed using apparent diffusion coefficient (ADC) 
derived from diffusion-weighted imaging, which has been shown to correlate with 
Gleason score and percentage of tumor on core biopsy (as surrogates for tumor 
aggressiveness).22,23 ADC values will be derived by drawing a region of interest 
on the confirmed tumors, and expressed as mean values and histograms. 
6.2 
Safety/tolerability 
 
 Analyses will be performed for all subjects having received at least one dose of study 
drug. The study will use the CTCAE version 4.0 for reporting of non-hematologic adverse 
events (http://ctep.cancer.gov/reporting/ctc.html) and modified criteria for hematologic 
adverse events . 
7.0 
ADVERSE EVENTS 
7.1 
Experimental Therapy 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 
7.1.1 
Contraindications: Enzalutamide is contraindicated in pregnancy. 
7.1.2 
Special Warnings and Precautions for Use: Seizure occurred in 0.9% of patients 
who received enzalutamide in a completed phase III trial. There is no clinical trial experience with 
enzalutamide in patients who have had a seizure, in patients with predisposing risk factors for 


________________________________________________________________________ 
32 
seizure, or in patients using concomitant medications that may lower the seizure threshold. 
Patients with a history of seizure or with predisposing risk factors for seizure are ineligible to 
participate in this study. 
7.1.3 
Interaction with other medications:  
In vitro studies show that enzalutamide and/or metabolite M2 are potential inhibitors of 
CYP2C8 and CYP2C19 with lesser potential for inhibitory effects on CYP2B6 and 
CYP2C9. Enzalutamide is a moderate CYP2C9 and CYP2C19 inducer in humans. For 
this study, substrates of CYP2B6, CYP2C8, CYP2C9, and CYP2C19 that have a narrow 
therapeutic index (e.g., paclitaxel, phenytoin, warfarin, omeprazole) are prohibited during 
the period of enzalutamide administration.  
 
In vitro studies show that enzalutamide is an inducer of CYP3A4. Induction of CYP3A 
occurs via activation of the nuclear pregnane X receptor (PXR), which is expected to 
result in co-induction of CYP2C. Co-administration of enzalutamide with CYP3A or 
CYP2C substrates may reduce oral bioavailability and/or accelerate elimination of these 
substrates. Enzalutamide is a strong CYP3A4 inducer in humans. For this study, narrow 
therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) 
are prohibited. 
 
In vitro studies show that enzalutamide is metabolized by CYP2C8 and CYP3A4/5. 
Strong inhibitors or inducers of these enzymes may affect enzalutamide exposures. Co-
administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area 
under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl 
enzalutamide in healthy volunteers. For this study, co-administration of enzalutamide and 
strong CYP2C8 inhibitors (e.g., gemfibrozil) is prohibited. Co-administration of a strong 
CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-
desmethyl enzalutamide by 1.3 fold in healthy volunteers. For this study, co-
administration of enzalutamide and strong inhibitors of CYP3A4/5 (e.g., clarithromycin, 
itraconazole, ketoconazole) are prohibited. 
 
Use caution when co-administering strong inducers of CYP2C8 (e.g., rifampin) or 
CYP3A4/5 (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) during 
enzalutamide treatment, as enzalutamide concentrations may decrease. 
 
In vitro studies show that enzalutamide and metabolite M2 are potential inhibitors of the 
efflux transporter P-gp. Co-administration of enzalutamide with P-gp substrates may 
increase the plasma concentrations of the P-gp substrate. Use caution when co-
administering sensitive P-gp substrates (e.g., colchicine, dabigatran etexilate, digoxin) 
during enzalutamide treatment. 
 
7.1.4 
Adverse Reactions 
 
The most common adverse reactions (>5%) reported in patients receiving enzalutamide 
in the completed randomized clinical trial, which included patients with metastatic castrate-
resistant prostate cancer who previously received docetaxel chemotherapy, included 
asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal 
pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower 
respiratory infection, spinal cord compression and cauda equine syndrome, hematuria, 
paresthesia, anxiety, and hypertension. Grade 3 and higher adverse reactions were reported 
among 47% of enzalutamide-treated patient and 53% of placebo-treated patients. 
 
PRES is a rare, reversible, neurological disorder which can present with rapidly evolving 
symptoms including seizure, headache, confusion, blindness, and other visual and neurological 


________________________________________________________________________ 
33 
disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation 
by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of enzalutamide 
in patients who develop PRES is recommended. Patients should be informed to contact the study 
physician as soon as possible if they experience rapidly worsening symptoms possibly indicative 
of PRES such as seizure, headache, confusion, reduced eye sight, or blurred vision. 
Three reported PRES cases include one clinical trial case assessed as unrelated to enzalutamide 
treatment and two post-marketing cases assessed as possibly associated with enzalutamide. 
One confirmed case of PRES, assessed as unrelated to enzalutamide, was reported in Study S-
3100-1-01 (first in man dose escalation study in castration-resistant prostate cancer patients). 
The onset of PRES symptoms occurred approximately 27 days after discontinuation of 
enzalutamide, and approximately 19 days after initiating treatment with an investigational insulin-
like growth factor (IGF) antibody (onset - 3 days after the second dose). PRES was likely 
associated with the investigational IGF antibody based on temporal relationship and positive 
dechallenge. 
Two post marketing cases of confirmed PRES were identified from the global safety database 
(estimated cumulative post marketing exposure of 17,704 patient treatment years as of 
30August2014). In the first case, reported symptoms (confusional syndrome and aphasia; 
symptom onset on treatment day 27) and MRI findings were consistent with a diagnosis of PRES. 
PRES was assessed as possibly associated with enzalutamide treatment in this case based on a 
plausible temporal relationship and the lack of an alternative etiology. The patient received acute 
treatment with intravenous corticosteroids. After discontinuing enzalutamide, reported symptoms 
resolved and a follow-up cerebral MRI revealed regression of abnormalities, indicative of positive 
dechallenge. In the second case, reported symptoms (altered mental status, confusion, and word-
finding difficulties; with a blood pressure of 188/97 mm Hg; symptom onset on treatment day 98) 
and MRI findings were consistent with a diagnosis of PRES. PRES was assessed as possibly 
associated with enzalutamide treatment in this case based on a plausible temporal relationship 
and the lack of an alternative etiology. The patient was treated with dexamethasone and an 
antihypertensive regimen of hydralazine and carvedilol. After discontinuing enzalutamide, 
reported symptoms resolved and follow-up cerebral MRI finding showed significant improvement, 
indicative of positive dechallenge. 
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial. Additionally, certain adverse events 
must be reported in an expedited manner to allow for optimal monitoring of subject safety 
and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study drug, 
will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
7.3 
Definitions 
7.3.1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a subject receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 


________________________________________________________________________ 
34 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.  
7.3.2 Severity of Adverse Events 
 
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The 
CTCAE v4 is available at http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
Life-threatening (grade 4): the subject was at risk of death at the time of the 
event. 
Fatal (grade 5): the event caused death. 
7.3.3 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 
Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
Is life-threatening. 
(the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were 
more severe). 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
Results in persistent or significant disability or incapacity. 
Is a congenital anomaly/birth defect 
Is an important medical event 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the subject, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
 


________________________________________________________________________ 
35 
7.3.4 
Unanticipated Problems: 
The term “unanticipated problem” is found, but not defined in the regulations for the 
Protection of Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. 
Guidance from the regulatory agencies considers unanticipated problems to include any 
incident, experience, or outcome that meets each of the following criteria: 
 
unexpected; and 
 
related or possibly related to participation in the research; and 
 
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
7.3.5 
Reporting 
Local events requiring expedited reporting, are submitted to the UTSW IRB through the 
UTSW eIRB and to the SCC DSMC Coordinator.  Hardcopies or electronic versions of 
the eIRB report; the NCI ADEERS, FDA Form #3500A forms, or other sponsor forms, if 
applicable; and/or any other supporting documentation available should be forwarded to 
the DSMC Coordinator.  The DSMC Coordinator forwards the information onto the DSMC 
Chairman who determines if immediate action is required.  Follow-up eIRB reports, and 
all subsequent SAE documentation that is available are also submitted to the DSMC 
Chair who determines if further action is required.    
  
The DSMC Chairperson reviews all serious adverse events within upon receipt from the 
DSMC Coordinator.  The DSMC Chairperson determines whether action is required and 
either takes action immediately, convenes a special DSMC session (physical or 
electronic), or defers the action until a regularly scheduled DSMC meeting.  
  
Telephone reports to: 
Kevin Courtney, MD, PhD at 214-648-4180 or Allison Beaver, RN at 214-645-8787 
 
UTSW SCC Data Safety Monitoring Committee Coordinator (if fax report is not 
available) within 1 working day to 214-648-7097. 
 
Written reports to: 
Kevin Courtney, MD, PhD, or Allison Beaver, RN at 214-645-8766 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-7018 or deliver to NB 2.418 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
1. 
Unexpected Adverse Events 
Non-serious adverse events which are classified as both unexpected (in terms of nature, 
severity and frequency) and possibly related require reporting to the UTSW IRB within 10 
working days of PI awareness.  


________________________________________________________________________ 
36 
2. 
SAEs 
i. Local unanticipated problems require expedited reporting, and are submitted to 
the UTSW IRB through the UTSW eIRB and to the SCC DSMC Coordinator.  
Hardcopies or electronic versions of the eIRB report; FDA Form #3500A forms, 
or other sponsor forms, if applicable; and/or any other supporting documentation 
available should be forwarded to the DSMC Coordinator.  The DSMC 
Coordinator forwards the information onto the DSMC Chairman who determines 
if immediate action is required.  Follow-up eIRB reports, and all subsequent SAE 
documentation that is available are also submitted to the DSMC Chair who 
determines if further action is required.    
 
ii. All local serious adverse events which occur on research subjects on protocols 
for which the SCC is the DSMC of record require reporting to the DSMC 
regardless of whether IRB reporting is required. Hardcopies or electronic 
versions of the FDA Form #3500A forms, or other sponsor forms, if applicable; 
and/or any other supporting documentation available should be forwarded to the 
DSMC Coordinator.   
 
iii. If the event occurs on a multi-institutional clinical trial coordinated by the Cancer 
Center, the DOT Manager or lead coordinator ensures that all participating sites 
are notified of the event and resulting action, according to FDA guidance for 
expedited reporting. DSMC Chairperson reviews all serious adverse events 
within upon receipt from the DSMC Coordinator.  The DSMC Chairperson 
determines whether action is required and either takes action immediately, 
convenes a special DSMC session (physical or electronic), or defers the action 
until a regularly scheduled DSMC meeting.  
 
 
Telephone reports to: 
Kevin Courtney, MD, PhD at 214-648-4180 or Allison Beaver at 214-645-8787 
 
UTSW SCC Data Safety Monitoring Committee Coordinator (if fax report is not 
available) within 1 working day to 214-648-7097. 
 
Written reports to: 
Fax – Kevin Courtney, MD, PhD or Allison Beaver, RN at 214-645-8766. 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-7018 or deliver to NB 2.418 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
 
3. 
Unanticipated Problems  
Unanticipated problems, including those that occur as non-local events, require reporting 
to the UTSW IRB within 10 working days of PI awareness of the event. 
For further guidance for Investigators regarding safety reporting requirements for INDs 
and BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM227351.pdf 
 


________________________________________________________________________ 
37 
7.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3:Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
Note:This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
 
the current known adverse events listed in the Agent Information Section of this 
protocol; 
 
the drug package insert; 
 
the current Investigator’s Brochure 
7.5 
Reporting Requirements for Adverse Events 
 
 
The FDA should be notified within 7 business days of any unexpected fatal 
or life-threatening adverse event with possible relationship to study drug, 
and 15 business days of any event that is considered: 1) serious, 2) 
unexpected, and 3) at least possibly related to study participation. 
 
INSERT PROPER REPORTING PROCEDURES REQUIRED BY SPONSOR  
 
Please email or fax the SAE Worksheet to:  
 
Astellas Pharma Global Development – United States 
 
Email: Safety-us@us.astellas.com 
 
Fax number: (847) 317-1241 
 
Follow-up information for the event should be sent promptly (within 7 days) as 
necessary. 
 
Full details of the SAE should also be recorded on the medical records and on 
the CRF. 
 
The following minimum information is required: 
 
ISN/Study number  
 
Subject number, sex and age 
 
The date of report 


________________________________________________________________________ 
38 
 
A description of the SAE (event, seriousness of the event) 
 
Causal relationship to the study drug 
 
The period for SAE reporting after the last intake of the study drug should be 
specified. 
 
Expedited Safety Reports: An unexpected adverse event is one for which the 
nature or severity is not consistent with the current Investigator’s Brochure. The 
Sponsor will make this assessment for all reported serious adverse events. An 
adverse event which is serious, related, and unexpected may be termed a 
Suspected Unexpected Serious Adverse Reaction (SUSAR). The Investigator will 
ensure that all relevant information is provided as soon as possible to Astellas in 
order that the Sponsor may meet their obligations to report any SUSAR.  
7.5.1 
Routine Reporting 
 
All other adverse events- such as those that are expected, or are unlikely or 
definitely not related to the study participation- are to be reported annually 
as part of regular data submission. 
7.6 
Unblinding Procedures 
This is an open-label study. Unblinding procedures will not be applicable. 
7.7 
Stopping Rules 
Based on experience from a completed phase III study, enzatlutamide is generally well 
tolerated when given in combination with a GnRH agonist. The most prominent safety 
concerns are primarily related to the risk of seizures. No completed study has examined 
the combination of enzalutamide with a GnRH agonist and concurrent radiation. The 
general tolerability of this combination is anticipated to be similar to that of radiation with 
concurrent GnRH agonist therapy. However, the absence of unexpected adverse events 
must be verified and is the primary endpoint of this study. Adverse events will be 
measured by NCI CTCAE criteria and will be monitored and recorded for a period of 12 
months from initiation of the combination of enzalutamide plus GnRH agonist. Enrollment 
in the trial will be halted if unacceptable levels of toxicity are found as defined by 3 or 
more patients withdrawing from the study due to AEs.  
8.0 
DRUG INFORMATION 
8.1 
Enzalutamide 
 
Other names for the drug: Xtandi, MDV3100 
 
 
Classification - type of agent: oral androgen receptor inhibitor 
 
 
Mode of action: inhibits androgen-induced receptor activation (binding of androgens 
to ARs in the cytosol), inhibits nuclear translocation of activated ARs, and inhibits the 
association of the activated AR with chromatin 
 
 
Storage and stability: Enzalutamide capsules should be stored at 20 C to 25 C (68 F 
to 77 F) in a dry place. Excursions are permitted from 15 C to 30 C (59 F to 86 F). 
 
 
Protocol dose: Subjects will take four 40 mg capsules (160 mg) daily.  Patients will be 
given one bottle of 120 capsules at every 4 week follow up visit. 
 
 
Route of administration for this study: oral 
 


________________________________________________________________________ 
39 
 
Availability: provided by sponsor free of charge  
 
 
Side effects: Adverse events associated with enzalutamide that are most likely to 
occur in this study include asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, 
peripheral edema, musculoskeletal pain, headache, upper respiratory infection, 
muscular weakness, dizziness, insomnia, lower respiratory infection, hematuria, 
paresthesia, anxiety, and hypertension. Please refer to the Xtandi (enzalutamide) 
package insert for a comprehensive list of adverse events. 
 
 
Nursing implications: 
 
8.2 
GnRH agonist – For the purposes of this study we are only using Lupron.  
Additonal GnRH agonists are listed below for informational purposes only. 
 
Description: GnRH agonists are long-acting analogs of the native GnRH peptide and are 
effective at reducing serum testosterone. Analogs approved by the FDA. 
 
Supply: Commercially available. 
 
Storage: GnRH analogs should be stored as directed by the commercial supplier. 
 
Administration: GnRH analogs are administered with a variety of techniques, including 
subcutaneous insertion of a solid plug in the abdominal wall (Zoladex), intramuscular injection 
(Lupron), subcutaneous injection (Eligard), or insertion of a long-acting cylinder that slowly 
Releases the agent (Viadur). The manufacturer’s instructions should be followed. 
 
Toxicity: Consult the package insert for comprehensive toxicity information. Class-related 
toxicity is generally a manifestation of the mechanism of action and due to low testosterone 
levels. In the majority of patients testosterone levels increased above baseline during the first 
week, declining thereafter to baseline levels or below by the end of the second week of 
treatment. The most common side effect of GnRH analogs is vasomotor hot flashes; edema, 
gynecomastia, bone pain, thrombosis, and gastrointestinal disturbances have occurred. 
Potential exacerbations of signs and symptoms during the first few weeks of treatment is a 
concern in patients with vertebral metastases and/or urinary obstruction or hematuria which, 
if aggravated, may lead to neurological problems such as temporary weakness and/or 
paresthesia of the lower limbs or worsening of urinary symptoms. Other side effects include 
impotence and loss of libido, weight gain, depression, dizziness, loss of bone density, 
anemia,increased thirst and urination, unusual taste in the mouth, skin redness or hives, pain 
at injection site, and muscle mass and strength loss, hair changes, penile length and 
testicular volume loss, increased cholesterol, hypertension, diabetes exacerbation, emotional 
lability,nausea, vomiting, and rarely allergic generalized rash and difficulty breathing.  
8.2.1 
Return and Retention of Study Drug 
Unused study drug (enzalutamide) will be documented and returned to the 
Simmons Comprehensive Cancer Center Pharmacy for destruction per Standard 
Operating Procedures 
 
8.2.2 
Subject compliance with the study agent, enzalutamide, will be monitored 
through use of a pill diary provided to each subject enrolled in the study. A new 
pill diary will be provided at every 4 week follow up visit for the duration of the 
administration of enzalutamide on the study.  
9.0 
CORRELATIVES/SPECIAL STUDIES 
 
The goal of the planned laboratory correlative studies is to evaluate the proposed mechanism of 
action of enzalutamide plus GnRH agonist on patient tumor samples. The proposed mechanism 
of action of enzalutamide has been established in pre-clinical studies. However, to date the 
molecular mechanism of action has not been reported in primary prostate cancer tumors from 


________________________________________________________________________ 
40 
patients. The purpose of the proposed laboratory correlative studies is to examine androgen 
signaling inhibition by enzalutamide in primary tumor samples from patients. Submission of 
samples for correlative studies is mandatory for participation in this trial. 
9.1 
Sample Collection Guidelines 
Up to 6 needle core biopsies will be collected using 18 gauge needles under TRUS-
guidance at each of two occasions as described in Section 4.4.2.2. Biopsies will be 
performed at study entry and following 8 weeks of treatment with combined enzalutamide 
plus GnRH agonist. Samples will be submitted to pathology laboratory for diagnosis and 
to UTSW tissue bank. Samples will be labeled with the subject’s de-identified study 
number and collection date and delivered for analysis to: 
Dr. Nima Sharifi, MD 
Cleveland Clinic and also to Dr. Payal Kapur and Dr. Yi Yin  at UT Southwestern 
Medical Center. 
 
9.2 
Assay Methodology 
9.2.1 
Immunohistochemistry for Androgen receptor (AR) and Ki-67 will be done using 
routine immunohistochemical assay in a CLIA certified clinical laboratory at UTSW. The 
slides will be analysed under a light microscope to access cellular localization of the 
antibody. Tissue procured for diagnosis will be processed using routine tissue processing 
protocols followed for pathologic diagnosis. 
 
 
9.2.2 
Gene expression studies  
Ligand-bound androgen receptor (AR) activity may be defined by the expression of 
androgen-responsive genes.  PSA, TMPRSS2 and FKBP5 are among the most widely 
studied and validated among these genes.24  RNA will be extracted from the collected 
prostate cancer tissue using the RNeasy system (Qiagen, Germantown, MD), and 1 μg 
RNA will be used in a reverse transcription reaction using the iScript cDNA Synthesis Kit 
(Bio-Rad, Hercules, CA).  Quantitative-PCR (qPCR) analysis will be performed in 
triplicate using previously published primers for PSA, TMPRSS2, FKBP5 and for the 
housekeeping gene large ribosomal protein P0 (RPLP0).25  Absolute qPCR SYBR Low 
Rox Mix (Fisher, Waltham, MA) will be used in 25 μl final reaction volume, in 96-well 
plates.  The thermocycling reaction will carried out in an ABI 7500 Real Time PCR 
machine (Applied Biosystems, Foster City, CA).  Accurate quantitation of each mRNA will 
be achieved by normalizing the sample values to RPLP0 and to vehicle treated cells. 
Samples will be labeled with the subject’s de-identified study number and collection date 
and delivered for gene expression analysis to  
 
Nima Sharifi, M.D. 
Kendrick Family Endowed Chair for Prostate Cancer Research 
Cleveland Clinic 
Lerner Research Institute 
Cancer Biology, NB40 
9500 Euclid Avenue 
Cleveland, OH 44195 
 
 
9.2.3 
Genomic sequence analysis of selected steroidogenic enzymes 
The first and rate-limiting step for metabolic flux from adrenal dehydroepiandrosterone 
(DHEA) to dihydrotestosterone (DHT) is catalyzed by 3β-hydroxysteroid 
dehydrogenase/isomerase, which is encoded by two isoenzymes, HSD3B1 and 
HSD3B2.26  Our unpublished observations suggest that genomic alterations of one or 
both of these genes may contribute to the development of resistance to various hormonal 
therapies in prostate cancer.  Genomic DNA will be prepared from collected samples 
(tumor and matched peripheral blood) using DNeasy Blood and Tissue Kit (QIAGEN, 


________________________________________________________________________ 
41 
Germantown, MD). PCR products of the promoter region, all exons, exon-intron junctions 
and the 3’-UTR will be sequenced to identify mutations in HSD3B1 and HSD3B2. The 
primers and annealing temperature were described previously.27 To sequence the 3’ 
flanking region of HSD3B1, primer set (Forward: 5’-ATGTGGAGGGAGGTGTGAGT-3’ 
and Reverse: 5’-ACGGAGATGGGTCTCTTCCA-3’) will be used with an annealing 
temperature of 62C. Genotyping PCR reaction (50 l) consisted of 30-100 ng genomic 
DNA, 1 x PCR buffer with 0.2 mM dNTP, 0.2 M of each primer, and 0.5 l Phusion High-
Fidelity DNA Polymerase (New England BioLabs Inc, Ipswich, MA).  Tumor and germline 
sequences will be compared in each individual patient to assess for somatically acquired 
mutations. Samples will be labeled with the subject’s de-identified study number and 
collection date and delivered for genomic sequence analysis to  
 
Nima Sharifi, M.D. 
Kendrick Family Endowed Chair for Prostate Cancer Research 
Cleveland Clinic 
Lerner Research Institute 
Cancer Biology, NB40 
9500 Euclid Avenue 
Cleveland, OH 44195 
 
9.3 
Specimen Banking 
The tissue used for diagnosis will be stored for 10 years in the CLIA certified clinical 
Pathology laboratory at UTSW. The tissue procured for research will be stored snap 
frozen in the UTSW tissue bank indefinitely or until used up. Serum and tissue may be 
used for future additional studies with specific consent from study subjects. If future use 
is denied or withdrawn by the subject, best efforts will be made to stop any additional 
studies and to destroy the specimens. 
 
The specimens, DNA, and their derivatives may have significant therapeutic or 
commercial value. The Informed Consent form contains this information and informs the 
subject that there is the potential for financial gain by UT Southwestern, the investigator, 
and the study sponsors Medivation, Inc. and Astellas Pharma US, Inc.  
 
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available: 
 
Diagnosis  
 
Collection time in relation to study treatment 
 
Clinical outcome – if available 
 
Demographic data 
10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 
This is an open-label, single-arm, single-center prospective pilot study of enzalutamide 
plus GnRH agonist treatment combined with EBRT in the treatment of men with high-risk 
localized or locally advanced prostate cancer. Select patients with regional lymph node 
involvement (N1 disease) are also eligible to participate in this study.  
 
Primary endpoint: to determine the safety and tolerability of combining enzlutamide plus a 
GnRH agonist with EBRT up to 12 months following initiation of treatment with 
enzalutamide plus GnRH agonist.  
 
Secondary endpoints: 
1. Molecular markers of androgen signaling and cell death in prostate biopsy samples 


________________________________________________________________________ 
42 
a. Inhibition of androgen-regulated gene expression (potential  targets to 
include NDRG1, FKBP5, TMPRSS2, and PSA) by qRT-PCR  
b. Inhibition of androgen receptor (AR) nuclear localization and enhancement 
of apoptotic cell death measured by immunohistochemistry (IHC) 
c. Androgen metabolism in prostate biopsy samples 
2. Serum PSA, testosterone, dehydroepiandrosterone (DHEA), and DHEA-sulfate 
(DHEA-S) following combination therapy with enzalutamide plus GnRH agonist 
therapy prior to initiation of radiation therapy 
3. Changes in prostate tumor volume and activity following 2 months of combined 
enzalutamide plus GnRH therapy compared to baseline as measured by multi-
parametric magnetic resonance imaging (MRI) 
 
The trial will be halted if unacceptable levels of toxicity are found as defined by 3 or more 
patients withdrawing from the study due to AEs or if 3 or more patients experience SAEs. 
 
10.2 
Sample Size and Accrual 
We propose to enroll ten subjects in this pilot study. The expected accrual rate is 7 
subjects over approximately 4 months. The primary endpoint is safety and tolerability of 
enzalutamide when combined with GnRH agonist and radiation therapy. Descriptive 
statistics will be computed to assess safety and tolerability. The highest AE score for 
each category over the 12 month period following initiation of treatment with 
enzalutamide plus GnRH agonist will be reported for each study subject in the summary 
statistics. Secondary endpoints assess mechanisms of enzalutamide plus GnRH action 
on prostate cancer tissue and quantitative imaging of localized prostate cancer response 
to enzalutamide plus GnRH therapy. As this is a pilot study, statistical power has not 
been calculated to determine the sample size, and descriptive statistics will be used to 
report outcomes.  
10.3 
Data Analyses Plans 
 
Primary endpoint: to determine the safety and tolerability of combining enzlutamide plus a 
GnRH agonist with EBRT up to 12 months following initiation of treatment with 
enzalutamide plus GnRH agonist. Data analysis plan: descriptive statistics to report the 
number and nature of AEs in all patients over 12 months. 
 
Secondary endpoints: 
1. Molecular markers of androgen signaling and cell death in prostate biopsy samples 
will be analyzed using descriptive statistics 
a. Inhibition of androgen-regulated gene expression (potential  targets to 
include NDRG1, FKBP5, TMPRSS2, and PSA) by qRT-PCR  
b. Inhibition of androgen receptor (AR) nuclear localization and enhancement 
of apoptotic cell death measured by immunohistochemistry (IHC) 
c. Androgen metabolism in prostate biopsy samples 
2. Serum PSA, testosterone, dehydroepiandrosterone (DHEA), and DHEA-sulfate 
(DHEA-S) following combination therapy with enzalutamide plus GnRH agonist 
therapy prior to initiation of radiation therapy will be reported using descriptive 
statistics for each patient. 
3. Changes in prostate tumor volume and activity following 2 months of combined 
enzalutamide plus GnRH therapy compared to baseline as measured by multi-
parametric magnetic resonance imaging (MRI) will be reported using descriptive 
statistics for each patient and summarized with mean change and standard deviation. 
 
 


________________________________________________________________________ 
43 
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the Conflict of Interest office.  All investigators will follow the 
University conflict of interest policy. 
 
11.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject  and by the person who conducted the 
informed consent discussion. 
11.2 
Registration Procedures  
All subjects must be registered with the Urology Research Office before enrollment to 
study. Prior to registration, eligibility criteria must be confirmed with the (Research Office) 
Study Coordinator. To register a subject, call 214-645-8787 Monday through Friday, 
9:00AM-5:00PM.  
11.3 
Data Management and Monitoring 
The UTSW Simmons Cancer Center (SCC) Data Safety Monitoring Committee (DSMC) 
is responsible for monitoring data quality and patient safety for all UTSW SCC clinical 
trials.  As part of that responsibility, the DSMC reviews all local serious adverse events in 
real time as they are reported and reviews adverse events on a quarterly basis.  The 
quality assurance activity for the Clinical Research Office provides for periodic auditing of 
clinical research documents to ensure data integrity and regulatory compliance.  
  
The SCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. 
11.4 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  


________________________________________________________________________ 
44 
11.4.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, an IRB modification form 
must be completed within five (5) business days of making the change. 
11.4.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the 
Principal Investigator and the IRB. According to the IRB, a protocol deviation is 
any unplanned variance from an IRB approved protocol that:  
 
Is generally noted or recognized after it occurs 
 
Has no substantive effect on the risks to research participants 
 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
 
Has harmed or increased the risk of harm to one or more research 
participants. 
 
Has damaged the scientific integrity of the data collected for the study. 
 
Results from willful or knowing misconduct on the part of the investigator(s). 
 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
11.5 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  When an amendment to the protocol 
substantially alters the study design or the potential risk to the patient, a revised consent 
form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
11.6 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 


________________________________________________________________________ 
45 
11.7 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
12.0 
REFERENCES 
 
1. 
Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen 
suppression and external irradiation in patients with locally advanced prostate cancer (an 
EORTC study): a phase III randomised trial. Lancet 2002;360:103-6. 
2. 
Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the 
treatment of prostate cancer. The New England journal of medicine 2009;360:2516-27. 
3. 
Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-
term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an 
EORTC randomised study. The lancet oncology 2010;11:1066-73. 
4. 
D'Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression 
and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA : the journal of the 
American Medical Association 2008;299:289-95. 
5. 
Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of radiation therapy oncology 
group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally 
advanced prostate cancer. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 2008;26:2497-504. 
6. 
Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive 
radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. International 
journal of radiation oncology, biology, physics 2005;61:1285-90. 
7. 
Souhami L, Bae K, Pilepich M, Sandler H. Impact of the duration of adjuvant hormonal 
therapy in patients with locally advanced prostate cancer treated with radiotherapy: a secondary 
analysis of RTOG 85-31. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 2009;27:2137-43. 
8. 
Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation 
therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet 2011;378:2104-
11. 
9. 
Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without 
radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase 
III trial. Lancet 2009;373:301-8. 
10. 
Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-
resistant prostate cancer: a phase 1-2 study. Lancet 2010;375:1437-46. 


________________________________________________________________________ 
46 
11. 
Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer 
after chemotherapy. The New England journal of medicine 2012;367:1187-97. 
12. 
Society AC. Cancer Facts & Figures 2012. In. Atlanta: American Cancer Society; 2012. 
13. 
Jung ME, Ouk S, Yoo D, et al. Structure-activity relationship for thiohydantoin androgen 
receptor antagonists for castration-resistant prostate cancer (CRPC). J Med Chem 2010;53:2779-
96. 
14. 
Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for 
treatment of advanced prostate cancer. Science 2009;324:787-90. 
15. 
Qayyum A, Coakley FV, Lu Y, et al. Organ-confined prostate cancer: effect of prior 
transrectal biopsy on endorectal MRI and MR spectroscopic imaging. AJR Am J Roentgenol 
2004;183:1079-83. 
16. 
Bloch BN, Lenkinski RE, Rofsky NM. The role of magnetic resonance imaging (MRI) in 
prostate cancer imaging and staging at 1.5 and 3 Tesla: the Beth Israel Deaconess Medical 
Center (BIDMC) approach. Cancer Biomark 2008;4:251-62. 
17. 
Wang Y, Alkasab TK, Narin O, et al. Incidence of nephrogenic systemic fibrosis after 
adoption of restrictive gadolinium-based contrast agent guidelines. Radiology 2011;260:105-11. 
18. 
Barentsz JO, Richenberg J, Clements R, et al. ESUR prostate MR guidelines 2012. Eur 
Radiol 2012;22:746-57. 
19. 
Hara N, Okuizumi M, Koike H, Kawaguchi M, Bilim V. Dynamic contrast-enhanced 
magnetic resonance imaging (DCE-MRI) is a useful modality for the precise detection and 
staging of early prostate cancer. Prostate 2005;62:140-7. 
20. 
Ukimura O, Hung AJ, Gill IS. Innovations in prostate biopsy strategies for active 
surveillance and focal therapy. Curr Opin Urol 2011;21:115-20. 
21. 
Villers A, Puech P, Mouton D, Leroy X, Ballereau C, Lemaitre L. Dynamic contrast 
enhanced, pelvic phased array magnetic resonance imaging of localized prostate cancer for 
predicting tumor volume: correlation with radical prostatectomy findings. J Urol 2006;176:2432-
7. 
22. 
Tamada T, Sone T, Jo Y, et al. Apparent diffusion coefficient values in peripheral and 
transition zones of the prostate: comparison between normal and malignant prostatic tissues and 
correlation with histologic grade. J Magn Reson Imaging 2008;28:720-6. 
23. 
Woodfield CA, Tung GA, Grand DJ, Pezzullo JA, Machan JT, Renzulli JF, 2nd. 
Diffusion-weighted MRI of peripheral zone prostate cancer: comparison of tumor apparent 
diffusion coefficient with Gleason score and percentage of tumor on core biopsy. AJR Am J 
Roentgenol 2010;194:W316-22. 
24. 
Mendiratta P, Mostaghel E, Guinney J, et al. Genomic strategy for targeting therapy in 
castration-resistant prostate cancer. J Clin Oncol 2009;27:2022-9. 
25. 
Evaul K, Li R, Papari-Zareei M, Auchus RJ, Sharifi N. 3beta-hydroxysteroid 
dehydrogenase is a possible pharmacological target in the treatment of castration-resistant 
prostate cancer. Endocrinology 2010;151:3514-20. 
26. 
Chang KH, Sharifi N. Prostate cancer-from steroid transformations to clinical translation. 
Nat Rev Urol 2012;9:721-4. 
27. 
Chang BL, Zheng SL, Hawkins GA, et al. Joint effect of HSD3B1 and HSD3B2 genes is 
associated with hereditary and sporadic prostate cancer susceptibility. Cancer Res 2002;62:1784-
9. 
 
 
 


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ICF_001.pdf: 
 
 
Page 1 of 16 
DO NOT DISCLOSE 
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Phase II study of enzalutamide (MDV3100) and gonadotropin-releasing hormone (GnRH) 
agonist before, during, and after radiation therapy in treatment of patients with high-risk 
localized prostate cancer 
 
 
NCT: NCT02064582 
 
Approved Date 8/18/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Page 2 of 16 
DO NOT DISCLOSE 
6-6-16 
The University of Texas Southwestern Medical Center  
Parkland Health & Hospital System 
Children’s Medical Center 
Retina Foundation of the Southwest 
Texas Scottish Rite Hospital for Children 
Texas Health Presbyterian Hospital Dallas 
 
CONSENT TO PARTICIPATE IN RESEARCH 
 
Title of Research: 
Phase II study of enzalutamide (MDV3100) and 
gonadotropin-releasing hormone (GnRH) agonist before, 
during and after radiation therapy in treatment of patients 
with high-risk localized prostate cancer 
 
Funding Agency/Sponsor: 
Sponsor- UTSouthwestern Medical Center 
 
Funding agency- Astellas Scientific and Medical Affairs, 
Inc.  
 
 
Study Doctors: 
Kevin Courtney, MD, PhD, Yull Arriaga, MD, Raquibul 
Hannan, MD, PhD,  
 
Michael Folkert, MD, Aaron Laine, MD, Neil Desai, MD 
 
 
You may call these study doctors or research personnel during regular office hours at 
214-645-8787.  At other times, you may call them at 214-645-4673. 
 
Instructions: 
Please read this consent form carefully and take your time making a decision about 
whether to participate.  As the researchers discuss this consent form with you, please ask 
him/her to explain any words or information that you do not clearly understand.  The 
purpose of the study, risks, inconveniences, discomforts, and other important information 
about the study are listed below.  If you decide to participate, you will be given a copy of 
this form to keep. 
 
Why is this study being done? 
The study is being done to find out whether combining the two FDA approved drugs 
enzalutamide (an androgen receptor blocker) and gonadotropin-releasing hormone 
agonist (GnRH agonist) along with radiation therapy for the treatment of prostate cancer 
is safe and well-tolerated. The combination of enzalutamide plus a GnRH agonist is a 
standard of care treatment option for patients with metastatic prostate cancer that no 
longer responds to treatment with a GnRH agonist alone. The combination of a GnRH 
agonist plus radiation therapy (with or without an older androgen receptor blocker drug) 
is a standard of care treatment option for patients with high-risk localized and locally 
advanced prostate cancer. The combination of all three (enzalutamide, GnRH agonist, 
and radiation therapy) has not been previously tested in patients with localized prostate 


 
 
Page 3 of 16 
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6-6-16 
cancer. It is possible that combining all three may provide more effective treatment for 
patients with high-risk localized or locally advanced prostate cancer.  At UTSW, we 
have decided to use Lupron® as the GnRH medication for the study purposes.   
 
Why is this considered research?  
This is a research study because these two drugs and radiation therapy have not been 
combined.  The researchers are interested in learning if this combination is safe and 
well-tolerated and possibly more effective in treating your condition/disorder.  
 
The following definitions may help you understand this study:  
 Standard medical care means the regular care you would receive from your 
personal doctor if you choose not to participate in this research. 
 Researchers means the study doctor and research personnel at the University of 
Texas Southwestern Medical Center at Dallas and its affiliated hospitals. 
 
Why am I being asked to take part in this research study? 
You are being asked to take part in this study because you have been diagnosed with 
high-risk localized or locally-advanced prostate cancer, OR you have physical 
examination findings (an abnormal prostate on a digital rectal examination) and findings 
from blood work (elevation in your PSA) that are concerning for the possibility that you 
may have high-risk localized or locally-advanced prostate cancer and warrant further 
evaluation by prostate biopsy.   
 
Do I have to take part in this research study? 
No.  You have the right to choose whether you want to take part in this research study.  
If you decide to participate and later change your mind, you are free to stop participation 
at any time. 
 
If you decide not to take part in this research study it will not change your legal rights or 
the quality of health care that you receive at this center. 
 
How many people will take part in this study? 
About 15 people will take part in this study at UT Southwestern. 
 
What is involved in the study? 
If you volunteer to take part in this research study, you will be asked to sign this consent 
form and will have the following tests and procedures.  Some of the procedures may be 
part of your standard medical care, but others are being done solely for the purpose of 
this study. 
 
 
 
Screening Procedures 
To help decide if you qualify to be in this study, the researchers will ask you 


 
 
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questions about your health, including medications you take and any surgical 
procedures you have had. The screening procedures could take from 30- 120 
minutes to complete.  The scans could be done on other days taking up to 2 hours to 
complete. 
 
You may also have to fill out certain forms or have the following exams, tests or 
procedures: 
 
 
Medical History 
 
Demographic information  
 
Review both eligibility criteria and other medications that you take 
 
Physical exam including vital signs, height and weight 
 
Questionnaire completion 
Blood tests – approximately 2 tablespoons of blood will be collected 
CT of the abdomen and pelvis  
Bone scan 
Chest x-ray or CT of the chest 
Pelvic MRI  
Prostate biopsies performed as standard of care and additional samples  for      
research purposes 
 
 
Study Medication/Intervention 
You will receive treatment with enzalutamide by mouth  plus Lupron ( the GnRH 
agonist) intramuscular ( into your muscle) for 8-10 weeks prior to starting your 
radiation therapy.   
 
During radiation therapy you will continue to receive the two medications for the 
duration of the radiation therapy.  This will be approximately 8-10 weeks. Each 
radiation visit could last from 30-120 minutes. 
 
After you have completed your radiation therapy you will continue to receive the two 
medications until you have reached a total of 24 weeks duration of the two 
medications.   
 
After you have completed the 24 weeks of the two drug combination you will 
continue to receive GnRH agonist therapy until you have reached 24-36 months of 
total GnRH agonist treatment. The decision to continue GnRH agonist treatment for 
a total of 24 vs 36 months will be at the discretion of your treating physician.   
 
Procedures and Evaluations during the Research 
One to two weeks prior to starting your treatment you will have a pelvic MRI and  
transrectal ultrasound (TRUS)-guided prostate biopsies. If you have not undergone 
previous prostate biopsies from which you have been diagnosed with high-risk 
prostate cancer, then both the standard diagnostic biopsies and research biopsies 


 
 
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will be performed at the same time. If you have previously undergone prostate 
biopsies and been diagnosed with high-risk prostate cancer, you will undergo an 
additional TRUS-guided biopsy procedure to obtain prostate tissue for research 
purposes.  This could take up to 2 hours to complete. 
 
Weeks 1-24 – prior to each cycle of enzalutamide and GnRH you will have the 
following tests done: 
 
 
Physical exam including vital signs 
Blood work – approximately 2 tablespoons of blood will be taken from a vein in 
your arm  
      This visit could take from 30 to 60 minutes. 
 
Week 8 – You will have magnetic resonance imaging (MRI) of your pelvis. For this 
procedure, you will lie quietly inside a large, doughnut-shaped magnet for about sixty  
minutes.  You will also have fiducial marker (gold seed) placement and TRUS-
guided targeted prostate biopsies.  This visit could take up to 120minutes to complete. 
 
Every 4 weeks after you have started taking enzalutamide you will have a physical 
exam with vital signs and blood drawn.  You will have approximately 2 tablespoons 
of blood drawn at each of these visits.  These visits can last from 30- 60 minutes. 
 
This table outlines your study visits: 
 
 
Pre-study 
Days -56 
to - 14 
Day 1 
Every 4 
weeks 
(weeks 4-
48)  
Week 8 
End of 
study visit  
Informed Consent 
X 
 
 
 
 
History and PE 
X 
X 
X 
 
X 
Performance 
Status 
X 
X 
X 
 
X 
Blood tests 
X 
X* 
X 
 
X 
CT abd/pelvis 
 
 
 
 
 
Chest X-ray or 
CT chest 
X 
 
 
 
 
Bone scan 
X 
 
 
 
 
MRI pelvis 
X 
 
 
X 
 
TRUS-guided 
prostate biopsy 
X 
 
 
X 
 
 *Blood tests will be repeated on day 1 if pre-screening blood work was done greater than 
28 days prior to day 1. 
 
The extra prostate biopsies and extra blood sample at the screening visit and two 
months on treatment in this study are designed for research, not for medical purposes.  
They are not useful for finding problems or diseases.  Even though the researchers are 
not looking at your research prostate biopsies and extra blood sample to find or treat a 


 
 
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medical problem, you will be told if they notice something unusual.  You and your 
regular doctor can decide together whether to follow up with more tests or treatment.  
Because the prostate biopsies and extra blood test done in this study are not for 
medical purposes, the research results will not be sent to you or to your regular doctor. 
The biopsies can take up to 120 minutes. 
 
Procedures for storing of extra or left over samples 
Some of your blood and prostate samples may be stored for future research.  These 
samples will have all identifying information removed including your name, date of 
birth, medical record number.  They will be labeled with a code that only the study 
staff will have access to.  These samples may be used for future research studies on 
prostate cancer or other diseases.   
 
How long can I expect to be in this study? 
You participation in this study may last up to 36 months.   
 
You can choose to stop participating for any reason at any time.  However, if you decide 
to stop participating in the study, we encourage you to tell the researchers.  You may be 
asked if you are willing to complete some study termination tests. 
 
What are the risks of the study? 
Study Procedure/Intervention 
Because of your participation in this study, you are at risk for the following side effects. 
You should discuss these with the researchers and your regular health care provider.  
 
Enzalutamide (MDV3100) may cause some, all or none of the side-effects listed below.  
 
You may experience side effects while on the study drug. Everyone taking part in the 
study will be watched carefully for any side effects.  However, doctors don't know all the 
side effects that may happen. Side effects may be mild or very serious. Your health care 
team may give you drugs to help lessen side effects. Side effects may go away soon 
after you stop taking study drug.  In some cases, side effects can be serious, long 
lasting, or may never go away.   
You should talk to your study doctor about any side effects that you may have while 
taking part in the study.   
In the Phase 3 study CRPC2, 800 patients were treated with enzalutamide 
(MDV3100)at a dose of 160 mg daily and 399 patients were treated with placebo (a 
substance that does not contain any active drug).  Side effects reported in at least 5% of 
enzalutamide (MDV3100)-treated patients and at a rate that was at least 2% higher than 
in placebo-treated patients included fatigue, diarrhea, hot flush, pain in muscles and 
bones, headache, trouble sleeping, anxiety, high blood pressure, and cold symptoms 
(congested nose and sore throat).  Other side effects reported in less than 5% of 
enzalutamide (MDV3100)-treated patients and at a higher rate than placebo-treated 


 
 
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patients included falls, dry skin, itchiness, thinking or memory problems, and 
hallucinations (seeing or feeling things that are not there).  Seizures (such as 
convulsions) have been infrequently reported in patients (less than 1% of patients) 
receiving enzalutamide (MDV3100) and not in placebo-treated patients.  Due to this 
potential risk of seizure, please inform your study doctor if you have ever had a 
condition that may increase the risk of seizures, such as prior history of seizure, brain 
injury, or brain tumor; stroke; or history of alcoholism.   
 
There are some medicines that are known to increase the chance of having a 
seizure.  These medicines include but are not limited to:  
• 
Aminophylline/theophylline 
• 
Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, 
ziprasidone) 
• 
Bupropion  
• 
Lithium 
• 
Meperidine (Demerol)  
• 
Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, , 
prochlorperazine, thioridazine) 
• 
Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, 
desipramine, doxepin, imipramine, maprotiline, mirtazapine) 
These medicines may increase your risk of developing seizures when used with 
enzalutimide  (MDV3100).  It is important for you to tell your study doctor all of the 
medicines you are taking.  
 
There have been rare reports of posterior reversible encephalopathy syndrome (PRES), 
a rare, reversible condition involving the brain, in patients treated with enzalutamide. If 
you have a seizure, worsening headache, confusion, blindness or other vision 
problems, please contact your doctor right away. Your doctor will stop enzalutamide if 
you develop PRES. 
 
In addition, some medicines may affect how enzalutamide (MDV3100) is broken down 
by your body.  Caution should be used when taking certain medicines or substances 
because they may increase the amount of enzalutamide (MDV3100) in your 
blood.  These include but are not limited to clarithromycin, gemfibrozil, grapefruit, 
itraconazole, and ketoconazole.  Also, caution should be used when taking certain 
medicines or substances because they may lower the amount of enzalutamide 
(MDV3100) in your blood.  These include but are not limited to carbamazepine, 
phenytoin, rifampin, and St. John’s wort. 
 
Because enzalutamide (MDV3100) blocks the action of the male sex hormone, it is 
expected to cause infertility and impotence and may contribute to loss of muscle and 
bone, hot flashes or breast growth. Because you can only be in this study if you are 
taking other drugs that decrease male sex hormones or have had a bilateral 
orchiectomy, you may or may not notice additional changes related to decreased male 


 
 
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sex hormone action after receiving enzalutamide (MDV3100).  Even though the risk of 
getting your partner pregnant while taking enzalutamide (MDV3100) is low, to 
participate in this study you must agree to utilize effective birth control methods to 
ensure that your partner does not become pregnant. 
Most men participating in this study may experience long term impotence due to the 
overall treatment for their prostate cancer.   
Possible risk and side effects related to the GnRH: 
Most Common (30% or more) 
• Hot flashes 
• Erectile Dysfunction 
• Feeling tired 
• Nausea 
Very Common (10% or more to less than 30%) 
• Constipation 
• Headache 
• Loss of appetite 
• Diarrhea 
• Dizziness 
• Skin rash, covering part or most of body 
• Joint pain 
• Increase in a type of fat in blood 
• Difficulty breathing during physical activity 
• Changes in electrocardiogram (QTc, length) 
• Hot flush 
• Bone or liver enzyme increased in blood 
• High blood sugar (glucose) 
• Dizziness 
• Protein in urine 
• Change in sense of taste 
• High blood pressure 
• Low white blood cells 
 
Patients receiving treatment with LHRH agonists should undergo periodic monitoring of 
blood glucose and/or glycosylated hemoglobin (HbA1c) for signs of developing diabetes 
or worsening of blood glucose control in patients with diabetes, and also for the signs 
and symptoms suggestive of the development of cardiovascular disease. 
 
MRI 
There are no known risks from exposure to magnetic fields.  You may experience 
nervousness and/or anxiety due to the loud banging made by the machine while it is 
taking pictures and from confinement in a tight space (claustrophobia). If you become 
anxious, you can stop the procedure at any time 
 


 
 
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You may also experience some discomfort and fatigue from lying still during imaging. 
 
If you have any metal clips or plates in your body, you should tell the investigator. 
MRI may not be appropriate if you are pregnant or are trying to become pregnant. MRI 
may not be appropriate if you have permanent eyeliner or eyebrows or any pieces of 
metal in your body, such as the following: 
 
 heart pacemaker, heart valve replacement, or aortic clips 
 metal fragments in your eyes, skin, or elsewhere in your body 
 brain clips or pieces of metal used in aneurysm surgery or intracranial 
bypass 
 venous umbrella 
 pieces of metal in the body resulting from work as a sheet-metal 
worker or welder 
 clips placed in an internal organ 
 prosthetic devices, such as middle ear, eye, joint, or penile implants 
 joint replacement. 
 hearing aid that cannot be removed 
 neurostimulator 
 insulin pump 
 intrauterine device (IUD) 
 shunts or stents 
 metal mesh or coil implants 
 metal plate, pin, screws, or wires, or any other metal implants  
 
You may receive a contrast agent that is FDA-approved and used routinely for MRI 
exams.  It contains a material called Gadolinium (dye solution used to highlight organs or 
tissues during imaging).  The injection of Gadolinium may cause discomfort like 
headache, nausea, strange taste, or coldness at site of injection.  These symptoms occur 
in less than 1 out of 20 patients receiving Gadolinium and go away quickly.   There is a 
small risk of a severe allergic reaction that can cause breathing difficulties and/or low 
blood pressure, and these symptoms are extremely rare (approximately 1 in 10,000 to 1 
in 100,000 administrations).  In the unlikely event you experience these symptoms, a 
physician and nursing staff will be available to evaluate and, if necessary, provide 
treatment.  
 
People with severe kidney failure who receive Gadolinium (dye solution used to highlight 
organs or tissues during imaging) are at risk of developing a disorder called Nephrogenic 
Systemic Fibrosis (NSF).  This disease can cause wide spread tissue scarring or 
hardening (fibrosis).  In rare cases NSF can lead to lung and heart problems and cause 
death.  If you have severe kidney failure and receive gadolinium, the risk of developing 
NSF is 1-5%.  We may perform a blood test 30 days before your MRI to check how well 
your kidneys are working before you receive the Gadolinium.  This test may be repeated 
closer to your MRI appointment if your medical condition has changed.  If your kidneys 


 
 
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are working at levels known to be at risk for NSF, you will not receive Gadolinium.  You 
will not receive Gadolinium for research purposes if you have sickle cell disease  (a 
disease of the blood cells) since it may put you at risk of developing hemolysis 
(breakdown of blood cells).  
 
Psychological Stress 
Some of the questions we will ask you as part of this study may make you feel 
uncomfortable.  You may refuse to answer any of the questions, take a break or stop 
your participation in this study at any time. 
 
Loss of Confidentiality 
Any time information is collected; there is a potential risk for loss of confidentiality.  
Every effort will be made to keep your information confidential; however, this cannot be 
guaranteed.  
 
Risks to Sperm, Embryo, Fetus or Breast-fed Infant 
Males: Being in this research may damage your sperm, which could cause harm to a 
child that you may father while on this study. If you take part in this study and are 
sexually active, you must agree to use a medically-acceptable form of birth control. 
Medically-acceptable forms of birth control include: 
(1) surgical sterilization (vasectomy), or 
(2) a condom used with a spermicide (a substance that kills sperm). 
 
 
______I agree to use medically acceptable birth control for 90 days after 
stopping Enzalutamide 
 
______ I do not agree to use medically acceptable birth control for 90 days after 
stopping Enzalutamide 
 
Risks of Radiation – Diagnostic Test 
The radiation dose that you will get from diagnostic tests is medically indicated for your 
condition and it is the same that you would get if you were not involved in this research 
study. 
 
Risks of Radiation – Radiation Therapy  
The radiation therapy used in this research is the standard radiation therapy for your 
health problem; therefore, the risk of harm to your body is the same.  Your radiation 
doctor will discuss the known risks of radiation therapy with you and ask you to sign a 
separate specific treatment site consent form. 
 
High-dose radiation treatments to or near a man’s testicles may produce harmful 
changes that could be passed on to children through a sperm. 
 
You must avoid fathering a child until ten weeks after the end of all radiation therapy.  


 
 
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After that period, there is much less risk of harmful changes to sperm.  Even then there 
is still an unknown amount of risk. 
 
Possible side effects of radiation therapy to the prostate include:  
Short Term effects: Inflammation of the bowel causing cramping and diarrhea; 
inflammation of the rectum and anus causing pain, spasm, discharge, bleeding; bladder 
inflammation causing burning, frequency, spasm, pain, and/or bleeding; skin changes:  
redness, irritation, scaliness, blistering or ulceration, coloration, thickening, hair loss; 
depression of blood counts leading to increased risk of infection and/or bleeding. 
 
Long Term effects:  bowel damage causing narrowing or adhesions of the bowel with 
obstruction, ulceration, bleeding, chronic diarrhea, or poor absorption of food elements 
and may require surgical correction or colostomy; bladder damage with loss of capacity, 
frequency of urination, blood in urine, recurrent urinary tract infections, pain, or spasm 
which may require urinary diversion and/or removal of the bladder; changes in skin 
texture and/or coloration, permanent hair loss, and scarring of skin; bone damager 
leading to fractures; testicular damage causing reduced sperm counts, infertility, 
sterility, or risk of birth defects; impotence (loss of erection) or sexual dysfunction; 
swelling of the genitalia or legs; nerve damage causing pain, loss of strength or feeling 
in legs, and/or loss of control of bladder or rectum; fistula between the bowel and other 
organs.   
 
Prostate Ultrasound and Biopsy:  The transrectal ultrasound may be associated with 
discomfort and very rarely, rectal bleeding.  A transrectal ultrasound involves inserting a 
probe into the rectum.  The machine visualizes (allows the doctor to see) the rectum 
and prostate by sending high frequency sound waves (signals) from the probe and 
measuring the waves as they are reflected back, producing images on a screen. 
 
During the prostate biopsy procedure, up to twelve very small samples of tissue are 
withdrawn from the prostate through a needle.  You may feel a stinging sensation each 
time a sample is taken, but usually any soreness or discomfort quickly passes.  After the 
biopsy, you may experience minor bleeding in the urine or rectum, or blood-tinged 
ejaculate (the fluid released by the prostate during sexual intercourse).  There are also 
small risks of temporary inability to urinate or infection.  An antibiotic is prescribed by 
your doctor to prevent infection. 
 
Risks of Blood Drawing 
Risks associated with drawing blood from your arm include minimal discomfort and/or 
bruising.  Infection, excess bleeding, clotting, and/or fainting also are possible, although 
unlikely. 
 
You will have 30 tablespoons of blood collected because you are in this research study. 
 
Other Risks 
There may possibly be other side effects that are unknown at this time. If you are 


 
 
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concerned about other, unknown side effects, please discuss this with the researchers. 
 
How will risks be minimized or prevented?   
You will be monitored periodically during the study through study visits to make sure 
that you are doing well.  If you have any problems, you can contact the study staff at the 
numbers on the front of this form.   
 
What will my responsibilities be during the study?   
While you are part of this study, the researchers will follow you closely to determine 
whether there are problems that need medical care.  It is your responsibility to do the 
following: 
 Ask questions about anything you do not understand. 
 Keep your appointments. 
 Follow the researchers’ instructions. 
 Let the researchers know if your telephone number or address changes. 
 Store study materials (tablets) in a secure place at home away from anyone who 
is unable to read and understand labels, especially children. 
 Tell the researchers before you take any new medication, even if it is prescribed 
by another doctor for a different medical problem or something purchased over 
the counter. 
 Tell your regular doctor about your participation in this study. 
 Carry information about the research medication in your purse or wallet. 
 Report to the researchers any injury or illnesses while you are on study even if 
you do not think it is related.  
 
If I agree to take part in this research study, will I be told of any new risks that 
may be found during the course of the study? 
Yes.  You will be told if any new information becomes available during the study that 
could cause you to change your mind about continuing to participate or that is important 
to your health or safety. 
 
What should I do if I think I am having problems? 
If you have unusual symptoms, pain, or any other problems while you are in the study, 
you should report them to the researchers right away.  Telephone numbers where they 
can be reached are listed on the first page of this consent form. 
 
If you have a sudden, serious problem, like difficulty breathing or severe pain, go to the 
nearest hospital emergency room, or call 911 (or the correct emergency telephone 
number in your area).  Tell emergency personnel about any medications you are taking, 
including any medications you are taking for this study.   
 
What are the possible benefits of this study? 
If you agree to take part in this study, there may or may not be direct benefits to you.  
The researchers cannot guarantee that you will benefit from participation in this 


 
 
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research. 
 
We hope the information learned from this study will benefit others with high-risk 
localized or locally advanced prostate cancer in the future.  Information gained from this 
research could lead to better treatment.   
 
What options are available if I decide not to take part in this research study? 
You do not have to participate in this research to receive care for your medical problem. 
Instead of being in this study, you have other options.  Standard of care treatment may 
include, depending on evidence of pelvic nodal involvement and your overall clinical 
status, androgen deprivation therapy combined with radiation therapy OR in some cases 
a radical prostatectomy.  Taking part in another study may also be an option. You may 
also elect not to receive any treatment after discussing with your personal physician about 
these options. 
 
Please talk to the researchers or your personal doctor about these options.  
 
Will I be paid if I take part in this research study? 
No. You will not be paid to take part in this research study.  There are no funds 
available to pay for transportation to and from the research center, lost time away from 
work and other activities, lost wages, or child care expenses. 
 
The study will pay for your parking at UT Southwestern during study related visits.  The 
study staff will stamp your parking ticket that you are given by the valet so that you will 
not have to pay for the study visits.  Please present your parking ticket to the study staff 
when you come in for your appointment. 
 
Will my insurance provider or I be charged for the costs of any part of this 
research study? 
No. Neither you, nor your insurance provider, will be charged for anything done only for 
this research study (i.e., the extra blood draw, research biopsies) .  The enzalutamide 
being used in this study is being provided by the study sponsor so you will not have to 
pay for this medication.   
 
However, the standard medical care for your condition (care you would have received 
whether or not you were in this study) is your responsibility (or the responsibility of your 
insurance provider or governmental program).  You will be charged, in the standard 
manner, for any procedures performed for your standard medical care. 
 
The GnRH agonist in this study is considered to be standard of care so you or your 
insurance company will be responsible for the costs of this medication.   
 
What will happen if I am harmed as a result of taking part in this study? 
It is important that you report any illness or injury to the research team listed at the top 
of this form immediately. 


 
 
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Compensation for an injury resulting from your participation in this research is not 
available from the University of Texas Southwestern Medical Center. 
 
You retain your legal rights during your participation in this research 
 
Can I stop taking part in this research study? 
Yes.  If you decide to participate and later change your mind, you are free to stop taking 
part in the research study at any time. 
 
If you decide to stop taking part in this research study, it will not affect your relationship 
with the UT Southwestern staff or doctors.  Whether you participate or not will have no 
effect on your legal rights or the quality of your health care. 
 
If you are a medical student, fellow, faculty, or staff at the Medical Center, your status 
will not be affected in any way. 
 
Your doctor is a research investigator in this study.  He is interested in both your 
medical care and the conduct of this research study.  At any time, you may discuss your 
care with another doctor who is not part of this research study.  You do not have to take 
part in any research study offered by your doctor. 
 
If I agree to take part in this research study, can I be removed from the study 
without my consent? 
Yes.  The researchers may decide to take you off this study if: 
 Your medical problem remains unchanged or becomes worse. 
 The researchers believe that participation in the research is no longer safe for 
you. 
 The researchers believe that other treatment may be more helpful. 
 The sponsor or the FDA stops the research for the safety of the participants. 
 The sponsor cancels the research. 
 You are unable to keep appointments or to follow the researcher’s instructions. 
 
Will my information be kept confidential? 
Medical information collected during this study and the results of any test or procedure 
that may affect your medical care may be included in your medical record. The 
information included in your medical record will be available to health care providers 
and authorized persons including your insurance company. 
 
You should know that certain organizations that may look at and/or copy your medical 
records for research, quality assurance, and data analysis include: 
 
• 
Astellas Pharma 
• 
Representatives of government agencies, like the U.S. Food and Drug 


 
 
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Administration (FDA), involved in keeping research safe for people; and 
• 
The UT Southwestern Institutional Review Board.  
 
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. 
 
In addition to this consent form, you will be asked to sign an "Authorization for Use and 
Disclosure of Protected Health Information."  This authorization will give more details 
about how your information will be used for this research study, and who may see 
and/or get copies of your information. 
 
Are there procedures I should follow after stopping participation in this research? 
Yes.  If you, the researchers, or the sponsor stops your participation in the research, 
you may be asked to do the following: 
 
 Let the researchers know immediately that you wish to withdraw from the 
research. 
 Return to the research center for tests that may be needed for your safety. 
 Return any unused study materials, including empty containers. 
 Discuss your future medical care, if any, with the researchers and/or your 
personal doctor. 
 
Is there anything else I should know before I decide? 
Drs. Margulis and Raj have financial interests in the company sponsoring this study.  
You should feel free to ask questions about this.   
 
Whom do I call if I have questions or problems? 
For questions about the study, contact Dr. Courtney at 214-645-8787 during regular 
business hours and at 214-645-4673 after hours and on weekends and holidays.   
 
For questions about your rights as a research participant, contact the UT Southwestern 
Institutional Review Board (IRB) Office at 214-648-3060. 
 
SIGNATURES: 
 
YOU WILL BE GIVEN A COPY OF THIS CONSENT FORM TO KEEP. 
 
Your signature below certifies the following: 
 
 You have read (or been read) the information provided above. 
 You have received answers to all of your questions and have been told who to 
call if you have any more questions. 


 
 
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 You have freely decided to participate in this research. 
 You understand that you are not giving up any of your legal rights. 
 You understand that a copy of this signed consent document, information about 
this study, and the results of any test or procedure that may affect your medical 
care, may be included in your medical record.  Information in your medical 
record will be available to health care providers and authorized persons 
including your insurance company. 
 
 
 
 
____________________________________________ 
 
 
Name of Participant (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Participant 
Date 
Time 
 
____________________________________________ 
 
 
Name of Person Obtaining Consent (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Person Obtaining Consent 
Date 
Time 
 
Interpreter Statement: 
I have interpreted this consent form into a language understandable to the participant 
and the participant has agreed to participate as indicated by their signature on the 
associated short form. 
____________________________________________ 
 
 
Name of Interpreter (Printed) 
 
 
____________________________________________ 
________ 
_______ AM / PM 
Signature of Interpreter 
Date 
Time