Clinical trial NCT02508636
Conditions: Prostatic Neoplasms Pelvic Nodal
Sponsor: University of California, San Francisco
Start date: 2015-12-22; Completion date: 2020-08-31
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies the safety of giving enzalutamide with leuprolide acetate before and after radiation therapy and to see how well it works in treating patients with prostate cancer that is at high risk of returning. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Most types of prostate cancer also need testosterone to grow and spread. After radiation therapy, patients often receive treatments to reduce testosterone to prevent the cancer from returning. Leuprolide acetate works by reducing the amount of testosterone that the body makes. Enzalutamide is a stronger treatment that may block testosterone from reaching cancer cells. Adding enzalutamide to treatment with leuprolide acetate after radiation therapy may help prevent high-risk prostate cancer from returning and improve patient survival.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the feasibility and safety of the combination of enzalutamide and leuprolide acetate (leuprolide) in patients undergoing definitive radiation therapy for high-risk prostate cancer or with pelvic nodal involvement.

II. To determine the prostate-specific antigen (PSA) complete response rate with the combination of enzalutamide and leuprolide (PSA-complete response (CR) as determined by PSA nadir =\< 0.3) in patients undergoing radiation therapy for high-risk prostate cancer or pelvic nodal involvement.

SECONDARY OBJECTIVES:

I. To determine time to biochemical failure as determined by the American Society for Radiation Oncology (ASTRO) Phoenix definition of nadir + 2 ng/mL, local progression, regional progression, and distant metastases.

II. To determine time to clinical progression free survival III. To assess changes in PSA nadir and PSA and testosterone levels. IV. To assess changes in hemoglobin A1c (HbA1c), fasting glucose, fasting insulin and fasting lipid and cholesterol levels.

V. To document changes in quality of life outcomes.

EXPLORATORY OBJECTIVES:

I. To identify potential mutations and changes gene copy number associated with enzalutamide resistance in patients with high risk prostate cancer.

II. To identify gene expression patterns, splice variants, and gene signatures associated with enzalutamide treatment and enzalutamide resistance in patients with high risk prostate cancer.

III. To identify changes in the immune response with enzalutamide treatment.

OUTLINE:

Patients receive enzalutamide orally (PO) once daily (QD) and leuprolide acetate intramuscularly (IM) every 1, 3, 4, or 6 months for 24 months. Patients also undergo standard of care intensity-modulated radiation therapy (IMRT) 5 days per week for 5 weeks beginning at week 8, followed by optional brachytherapy. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 6 weeks, 3-4 months, 6, 12, 18, 24, and 36 months.

Arms: arm 1: Participants will receive Enzalutamide: 160 mg per day, to begin within 0-7 days of the date of the first Luteinizing Hormone-Releasing Hormone (LHRH) agonist administration for total duration of 24 months as well as a single Leuprolide 7.5mg injection every month; single 22.5 mg injection every 3 months; single 30mg injection every 4 months; single 45 mg injection every 6-months based on the manufacturer for a total of 24 months.

Radiation therapy should begin approximately 8 weeks (+/- 1 week) after the date of the first LHRH agonist/antagonist injection of hormone therapy is given and continue for a total of 5 weeks.
Interventions: intervention 1: Enzalutamide intervention 2: Leuprolide intervention 3: Intensity-Modulated Radiation Therapy
Intervention descriptions: intervention 1: Given orally intervention 2: Given via intramuscular injection intervention 3: A total dose of 45 Gy in 25 fractions of 1.8 Gy each.

Protocol documents:
Prot_SAP_000.pdf: 
Version 1.0 
02-18-2015
Version 2.0 
06-04-2015
Version 2.1 
08-28-2015
Version 2.2 
09-09-2015
Version 3.1 
02-16-2017
Version 3.2 
09-05-2017
Phase II Trial of Definitive Radiotherapy with 
Leuprolide and Enzalutamide in High Risk Prostate 
Cancer 
Protocol Number: CC #15558 
Study Drug: Enzalutamide 
Version Number: 3.2 
Version Date: 09-05-2017 
Principal Investigator (Sponsor-Investigator) 
Hao Nguyen, M.D., Ph.D.  
Department of Urologic Oncology 
University of California, San Francisco 
 
 
 
 
 
  
Co-Investigators 
Lawrence Fong, MD 
I. Chow Joe Hsu, MD
Statistician 
Li Zhang, Ph.D. 
Investigator Initiated Trial Supported by National Comprehensive Cancer Network (NCCN) 
Revision History 
NCT# 02508636


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Protocol Signature Page 
Protocol No.: 15558 
Version Date: 09-05-2017 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review
Committee (PRC), Committee on Human Research (CHR), and Data Safety
Monitoring Committee (DSMC).
2. I will conduct the study in accordance with applicable CHR requirements, Federal
regulations, and state and local laws to maintain the protection of the rights and
welfare of study participants.
3. I certify that I, and the study staff, have received the requisite training to conduct
this research protocol.
4. I have read and understand the information in the Investigators’ Brochure (or
Manufacturer’s Brochure) regarding the risks and potential benefits. I agree to
conduct the protocol in accordance with Good Clinical Practices (ICH-GCP), the
applicable ethical principles, the Statement of Investigator (Form FDA 1572), and
with local regulatory requirements. In accordance with the FDA Modernization
Act, I will ensure the registration of the trial on the www.clinicaltrials.gov website.
5. I agree to maintain adequate and accurate records in accordance with CHR
policies, Federal, state and local laws and regulations.
UCSF Principal Investigator / Study Chair 
Printed Name 
Signature 
Date 
Participating Site(s): To be determined 
Principal Investigator 
Site 
Printed Name 
Signature 
Date 


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Phase II – Enzalutamide and Radiation 
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Abstract 
Title 
Phase II Trial of Definitive Radiotherapy with Leuprolide and Enzalutamide 
in High Risk Prostate Cancer 
Patient 
population 
53 Patients with high-risk, localized prostate cancer as defined by: 
1) Histologically confirmed diagnosis of adenocarcinoma of the
prostate within 180 days prior to registration at very high risk of
recurrence as determined by 2 or more of the following
combinations:
a) cT3a/b
b) PSA ≥20
c)
Gleason score 8-10
d) ≥33% core involvement
OR 
any patient with pelvic lymph node involvement ≥ 1 cm as determined 
by pelvic CT or MRI imaging will meet eligibility criteria for enrollment. 
Rationale for 
Study 
Long-term androgen deprivation therapy consisting of a LHRH agonist, with 
or without the addition of an anti-androgen, with radiation therapy improves 
the survival of patients with high risk prostate cancer.1, 2    Enzalutamide is a 
potent anti-androgen with at least 9-fold higher binding affinity than other 
anti-androgens such as bicalutamide. Thus, more profound androgen 
deprivation therapy with the addition of enzalutamide to LHRH agonist 
therapy may improve the clinical outcomes of patients. The primary 
objective is to assess the safety, tolerability, and feasibility of the addition of 
enzalutamide to LHRH agonist therapy in patients with very high-risk 
prostate cancer or pelvic node positive disease receiving radiation therapy. 
Also, the potential efficacy of enzalutamide and leuprolide in combination 
with radiation therapy for improving the PSA complete response will be 
assessed. 
Primary 
Objective 
1) To determine the feasibility and safety of the combination of
enzalutamide and leuprolide in patients undergoing definitive radiation
therapy for high-risk prostate cancer or with pelvic nodal involvement.
2) To determine the PSA complete response rate with the combination of
enzalutamide and leuprolide (PSA-CR as determined by PSA nadir ≤0.3) in
patients undergoing radiation therapy for high-risk prostate cancer or pelvic
nodal involvement.


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Secondary 
Objectives 
1)  To determine time to biochemical failure as determined by the ASTRO 
Phoenix definition of nadir + 2 ng/mL, local progression, regional 
progression, and distant metastases. 
2)  To determine time to clinical progression free survival 
3)  To assess PSA nadir and PSA and testosterone levels at 3-4, 6, 12, 
and 24 months. 
4)  To assess changes in HbA1c, fasting glucose, fasting insulin and 
fasting lipid and cholesterol levels. 
5)  To document changes in quality of life outcomes. 
Correlative 
Objectives 
1) To identify potential mutations and changes gene copy number 
associated with enzalutamide resistance in patients with high risk prostate 
cancer. 
2) To identify gene expression patterns, splice variants, and gene 
signatures associated with enzalutamide treatment and enzalutamide 
resistance in patients with high risk prostate cancer. 
3) To identify changes in the immune response with enzalutamide 
treatment. 
Study Design 
 
Phase II study to evaluate the safety, toxicity, and feasibility of the addition 
of enzalutamide to leuprolide in patients with high-risk prostate cancer or 
pelvic node positive disease receiving radiotherapy.  High-risk prostate 
cancer is defined as 2 or more of the following characteristics: 1) cT3a/b, 2) 
PSA ≥20 and <150, 3) Gleason 8-10, and 4) ≥33% core involvement. The 
proportion of patients obtaining a PSA complete response at day 120 will 
be determined. Safety will be assessed by the National Cancer Institute 
Common Terminology Criteria for Adverse Events v. 4.0 criteria 
Number of 
patients 
53 patients. Approximately 3 patients a month are expected to be accrued with a 
goal complete accrual by 24 months. 


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Duration of 
Therapy 
Patients will receive a total duration 24 months of androgen deprivation therapy 
including leuprolide and enzalutamide with radiation therapy. The initial phase of 
radiation therapy will be delivered Monday-Friday, except for holidays, for a total of 
15 treatment days. The boost phase (phase 2) of radiation therapy is one day for 
brachytherapy. 
Duration of 
Follow up 
Patients will be followed for up to 36 months after completion of radiation treatment 
Duration of 
study 
60 months 
Study 
Treatment 
Combined androgen blockade with leuprolide and enzalutamide will be 
administered with whole pelvic radiotherapy to a total dose of 45 Gy 
followed by brachytherapy boost. 
Safety 
Assessments 
Safety will be assessed through a summary of adverse events evaluated by 
NCI CTCAE v. 4.0. 


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List of Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
AUC 
area under the curve 
CBC 
complete blood cell (count) 
CHR 
Committee on Human Research (UCSF IRB) 
CR 
complete response 
CRC 
Clinical Research Coordinator 
CRF 
case report form 
CT 
computerized tomography 
CTCEA 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDFCCC 
Helen Diller Family Comprehensive Cancer Center 
HGB 
hemoglobin 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
IV 
intravenous 
LFT 
liver function test 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
PD 
disease progression 
PR 
partial response 
PRC 
PSA 
Protocol Review Committee (UCSF) 
Prostate Specific Antigen 
QOL 
Quality of Life 
SD 
stable disease 
SD 
standard deviation 
ULN 
upper limit of normal 


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Table of Contents 
 
Protocol Signature Page ................................................................................................. 2 
List of Abbreviations ........................................................................................................ 6 
Table of Contents ............................................................................................................ 7 
 
1 
B ackground: ......................................................................................................... 10 
1.1 
High-Risk Prostate Cancer ...................................................................... 10 
1.2 
Enzalutamide ........................................................................................... 10 
1.3 
Rationale of the Proposed Study ............................................................. 11 
1.4 
Rationale for Correlative Studies ............................................................ 11 
2 
Objectives of the Study ........................................................................................ 12 
2.1 
Primary .................................................................................................... 12 
2.2 
Secondary ................................................................................................ 12 
2.3 
Correlative Studies .................................................................................. 13 
2.4 
Endpoints ................................................................................................. 13 
2.4.1 
Primary Endpoint................................................................................. 13 
2.4.2 
Secondary Endpoints ........................................................................... 13 
2.4.3 
Correlative Science Endpoints............................................................. 14 
3 
Study Design........................................................................................................ 15 
3.1 
Characteristics ......................................................................................... 15 
3.2 
Number of Subjects ................................................................................. 16 
3.3 
Eligibility Criteria.................................................................................... 16 
3.3.1 
Inclusion Criteria ................................................................................. 16 
3.3.2 
Conditions for Patient Ineligibility ...................................................... 17 
3.4 
Discontinuation Criteria .......................................................................... 18 
3.5 
Criteria for Termination of Protocol ....................................................... 18 
3.6 
Duration of Therapy ................................................................................ 18 
3.7 
Duration of Follow up ............................................................................. 19 
3.8 
Study Timeline ........................................................................................ 19 
3.8.1 
Primary Completion ............................................................................ 19 
3.8.2 
Study Completion ................................................................................ 19 
4 
Radiation Therapy ................................................................................................ 19 
4.1 
Two Stage Radiation Plan ....................................................................... 19 
4.1.1 
Phase 1: Whole pelvis including prostate and seminal vesicles. ......... 19 
4.1.2.  Phase 2: Reduced volume to boost prostate and seminal vesicles ........ 20 
4.2 
Technical Factors .................................................................................... 20 
4.2.1 
IMRT Localization, Simulation, and Immobilization ......................... 20 
4.2.2 
Treatment Planning/Target Volumes................................................... 21 
4.2.3 
Target Volume for Step 2 .................................................................... 22 
4.2.4 
Target and Normal Critical Structures: ............................................... 23 
4.3 
Dose Specification/Technical Considerations: IMRT............................. 23 
4.4 
IMRT Treatment Verification ................................................................. 24 
4.5 
Dose Specifications/Technical Considerations: LDR Brachytherapy..... 24 


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Table of Contents 
 
4.6 
Dose Specifications/Technical Considerations: HDR Brachytherapy .... 25 
5 
Drug Therapy ....................................................................................................... 27 
5.1 
Dosage and Administration ..................................................................... 27 
5.1.1.................................................................................................................. 27 
5.1.1 
Leuprolide............................................................................................ 30 
6 
Study Procedures and Observations .................................................................... 31 
6.1 
Schedule of Procedures and Observations .............................................. 31 
6.1.1 
Pretreatment Period ............................................................................. 31 
6.1.2 
4-6 weeks after initiation of Androgen Deprivation Therapy ............. 32 
6.1.3 
8 weeks after initiation of Androgen Deprivation Therapy................. 33 
6.1.4 
Post-Treatment Assessment................................................................. 33 
6.1.5 
Discontinuation of Therapy ................................................................. 34 
6.2 
Usage of Concurrent/Concomitant Medications ..................................... 36 
7 
Reporting and Documentation of Results ............................................................. 36 
7.1 
Definitions ............................................................................................... 36 
7.2 
Evaluation of Safety ................................................................................ 36 
7.3 
Definitions of Adverse Events ................................................................ 36 
7.3.1 
Serious Adverse Event......................................................................... 36 
7.3.2 Adverse reaction .................................................................................. 37 
7.4 
Recording of an Adverse Event............................................................... 38 
7.5 
Follow-up of Adverse Events .................................................................. 39 
7.6 
Adverse Events Monitoring..................................................................... 39 
7.7 
Expedited Reporting................................................................................ 39 
8 
Tissue/Specimen Collection ................................................................................. 41 
8.1 
Specimen Collection Summary for Translational Research.................... 41 
8.1.1 
Plasma/Serum/Peripheral Blood Mononuclear Cell (PMBC) Banking41 
8.1.2 
Tumor biopsy....................................................................................... 41 
9 
Statistical Considerations and Evaluation of Results ............................................ 42 
9.1 
Study Design ........................................................................................... 42 
9.2 
Determination of Sample Size and Accrual Rate .................................... 42 
9.2.1 
Sample Size and Power Estimate ........................................................ 42 
9.2.2 
Accrual estimates................................................................................. 43 
9.3 
Interim Analyses and Stopping Rules ..................................................... 43 
9.4 
Analyses Plans......................................................................................... 43 
9.4.1 
Analysis Population ............................................................................. 43 
9.4.2 
Primary Analysis (or Analysis of Primary Endpoints) ........................ 43 
9.4.3 
Secondary Analysis (or Analysis of Secondary Endpoints) ................ 43 
10 
Study Management .............................................................................................. 44 
10.1 
Pre-study Documentation ........................................................................ 44 
10.2 
Institutional Review Board Approval...................................................... 44 
10.3 
Informed Consent .................................................................................... 44 
10.4 
Changes in the Protocol........................................................................... 44 


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Table of Contents 
 
10.5 
Handling and Documentation of Clinical Supplies ................................. 45 
10.6 
Case Report Forms (CRFs) ..................................................................... 45 
10.7 
Oversight and Monitoring Plan ............................................................... 46 
10.8 
Record Keeping and Record Retention ................................................... 46 
11 
Protection of Human Subjects .............................................................................. 47 
11.1 
Protection from Unnecessary Harm ........................................................ 47 
11.2 
Protection of Privacy ............................................................................... 47 
Appendices 
49 
Appendix 1 
Performance Status Criteria.................................................................. 49 
Appendix 2 
Data and Safety Monitoring Plan for Multicenter Institutional Study 
(Phase 2 or 3 Institutional Study) .......................................................... 50 
Appendix 3 
UCSF Policy/Procedure for Required Regulatory Documents for a 
UCSF Multicenter Investigator-Initiated Oncology Clinical Trials 
with an Investigator held Investigational New Drug (IND)...................... 53 
 
List of Tables 
Table 1:  IMRT Dose Objectives for Phase 1 – Pelvic and Prostate Radiation ................ 20 
 
Table 2:  Treatment Modalities and Prescription Dose for Phase 2 ................................. 20 
 
Table 3:  Target and Normal Critical Structures............................................................... 23 
 
Table 4:  Dose Specifications/Technical Considerations IMRT....................................... 23 
 
Table 5:  Adverse Reactions ............................................................................................. 28 
 
Table 6:  Schedule of Assessments ................................................................................... 35 


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1 Background: 
 
1.1 
High-Risk Prostate Cancer 
 
The majority of patients with lethal prostate cancer present with clinically localized high- 
risk disease and will experience disease recurrence as manifested by persistently 
elevated or increasing PSA levels after definitive radiation therapy.  Strategies to 
improve the outcome of these patients with high-risk disease are an unmet need. 
 
In patients with high-risk prostate cancer receiving radiation therapy, addition of 2-3 years 
of androgen deprivation therapy (ADT) is the standard of care based on phase III trials 
demonstrating an overall survival (OS) benefit.1, 2, 3   Five-year disease free survival (DFS) 
is approximately 50%. To improve outcomes, Radiation Therapy Oncology Group 
(RTOG) 9902 evaluated the role of adjuvant paclitaxel, estramustine, and etoposide 
(TEE) chemotherapy after combined androgen blockade with radiation therapy.  This 
study failed accrual due to toxicity and did not show clinical benefit with TEE.  Similarly, 
the GETUG-12 study evaluated the addition of docetaxel and estramustine to androgen 
suppression and radiation therapy in high-risk localized prostate cancer, but also did not 
show a significant benefit in the primary endpoint, progression free survival (PFS). Thus 
improvements in clinical outcome in patients with high-risk prostate cancer without 
added toxicity are an unmet need. 
 
Although long-term androgen deprivation therapy improved outcomes in patients with 
high-risk localized prostate cancer receiving radiation, no study has evaluated the 
efficacy of more profound androgen blockade with enzalutamide in the same setting. 
Greater androgen suppression improved clinical outcomes in patients with hormone- 
sensitive metastatic prostate cancer. In a large phase III study, patients were 
randomized to greater androgen suppression with the combination of flutamide and 
leuprolide or to leuprolide alone.  Combined androgen blockade with leuprolide and 
flutamide improved clinical response, PFS, and OS.4  The greatest benefit in OS was 
seen in patients with limited hormone-sensitive metastatic prostate cancer,4 which is the 
next step in progression after localized high-risk prostate cancer. Therefore, greater 
androgen blockade in patients with high-risk localized prostate cancer may also lead to 
improvements in clinical outcome. 
 
1.2 
Enzalutamide 
 
Enzalutamide is a non-steroidal androgen receptor (AR) inhibitor.  Enzalutamide inhibits 
the binding of androgens to the AR, inhibits the translocation of the AR to the nucleus, 
and inhibits AR mediated DNA binding.  Enzalutamide has high affinity binding to the AR 
with 9-fold greater affinity than bicalutamide.  Pre-clinical studies demonstrate that 
enzalutamide suppresses the proliferation of prostate cancer cells with AR gene 
amplification and can modulate the immune system to enhance immune recognition.5   In 
two phase III trials, enzalutamide was demonstrated to improve the overall survival in 
patients with castrate resistant prostate cancer when compared with placebo.6, 7 
Interestingly, a large proportion of patients experienced greater than 90% reduction in 
PSA level in these two phase III studies6, 7 when no further reductions were expected. 
 
Recently, enzalutamide was demonstrated to be active in men with hormone-naïve 
prostate cancer, with 92.5% of men experiencing a decline of ≥80% in PSA. 
Approximately 25% of patients in this study had undergone radiotherapy and treatment 
was well tolerated.8 


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In the current study, we propose to investigate the role of more profound androgen 
suppression with enzalutamide in combination with an LHRH agonist in patients with 
high-risk prostate cancer receiving radiation therapy.  Given the survival benefit with 
more profound androgen deprivation therapy in the hormone-sensitive setting along with 
the addition of 2-3 years of LHRH to radiation therapy, greater androgen blockade with 
the addition of enzalutamide to LHRH agonist therapy may provide an additional benefit 
in survival. 
 
Enzalutamide, as demonstrated in phase II and phase III trials, is well tolerated. Adverse 
events that may occur with enzalutamide include fatigue, diarrhea, musculoskeletal pain, 
and headache. Recently, a phase II trail demonstrated safety with the addition of 
enzalutamide in the adjuvant setting after radiation therapy.8   However, 
no study has been reported regarding the combination of enzalutamide with LHRH 
agonist and concurrent radiation. 
 
1.3 
Rationale of the Proposed Study 
 
Long-term androgen deprivation therapy consisting of a LHRH agonist, with or without the 
addition of an anti-androgen, with radiation therapy improves the survival of patients with 
high risk prostate cancer.1, 2    Enzalutamide is a potent anti-androgen with at least 9- fold 
higher binding affinity than other anti-androgens such as bicalutamide. Thus, more 
profound androgen deprivation therapy with the addition of enzalutamide to LHRH 
agonist therapy may improve the clinical outcomes of patients. The primary objective is 
to assess the safety, tolerability, and feasibility of the addition of enzalutamide to LHRH 
agonist therapy in patients with very high-risk prostate cancer or pelvic node positive 
disease receiving radiation therapy.  Also, the potential efficacy of enzalutamide and 
leuprolide in combination with radiation therapy for improving the PSA complete 
response will be assessed. We hypothesize that greater androgen blockade with 
addition of enzalutamide to LHRH agonist therapy will improve the PSA complete 
response and provide additional clinical benefit. The primary endpoint is to assess the 
impact of the addition of enzalutamide to LHRH agonist therapy in improving PSA 
complete response (PSA-CR) after radiation therapy. PSA-CR is defined as a PSA ≤0.3 
ng/mL. This metric has been validated as a predictor of clinical outcome including 
disease-specific survival, distant metastasis, and biochemical failure in two large studies 
(RTOG 9413, n=1070; MSKCC, n=1045).9, 10   In these studies, approximately 30% of 
patients failed to achieve a PSA-CR while on combined androgen blockade.  Failure to 
obtain a PSA-CR was associated with significantly worse disease-specific survival, 
worse disease-free survival, higher incidence of distant metastases, and increased 
biochemical failure.  Based on prior studies evaluating PSA response with enzalutamide, 
we would expect that addition of enzalutamide reduce the proportion of patients failing to 
achieve a PSA-CR to at least 0.15. 
 
1.4 
Rationale for Correlative Studies 
 
Mechanisms of enzalutamide resistance including AR gene amplification, truncation 
mutations, gain-of-function mutations, and glucocorticoid receptor overexpression have 
been shown in preclinical and mCRPC patient samples.  However, the mechanisms of 
enzalutamide resistance have not been extensively studied in patients with high-risk or 
pelvic node positive prostate cancer.  No study has evaluated the evolution of genetic 
alterations through primary treatment of prostate cancer.  Castration and enzalutamide 
resistant clones may be already present in the primary tumor in patients with very high- 
risk, localized disease, well before the development of metastatic disease. This is 
suggested by the lack of a PSA-CR in 30% of patients with high-risk disease on 


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androgen blockade. Further evidence comes from continued AR signaling despite 
combined androgen blockade in localized prostate cancer.  In the current proposal, 
mutational analysis and gene expression/gene splicing changes leading to enzalutamide 
resistance will be investigated in very high-risk or pelvic node positive prostate cancer. 
 
Recently, androgen deprivation has been shown to enhance the immune response to 
prostate cancer as testosterone may be immunosuppressive.  Androgen ablation in a 
mouse model reversed T-cell tolerance to a prostate restricted tumor antigen.  Also, 
surgical castration of mice undergoing vaccination with a prostate-specific antigen 
enhanced CD8 T-cell response.  Lastly, in patients with prostate cancer undergoing 
ADT, an increase in T-cell infiltration into the prostate was observed. Thus, testosterone 
may suppress T-cell response to tumor antigens. The mechanisms by which androgen 
blockade, especially with enzalutamide, regulate the immune system will be an 
exploratory objective in this proposal. 
 
In summary, the goal of the correlative studies is to identify changes associated with 
enzalutamide response and resistance in high-risk or node positive prostate cancer. 
Serial biopsies and blood collection will be obtained.  Genetic mutations, gene 
expression changes, and immune response will be evaluated from these biopsies and 
blood.  By integrating the information gained through serial assessment, a global view of 
the temporal changes within the tumor(s) is obtained. These analyses will provide 
insight into the mechanisms of enzalutamide resistance in the very high-risk and pelvic 
node positive setting.  Understanding the mechanisms of enzalutamide resistance in the 
very high-risk and node positive setting will facilitate the selection of patients benefitting 
from enzalutamide treatment and the development of effective treatment regimens for a 
personalized treatment approach. 
 
2 Objectives of the Study 
 
2.1 
Primary 
 
1.  To determine the feasibility and safety of the combination of enzalutamide and 
leuprolide in patients undergoing definitive radiation therapy for high-risk prostate 
cancer or with pelvic nodal involvement. 
 
2.  To determine the PSA complete response rate with the combination of 
enzalutamide and leuprolide (PSA-CR as determined by PSA nadir ≤0.3) in 
patients undergoing radiation therapy for high-risk prostate cancer or pelvic nodal 
involvement. 
 
2.2 
Secondary 
 
1.  To determine time to biochemical failure as determined by the ASTRO Phoenix 
definition of nadir + 2 ng/mL, local progression, regional progression, and distant 
metastases. 
 
2.  To determine time to clinical progression free survival 
 
3.  To assess PSA nadir and PSA and testosterone levels at 3-4, 6, 12, and 24 
months. 
 
4.  To assess changes in HbA1c, fasting glucose, fasting insulin and fasting lipid and 
cholesterol levels. 


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5.  To document changes in quality of life outcomes. 
 
2.3 
Correlative Studies 
 
1.  To identify potential mutations and changes gene copy number associated with 
enzalutamide resistance in patients with high risk prostate cancer. 
 
2.  To identify gene expression patterns, splice variants, and gene signatures 
associated with enzalutamide treatment and enzalutamide resistance in patients 
with high risk prostate cancer. 
 
3.  To identify changes in the immune response with enzalutamide treatment. 
 
2.4 
Endpoints 
 
2.4.1 
Primary Endpoint 
 
1.  The primary endpoint of the study is to determine the rate of acute toxicity (≤90 
days within the completion of radiotherapy) and late toxicity (≥91 days within the 
completion of radiotherapy).  Adverse events will be defined according to CTCAE 
v. 4.0 criteria.  Patients will be monitored at least weekly during treatment and 
every 3-6 months up to 24 months and at 36 months after radiation therapy. 
 
2.  A PSA measurement will be obtained at 120-127 days after initiation of androgen 
deprivation therapy. The proportion of patients achieving a PSA-CR (PSA nadir 
≤0.3) at 120-127 days will be determined. The historical proportion of patients 
(0.7) attaining a PSA-CR from RTOG 9413 will be utilized for comparison. 
 
2.4.2 
Secondary Endpoints 
 
1.  PSA and testosterone measurements will be made at 6 weeks and then at 3-4 
months, 6 months, 12 months, 18 months, 24 months, and at 36 months as part 
of standard of care. The time to biochemical failure will be defined from the date 
of randomization to the date of a rise by ≥2 ng/mL from the nadir PSA per the 
Phoenix Definition.  PSA nadir and PSA and testosterone levels will be 
documented at 4, 6, 12, and 24 months. 
 
2.  The time to local failure will be defined from the date of randomization to the date 
of biopsy proven recurrence within the prostate gland. 
 
3.  The date of regional or distant metastases will be defined as the date from 
randomization to the date of imaging or biopsy demonstrated evidence for 
recurrence in the pelvic lymph nodes (regional) or systemically.  Biopsy is not 
required to define regional or distant metastasis; however, in absence of rising 
PSA, biopsy is encouraged. 
 
4.  The time to clinical progression will be defined from the date of randomization to 
the date of PSA failure, local failure, regional or distant metastases.  Deaths prior 
to any of these events are treated as censoring for this endpoint. 
 
5.  Changes in HbA1c, fasting glucose, fasting insulin and fasting lipid and 
cholesterol levels will be assessed at 12 and 24 months during treatment. 
 
6.  Quality of life will be monitored.  Changes in patient reported quality of life would 
be measured by the Expanded Prostate Cancer Index Composite (EPIC). 


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Changes in fatigue from baseline to 1 year will be measured by PROMIS. 
Assessment of quality adjusted survival will be performed using the EQ-5D. 
 
2.4.3 
Correlative Science Endpoints 
 
1.  To identify mutations, insertions/deletions, and changes in gene copy number 
associated with enzalutamide treatment and resistance, whole exome 
sequencing will be performed on mapped biopsies pre-enzalutamide treatment, 
5-weeks post-initiation of enzalutamide therapy at the time of fiducial marker 
placement, and after 5 weeks of external radiotherapy.  Computational analysis 
of raw exome data will be performed.  Somatic point mutations and 
insertions/deletions nominated as clinically informative will be amplified and 
sequenced for validation. 
 
Reads from exome sequencing of tumor and patient-matched blood cells will be 
aligned to target capture regions, including exons, intron/exon boundaries, and 
many 5’ transcribed portions of promoter regions. Quality control and 
recalibration will be applied. To detect substitution mutations, we will use muTect 
(provided by K. Cibulskis/G. Getz, Broad Institute).  For insertion and deletion 
detection, PinDel will be employed.  Variant nucleotides will be merged and 
annotated with Annovar, followed by filtering, output, and reporting.  Variant 
frequencies will be compared across samples as an indirect measure of non- 
tumor cell contamination level and abundance of mutations within the tumor cell 
population.  Clinically informative mutations will be validated by Sanger 
sequencing. Tumor purity estimates from exome sequencing will be compared to 
estimates from tissue analyses.  Tumor phylogenies will be constructed from 
mutations and/or copy number changes in longitudinally collected samples to 
understand the clonal relationships between pre and post treatment tumor 
biopsies. 
 
2.  To identify changes in gene expression, splice variants, and expression 
signatures associated with enzalutamide treatment and resistance, gene 
expression profiling will be performed with the Affymetrix GeneChip Human 
Transcriptome Array 2.0 in collaboration with GenomeDx.  This array chip 
assesses the expression of over 1.4 million RNA features including ~22,000 
known protein-coding genes as well as many thousands of non-coding RNAs. 
This will allow us to examine relative gene expression, splice variants, and 
immune response signatures. 
 
Normalization and summarization of data will be performed using the SCAN 
Algorithm. Genes with at least a 2-fold difference in expression will be selected. 
All statistical analysis will be performed using the MultiExperiment Viewer. 
Principal component analysis will be performed by eigenvalue decomposition of 
the 3 principal components for tridimensional classification of the samples and an 
unsupervised hierarchical cluster by Pearson’s correlation will be selected to 
group the samples. The significance analysis of microarrays statistical technique 
will be performed for descriptive and comparative purposes. We will use the R 
package DESeq to perform differential gene expression analysis between 
response and nonresponse patients. We will use the R package GoSeq to 
perform over- and under-representation analysis (ORA) of gene sets taking 
length bias into account. 


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3.  Immune response signatures will be evaluated with the Affymetrix Gene Chip 
Array as described above.  In addition, to examine the effect on T cell subsets, T 
cell turnover and T cell diversity, peripheral blood will be collected at pre- 
enzalutamide treatment, 5-weeks post-initiation of enzalutamide therapy at the 
time of fiducial marker placement, after 5 weeks of external radiotherapy, and at 
4 months after completion of radiation therapy. T cell diversity will be performed 
using deep T Cell Receptor (TCR) sequencing and T cell turnover will be 
assessed by evaluating the number of TCR excision circles. 
 
3 Study Design 
 
 
 
3.1 
Characteristics 
 
This is a phase II study to evaluate the safety, toxicity, and feasibility of the addition of 
enzalutamide to leuprolide for a total duration of 24 months in patients with high-risk 
prostate cancer or pelvic node positive disease receiving radiotherapy.  High-risk 
prostate cancer is defined as 2 or more of the following characteristics: 1) cT3a/b, 2) 
PSA ≥20 and <150, 3) Gleason 8-10, and 4) ≥33% core involvement. 
 
Pre-Radiation Treatment 
 
To be eligible, patients must have biopsy proven prostate cancer.  MRI/US fusion-guided 
biopsy is encouraged, but not mandatory, of the dominant lesion(s), if available. 
Patients must also undergo serum PSA and testosterone measurement <45 days prior 
to biopsy or at least 18 days after biopsy. The serum PSA half life is 2.2 days, therefore 
any elevation due to biopsy or instrumentation of the prostate should resolve by 18 days 
(>5 half-lives).  Patients must undergo blood sample collection prior to initiation of 
androgen deprivation therapy.  All patients should complete the EPIC-26, PROMIS, and 
EQ-5D questionnaires prior to enrollment.  Enrollment will begin once standard staging 
including above studies are completed. 
 
4-6 wks after initiation of ADT 


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Patients will undergo repeat PSA and testosterone testing at 4-6 weeks after initiation of 
ADT.  Blood collection should be performed at the time of PSA and testosterone testing. 
Patients should undergo fiducial marker placement to optimize patient positioning and 
account for prostate motion for future radiation treatment.  During the fiducial marker 
procedure, a biopsy of the dominant lesion(s) will be obtained. The risks and discomfort 
of the limited biopsy are minimal as a needle is already being introduced under 
ultrasound guidance for fiducial marker placement as part of the standard of care. The 
biopsy should be mapped under MRI-guidance if available. 
 
At time of brachytherapy (if being performed) 
 
After 5 weeks of conventional whole pelvic radiotherapy, brachytherapy may be 
performed.  At the time of brachytherapy, a biopsy of the dominant lesion(s) will be 
performed.  The risks and discomfort of the limited biopsy are minimal as multiple 
catheters (larger in diameter) are already being introduced under ultrasound guidance 
into the prostate as part of the HDR procedure. Patients should complete the QOL 
questionnaires including EPIC-26, PROMIS, and EQ-5D. 
 
Post-Radiation Therapy 
 
Serum PSA and testosterone should be measured at each follow up visit as described. 
These follow-up visits should occur at 6 wks post-treatment, 3-4 months, 6 months, 12 
months, 18 months, 24 months, and at 36 months. 
 
Number of Subjects 
 
A total of 53 patients with high-risk prostate cancer or with pelvic nodal involvement 
without distant metastases will be enrolled. 
 
3.2 
Eligibility Criteria 
 
Patients must have baseline evaluations performed prior to the first dose of study drug 
and must meet all inclusion and exclusion criteria. In addition, the patient must be 
thoroughly informed about all aspects of the study, including the study visit schedule and 
required evaluations and all regulatory requirements for informed consent. The written 
informed consent must be obtained from the patient prior to enrollment. The following 
criteria apply to all patients enrolled onto the study unless otherwise specified. 
 
3.2.1 
Inclusion Criteria 
 
1.  Histologically confirmed diagnosis of adenocarcinoma of the prostate within 25 
weeks prior to registration at very high risk of recurrence as determined by 2 or 
more of the following combinations: 
 
• 
cT3a/b 
• 
PSA ≥20 
• 
Gleason score 8-10 
• 
≥33% core involvement 
 
OR 
 
any patient with pelvic lymph node involvement >1cm as determined by pelvic 
CT or MRI imaging will meet eligibility criteria for enrollment. 


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2.  Standard staging exams for patients with high-risk prostate cancer including 
bone scan or NaF PET/CT scan, and pelvic and prostate MRI. 
 
3.  No distant metastases (M0) on bone scan or NaF PET/CT within 14 weeks prior 
to registration.  Equivocal bone scan findings are allowed if the physician 
determines that distant metastases are unlikely based on clinical judgment. 
 
4.  Zubrod Performance Status 0-2 within 14 weeks prior to enrollment. 
 
5.  Age ≥18 
 
6.  CBC with differential obtained within 14 weeks prior to registration on study, 
with adequate bone marrow function defined as follows: 
 
a.  Absolute neutrophil count (ANC) ≥1,800 cells/mm3 
b.  Platelets ≥100,000 cells/mm3 
c.   Hemoglobin ≥8.0 g/dl (The use of transfusion or other intervention to achieve 
Hgb ≥ 8.0 g/dl is acceptable) 
d.  Serum creatinine <2.0 mg/dl and creatinine clearance >40 mL/min 
e.  Bilirubin <1.5 x ULN  
f.    ALT or AST <2 × ULN  
 
7.  Patients, even if surgically sterilized (i.e., status post vasectomy), who: 
 
a.  Agree to practice effective barrier contraception during the entire study 
treatment period and for 4 months (120 days) after the last dose of study 
drug, or 
b.  Agree to completely abstain from intercourse 
 
8.  Patient must be able to provide study-specific informed consent prior to study 
entry. 
 
3.2.2 
Conditions for Patient Ineligibility 
 
1)  Definite evidence of metastatic disease 
 
2)  Prior radical prostatectomy or bilateral orchiectomy for any reason 
 
3)  Prior invasive malignancy (except non-melanoma skin cancer) unless disease- 
free or not requiring systemic therapy for a minimum of 3 years. 
 
4)  Prior systemic chemotherapy for prostate cancer (Note that prior chemotherapy 
for a different cancer is allowed). 
 
4)  Prior radiotherapy, including brachytherapy, to the region of the prostate that 
would result in overlap of radiation therapy fields. 
 
5)  Previous hormonal therapy such as LHRH agonists (e.g. goserelin, leuprolide), 
anti-androgens (e.g. flutamide, bicalutamide), estrogens (e.g. DES), or surgical 
castration (orchiectomy) 


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6)  Known hypersensitivity to enzalutamide or related compounds 
 
7)  History of adrenal insufficiency 
 
8)  Patients who are sexually active and not willing/able to use medically acceptable 
forms of contraception; this exclusion is necessary because the treatment 
involved in this study may be significantly teratogenic. 
 
9)  Prior allergic reaction to the drugs involved in this protocol. 
 
11) Cushing’s syndrome 
 
12) Severe chronic renal disease (serum creatinine >2.0 mg/dl and confirmed by 
creatinine clearance <40 mL/minute) 
 
13) Chronic liver disease (bilirubin >1.5x ULN, ALT or AST >2x ULN) 
 
14) Active/Uncontrolled Viral Hepatitis 
 
15) Chronic treatment with glucocorticoids within one year. 
 
16) History of seizure including febrile seizure or any condition that may predispose 
to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with 
loss of consciousness requiring hospitalization). Also, current or prior treatment 
with antiepileptic medications for the treatment of seizures or history of loss of 
consciousness or transient ischemic attack within 12 months prior to 
randomization. 
 
17) Clinically significant cardiovascular disease including: 
a.  Myocardial infarction within 6 months prior to screening 
b.  Uncontrolled angina within 3 months prior to screening 
c.   Congestive heart failure NYHA class 3 or 4, or subjects with history of 
congestive heart failure NYHA class 3 or 4 in the past, unless a screening 
echocardiogram or MUGA scan performed within 3 months results in a 
left ventricular ejection fraction that is ≥45%; 
d.  History of clinically significant ventricular arrhythmias (e.g. ventricular 
tachycardia, ventricular fibrillation, torsades de pointes); 
e.  History of Mobitz II second degree or third degree heart block without a 
permanent pacemaker in place; 
f. Uncontrolled hypertension as indicated by a resting systolic blood 
pressure >170 mm Hg or diastolic blood pressure >105 mm Hg at 
screening.  Patients with initially elevated systolic blood pressure >170 
mm Hg or diastolic blood pressure >105 mm Hg are eligible if they 
undergo medical management and are re-screened. 
 
3.3 
Discontinuation Criteria 
 
If a patient decides to discontinue protocol treatment or progression of disease is 
detected, follow up and data collection will continue as specified in the protocol. 
 
3.4 
Criteria for Termination of Protocol 
 
The trial will be terminated if there is a greater than 12% clinically significant, treatment- 


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related grade 3 or higher toxicity.  The 12% clinically significant, treatment-related acute 
grade 3 or higher toxicity rate is acceptable as prior studies have demonstrated a 12% 
acute grade 3 GU and GI toxicity.  The use of a urinary catheter or bladder irrigation 
within 14 days after brachytherapy will not be considered grade 2 toxicity as this may be 
a standard procedure after brachytherapy. The trial will not be terminated for non-related 
or non-clinically significant toxicities. 
 
3.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue for 
up 24 months or until: 
 
• 
Disease progression 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
Significant patient non-compliance with the protocol 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
3.6 
Duration of Follow up 
 
After completion of radiation treatment, patients will be followed at 6 weeks, month 3-4, 
month 6, month 12, month 18, month 24, and at 36 months per standard of care. 
Patients removed from study for unacceptable treatment related adverse event(s) will be 
followed until resolution or stabilization of all treatment related adverse events to Grade 
2 or lower. 
 
3.7 
Study Timeline 
 
3.7.1 
Primary Completion 
 
Study accrual is to be completed by 24 months 
 
3.7.2 
Study Completion 
 
Study completion is projected approximately 60 months from the time the study is open 
to accrual. 
 
4 Radiation Therapy 
 
Radiation therapy should begin approximately 8 weeks (+/- 1 week) after the date of the 
first LHRH agonist/antagonist injection of hormone therapy is given. 
 
4.1 
Two Stage Radiation Plan 
 
4.1.1 
Phase 1: Whole pelvis including prostate and seminal vesicles. 
 
IMRT will be utilized for treatment delivery. 
 
Prescription Dose (See Table 1): 
 
45 Gy to cover 98% of PTV 
 
• 
Minimum dose within PTV – 95% of prescribed dose and for a volume 


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that is 0.03 cc. 
• 
Maximum dose within the PTV – 107% of prescribed dose and for a 
volume that is 0.03 cc. 
 
 
Table 1:  IMRT Dose Objectives for Phase 1 – Pelvic and Prostate Radiation 
 
PTV Dose 
(encompassing 
98% of PTV 
Minimum PTV 
dose for a point 
with a volume 
of 0.03 cc 
Maximum PTV 
dose to a 
volume of 0.03 
cc of PTV1 
(Per Protocol) 
Maximum PTV 
dose to a 
volume of 0.03 
cc of PTV1 
(Variation 
Acceptable) 
Maximum PTV 
dose to a 
volume of 0.03 
cc of PTV1 
(Deviation 
unacceptable) 
45 Gy 
42.8 Gy 
48.2 Gy 
>48.2 – 49.5 
Gy 
>49.5 Gy 
 
 
4.1.2.  Phase 2: Reduced volume to boost prostate and seminal vesicles 
 
Acceptable Treatment Modalities: IMRT, Stereotactic body radiotherapy, 
permanent prostate implant (PPI) brachytherapy or high-dose rate (HDR) 
brachytherapy 
 
Table 2:  Treatment Modalities and Prescription Dose for Phase 2 
 
Acceptable Treatment Modalities 
Prescription Dose 
Intensity-Modulated Radiotherapy 
34.2 Gy in 19 fractions of 1.8 Gy each 
Stereotactic Body Radiotherapy 
19 Gy in 2 fractions of 9.5 Gy each 
Permanent Prostate Seed Implant 
(PPI) 
• 
108 Gy for I-125 
• 
90 Gy for Pd-103 
HDR brachytherapy 
15 Gy in one fraction 
 
 
4.2 
Technical Factors 
 
For Phase I, IMRT is necessary to achieve conformality.   No specific field arrangement 
is required.   External beam radiotherapy will be delivered with megavoltage equipment 
at energies ≥6 MV. 
 
4.2.1 
IMRT Localization, Simulation, and Immobilization 
 
Simulation will be CT-based in all cases. A MRI is recommended to define the extent of 
disease and for delineation of the urethra. Rectal contrast is discouraged because it 
may distend the rectum and artificially displace the prostate in the anterior direction.  IV 
contrast is permitted to assist in identifying the pelvic vessels. Patients will be 
positioned supine on a flat tabletop with a customized thermoplastic immobilization 
cast or a 


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molded foam cradle 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 or 
adaptive treatments are not implemented). The rectum should be kept as empty as 
possible; consider an enema 1-2 hours prior to simulation. CT images should be 
acquired at a slice thickness of ≤3 mm from the top of the iliac crests superiorly to the 
perineum inferiorly. Target volumes and normal critical structures will be defined in 
the slices in which they are visualized. 
 
4.2.2 
Treatment Planning/Target Volumes 
 
4.2.2.1 Target Volume for Step 1 
 
The target volume (CTV1/PTV1) for step 1 will be the pelvic lymph node, which include 
the internal iliac, external iliac, obturator, and common iliac nodes, prostate, and seminal 
vesicles. The presacral nodes may be included if desired depending if dose constraints 
to the rectum are achievable.  Sentinel lymph node imaging may be utilized to guide 
target volume delineation of CTV1.  A total dose of 45 Gy in 25 fractions of 1.8 Gy each 
will be delivered to this volume with intensity modulated radiation therapy. 
 
4.2.2.2 Step 1 Pelvic Lymph Node Irradiation 
 
The Clinical Target Volume 1 (CTV1) will include the obturator, external iliac, proximal 
internal iliac and common iliac nodes, using the vascular structures, up to a level 
corresponding to the top of L4-L5.  Also included will be the prostate and seminal 
vesicles.  Please refer to the pelvic nodal atlas at the RTOG Web site (Pelvic Lymph 
Node Volumes for Prostate Cancer Atlas; 
http://www.rtog.org/atlases/PelvicLymphNodeProstateAtlas/main.html). 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). The CTV1 will extend superiorly 
from L4-L5 to 0.5 cm below the tip of the urethral contrast dye (if used) and no less than 
the entire prostate gland. 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 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. 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. In addition, sentinel lymph node imaging may be utilized to 
guide CTV1 target delineation. 
 
 
For patients with gross nodal involvement (cN1) as determined by CT or MRI, a 
sequential boost to 59.4 Gy in 9 fractions of 1.8 Gy each is allowed to the involved 
node(s). It is critical to maintain small bowel dose constraints as listed in Table 4 If 
bowel dose constraints are unable to be met, the gross nodal boost dose should be 
reduced to 57.6 Gy or 55.8 Gy to meet the small bowel dose constraint. The final dose 
should be recorded if a gross nodal boost dose is utilized. 
 
4.2.2.3 Planning Target Volume 1 (PTV1) 
 
The PTV1 will provide a margin around the CTV1 to compensate for the variability of 
treatment set up and internal organ motion. A 5-7 mm margin around the CTV is 
suggested to define each PTV1. Individual selection of a PTV margin should be based 


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on the physician’s level of confidence in patient set-up and the availability of image 
guidance.  Superior and inferior margins (capping) is suggested to be 5-7 mm 
depending on the thickness and spacing of the planning CT scan. Careful 
consideration should be made when defining the margin in 3 dimensions. 
 
4.2.3 
Target Volume for Step 2 
 
The target volume (CTV2/PTV2) for step 2 will be the prostate and seminal vesicle 
volume.  The radiation for step 2 may be delivered via IMRT, LDR, or HDR treatment.  If 
IMRT is used, the dose to CTV2/PTV2 will be 34.2 Gy in 19 fractions of 1.8 Gy each. If 
LDR brachytherapy is used, the dose will be 108 Gy for I-125 and 90 Gy for Pd-103.  For 
HDR brachytherapy implant, the dose will be 15 Gy in 1 fraction. 
The definition of GTV, CTV, and PTV will be in accordance with the ICRU Report #50: 
Prescribing, Recording, and Reporting Photon Beam Therapy. 
 
4.2.3.1 Step 2 Prostate +/- Proximal Seminal Vesicle 
 
Gross Target Volume:  Gross Target Volume (GTV2) is defined by the physician as all 
known disease as defined by the planning CT, MRI, urethrogram, and clinical 
information. If an 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.   
 Clinical Target Volume 1 (CTV2) will include the prostate +/- the proximal seminal 
vesicles (SV).   
Planning Target Volume:  The PTV2 margins should be a minimum of 0.2 cm and a 
maximum of 0.5 cm in all dimensions . 
Critical Structure: The bladder, rectum (from origin at rectosigmoid flexure superiorly or 
bottom of SI joints, whichever is more inferior to the inferior-most extent of the ischial 
tuberosities, urethra, and bowel, bilateral femora (to the level of ischial tuberosity), penile 
bulb, and skin should be defined on the treatment planning scan. 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. 
 
 
4.2.4 
Target and Normal Critical Structures: 
 
Will be defined as above for Phase I. 
 
 
Table 3: Target and Normal Critical Structures 
 
Standard Name 
Description 
GTV 
Gross Target Volume 
CTV1 
Clinical Target Volume 1 – obturator, external iliac, proximal 
internal iliac and common iliac nodes, +/- presacral lymph nodes, 
prostate + seminal vesicles 
CTV2 
Clinical Target Volume 2 - prostate + seminal vesicles 
PTV1 
Planning Target Volume 1 
PTV2 
Planning Target Volume 2 
BLADDER 
Bladder 
FEMUR_LT 
Left Femoral Head 
FEMUR_RT 
Right Femoral Head 
PENILE_BULB 
Penile Bulb 


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RECTUM 
Rectum 
SKIN 
External patient Contour 
 
 
4.3 
Dose Specification/Technical Considerations: IMRT 
 
Table 4:  Dose Specifications/Technical Considerations IMRT 
 
Normal Organ 
No More than 
15% volume 
receives dose 
that exceeds 
No more than 
25% volume 
receives dose 
that exceeds 
No more than 
35% volume 
receives dose 
that exceeds 
No more than 
50% volume 
receives dose 
that exceeds 
Bladder 
80 Gy 
75 Gy 
70 Gy 
65 Gy 
Rectum 
75 Gy 
70 Gy 
65 Gy 
60 Gy 
Bowel 
Max point dose 0.03 cc <56 Gy, 1 cc <54 Gy 
Penile Bulb 
Mean dose less than or equal to 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.  A 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. 
 
4.4 
IMRT Treatment Verification 
 
For IMRT, daily on-line target localization with kilovoltage or megavoltage CT imaging of 
pelvic anatomy, alignment with the prostate fiducial markers using orthogonal pair 
imaging, or alignment to Calypso markers by radiofrequency localization is required prior 
to treatment delivery to ensure accurate positioning. For SBRT, orthogonal films with or 
without cone beam CT (if available) will be performed prior to treatment with matching 
fiducial markers placed in the prostate.  During SBRT treatment delivery, orthogonal 
films will be performed to account for intrafraction motion. 
 
4.5 
Dose Specifications/Technical Considerations: LDR Brachytherapy 
 
Low dose rate (LDR) implants will only be offered to patients with a prostate volume 
documented to be <60 cc by transrectal ultrasound examination. The implant may be 
performed under either general or spinal anesthesia. 
Preplanning: This will be carried out prior to the procedure or intra-operatively via 
transrectal ultrasound examination. The prostate will be defined from base to apex in the 
axial plane at 5 mm slice intervals. The treatment length and prostate volume will be 
recorded. The PTV may be the same as the CTV or a 2-3 mm margin may be added 


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anteriorly and laterally and up to 5 mm craniocaudally at the discretion of the treating 
physician. The CTV is the prostate gland and the seminal vesicles. 
Isotope Selection: Iodine-125 or Palladium-103 seeds may be used. The sources will 
be received and inventoried in accordance with state and federal regulations. If 
nonsterile loose sources or cartridges are used, at least 10% of the sources will be 
assayed in such a manner that direct traceability to either the National Institute of 
Standards and Technology (NIST), an Accredited Dosimetry Calibration Lab (ADCL) or 
for international participants, the national standards laboratory in their respective 
country, is maintained. NIST 1999 standards will be used. If sterile source assemblies or 
strands are used, alternatively non-stranded loose seeds equal to 5% of the total, or five 
seeds, whichever is fewer, may be ordered and assayed. Agreement of the average 
measured source strength shall agree with that indicated in the vendor’s calibration 
certificate to within 5%. No measured source strengths should fall outside 10% of that 
indicated in the vendor’s calibration certificate. 
• 
For I-125, the allowable source strength for each seed is 0.277 U to 0.650 U (NIST 
99 or later). For Pd-103 sources, this range is 1.29 U to 2.61 U (NIST 99 or later). 
• 
The vendor’s stated source strength shall be used in all dosimetry calculations. 
Calculations will be performed in accordance with NIST 1999 calibration standards, 
the point source formalism described in the report generated by AAPM Task Group 
43 and subsequent. 
Prescription Doses:  The prescription dose for permanent seed interstitial boost will be 
108 Gy for I-125 and 90 Gy  for Pd-103. Doses will be prescribed as minimal peripheral 
dose to the PTV. 
Postimplant Imaging:  A pelvic x-ray with seed count verification will be obtained 
immediately postimplant. If the seed count does not match the number of seeds 
implanted, PA and lateral chest x-rays will be obtained to rule out pulmonary seed 
migration. CT scan for postimplant dosimetric analysis will be obtained following implant 
completion. Use of a Foley catheter for this test is encouraged for accurate urethral 
dosimetry but not required. This may be obtained immediately postoperative on the day 
of the implant if desired but no later than 5 weeks post implant. The use of intravesical 
contrast is encouraged. CT slices should be acquired at ≤3 mm thickness and should 
encompass the pelvis from, at minimum, the bottom of the sacroiliac joints superiorly to 
2 cm caudal to the prostatic apex. 
• 
Structures defined will include the prostate, bladder, rectum, and penile bulb. The 
rectum will be defined from the bottom of the sacroiliac joints to the ischial 
tuberosity and will extend to the outer surface of the visualized rectal wall. The 
postimplant, CT-defined prostate will be defined as the “evaluated target volume” 
(ETV) and will form the basis for dosimetric analysis. 
• 
Post implant evaluation will be performed on equipment capable of providing 
structural and volume-based dosimetric assessment on both the target and critical 
structures. Volume acquisition will be based on contiguous axial CT slices as 
described above. Both target volume and critical structures will be contoured on 
each applicable axial slice. Isodose line displays and dose-volume histograms for 
all structures will be generated. 
 
o The calculation grid should be set no larger than (2 mm x 2 mm x 
axial slice width). 
o Guidelines established by the American Brachytherapy Society 
(Nag 2000) are to be  followed. DVH-based analysis must be 
used in the post plan evaluation. The following values shall be 
reported. Vn is the percentage of the ETV that received at least 
n% of the prescription dose. Dm is the minimum dose received by 
m% of the ETV. 


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o Target coverage will be documented in terms of V100, V90, V80, 
D90. 
o Dose uniformity will be expressed in terms of V150. 
 
o The rectum will be defined from the bottom of the SI joints to the 
ischial tuberosity. The  maximum rectal dose as well as the 
volume and percentage of rectum receiving > 100% of  the 
prescription dose will be recorded. 
 
 
Compliance Criteria 
Per protocol: D90 for the ETV is greater than 90% of the prescription dose but less than 
130% of the prescription dose. 
Variation acceptable: D90 for the ETV is greater than 80% of the prescription dose, but 
less than 90% of the prescription dose, or greater than 130% of the prescription dose. 
Deviation unacceptable: D90 for the ETV is less than 80% of the prescription dose. 
 
4.6 
Dose Specifications/Technical Considerations: HDR Brachytherapy 
 
HDR brachytherapy is permitted at the discretion of the treating radiation oncologist in 
conjunction with HT.  High dose rate implants will only be offered to patients with a 
prostate volume documented to be <150 cc by transrectal ultrasound examination and 
no large TURP defects. The implant must be performed after intensity-modulated 
radiotherapy. 
• 
All implants will be performed under transrectal ultrasound guidance. Epidural, 
spinal, or general anesthesia may be used. Epidural analgesia may be used for 
pain control. 
• 
At least 14 treatment catheters should be used to ensure adequate target coverage 
with acceptable dose heterogeneity. 
• 
The use of intraoperative cystoscopy is encouraged to ensure the absence of 
treatment catheters within the urethra or bladder. The cystoscope should be 
retroflexed within the bladder for visualization of the bladder neck. Light pressure 
on the treatment catheters should result in mucosal tenting confirming adequate 
coverage at the prostatic base. 
 
All patients will be treated with a single implant and single HDR fraction of 15 Gy. 
Treatment will be delivered within a single 24-hour period measured from the beginning 
of the implant procedure. 
 The treatment planning CT scan must be performed with the patient in the supine 
position  with the Foley catheter in place. Metallic obturators or non-CT compatible 
dummy ribbons must be removed prior to the CT scan. If contrast material is used, it 
should be diluted to 10% or less to minimize CT artifact. The scan must include all of the 
CTV with at least 9 mm superior and inferior margin, and the scan must include the tips 
of all the implanted catheters. The scan thickness must be ≤0.3 cm and the slices must 
be contiguous. The brachytherapy target volume and normal critical structures must be 
outlined on all CT slices including the prostate, penile bulb, urethra, bladder, and rectum. 
• 
Transrectal ultrasound-based planning and treatment is acceptable. However, all 
implant dosimetry data must be submitted on a treatment planning CT scan and 
evaluation of the quality of the implant will be based on the CT using criteria 
defined below. 
• 
Dwell times in positions located outside of the PTV should be turned down or off to 
minimize normal tissue irradiated. A dwell time optimization program based on 
implant geometry or an inverse planning algorithm may be used. Manual 
optimization is also accepted. 


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• 
The CTV is the prostate gland and the seminal vesicles. 
• 
Critical structures to be defined using CT planning include the bladder, rectum, 
urethra, and penile bulb within the volume of interest. The outermost extent of the 
bladder/rectal wall will define those structures. The urethra is defined by the outer 
surface of the Foley catheter. 
 
o The volume of bladder and rectum receiving 75% of the prescription dose 
must be kept to less than 1 cc (V75 <1 cc) and the volume of urethra 
receiving 125% of the prescription dose must be kept to less than 1 cc 
(V125 <1 cc) and urethral V150 should be 0%. If the dose to normal 
critical structures cannot be kept below the specified level, we 
recommend readjusting the implant or repeating the implant procedure 
until a more optimal implant is obtained. 
 
o Compliance Criteria:  A prescription dose of 15 Gy in one fraction will be 
delivered to the PTV1. Ninety percent coverage of the PTV with the 
prescription dose is considered per protocol, ≥85% but <90% is 
considered variation acceptable, and <85% coverage is considered 
deviation unacceptable. 
o Catheter Position Verification:  Visual inspection of the catheters prior to 
delivery of each treatment is required. Fluoroscopy or CT may be also 
used to verify the position of the catheters in relation to the Foley catheter 
balloon and fiducial markers. The physician may adjust the catheters if 
catheter displacement is identified prior to the treatment. If the catheters 
cannot be satisfactorily repositioned and the PTV and normal critical 
structure DVH parameters are not met with a new plan, then the treatment 
should be postponed until a satisfactory implant is done. If the planning 
process is repeated, then a second set of data should be submitted. 
 
o Catheter Removal:  After completion of the treatment all catheters will be 
removed. 
 
5 Drug Therapy 
 
5.1 
Dosage and Administration 
 
Treatment will be administered on an outpatient basis. All eligible patients receive 
neoadjuvant, concurrent, and adjuvant androgen deprivation therapy consisting of 
enzalutamide combined with a LHRH (luteinizing hormone releasing hormone) agent 
with radiation therapy.  Use of both drugs is considered combined androgen blockade 
(CAB).  Protocol treatment must begin within 14 weeks after enrollment.  
Radiotherapy should begin at least 8 weeks (+/- 1 week) after starting LHRH agonist 
injection. 
 
5.1.1  Anti-Androgen Therapy:  Enzalutamide 
 
Timing: Enzalutamide therapy will begin within 0-7 days (can begin before or same day 
as, or after) of the date of the first LHRH agonist administration and continue for a total 
duration of 24 months. The total duration of administered anti-androgen therapy must 
be documented and submitted. 
 
Description:  Enzalutamide is a nonsteroidal androgen receptor antagonist developed by 
the pharmaceutical company Medivation/Astellas. The chemical name is 4-(3-(4-Cyano- 
3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N- 
methylbenzamide.  Enzalutamide has approximately 9-fold greater binding affinity to the 
androgen receptor compared to the antiandrogen bicalutamide.  As opposed to 


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bicalutamide, enzalutamide does not promote translocation of the androgen receptor to 
the nucleus and in addition prevents binding of the androgen receptor to DNA and to 
coactivator proteins.  In two clinical trials in patients with metastatic castration-resistant 
prostate cancer pre- and post-docetaxel (PREVAIL and AFFIRM, respectively), 
enzalutamide demonstrated improvements in overall survival and was well-tolerated. 
 
Supply: From Medivation/Astellas through  NCCN’s vendor  CRMG 
 
Storage: Enzalutamide should be stored in a dry place at room temperature between 
68°-77°F. 
 
Administration:  Enzalutamide is administered orally at a dose of 160 mg (for 40 mg 
capsules) per day.  Enzalutamide can be taken with or without food.  Swallow capsules 
whole.  Do not chew, dissolve, or open the capsules. 
 
Administration will be suspended only if there is an apparent or suspected reaction to the 
drug. During RT interruptions, enzalutamide will be continued. Any treatment 
interruptions or failure of the patient to comply with the prescribed medication schedule 
must be documented. 


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Toxicity:  Consult the package insert for comprehensive toxicity information (Table 5). 
 
Table 5:  Adverse Reactions 
 
ENZALUTAMIDE (N=800) 
PLACEBO (N=399) 
General Disorders 
Grade 1- 
4(%) 
Grade 3-4(%) 
Grade 1-4(%) 
Grade 3-4(%) 
Asthenic Conditions 
50.6 
9.0 
44.4 
9.3 
Peripheral Edema 
15.4 
1.0 
13.3 
0.8 
Musculoskeletal and Connective Tissue Disorders 
Back Pain 
26.4 
5.3 
24.3 
4.0 
Arthralgia 
20.5 
2.5 
17.3 
1.8 
Musculoskeletal 
Pain 
15.0 
1.3 
11.5 
0.3 
Muscular 
Weakness 
9.8 
1.5 
6.8 
1.8 
Musculoskeletal 
Stiffness 
2.6 
0.3 
0.3 
0.0 
Gastrointestinal Disorders 
Diarrhea 
21.8 
1.1 
17.5 
0.3 
Vascular Disorders 
Hot Flush 
20.3 
0.0 
10.3 
0.0 
Hypertension 
6.4 
2.1 
2.8 
1.3 
Nervous System Disorders 
Headache 
12.1 
0.9 
5.5 
0.0 
Dizziness 
9.5 
0.5 
7.5 
0.5 
Spinal Cord 
Compression and 
Cauda Equina 
Syndrome 
7.4 
6.6 
4.5 
3.8 
Paresthesia 
6.6 
0.0 
4.5 
0.0 
Mental Impairment 
Disordersd 
4.3 
0.3 
1.8 
0.0 


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Hypoesthesia 
4.0 
0.3 
1.8 
0.0 
Infections and Infestations 
Upper Respiratory 
Tract Infectione 
10.9 
0.0 
6.5 
0.3 
Lower Respiratory 
Tract and Lung 
Infectionf 
8.5 
2.4 
4.8 
1.3 
Psychiatric Disorders 
Insomnia 
8.8 
0.0 
6.0 
0.3 
Anxiety 
6.5 
0.3 
4.0 
0.0 
Renal and Urinary Disorders 
Hematuria 
6.9 
1.8 
4.5 
1.0 
Pollakiuria 
4.8 
0.0 
2.5 
0.0 
Injury, Poisoning, and Procedural Complications 
Fall 
4.6 
0.3 
1.3 
0.0 
Non-pathologic 
Fractures 
4.0 
1.4 
0.8 
0.3 
Skin and Subcutaneous Tissue Disorders 
Pruritis 
3.8 
0.0 
1.3 
0.0 
Dry Skin 
3.5 
0.0 
1.3 
0.0 
Respiratory Disorders 
Epistaxis 
3.3 
0.1 
1.3 
0.3 
 
 
The safety and tolerability of enzalutamide as monotherapy have been evaluated in a 
combined safety analysis including metastatic castration resistant prostate cancer 
patients from 2 large randomized, placebo-controlled phase 3 studies (PREVAIL and 
AFFIRM). Overall enzalutamide was generally well tolerated.  In these studies, adverse 
events included fatigue, constipation, diarrhea, hot flush, asthenia, headache, insomnia, 
hypertension. 
 
Dose Modifications: If a patient experiences a ≥ Grade 3 toxicity or an intolerable side 
effect, withhold dosing for one week and until symptoms improve to ≤Grade 2, then 
resume at the same or a reduced dose (120 mg or 80 mg), if warranted. 
 
Drug-Drug Interactions:  The concomitant use of strong CYP2C8 inhibitors should be 
avoided if possible. If patients must be co-administered a strong CYP2C8 inhibitor, 


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reduce the enzalutamide dose to 80 mg once daily.  If co-administration of the strong 
inhibitor is discontinued, the enzalutamide dose should be returned to the dose used 
prior to initiation of the strong CYP2C8 inhibitor. 
 
a)  Drugs that inhibit or induce CYP2C8 - Co-administration of a strong CYP2C8 
inhibitor (gemfibrozil) increased the composite area under the plasma 
concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide 
by 2.2-fold in healthy volunteers. Co-administration of enzalutamide with strong 
CYP2C8 inhibitors should be avoided if possible. If co-administration of 
ENZALUTAMIDE with a strong CYP2C8 inhibitor cannot be avoided, reduce the 
dose of enzalutamide. The effects of CYP2C8 inducers on the pharmacokinetics 
of enzalutamide have not been evaluated in vivo. Co-administration of 
enzalutamide with strong or moderate CYP2C8 inducers (e.g., rifampin) may 
alter the plasma exposure of enzalutamide and should be avoided if possible. 
Selection of a concomitant medication with no or minimal enzalutamide induction 
potential is recommended. 
 
b)  Drugs that inhibit or induce CYP3A4 - 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. 
 
The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have 
not been evaluated in vivo. Co-administration of enzalutamide with strong 
CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, 
rifampin, rifapentine) may decrease the plasma exposure of enzalutamide and 
should be avoided if possible. Selection of a concomitant medication with no or 
minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 
inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s 
Wort may also reduce the plasma exposure of enzalutamide and should be 
avoided if possible. 
 
c)  Effect of enzalutamide on drug metabolizing enzymes 
 
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and 
CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma 
exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and 
omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow 
therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, 
cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 
(e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their 
exposure. If co-administration with warfarin cannot be avoided, conduct 
additional INR monitoring. 
 
5.1.1 
Leuprolide 
 
For additional information, consult the package inserts. 
 
Timing: The first leuprolide administration will occur together with the start of anti- 
androgen treatment 2 months (+/- 1 week) prior to the start of RT. The total duration of 
Leuprolide therapy will be 24 months and will be determined by the physician. The total 
administered duration as well as the specific agent used must be documented. 


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Description:  Leuprolide is a long-acting analog of the native LHRH peptide and are 
effective at reducing serum testosterone. 
 
Supply:  Commercially available. 
Storage: Leuprolide should be stored as directed by the commercial supplier. 
Administration:  By intramuscular injection. Any duration formulation (1, 3, 4, or 6-month 
based on the manufacturer) is permitted to allow the duration of hormonal therapy to 
total 24 months at the physician’s discretion. 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 related to low 
testosterone levels. In the majority of patients testosterone levels increase above normal 
in 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 leuprolide 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 liability, nausea, vomiting, and  rarely, 
allergic generalized rash and difficulty breathing. 
 
6 Study Procedures and Observations 
 
6.1 
Schedule of Procedures and Observations 
 
Screening assessments must be performed within 8 weeks prior to the first dose of 
neoadjuvant androgen deprivation therapy.  Any results falling outside of the reference 
ranges may be repeated at the discretion of the investigator. All on-study visit 
procedures are allowed a window of ±14 days unless otherwise noted. Treatment or 
visit delays for public holidays or weather conditions do not constitute a protocol 
violation. 
 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a 
copy will be filed in the medical record. The original will be kept on file with the study 
records. 
 
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller 
Family Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The 
system is password protected and meets HIPAA requirements. 
 
6.1.1 
Pretreatment Period 
 
Patients will be seen for an initial consultation for discussion of treatment options. Once 
the patient has consented to enrollment onto study, all pre-study assessments must be 


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completed and eligibility verified by the clinical research coordinator prior to initiation of 
study treatment. 
 
The Screening procedures and assessments must be completed within 14 weeks of the 
Day 1 Visit unless otherwise noted below. 
 
• 
Detailed history and physical exam including height, weight, and baseline 
evaluation of symptoms, pain, and medications 
 
• 
Baseline urinary, bowel, and sexual function will be assessed with the EPIC-26, 
PROMIS, and EQ-5D Questionnaires 
 
• 
Liver transaminases for patients undergoing androgen deprivation therapy.  AST or 
ALT must be < 2x upper limit of normal within 60 days of initiating androgen 
deprivation therapy. 
• 
Total bilirubin 
 
• 
MRI pelvis and prostate to define the extent of disease as part of routine staging 
for high risk prostate cancer and to aid in treatment planning. 
• 
PSA should be obtained before or at least 20 days after prostate biopsy. The PSA 
half-life is approximately 2.2 days. The 20-day period will allow for approximately 9 
half-lives to elapse, thus minimizing the flare effect from biopsy on actual PSA 
value.  Also, every effort should be made to obtain all serum PSA values within the 
year prior to treatment for calculation of PSA kinetics. 
• 
Testosterone level 
• 
CBC with differential 
• 
Basic metabolic panel 
• 
Hepatitis B and C testing 
• 
Fasting lipid panel, glucose level, and HbA1c 
 
• 
Patients must also undergo 50 mL blood sample collection.  Blood collection 
should be performed at time of PSA, testosterone, or other lab testing. 
• 
TRUS biopsy – may be completed up to 25 weeks prior to enrollment. 
• 
Collection of archival tissue from a prior prostate biopsy if available 
• 
NaF PET/CT or Tc99m bone scan 
 
6.1.2 
4-6 weeks after initiation of Androgen Deprivation Therapy 
 
• 
PSA level 
• 
Testosterone level 
• 
CBC with differential 
• 
Basic metabolic panel 
• 
AST, ALT, and total bilirubin 
• 
Patients will undergo 50 mL blood collection at the time of lab testing. 
• 
AE assessment 
 
• 
After PSA testing, patients should undergo fiducial marker placement to optimize 
patient positioning and account for prostate motion during radiation treatment. 
During the fiducial marker procedure, a biopsy of the dominant lesion(s) should be 


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obtained. The additional risks and discomfort of the limited biopsy during the 
fiducial marker placement are minimal and include bleeding as a needle is already 
being introduced under ultrasound guidance for fiducial marker placement as part 
of the standard of care. If available, the biopsy should be mapped under MRI- 
guidance. 
• 
Refer to section 5.0 for details regarding androgen deprivation therapy. 
 
6.1.3      8 weeks after initiation of Androgen Deprivation Therapy 
 
• 
Refer to section 4.0 for details regarding radiation therapy. 
• 
Patients should complete the EPIC-26, PROMIS, and EQ-5D questionnaires up to 
5 days before the first day of radiation therapy. 
 
• 
AE assessment - all patients will undergo weekly assessment by the radiation 
oncologist for any signs of acute toxicity 
 
• 
After 5 weeks of conventional whole pelvic radiotherapy, patients should complete 
the EPIC-26, PROMIS, and EQ-5D questionnaires. 
• 
After 5 weeks of conventional whole pelvic radiotherapy, brachytherapy may be 
performed as part of the radiation boost procedure (phase 2).  At the time of 
brachytherapy, a biopsy of the dominant lesion(s) may be performed.  The risks 
and discomfort of the limited biopsy are minimal as multiple catheters (larger in 
diameter) are already being introduced under ultrasound guidance into the prostate 
as part of the HDR procedure. 
 
• 
After 5 weeks of conventional whole pelvic radiotherapy and within the first 3 days 
of phase 2 boost procedure (days 1-3), 50 ml blood collection will be performed. 
 
6.1.4      Post-Treatment Assessment 
 
Patients will be assessed at 6 weeks after completion of radiotherapy, month 3-4, month 
6, month 12, month 18, month 24, and at month 36 per standard of care.  All toxicity and 
adverse events according to CTCAE v. 4.0 criteria will be documented.  At each visit, the 
following will be collected: 
 
• 
AE assessments 
• 
Pertinent interval history and physical exam 
 
• 
Urinary, bowel, and sexual function will be assessed weekly with the EPIC-26, 
PROMIS, EQ-5D questionnaires 
• 
PSA and testosterone levels 
• 
50 mL Blood collection will be performed at the 3-4 month follow-up visit. 
• 
Fasting lipid panel, glucose level, and HbA1c 
• 
CBC with differential 


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• 
Basic metabolic panel 
• 
AST, ALT, and total bilirubin 
• 
PSA failure will be defined as PSA nadir + 2 ng/mL.  At the time of PSA failure, 
workup will include bone scan and/or sodium fluoride PET/CT scan and MRI of the 
prostate to evaluate for a source of treatment failure.  Distant metastases will be 
noted as any site located out of the true pelvis (i.e. out of radiation field). If a local 
recurrence is suspected within the prostate, a transrectal ultrasound-guided biopsy 
of the prostate is recommended.  Local recurrence will be defined as recurrence 
within the prostate.  Regional recurrence will be documented as any site in the 
pelvic lymph nodes within the radiation field. 
 
6.1.5 
Discontinuation of Therapy 
 
If a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect, withhold dosing 
for one week and until symptoms improve to ≤Grade 2, then resume at the same or a 
reduced dose (120 mg or 80 mg), if warranted. 
 
In addition, the following safety/compliance events will result in the removal of patients 
from therapy either permanently or until the etiology of the problem has been identified 
and resolved: 
 
• 
Any adverse event that is intolerable to the patient and that cannot be 
ameliorated by the use of adequate medical intervention, or that in the opinion of 
the investigator would lead to undue risk to the patient if dosing continued. 
 
• 
Any seizure 
 
• 
Creatinine >4.0 mg/dL 
 
• 
Liver function tests (AST, ALT, or total bilirubin) >2 times the upper limit of 
normal 
 
• 
An absolute neutrophil count ≤750/µL 
 
• 
A platelet count of <50,000/µL 
 
• 
Patients who are in the opinion of the investigator or the medical monitor non- 
compliant with the protocol’s requirements 
 
The Investigator will withdraw a patient whenever continued participation is no longer in 
the patient’s best interests.  Reasons for withdrawing a patient include, but are not 
limited to, disease progression, the occurrence of an adverse event or a concurrent 
illness, a patient’s request to end participation, a patient’s non-compliance or simply 
significant uncertainty on the part of the Investigator that continued participation is 
prudent. There may also be administrative reasons to terminate participation, such as 
concern about a patient’s compliance with the prescribed treatment regimen. 


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Table 6:  Schedule of Assessments 
 
Study Assessments 
Pre-Radiation Treatment 
During Radiation 
Post-Radiation 
Treatment 
Time period 
Baseline 
(Diagnosis) 
4-6 week 
after initiation 
of ADT (at 
placement of 
fiducial 
marker) 
At Time of 
Brachytherapy 
Procedure (After 
fractionated whole 
pelvic radiotherapy) 
Each follow up visit (6 wk, 
month 3-4, month 6, 
month 12, month 18, 
month 24, and month 36)a 
Detailed medical 
history and physical 
exam 
X 
X (pertinent interval history 
and physical exam) 
Collection of archival 
biopsy tissue if 
available 
X 
TRUS biopsy of 
dominant lesion(s)b 
X 
X 
X 
Serum PSA, 
testosterone 
X 
X 
X 
X 
CBC with differential 
X 
X 
X 
X 
Basic Metabolic Panel 
X 
X 
X 
X 
Liver Function Tests 
including AST, ALT, 
and Total Bilirubin 
X 
X 
X 
X 
Hepatitis B and C 
Testing 
X 
Fasting Lipid Panel, 
glucose level, and 
HbA1c 
X 
X 
50 mL blood sample 
collection 
Y 
Y 
Y 
Y (month 3-4) 
MRI prostate and pelvis 
X 
X (At time of PSA failure) 
NaF PET/CT or Tc99m 
Bone Scan 
X 
X (At time of PSA failure) 
EPIC-26, PROMIS, 
EQ-5D 
X 
X (Before start of 
radiation therapy 
and after 5 weeks 
of conventional 
pelvic radiotherapy) 
X 
AE assessments 
X 
Each week during 
external beam 
radiation therapy 
X 
X = Assessments as determined by standard of care; Y = Additional procedure as part of study 
a     Patients will be assessed at 6 weeks after completion of radiotherapy and then at least every 6 months 
thereafter for the first 2 years. 
b  TRUS biopsies are optional and at provider discretion


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6.2 
Usage of Concurrent/Concomitant Medications 
 
Clinical discretion may be used in managing radiotherapy-related and androgen 
deprivation-related side effects. 
 
Bowel:  Patients will be asked to adhere to a low gas, low motility diet commencing one 
day prior to treatment.  Patients experiencing diarrhea/rectal frequency/urgency may be 
managed initially with psyllium fiber supplements can be used to help increase bulkiness 
of bowel movements.  If diarrhea persists, they may then be managed with 
diphenoxylate or loperamide. 
 
Urinary:  Bladder irritation may be mitigated with phenazopyridine. Urinary 
frequency/urgency can be managed with anticholinergic agents or alpha-blockers such 
as tamsulosin. 
 
Erectile Dysfunction:  Erectile dysfunction can be managed with phosphodiesterase 
(PDE) inhibitors such as sildenafil. 
 
Abnormal liver function tests: If liver transaminases (AST) or (ALT) are >2x the upper 
limit of normal, the anti-androgen may be discontinued. 
 
Hot flashes:  Frequent and bothersome hot flashes can be managed with a serotonin- 
norepinephrine reuptake inhibitor, venlafaxine. 
 
Bone Health: Osteopenia and minimization of risk of osteoporosis can be managed with 
Calcium + Vitamin D supplementation. 
 
7 Reporting and Documentation of Results 
 
7.1 
Definitions 
 
Evaluable for toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with the 
study drug until 24 months after last dose of enzalutamide treatment. 
 
7.2 
Evaluation of Safety 
 
Analyses will be performed for all patients. The study will use the  CTCAE v4.0 for 
reporting of adverse events. 
 
Safety will be assessed through a summary of adverse events. The maximum severity of 
each adverse event assessed by NCI CTCAE v. 4.0 will be summarized using summary 
statistics, graphical techniques, and categorical methods.  Shift tables using CTCAE 
grades will be used to compare baseline to on-treatment values. 
 
7.3 
Definitions of Adverse Events 
 
7.3.1 
Serious Adverse Event 
 
The term “Serious Adverse Event” (or “SAE”) shall mean any adverse drug experience 
occurring at any dose that results in any of the following outcomes: death, is life 
threatening, as defined below, requires inpatient hospitalization or prolongation of an 
existing hospitalization, results in a persistent or significant disability or incapacity, 
results in a congenital anomaly or birth defect, results in cancer, or results in an 


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important medical event. Important medical events which are AEs that may not result in 
death, be Life-Threatening, or require hospitalization may be considered SAEs when, 
based upon appropriate medical judgment, they may jeopardize the Study Participant 
and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
 
All SAES must be reported to ORP 
. 
 
7.3.2 
Adverse reaction 
 
An adverse reaction is defined as any adverse event caused by the use of a treatment or 
procedure.  Adverse reactions are a subset of all suspected adverse reactions for which 
there is reason to conclude that the treatment or procedure caused the event.  Adverse 
events will be followed up to 60 months post-initiation of androgen deprivation therapy. 
 
7.3.2.1 Suspected 
 
A suspected adverse reaction is defined as any adverse event for which there is a 
reasonable possibility that the treatment or procedure caused the adverse event. For the 
purposes of IND safety reporting, “reasonable possibility” indicates that there is evidence 
to suggest a causal relationship between the treatment or procedure and the adverse 
event.  A suspected adverse reaction implies a lesser degree of certainty about causality 
than an adverse reaction. 
 
7.3.2.2 Unexpected 
 
An adverse event or suspected adverse reaction is considered unexpected if it is not 
listed in the investigator brochure or package insert(s), or is not listed at the specificity or 
severity that has been observed, or, if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application. 
 
“Unexpected,” as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring with a 
class of treatment or procedure or as anticipated from the pharmacological properties of 
the treatment or procedure, but are not specifically mentioned as occurring with the 
particular treatment or procedure under investigation. 
 
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in 
the investigator brochure.  For example, a certain number of non-acute deaths in a 
cancer trial would be anticipated as an outcome of the underlying disease, but such 
deaths would generally not be listed as a suspected adverse reaction in the investigator 
brochure. 
 
Some adverse events are listed in the Investigator’s Brochure as occurring with the same 
class of treatment, or as anticipated from the pharmacological properties of the drug, 
even though they have not been observed with the drug under investigation.  Such 
events would be considered unexpected until they have been observed with the drug 


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under investigation. For example, although angioedema is anticipated to occur in some 
patients exposed to drugs in the ACE inhibitor class and angioedema would be 
described in the investigator brochure as a class effect, the first case of angioedema 
observed with the drug under investigation should be considered unexpected for 
reporting purposes. 
 
7.3.2.3 Life-threatening 
 
An adverse event or suspected adverse reaction is considered life-threatening if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
 
7.4 
Recording of an Adverse Event 
 
All grade 3 and above adverse events will be entered into OnCore®, whether or not the 
event is believed to be associated with use of the study drug.  Data about these events 
and their severity will be recorded using the NCI CTCAE v4.0. 
 
The Investigator will assign attribution of the possible association of the event with use of 
the investigational drug, and this information will be entered into OnCore® using the 
classification system listed below: 
 
Relationship 
Attribution 
Description 
 
Unrelated to 
investigational 
 
Unrelated 
The AE is clearly NOT related to the 
intervention 
drug/intervention 
Unlikely 
 
Possible 
The AE is doubtfully related to the 
intervention 
The AE may be related to the intervention 
Related to investigational 
drug/intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the 
intervention 
 
 
Signs or symptoms reported as adverse events will be graded and recorded by the 
Investigator according to the CTCAE. When specific adverse events are not listed in the 
CTCAE they will be graded by the Investigator as none, mild, moderate or severe 
according to the following grades and definitions: 


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Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, 
cautery) indicated; limiting age-appropriate instrumental activities of daily 
living (ADL) 
Grade 
3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL 
Grade 
4: 
Life-threatening consequences; urgent intervention indicated 
Grade 
5: 
Death related to AE 
 
7.5 
Follow-up of Adverse Events 
 
All adverse events will be followed with appropriate medical management until resolved. 
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  For selected adverse events for which 
administration of the treatment or procedure was stopped, a re-challenge of the subject 
with the investigational treatment or procedure may be conducted if considered both 
safe and ethical by the Investigator. 
 
7.6 
Adverse Events Monitoring 
 
All adverse events, whether or not unexpected, and whether or not considered to be 
associated with the use of the study drug, will be entered into OnCore®, as noted above. 
 
The Investigator will assess all adverse events and determine reportability requirements 
to the UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional 
Review Board, the Committee on Human Research (CHR); and, when the study is 
conducted under an Investigational New Drug Application (IND), to the Food and Drug 
Administration (FDA) if it meets the FDA reporting criteria. 
 
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis. The Site Committee 
will review and discuss at each weekly meeting the selected toxicity, the toxicity grade, 
and the attribution of relationship of the adverse event to the administration of the 
treatment or procedure. 
 
In addition, all adverse events and suspected adverse reactions considered “serious,” 
entered into OnCore® will be reviewed and monitored by the Data and Safety Monitoring 
Committee on an ongoing basis and discussed at DSMC meetings which take place 
every six (6) weeks. 
 
7.7 
Expedited Reporting 
 
Within 24 hours of awareness of a serious adverse event, whether or not related to the 
study drug, the Investigator will complete and submit a Medwatch 3500A Form to FDA, 
containing all required information (reference 21 CFR 312.32). The Investigator will 
submit a copy of this MedWatch 3500A form to Astellas by either e-mail or fax, within the 


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same timeframe. If submission of this SAE to FDA, NCCN or Astellas is not possible 
within 24 hours, the Investigator’s local drug safety contact (IRB, etc.) should be 
informed by phone. 
 
The SAE documentation, including the Medwatch 3500A Form and available source 
records should be emailed or faxed to: 
 
• 
Astellas Pharma Global Development – United States 
• 
Email: 
 
• 
Fax number: 
 
 
In addition, email or fax to NCCN 
. The 
following minimum information is required: 
 
• 
Study number/IIT regulatory identifier 
• 
Subject number, sex and age 
• 
The date of report 
• 
A description of the SAE (event, seriousness of the event) 
• 
Causal relationship to the study drug 
 
Follow-up information for the event should be sent promptly (within 7 days) as 
necessary. 
 
Reporting to the Data and Safety Monitoring Committee 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the treatment or procedure and it is determined to be related either to 
the treatment or procedure, the Investigator or his/her designee must notify the DSMC 
Chair (or qualified alternate) within 1 business day of knowledge of the event. The 
contact may be by phone or e-mail. 
 
Reporting to UCSF Committee on Human Research (Institutional Review Board) 
The Principal Investigator must report events meeting the UCSF CHR definition of 
“Unanticipated Problem” (UP) within 5 business days of his/her awareness of the event. 


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8 Tissue/Specimen Collection 
 
8.1 
Specimen Collection Summary for Translational Research 
 
Specimens Taken From Patient 
Time of Collection 
Diagnostic Core Biopsy Specimen(s) 
1)   Pre-treatment 
2)   4-6 wks after initiation of androgen 
deprivation therapy (at time of fiducial 
marker placement) 
3)   At the time of brachytherapy (if 
brachytherapy is being performed) 
Whole blood: 50 mL of whole blood will be 
collected into green top tubes (sodium 
heparin). This should be collected, if possible, 
at the time of each blood draw for PSA and 
testosterone. 
1)   Pre-Treatment 
2)   4-6 wks after initiation of androgen 
deprivation therapy (at time of fiducial 
marker placement) 
3)   W ithin first 3 days of phase 2 
brachytherapy 
4)   Month 3-4 post-radiation therapy 
 
 
Core biopsy specimens will be snap frozen in liquid nitrogen and stored at -80oC. 
Plasma and whole blood samples will be processed and stored frozen at -80oC. 
All samples will be de-identified and labeled with a case number.  Samples will be sent 
frozen on dry ice via overnight carrier stored in a locked -80 oC freezer. 
 
8.1.1 
Plasma/Serum/Peripheral Blood Mononuclear Cell (PMBC) 
Banking 
 
Immediately prior to each time point indicated above, the clinical research coordinator 
will assign unique specimen log numbers to be written on the specimen vials; this will 
ensure patient confidentiality.  At the specified time points, 50 cc of whole blood will be 
collected in one green (sodium heparin) top tube that has been properly labeled with the 
unique specimen log number provided and stored at –80°C. 
 
8.1.2 
Tumor biopsy 
 
Image guided biopsies will be performed prior to any treatment as part of the patient’s 
diagnosis (may be performed up to 180 days prior to registration to confirm diagnosis of 
adenocarcinoma of the prostate; archival tissue will be collected if available), at 5 weeks 
post-initiation of enzalutamide therapy at the time of gold marker placement, and after 5 
weeks of external beam radiation therapy at the time of brachytherapy (if patient decides 
to undergo brachytherapy).  The biopsies will be performed by urologic surgical oncology 
and radiation oncology under transrectal ultrasound guidance with a 16-18 gauge 
needle. There will be minimal risk to these biopsies as similar or larger-gauge needles 
are already being inserted for fiducial marker placement (routinely used for daily setup 
for external beam radiation therapy) and HDR brachytherapy.  Core biopsies will be 
extracted and will be immediately frozen on a pre-frozen bed of OCT (Optimal Cutting 
Temperature compound used for frozen sections), covered with additional OCT, and 
kept on dry ice or at –80°C. 


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All biopsies and blood samples will be delivered to the laboratory of Dr. Lawrence Fong 
at UCSF, 
 or to the laboratory of Dr. Hao 
Nguyen at UCSF, 
. Both locations are secured, 
locked rooms with a locked liquid nitrogen storage tank and –80°C freezer. These 
samples will receive a patient-insensitive identifier and the link to patient identity will be 
kept in a locked file with access only by the principal investigators and the clinical 
research coordinator. Other co-investigators will have access to samples by submitting 
a request to the Committee on Human Research.  Patients have the right at any time to 
request that all remaining samples be destroyed.  Patients will be asked to consent to 
future, additional research on stored samples.  Additional written consent will be 
required if additional samples are to be taken. 
 
Deep whole exome sequencing of the tumor specimens with matched germ line samples 
(blood) will be performed on paired samples pre- and 5 weeks post-initiation 
enzalutamide treatment. The results will be compared across patients that do and do 
not obtain a biochemical complete response. Whole exome sequencing will allow for the 
identification of mutations, insertions/deletions, and copy number alterations involved in 
enzalutamide resistance.  For exome sequencing, exons will be captured in solution 
from one microgram of sonicated genomic DNA using an Agilent SureSelect target 
capture system.  Libraries of captured exons will be sequenced using 75 bp paired-end 
sequencing on an Illumina HiSeq with a goal of 100X coverage.  Libraries will be 
constructed with indexing to allow sequencing of 3 or more exomes/lane. Computational 
analysis will of raw exome data will be performed as described by our group.  Somatic 
point mutations and indels nominated as clinically informative will be amplified and 
sequenced for validation. 
 
Total RNA will be extracted, amplified, fragmented, and labeled.  Gene expression 
profiling will be performed with the Affymetrix GeneChip Human Transcriptome Array 
2.0. This microarray chip assesses the expression of over 1.4 million RNA features 
including ~22,000 known protein-coding genes as well as many thousands of non- 
coding RNAs. This will allow us to examine relative gene expression, splice variants, 
and immune response signatures. 
 
9 Statistical Considerations and Evaluation of Results 
 
9.1 
Study Design 
 
Phase II single arm study evaluating the potential efficacy in improving the PSA-CR with 
combined enzalutamide and leuprolide therapy in patients with high-risk prostate cancer 
or pelvic node involvement undergoing definitive radiation therapy.  Also the safety and 
feasibility of combined enzalutamide and leuprolide therapy in patients undergoing 
radiation therapy will be determined. 
 
9.2 
Determination of Sample Size and Accrual Rate 
 
9.2.1 
Sample Size and Power Estimate 
 
Sample size is determined based on the primary objective of the PSA-CR. This is a 
single arm study with the primary endpoint evaluating the proportion of patients 
experiencing a PSA-CR. From historical controls (RTOG 9413 and MSKCC as 
mentioned in background information), we expect 70% of patients to experience a PSA- 
CR. With addition of enzalutamide, at least 85% of patients are expected to attain a 
PSA-CR. With 53 patients (10% dropout rate), we would have 80% power to detect thus 
improvement at significance level of 0.05 based on directional binomial test. 


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As we expect the combined enzalutamide and leuprolide regimen does not significantly 
increase grade 3 or greater acute or late toxicity for treatment of intermediate- to high- 
risk prostate cancer and the usual rate of 3 or greater toxicity is approximately 12%. If 
the true grade 3 or greater acute or late toxicity rate is 12%, with 47 patients we will have 
80% confidence in the toxicity rate estimate with precision of 4.7% (i.e. a confidence 
interval width of 9.4%). 
 
9.2.2 
Accrual estimates 
 
A total of 53 patients with very high-risk prostate cancer or with pelvic nodal involvement 
without distant metastases will be enrolled.  Study accrual is anticipated to be 
approximately 3 patients per month, with a goal complete accrual by 24 months. 
 
9.3 
Interim Analyses and Stopping Rules 
 
Continuous safety monitoring will be performed throughout the trial. The trial will be 
terminated if there is a greater 12% acute grade 3 toxicity.  This rate is acceptable as 
prior studies have demonstrated 8-15% acute grade 3 GU and GI toxicity when 
irradiating the pelvis using standard fractionated technique to 45 Gy in 1.8 Gy fractions 
followed by brachytherapy boost 
 
9.4 
Analyses Plans 
 
9.4.1 
Analysis Population 
 
Analyses will be performed for all patients. The study will use the NCI CTCAE v4.0. 
 
9.4.2 
Primary Analysis (or Analysis of Primary Endpoints) 
 
Point estimates and 95% confidence intervals of PSA-CR will be obtained. The PSA-CR 
will be compared with the historical rate by binomial test. 
 
Toxicity will be assessed by CTCAE v4.0.  Point estimation and its 95% confidence 
interval will be calculated for the rate of acute Grade 3 or greater toxicity within 24 
months of completing treatment with radiotherapy.  Furthermore, one sample proportion 
test will be used to test hypothesis that the addition of enzalutamide to leuprolide and 
radiation therapy does not significantly increase acute or late toxicity. 
 
9.4.3 
Secondary Analysis (or Analysis of Secondary Endpoints) 
 
The time to local failure will be defined from the date of randomization to the date of 
biopsy proven recurrence within the prostate gland. The distribution of the time to event 
data will be estimated by Kaplan-Meier method. 
 
The time to clinical progression will be defined from the date of randomization to the date 
of PSA failure, local failure, regional or distant metastases.  Deaths prior to any of these 
events are treated as censoring for this endpoint. The distribution of the time to event 
data will be estimated by Kaplan-Meier method. 
 
To assess PSA nadir, PSA, testosterone levels, HbA1c, fasting glucose, fasting insulin 
and fasting lipid and cholesterol levels at each time point, the summary statistics for 
continuous variables will be used. 


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To assess their changes across the time, the random effect model for longitudinal data 
will be used for each outcome measurement. 
 
Patient-reported quality of life outcomes will be assessed by EPIC, PROMIS, and EQ-5D 
questionnaires and will be described by summary statistics for categorical data. 
 
10 Study Management 
 
10.1 Pre-study Documentation 
 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with 
GCP and all applicable regulatory requirements. 
 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject 
recruitment materials, and any other written information to be provided to subjects before 
any protocol related procedures are performed on any subjects. 
 
The clinical investigation will not begin until either FDA has determined that the study 
under the Investigational Drug Application (IND) is allowed to proceed or the Investigator 
has received a letter from FDA stating that the study is exempt from IND requirements. 
 
The Investigator must comply with the applicable regulations in Title 21 of the Code of 
Federal Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all 
applicable regulatory requirements. The IRB must comply with the regulations in 21 
CFR §56 and applicable regulatory requirements. 
 
10.2 Institutional Review Board Approval 
 
The protocol, the proposed informed consent form, and all forms of participant 
information related to the study (e.g. advertisements used to recruit participants) will be 
reviewed and approved by the UCSF CHR (UCSF Institutional Review Board).  Prior to 
obtaining CHR approval, the protocol must be approved by the Helen Diller Family 
Comprehensive Cancer Center Site Committee and by the Protocol Review Committee 
(PRC). The initial protocol and all protocol amendments must be approved by the IRB 
prior to implementation. 
 
10.3 Informed Consent 
 
All participants must be provided a consent form describing the study with sufficient 
information for each participant to make an informed decision regarding their 
participation.  Participants must sign the CHR-approved informed consent form prior to 
participation in any study specific procedure. The participant must receive a copy of the 
signed and dated consent document. The original signed copy of the consent document 
must be retained in the medical record or research file. 
 
10.4 Changes in the Protocol 
 
Once the protocol has been approved by the UCSF CHR, any changes to the protocol 
must be documented in the form of an amendment. The amendment must be signed by 
the Investigator and approved by PRC and the CHR prior to implementation. 


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If it becomes necessary to alter the protocol to eliminate an immediate hazard to 
patients, an amendment may be implemented prior to CHR approval.  In this 
circumstance, however, the Investigator must then notify the CHR in writing within five 
(5) working days after implementation. The Study Chair and the UCSF study team will 
be responsible for updating any participating sites. 
 
10.5 Handling and Documentation of Clinical Supplies 
 
The UCSF Principal Investigator and each participating site will maintain complete 
records showing the receipt, dispensation, return, or other disposition of all 
investigational drugs. The date, quantity and batch or code number of the drug, and the 
identification of patients to whom study drug has been dispensed by patient number and 
initials will be included. The sponsor-investigator will maintain written records of any 
disposition of the study drug. 
 
The Principal Investigator shall not make the investigational drug available to any 
individuals other than to qualified study patients. Furthermore, the Principal Investigator 
will not allow the investigational drug to be used in any manner other than that specified 
in this protocol. 
 
10.6 Case Report Forms (CRFs) 
 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate 
and accurate participant case histories with observations and data pertinent to the study. 
Study specific Case Report Forms (CRFs) will document safety and treatment outcomes 
for safety monitoring and data analysis.  All study data will be entered into OnCore® via 
standardized CRFs in accordance with the CTMS study calendar, using single data entry 
with a secure access account. The Clinical Research Coordinator (CRC) will complete 
the CRFs as soon as possible upon completion of the study visit; the Investigator will 
provide oversight. 
 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained 
by UCSF personnel.  All source documentation should be kept in separate research 
folders for each patient. 
 
In accordance with federal regulations, the Investigator is responsible for the accuracy 
and authenticity of all clinical and laboratory data entered onto CRFs. The PI will 
approve all completed CRFs to attest that the information contained on the CRFs is true 
and accurate. 
 
All source documentation and CTMS data will be available for review/monitoring by the 
UCSF DSMC and regulatory agencies. 
 
The Principal Investigator will be responsible for ensuring the accurate capture of study 
data.  At study completion, when the CRFs have been declared to be complete and 
accurate, the database will be locked.  Any changes to the data entered into the CRFs 
after that time can only be made by joint written agreement among the Study Chair, the 
Trial Statistician, and the Protocol Project Manager. 
 
Each participating site will complete study specific CRFs for safety monitoring and data 
analysis.  Each site will enter the study data into OnCore® via standardized CRFs in 
accordance with the CTMS study calendar, using single data entry with a secure access 
account. The participating site’s Clinical Research Coordinator (CRC) will complete the 


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CRFs; the Investigator will review and approve the completed CRFs – this process must 
be completed within 10 business days of the visit. Study data from the participating site 
will be reported and reviewed in aggregate with data from patients enrolled at the 
coordinating center, UCSF.  All source documentation and CTMS data will be available 
for review/monitoring as needed. 
 
10.7 Oversight and Monitoring Plan 
 
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the 
monitoring entity for this study.  The UCSF DSMC will monitor the study in accordance 
with the NCI-approved Data and Safety Monitoring Plan (DSMP).  The DSMC will 
routinely review all adverse events and suspected adverse reactions considered 
“serious”. The DSMC will audit study-related activities to ensure that the study is 
conducted in accordance with the protocol, local standard operating procedures, FDA 
regulations, and Good Clinical Practice (GCP).  Significant results of the DSMC audit will 
be communicated to the IRB and the appropriate regulatory authorities at the time of 
continuing review, or in an expedited fashion, as applicable.  See Appendix 2 Data and 
Safety Monitoring Plan for a Phase 2 or 3 Institutional Study, for additional information. 
 
10.8 Record Keeping and Record Retention 
 
The Principal Investigator is required to maintain adequate records of the disposition of 
the drug, including dates, quantity, and use by subjects, as well as written records of the 
disposition of the drug when the study ends. 
 
The Principal Investigator is required to prepare and maintain adequate and accurate 
case histories that record all observations and other data pertinent to the investigation 
on each individual administered the investigational drug or employed as a control in the 
investigation. Case histories include the case report forms and supporting data including, 
for example, signed and dated consent forms and medical records including, for 
example, progress notes of the physician, the individual's hospital chart(s), and the 
nurses' notes. The case history for each individual shall document that informed consent 
was obtained prior to participation in the study. 
 
Study documentation includes all CRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, CHR 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. 
 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 
years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified. 


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11 Protection of Human Subjects 
 
11.1 Protection from Unnecessary Harm 
 
Each clinical site is responsible for protecting all subjects involved in human 
experimentation. This is accomplished through the CHR mechanism and the process of 
informed consent. The CHR reviews all proposed studies involving human 
experimentation and ensures that the subject’s rights and welfare are protected and that 
the potential benefits and/or the importance of the knowledge to be gained outweigh the 
risks to the individual. The CHR also reviews the informed consent document associated 
with each study in order to ensure that the consent document accurately and clearly 
communicates the nature of the research to be done and its associated risks and 
benefits. 
 
11.2 Protection of Privacy 
 
Patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, 
they will be asked to sign the HIPAA form and informed consent documents. The original 
signed document will become part of the patient’s medical records, and each patient will 
receive a copy of the signed document. The use and disclosure of protected health 
information will be limited to the individuals described in the informed consent document. 


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REFERENCES: 
 
1. 
Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, Venkatesan V, et al. 
Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant 
hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the 
prostate: the Radiation Therapy Oncology Group Protocol 92-02. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 
2003, 21(21): 3972-3978. 
 
2. 
Bolla M, de Reijke TM, Van Tienhoven G, Van den Bergh AC, Oddens J, 
Poortmans PM, et al. Duration of androgen suppression in the treatment of 
prostate cancer. The New England journal of medicine 2009, 360(24): 2516- 
2527. 
 
3. 
Pilepich MV, W inter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, 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(5): 1285-1290. 
 
4. 
Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, 
et al. A controlled trial of leuprolide with and without flutamide in prostatic 
carcinoma. The New England journal of medicine 1989, 321(7): 419-424. 
 
5. 
Ardiani A, Farsaci B, Rogers CJ, Protter A, Guo Z, King TH, et al. Combination 
therapy with a second-generation androgen receptor antagonist and a metastasis 
vaccine improves survival in a spontaneous prostate cancer model. Clinical 
cancer research : an official journal of the American Association for Cancer 
Research 2013, 19(22): 6205-6218. 
 
6. 
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased 
survival with enzalutamide in prostate cancer after chemotherapy. The New 
England journal of medicine 2012, 367(13): 1187-1197. 
 
7. 
Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. 
Enzalutamide in metastatic prostate cancer before chemotherapy. The New 
England journal of medicine 2014, 371(5): 424-433. 
 
8. 
Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, 
et al. Enzalutamide monotherapy in hormone-naive prostate cancer: primary 
analysis of an open-label, single-arm, phase 2 study. The lancet oncology 2014, 
15(6): 592-600. 


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Page 49 of 55 
 
 
 
 
Appendices 
 
Appendix 1  Performance Status Criteria 
 
ECOG (Zubrod) Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity 
Fully active, able to carry on all pre-disease 
performance without restriction 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office 
work) 
2 
In bed < 50% of the time 
Ambulatory and capable of all self-care, but 
unable to carry out any work activities 
Up and about more than 50% of waking hours 
3 
In bed > 50% of the time 
Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
5 
Dead 


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Appendix 2  Data and Safety Monitoring Plan for Multicenter Institutional 
Study (Phase 2 or 3 Institutional Study) 
 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and 
Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and 
subject safety for all HDFCCC institutional clinical studies. A summary of DSMC 
activities for this study includes: 
 
• 
Review of subject data 
• 
Review of suspected adverse reactions considered “serious” 
• 
Monthly monitoring (depending on study accrual) 
• 
Minimum of a yearly regulatory audit 
 
Monitoring and Reporting Guidelines 
 
All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk 
assessment. The data is monitored every six months, with twenty percent of the subjects 
monitored (or at least three subjects if the calculated value is less than three). 
 
The UCSF Coordinating Center provides administration, data management, and 
organizational support for the participating sites in the conduct of a multicenter clinical 
trial. The UCSF Coordinating Center will also coordinate quarterly conference calls with 
the participating sites to communicate the review of adverse events, safety data, and 
other study matters. 
 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study 
Chair. The Study Chair is responsible for the overall conduct of the study and for 
monitoring its safety and progress at all participating sites. The Study Chair will conduct 
continuous review of data and subject safety and discuss each subject’s treatment at 
monthly UCSF Site Committee meetings. The discussions are documented in the UCSF 
Site Committee meeting minutes. 
Multicenter communication 
 
The UCSF Coordinating Center provides administration, data management, and 
organizational support for the participating sites in the conduct of a multicenter clinical 
trial. The UCSF Coordinating Center will also coordinate, at minimum, monthly 
conference calls with the participating sites at the completion of each cohort or more 
frequently as needed to discuss risk assessment. The following issues will be discussed 
as appropriate: 
• 
Enrollment information 
 
• 
Adverse events (i.e. new adverse events and updates on unresolved adverse 
events and new safety information) 
• 
Protocol violations 
• 
Other issues affecting the conduct of the study 
 
Adverse events reporting to the DSMC will include reports from both the UCSF 
Coordinating Center, as well as the participating sites. The DSMC will be responsible for 
monitoring all data entered in OnCore® at the UCSF Coordinating Center and the 
participating sites. The data (i.e. copies of source documents) from the participating 
sites will be sent electronically or faxed over to the UCSF Coordinating Center prior to 


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the monitoring visits in order for the DSMC to monitor the participating site’s compliance 
with the protocol, patient safety, and to verify data entry. 
 
Adverse Event Review and Monitoring 
 
Adverse Event Monitoring 
 
All Grade 3-5 Adverse Events, whether or not unexpected, and whether or not 
considered to be associated with the use of study drug, will be entered into OnCore®, 
UCSF’s Clinical Trial Management System. 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the UCSF Site Committee meetings. All clinically significant adverse events must be 
reported to the UCSF Coordinating Center by the participating sites within 10 business 
days of becoming aware of the event or during the next scheduled quarterly conference 
call, whichever is sooner. The UCSF Site Committee will review and discuss the 
selected toxicity, the toxicity grade, and the attribution of relationship of the adverse 
event to the administration of the study drug(s) from the UCSF Coordinating Center and 
the participating sites. 
 
In addition, all suspected adverse reactions considered “serious” must be entered in 
OnCore® and reported to the UCSF Coordinating Center within 1 business day. The 
suspected adverse reactions considered “serious” will be reviewed and monitored by the 
Data and Safety Monitoring Committee on an ongoing basis and discussed at the DSMC 
meeting, which take place every six (6) weeks. 
 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the 
investigational drug or any research related procedure, the Study Chair at the UCSF 
Coordinating Center or the assigned designee must be notified within 1 business day 
from the participating site(s) and the Study Chair must then notify the DSMC Chair or 
qualified alternate within 1 business day of this notification. The contact may be by 
phone or e-mail. 
 
Increase in Adverse Event Rates 
 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported 
in the Investigator Brochure or package insert), the Study Chair at the UCSF 
Coordinating Center is responsible for notifying the DSMC at the time the increased rate 
is identified. The report will indicate if the incidence of adverse events observed in the 
study is above the range stated in the Investigator Brochure or package insert. 
 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, 
the DSMC Chair and DSMC Manager must be notified within 1 business day via e-mail. 
The DSMC must receive a formal letter within 10 business days and the CHR must be 
notified. 


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Data and Safety Monitoring Committee Contacts: 
 
DSMC 
Chair:  
 
DSMC Monitors  
Phone:  
Email: 
Address:  
 
 
Box 1705 
UCSF 
San Francisco, CA 94158 
Box 0128 
UCSF Helen Diller 
Family Comprehensive 
Cancer Center 
San Francisco, CA 
94143 
 
 
 
*  DSMP approved by NCI 09/February2012 


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Page 53 of 55 
 
 
 
 
Appendix 3  UCSF Policy/Procedure for Required Regulatory Documents 
for a UCSF Multicenter Investigator-Initiated Oncology Clinical Trials with 
an Investigator held Investigational New Drug (IND) 
 
Purpose 
 
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive 
Cancer Center (HDFCCC) where the Principal Investigator (PI) holds the IND. 
 
Background 
 
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) 
Guidelines define Essential Regulatory Documents as those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of 
data produced. These documents serve to demonstrate compliance with standards of 
GCP and with all applicable regulatory requirements. Filing essential documents in a 
timely manner can greatly assist in the successful management of a clinical trial. 
 
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, 
as well as paper files in the Regulatory Binders for both the Coordinating Site and the 
Participating Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials. 
 
 
 
 
Procedures 
 
1.  HDFCCC Essential Regulatory Documents 
Documents Filed in iMedRIS: 
 
• 
CHR approvals for initial submission of application, all modifications, and 
continuing annual renewals 
• 
Current and prior approved protocol versions with signed protocol signature 
page(s) 
• 
Committee for Human Research (CHR) approval letters and Informed Consent 
Form(s) (ICF) 
• 
Current and prior versions of the Investigator Brochure (IB). 
• 
Serious Adverse Event Reporting 
• 
Protocol Violations and Single Patient Exception (SPE) Reports to CHR with 
supporting fax documentation 
 
Documents Filed in OnCore®: 
 
• 
Package Insert (if the study drug is commercial) or Investigator Brochure 
• 
Protocol Review Committee (PRC) approved protocols, protocol amendments 
and Summary of Changes (SOC) 
• 
Patient handouts 
• 
Screening/enrollment log 
• 
Data and Safety Monitoring Committee (DSMC) monitoring reports 
• 
OnCore® Case Report Form (CRF) completion manual 


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Documents Filed in Regulatory Binder: 
 
• 
Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator’s signature 
• 
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will 
need Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency 
(DEA) Licenses, and Staff Training Documents (i.e. Collaborative Institute 
Training Initiative (CITI), etc.) 
• 
Site Initiation Visit (SIV) minutes and correspondence with participating site(s). 
• 
As applicable, approvals for Biosafety Committee, Radiation Committee, and 
Infusion Center 
• 
Serious Adverse Event (SAE) reports to CHR and sponsor. 
• 
MedWatch reporting to FDA and sponsor 
• 
Delegation of Authority Form 
• 
Drug Destruction Standard Operating Procedure (SOP) 
• 
For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges 
 
2.  Additional Essential Documents for Multicenter Trials for the 
Coordinating Center (filed in Regulatory Binder or OnCore) 
 
• 
Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent 
Form (ICF), and Health Insurance Portability and Accountability Act (HIPAA) 
Consent Form for the Participating Site(s) 
• 
For all Principal Investigators and Sub-Investigators listed on the 1572 at the 
Participating Site(s) – Financial Disclosure Forms, CVs, MD Licenses, and Staff 
Training documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for 
Investigational New Drug Application 
• 
Site Initiation Visit (SIV) minutes and correspondence with Participating Site(s). 
• 
As applicable, approvals for Biosafety Committee, Radiation Committee, and 
Infusion Center for the Participating Site(s) 
• 
Protocol Violations and Single Patient Exception (SPE) reports to IRB with 
supporting fax documentation for Participating Site(s) 
• 
Drug Destruction Standard Operating Procedure (SOP) for the Participating 
Site(s) 
• 
Data and Safety Monitoring Committee (DSMC) monitoring reports for the 
Participating Site(s) 
• 
For all laboratories listed on FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges 
for the Participating Site(s) 
• 
Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all 
participating site(s) in Multicenter studies or Contract Research Organization 
(CRO) Monitoring Plan (if an outside CRO is used for the study) 
• 
Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor 
for the Participating Site(s) 
 
 
 
 
 
27 April 2012 


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Required Regulatory Documents for Sub-sites Participating in a UCSF 
Investigator Initiated Multicenter Trial (Checklist) 
 
Directions: 
 
1)  Fax the documents listed below to the UCSF Coordinating center 
 or 
 
2)  Scan the documents and upload to OnCore® and create a Note to File for the on-site 
Regulatory binder to indicate where these documents may be found 
 
1572 
PI and Sub investigators: 
CV and Medical license 
Financial disclosure form 
NIH or CITI human subject protection training certification 
Laboratories 
 
CLIA and CAP 
CV of Lab Director and Lab Licenses 
Laboratory reference ranges 
 
Local Institutional Review Board 
 
IRB Approval letter 
Reviewed/Approved documents 
• Protocol version date: 
  
 
• Informed consent version date:    
 
• Investigator Brochure version date:    
 
• HIPAA 
Current IRB Roster 
 
Other 
 
Delegation of Authority Log 
 
• 
Include NIH or CITI human subject protection training certificates or GCP training 
certification 
Pharmacy 
• 
Drug destruction SOP and Policy 
Protocol signature page 
Executed sub contract 

ICF_001.pdf: 
ICF 09-13-2018
PAGE 1 OF 18
CC#15558
Hao Nguyen, MD, PhD
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
CC#15558: Phase II Trial of Definitive Radiotherapy with Leuprolide and 
Enzalutamide in High Risk Prostate Cancer 
This is a clinical trial, a type of research study. Your study doctor, Hao Nguyen, MD, 
PhD, or one of his associates at the University of California, San Francisco (UCSF) 
Department of Radiation Oncology will explain the clinical trial to you. 
Clinical trials include only people who choose to take part. Please take your time to 
make your decision about participating. You may discuss your decision with your family 
and friends and with your health care team. If you have any questions, you may ask 
your study doctor.
You are being asked to take part in this study because you have high risk prostate 
cancer or with pelvic node involvement. 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to test the safety of the combination of enzalutamide and 
leuprolide in patients undergoing standard of care radiation therapy treatment and to 
determine the response rate of the combination. 
Leuprolide is used to treat advanced prostate cancer in men. It is not a cure. Most types 
of prostate cancer need the testosterone to grow and spread. Leuprolide works by 
reducing the amount of testosterone that the body makes, but does not completely 
block the production of testosterone. 
Enzalutamide is a drug that can block the binding of testosterone to the receptors on 
prostate cancer cells. Enzalutamide is approximately 9-fold more effective in blocking 
testosterone from its receptor when compared to bicalutamide, a drug that is often used 
in combination with leuprolide. Enzalutamide is approved the US Food and Drug 
Administration (FDA) for the treatment of metastatic (cancer that has spread) castration- 
resistant prostate cancer (CRPC). More profound testosterone blockade with the 
combination of enzalutamide and leuprolide may improve the outcome of patients with 
high risk prostate cancer. However, the combination of enzalutamide with leuprolide 
with radiation therapy (radiotherapy) is considered investigational and has not been 
approved by the FDA. 
Astellas Pharma, the makers of enzalutamide, is providing the drug at no cost for the 
study. The National Comprehensive Cancer Network (NCCN) is providing funding to 
UCSF to conduct this research trial. UCSF is sponsoring this study.
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


ICF 09-13-2018
PAGE 2 OF 18
CC#15558
Hao Nguyen, MD, PhD
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 53 people will take part in this study at clinical sites in the United States with 
about 40 people at UCSF. 
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY? 
Patients will receive enzalutamide in combination with leuprolide for about 24 months 
along with conventional whole pelvis radiation therapy for 25 treatments (5 weeks). 
Following the initial radiation therapy treatments, patients will undergo a radiation boost 
to the prostate with internal radiation (termed as brachytherapy).  This form of radiation 
therapy is part of the standard of care. 
After radiation therapy is completed, you will be seen by your radiation oncologist at 
least every three to six months for the first 24 months. This is also the standard of care 
follow-up for patients with prostate cancer.  At each visit, you will be asked questions 
about your general health, changes in health, and symptoms related to treatment and to 
your prostate cancer. You will also be asked to complete quality of life questionnaires 
regarding your overall general well-being, urinary symptoms, bowel symptoms, and 
sexual function. 
Before you begin the main part of the study... 
You will need to have the following exams, tests or procedures to find out if you can be 
in the main part of the study. These exams, tests or procedures are part of regular 
cancer care and may be done even if you do not join the study. If you have had some of 
them recently, they may not need to be repeated. This will be up to your study doctor. 
You must complete your screening procedures within 14 weeks prior to receiving the 
treatment, unless otherwise indicated. Your screening visit may take up to 4-5 hours 
depending on which procedures you have. The following procedures will occur: 
<0000> Physical exam, including review of your full medical history 
<0000> Standard  of  care  staging  exams  which  may  include  MRI,  Sodium  Flouride 
Pet/CT, or bone scan. 
o
For the MRI, you may be given a "contrast material" (a special dye that
makes it easier for doctors to see different tissues in your body). Gadolinium 
is contrast material that causes some tumors to appear much brighter than 
normal tissue on MRI scans (these tumors may not be visible without 
gadolinium).  The contrast material may be given to you in your arm 
through an intravenous catheter (a tiny tube inserted into a vein).  You will 
then lie down on a narrow bed which will be placed in a tunnel that is 6 feet 
long by 22 inches wide and open at each end.   You will lie there quietly 
for about one hour, during which time you will hear a loud machine- 
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


ICF 09-13-2018
PAGE 3 OF 18
CC#15558
Hao Nguyen, MD, PhD
o 
like noise.  The MRI scan is done in the radiology department and takes 
approximately an hour and a half to complete. 
For the Sodium Flouride (NaF) Pet/CT, this is a special type of scan of the 
entire skeletal system that produces images of the bones. These images 
are used to detect areas of abnormal bone growth associated with tumors 
that may have spread from different organs, such as the prostate. You will 
be asked to not eat for six hours prior to the scan and to drink at least two 
large glasses of water within one hour of the study. Your NaF PET/CT 
scan will begin with an injection of a radioactive substance into a vein in 
your arm. You will be asked to rest quietly for a period of time (usually 
about 60 minutes) as the radioactive substance circulates throughout your 
body. After this time, you will be positioned within a large ring (similar to a 
big donut hole) on a scanning bed.  Once positioned properly, the bed will 
move you into the scanner.  As pictures are being taken, you will be asked 
to remain very still so clear images will be taken. The imaging time takes 
about 30 minutes.
o
A bone scan is a test that makes detailed images of your bones and any
tumors on them. Before the bone scan a small amount of radioactive 
substance is injected into your vein. About 3 hours later you will lie on a 
table under a machine which will make an image of your bones. The test 
itself will take about 1 hour, but the whole process takes up to 4 hours. 
<0000> Blood (about 2-3 tablespoons) will be drawn 
o
For routine safety tests
o
To check for hepatitis B and C
o
To check liver function
o
To check PSA levels - this test is used to measure the amount of protein
produced by the prostate that is in your blood and can help determine if 
you are responding to treatment
o
To check testosterone levels
<0000> Prostate Biopsy – You will be given an enema at least 1 hour prior to the 
procedure, and you will be given oral antibiotics at least 30 minutes prior to the 
procedure. You will then undergo a Transrectal Ultrasound (TRUS).  A 
transrectal ultrasound is routinely performed at the time of initial diagnosis of 
prostate cancer, at the time of gold marker placement to improve the accuracy of 
patient setup before radiation treatment delivery, and at the time of
brachytherapy. Thus, an ultrasound will be performed as part of routine care for 
patients with high-risk prostate cancer undergoing radiation therapy.  The test is 
safe and simple to perform. As you lie on your right or left side on an
examination table, an image of the prostate will be obtained. A small probe, the 
size and shape of an index finger and covered with a rubber shield, is gently 
inserted into your rectum. You will feel a sensation similar to a rectal
examination. 
The doctor will then perform a prostate biopsy which can be obtained accurately 
with the guidance of ultrasound. The biopsy is performed through the rectum 
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


ICF 09-13-2018
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CC#15558
Hao Nguyen, MD, PhD
with a needle. No numbing medication is necessary for this procedure since the 
needle is thin and the rectal wall is not sensitive to pain. You may feel some 
pressure, however, or experience a mild stinging sensation in your prostate when 
the doctor performs the biopsy. You can leave immediately after the procedure. 
o
If you have had a prostate biopsy and ultrasound within the past 6 months,
you may not need to repeat the procedures.
For research purposes 
<0000> Questions about how your disease is affecting your daily life 
<0000> EPIC 26, PROMIS, and EQ-5D Questionnaires - You will be asked to complete 
questionnaires to find out how prostate cancer affects your quality of life. 
<0000> Blood (about 3-4 tablespoons) will be drawn for research purposes. Blood will be 
used to identify potential changes in the genes (DNA) associated with 
enzalutamide resistance, gene expression patterns, and any changes in the 
immune response with enzalutamide treatment 
<0000> Collection of leftover, “archival”, tissue from a previous prostate biopsy if 
available. Tissues collected from a prior biopsy and during your participation in 
this study will be used for genetic testing to evaluate whether changes in a 
person’s DNA are involved in the response to enzalutamide. The tissue will also 
be used to evaluate gene (DNA) expression and changes and their relationship 
to the immune response. Please see the About Using Tissue For Research at 
the end of this consent form for more information. 
During the main part of the study...
If the exams, tests and procedures show that you can be in the main part of the study, 
and you choose to take part, then you will have the procedures listed below. 
Day 0 – begin androgen deprivation therapy with enzalutamide and leuprolide treatment 
<0000> Enzalutamide – Once every three months, you will receive a 3 month supply of 
enzalutamide during your clinic visits. Enzalutamide can be taken with or without 
food once a day. Please take the medication at the same time each day. 
Swallow capsules whole. Do not chew, dissolve, or open the capsules. 
<0000> Leuprolide - You will receive an injection of leuprolide during your clinic visits. 
The administration schedule for leuprolide may vary per patient; it can be given 
monthly or every 3-, 4-, or 6-months. Your study doctor will let you know which 
schedule you will follow. 
4-6 weeks after initiation of androgen deprivation therapy
This visit will take about 2-3 hours.  The following assessments will be performed. 
<0000> Blood (about 2-3 tablespoons) will be drawn 
o
For routine safety tests
o
To check liver function
o
To check PSA levels
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


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CC#15558
Hao Nguyen, MD, PhD
o
To check testosterone levels
<0000> Radiation Treatment Planning 
<0000> Your radiation doctor (radiation oncologist) will schedule a special CT 
scan (CT simulation scan). This scan will be done in a simulated treatment 
position so that your treating team can appropriately design the radiation 
treatment. Procedure will take approximately 1 hour. 
A CT scan uses special x-ray equipment to make detailed pictures of
body tissues and organs.   For these scans, no intravenous (IV)
contrast will be necessary.  You will lie flat on a table that will move
you into the CT scan machine.  You will be asked to lie still and may
be asked to hold your breath for a few seconds.   The CT scan is
done in the radiology department and takes about half an hour.
<0000> At the time of CT simulation, patients will be immobilized with a custom 
mold. While immobilized, the patient will be scanned. CT scan images 
obtained in this treatment position are sent to a radiation therapy-planning 
computer where your oncologist and his team design and calculate the 
appropriate radiation treatment. These calculations are double-checked 
and verified before the treatment starts. This process may take several 
days to complete.
<0000> On your first treatment day, radiation therapists will place you in exactly 
the same position as you were on the simulation CT scan. 
<0000> Prostate biopsy – may be performed per standard of care if the study doctor 
suspects your cancer has recurred 
For research purposes 
<0000> Review of any side effects 
<0000> Blood (about 3-4 tablespoons) will be drawn for research purposes. 
8 weeks after initiation of androgen deprivation therapy 
This visit will take about 1 hour.  The following assessments will be performed. 
<0000> Begin radiation therapy – 5 days a week for up to 5 weeks 
o
You will be monitored for any side effects weekly by the radiation
oncologist 
For research purposes 
<0000> Review of any side effects 
<0000> Questionnaires – about 5 days before the start of radiation therapy
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


ICF 09-13-2018
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CC#15558
Hao Nguyen, MD, PhD
Phase 2 Radiation Therapy  
This visit will take about 2-3 hours.  The following assessments will be performed. 
<0000> You will undergo a radiation boost to the prostate with internal radiation (termed 
as brachytherapy). 
<0000> Blood (about 2-3 tablespoons) will be drawn 
o
For routine safety tests
o
To check liver function
o
To check PSA levels
o
To check testosterone levels
<0000> Prostate biopsy – may be performed per standard of care if the study doctor 
suspects your cancer has recurred 
For research purposes 
<0000> Review of any side effects
<0000> Blood (about 3-4 tablespoons) will be drawn for research tests 
When you are finished receiving radiation… 
You will be asked to come into the clinic for follow up on your health status. The first 
visit will be 6 weeks after the end of your radiation treatment and then month 3-4, 
month 6, month 12, month 18, month 24, and month 36. If you no longer wish to 
participate in this follow-up period, please let your study doctor know. The following 
tests and procedures will be done during the clinic visits; the visits will take less than 1 
hour. 
<0000> Physical exam, including review of your medical history 
<0000> Blood (about 2-3 tablespoons) will be drawn
o
For routine safety tests
o
To check liver function
o
To check PSA levels
o
To check testosterone levels
<0000> Standard of care staging exams which may include MRI, NaF Pet/CT, or bone 
scan- to be performed if blood tests indicate PSA levels are rising
For research purposes 
<0000> Review of any side effects 
<0000> Questionnaires 
<0000> Blood (about 3-4 tablespoons) will be drawn for research tests – only at 
month 3-4 
Study location: All study procedures will be done at the Helen Diller Family
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


ICF 09-13-2018
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CC#15558
Hao Nguyen, MD, PhD
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019
Comprehensive Cancer Center. 
HOW LONG WILL I BE IN THE STUDY? 
You will receive enzalutamide and leuprolide for up to 2 years as long as you do not 
have severe side effects or until you decide to withdraw your consent to participate in 
this study or the study is closed. Though clinical guidances indicate that patients with 
high risk prostate cancer have the option of receiving androgen deprivation therapy 
anywhere from 2-3 years; at UCSF, the standard duration for hormone therapy is 2 
years.  The 2 year course of therapy is used in many institutions nationally and was also 
the standard dose used on the most recent national cooperative group clinical trial. 
There is no data that a period of greater than 2 years is beneficial over 2 years. The 
side effects of androgen deprivation therapy may also affect the your quality of life. You 
will receive radiation treatment for approximately 5 weeks. After you 
3 
are finished with 
radiotherapy ask you to visit the office for follow-up exams for up to 3 years.
CAN I STOP BEING IN THE STUDY? 
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about 
stopping or decide to stop they will tell you how to stop safely. 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
the study treatment can be checked by your doctor. Another reason to tell your doctor 
that you are thinking about stopping is to talk about what follow-up care and testing 
could be most helpful for your cancer treatment.
The study doctor may stop you from taking part in this study at any time if they believe it 
is in your best interest, if you do not follow the study rules, or if the study is stopped. 
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY? 
You may have side effects while on the study. 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 medicines to help lessen side effects. Many side effects go away soon after 
you stop radiation. In some cases, side effects can be serious, long lasting, or may 
never go away. There also is a risk of death. 
You should talk to your study doctor about any side effects that you experience while 
taking part in the study. 
3


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Risks and side effects related to the standard radiation therapy regimen 
Likely 
<0000> Feeling tired 
<0000> Increased urinary frequency 
<0000> Burning upon urination 
<0000> Urinary hesitancy 
<0000> Urinary urgency 
<0000> Loose stools or diarrhea 
Less Likely
<0000> Nausea
<0000> Vomiting
<0000> Decreased production of blood cells that may cause you to get infections 
Rare, but Serious 
<0000> Blockage or swelling of the intestines 
<0000> Fractures in bones of the spine 
<0000> Pain caused by nerve swelling
<0000> Ulceration of the rectum or bladder 
<0000> Skin toxicity 
Risks and side effects related to leuprolide 
Likely 
<0000> vasomotor hot flashes 
<0000> edema 
<0000> gynecomastia 
<0000> bone aches 
<0000> gastrointestinal disturbances 
<0000> decreased libido 
<0000> erectile dysfunction 
Less likely 
<0000> weight gain 
<0000> depression 
<0000> dizziness 
<0000> loss of bone density 
<0000> anemia 
<0000> increased thirst and urination 
<0000> unusual taste in the mouth 
<0000> skin redness or hives 
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


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<0000> pain at injection site 
<0000> and muscle mass and strength loss 
<0000> hair changes 
<0000> penile length and testicular volume loss 
<0000> increased cholesterol 
<0000> hypertension 
<0000> diabetes exacerbation 
<0000> emotional lability 
<0000> nausea
<0000> vomiting
<0000> rarely - allergic generalized rash and difficulty breathing, osteopenia or 
osteoporosis (bone mineral loss) 
Rare but serious
<0000> heart attack 
<0000> stroke 
<0000> bone fracture from osteoporosis (bone mineral loss) 
Risks and side effects related to enzalutamide 
Likely 
<0000> Fatigue (tiredness) 
<0000> Back pain 
<0000> Diarrhea 
<0000> Joint pain 
<0000> Hot flashes 
<0000> Peripheral edema (swelling of the legs, ankles, arms, etc) 
<0000> Muscle and bone pain 
<0000> Headache 
<0000> Upper/lower respiratory infection (cough)
<0000> Muscle weakness 
<0000> Dizziness 
<0000> Insomnia (being able to sleep at night) 
<0000> Spinal cord compression and cauda equina syndrome (symptoms of cauda 
equine include but are not limited to severe back pain, loss of sensation around 
your pelvis and midsection, unable to hold your urine or bowels, and sexual 
dysfunction) 
<0000> Hematuria (blood in your urine) 
<0000> Paresthesia (tingling or prickling sensation on your skin) 
<0000> Anxiety 
<0000> Hypertension (high blood pressure) 
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


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Less likely 
<0000> Falls, and fractures caused by falling 
<0000> Dry skin 
<0000> Itchiness 
<0000> Thinking or memory problems 
<0000> Hallucinations (seeing or feeling things that are not there) 
<0000> Heightened reactions by the body’s immune system, which can sometimes lead to fluid 
build-up in the face, tongue, upper-throat, or lip 
<0000> Narrowing of the blood vessels that lead to your heart, which can result in not 
enough blood supply to the heart, and sometimes can be fatal (ischemic heart disease) 
Rare but serious 
<0000> Brain disorder characterized by headache, seizure, blindness (also known as 
Reversible Posterior Leukoencephalopathy Syndrome) 
<0000> Seizures (convulsions)
<0000> Hemolytic Anemia (a condition in which red blood cells are destroyed and 
removed from the bloodstream before their normal lifespan is over). 
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 brain injury or tumor; or 
history of alcoholism. The risks related to the drug that are listed above are the same 
regardless of whether you receive enzalutamide by participating in the study or not. 
There are some medicines that are known to increase the chance of having a seizure. 
These medicines include but are not limited to:
<0000> Aminophylline/theophylline 
<0000> Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone) 
<0000> Bupropion 
<0000> Lithium 
<0000> Pethidine 
<0000> Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine,
prochlorperazine, thioridazine) 
<0000> Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, 
doxepin, imipramine, maprotiline, mirtazapine) 
Study Drug Combination risks: The side effects of the combination of enzalutamide, 
leuprolide, and radiation therapy are not yet known. It is possible that this combination 
of drugs will cause new or more serious side effects than taking these drugs separately. 
You will be monitored closely for side effects and your doctor may change your 
medications if it appears that this combination is causing serious side effects. You 
should tell your doctor about any side effects you experience while on this study. When 
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IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


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•
Radiation risks: This study involves exposure to radiation. This radiation
exposure is part of routine clinical care and is not related to research. You will not
receive additional radiation as a result of participating in this study. The goal of
the study is to determine whether the radiations risks occur less frequently with
the shorter treatment compared to standard treatment. If you have any questions
regarding the use of radiation or the risks involved, please consult the physician
conducting the study.
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019
additional information about side effects is known, you will be notified of any further 
study drug related effects. 
Blood Drawing (venipuncture) risks: Drawing blood may cause temporary discomfort 
from the needle stick, bruising, and infection. 
Questionnaire risks: Answering the Quality of Life questionnaire may be an 
inconvenience. Some of the questions may remind you of unpleasant aspects of your 
therapy or disease, and you may experience some discomfort, anxiety or distress in 
answering such questions. You are free to decline to answer any questions you do not 
wish to answer, or to stop participating at any time. 
Prostate biopsy risks: If you are taking blood thinners, such as aspirin, persantine, or 
coumadin, you should notify your doctor prior to the TRUS/biopsy. These medicines 
may cause serious bleeding complications after the biopsy, and will need to be stopped 
at least one week before the biopsy. Even without being on these medications there is 
a small (less than 5%) but real risk of bleeding from the biopsy site. Other risks include 
pain associated with the procedure, and infection despite the administration of 
antibiotics. 
You will need to avoid heavy exercise or pressure on the prostate (bicycle riding, etc.) 
or sexual activity for 24 hours. You may notice some blood in your urine, stools, or 
semen for several days. You will need to take all of the antibiotics even if you have no 
symptoms. If you develop a fever higher than 101 degrees with chills, or you continue 
to have a large amount of blood in your urine or stool, you should notify your doctor 
immediately or go to the hospital emergency room. 
Genetic testing of tissue samples risks: Genetic information about your tumor that 
results from this study does not have medical or treatment importance at this time, so 
you will not receive the results of this testing.  However, there is a risk that information 
about taking part in a genetic study may influence insurance companies and/or 
employers regarding your health. Since some genetic variations can help to predict the 
future health problems of you and your relatives, this information might be of interest to 
employers, health providers, insurance companies, and others. Patterns of genetic 
variation also can be used by law enforcement agencies to identify a person or his/her 
relatives. Therefore, your genetic information potentially could be used in ways that 
could cause you or your family distress, such as by revealing that you (or a relative) 
carry a genetic disease or by leading to the denial of employment or insurance for you 
(or a relative). To further safeguard your privacy, genetic information obtained in this 
study will not be placed in your medical record. 
Radiation/Scan Procedures: 


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<0000> MRI risks: Because the MRI machine acts like a large magnet, it could move 
iron-containing objects in the MRI room during your examination, which in the 
process could possibly harm you.  Precautions have been taken to prevent such 
an event from happening; loose metal objects, like pocket knives or key chains are 
not allowed in the MRI room.  If you have a piece of metal in your body, such as a 
fragment in your eye, aneurysm clips, ear implants, spinal nerve stimulators, or a 
pacemaker, you will not be allowed into the MRI room and cannot have an MRI. 
Having an MRI may mean some added discomfort for you.  In particular, you may 
be bothered by feelings of claustrophobia and by the loud banging noise during the 
study.  Temporary hearing loss has been reported from this loud noise.  This is why 
you will be asked to wear earplugs.  At times during the test, you may be asked to 
not swallow for a while, which can be uncomfortable. 
Contrast agent (gadolinium) risks: A few side effects of gadolinium injection 
such as mild headache, nausea, and local pain may occur. Rarely (less than 1% of 
the time) low blood pressure and lightheadedness occurs. This can be treated 
immediately with intravenous fluids. Very rarely (less than one in one thousand), 
patients are allergic to gadolinium. These effects are most commonly hives and 
itchy eyes, but more severe reactions have been seen which result in shortness 
of breath. 
Patients  with  severe  kidney  disease  sometimes  have  a  bad  reaction  to 
gadolinium contrast. The condition is called nephrogenic systemic fibrosis (NSF). 
It can cause skin to tighten or scar and can damage internal organs. Sometimes 
it can be life-threatening. There are no reports of NSF in patients with normal kidney 
function. Before you have a MRI scan requiring an injection of gadolinium contrast, 
you will have a blood test in order to check the function of your kidneys. Based on 
your medical history and the results of the test, a doctor will decide whether it 
is safe for you to undergo the MRI scans.
<0000> CT scan risks: CT scans involve the risks of radiation (see above). 
Having a CT scan may mean some added discomfort for you.  In particular, you 
may be bothered by feelings of claustrophobia when placed inside the CT scanner, 
or by lying in one position for a long time. 
<0000> NaF Pet/CT scan risks: The PET/CT scan exposes your body to radiation, see 
radiation risk above. The radiation levels come from a tracer which is a 
radioactive chemical injected into a vein in your arm. The tracer lets the doctor 
see how your cells are functioning and the radiation levels are very low. You may 
have an allergic reaction to the chemical used in the scan. For some patients, 
having to lie still on the scanning table for the length of the procedure may cause 
some discomfort or pain. After the scan your arm may be a little bit sore or have 
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


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some redness where the IV was placed in your arm. The radioactive solution 
does not remain in your system for a long period of time. However, you should 
wait 2 hours before holding an infant or getting close to a pregnant woman to 
avoid exposing them to radiation.  You should drink fluids after the scan to help 
remove the solution from your system. 
Reproductive risks: You should not father a baby while on this study because the 
drugs in this study can affect an unborn baby.  It is important to understand that you 
need to use birth control while on this study and for up to 4 months (120 days) after the 
last dose of study drug or agree to completely abstain from intercourse. Check with 
your study doctor about what kind of birth control methods to use and how long to use 
them. Some methods might not be approved for use in this study. 
Unknown Risks: The experimental treatments may have side effects that no one 
knows about yet. The researchers will let you know if they learn anything that might 
make you change your mind about participating in the study. 
For more information about risks and side effects, ask your study doctor. 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
Taking part in this study may or may not make your health better. We do know that the 
information from this study will help doctors learn more about the combination of 
enzalutamide and leuprolide along with radiotherapy as a treatment for cancer. This 
information could help future cancer patients.
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
Your other choices may include: 
<0000> Getting radiation treatment or care for your cancer without being in a study 
(fractionated radiation therapy with or without leuprolide) 
<0000> Taking part in another study 
<0000> Getting comfort care, also called palliative care - this type of care helps reduce 
pain, tiredness, appetite problems and other problems caused by the cancer; 
comfort care does not treat the cancer directly, it works to improve how you feel 
and keep you as active and comfortable as possible 
<0000> Getting no treatment 
Your physician will discuss these other options with you. Please talk to your doctor 
about your choices before deciding if you will take part in this study.
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


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WILL MY MEDICAL INFORMATION BE KEPT PRIVATE? 
We will do our best to make sure that the personal information in your medical record is 
kept private. However, we cannot guarantee total privacy. Your personal information 
may be given out if required by law. If information from this study is published or 
presented at scientific meetings, your name and other personal information will not be 
used.
Organizations that may look at and/or copy your medical records for research, quality 
assurance, and data analysis include: 
<0000> Astellas Pharma and their associates 
<0000> National Comprehensive Cancer Network (NCCN) 
<0000> The National Cancer Institute (NCI) and other government agencies, e.g., the 
Food and Drug Administration (FDA), involved in overseeing research 
<0000> The University of California 
Participation in research may involve a loss of privacy, but information about you will be 
handled as confidentially as possible. A medical record will be created because of your 
participation in this study. Your consent form and some of your research test results will 
be included in this record.  Therefore, your other doctors may become aware of your 
participation. Hospital regulations require that all health care providers treat information 
in medical records confidentially.
California regulations require laboratories to report new cases of HIV, hepatitis B, and 
hepatitis C infection to the county public health department. The reports include the 
patient’s name, social security number, and other identifying information. Information 
about these new infections is used to track these diseases statewide and nationwide. 
Other than this required reporting, your results will be treated confidentially by the study 
staff. Personally identifying information will not be reported to other departments or 
agencies. 
WHAT ARE THE COSTS OF TAKING PART IN THE STUDY? 
You and/or your health plan/insurance company will need to pay for some or all of the 
costs of treating your cancer in this study. Some health plans will not pay these costs 
for taking part in studies. Check with your health plan/insurance company to find out 
what they will pay for. Your study doctors or their clinical staff will obtain authorization 
from your insurance company prior to beginning your treatment. Taking part in this 
study may or may not cost you or your insurance company more than the cost of getting 
regular cancer treatment. 
Astellas Pharma is supplying enzalutamide free of charge. You will not be billed for any 
of the tests or procedures required specifically by the study. These tests and
procedures noted above as “for research purposes” (questionnaires and blood draw for 
research) in this consent form.  Other procedures, which are also done in this research 
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IRB EXPIRATION DATE: 06/25/2019


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study but are part of your routine care, will be paid for by you or your insurance. This 
includes leuprolide, radiation therapy, scans, blood tests, and physical exams that are 
considered part of the standard treatment for your cancer. 
For more information on clinical trials and insurance coverage, you can visit the National 
Cancer Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance- 
coverage. You can print a copy of the "Clinical Trials and Insurance Coverage" 
information from this Web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and 
ask them to send you a free copy. 
WILL I BE PAID FOR TAKING PART IN THIS STUDY? 
You will not be paid for taking part in this study. 
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY? 
It is important that you tell your study doctor Hao Nguyen, MD, PhD if you feel that you 
have been injured because of taking part in this study. You can tell him in person or call 
him 
. 
Treatment and Compensation for Injury: If you are injured as a result of being in this 
study, the University of California will provide necessary medical treatment. The costs of 
the treatment may be billed to you or your insurer just like any other medical costs, or 
covered by the University of California depending on a number of factors. The 
University does not normally provide any other form of compensation for injury. For 
further information about this, you may call the office of the Committee on Human 
Research at 415- 476-1814. 
WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY? 
Taking part in this study is your choice. You may choose either to take part or not to 
take part in the study. If you decide to take part in this study, you may leave the study at 
any time. No matter what decision you make, there will be no penalty to you and you will 
not lose any of your regular benefits. Leaving the study will not affect your medical care. 
You can still get your medical care from our institution. 
We will tell you about new information or changes in the study that may affect your 
health or your willingness to continue in the study. 
In the case of injury resulting from this study, you do not lose any of your legal rights to 
seek payment by signing this form. 
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


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WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
You can talk to your study doctor about any questions, concerns, or complaints you 
have about this study. Contact your study doctor Hao Nguyen, MD, PhD 
If you wish to ask questions about the study or your rights as a research participant to 
someone other than the researchers or if you wish to voice any problems or concerns 
you may have about the study, please call the Office of the Committee on Human 
Research at 415-476-1814. 
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. 
************************************************************ 
Please note: This section of the informed consent form is about additional research 
studies that are being done with people who are taking part in the main study. You may 
take part in these additional studies if you want to. You can still be a part of the main 
study even if you say "no" to taking part in any of these additional studies. 
About Using Blood and Tissue For Research
While you are participating in this study, you will have a series of biopsies performed and 
blood drawn specifically for research purposes. The study team will collect leftover 
tissue from the biopsy procedures and blood drawn for research for genetic testing to 
evaluate whether changes in a person’s DNA are involved in the response to 
enzalutamide. The tissue and blood samples will also be used to evaluate gene (DNA) 
expression and changes and their relationship to the immune response. The tissue and 
blood samples will be stored indefinitely at UCSF. All samples will be de-identified (your 
name and any identifiable information will not be included with the samples) and labeled 
with a case number. The study team would like your permission to conduct future 
research to learn more about cancer and other diseases on the stored samples. 
Reports about research done with your tissue and blood sample will not be given to you 
or your doctor. These reports will not be put in your health record. The research will not 
have an effect on your care. 
Things to Think About 
The choice to let us perform additional future research on the stored samples is up to 
you. No matter what you decide to do, it will not affect your care. 
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


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If you decide now that additional research can be performed, you can change your mind 
at any time. Just contact the study doctor Hao Nguyen, MD, PhD at the following 
address, and let him know that you do not want him to use your tissue and blood 
samples. Then any samples that remain will no longer be used for future research. 
Hao Nguyen, MD, PhD  
University of California San Francisco 
 
In the future, people who do research may need to know more about your health. While 
UCSF may give them reports about your health, it will not give them your name, 
address, phone number, or any other information that will let the researchers know who 
you are.
Your tissue and blood samples will be used only for research and will not be sold. The 
research done with your stored samples may help to develop new products in the 
future. You will not be paid for allowing your blood and tissue samples to be used in 
research even though the research done with your samples may help to develop new 
products in the future. You will not receive any payment or financial benefit from any 
products, tests, or discoveries derived from these samples. 
Benefits 
The research that may be done with your tissue and blood samples is not designed 
specifically to help you. It might help people who have cancer and other diseases in the 
future. 
The benefits of research using tissue and blood include learning more about what 
causes cancer and other diseases, how to prevent them, and how to treat them. 
Risks 
The greatest risk to you is the release of information from your health records. We will 
do our best to make sure that your personal information will be kept private. The chance 
that this information will be given to someone else is very small.
Making Your Choice 
Please read each sentence below and think about your choice. After reading each 
sentence, put your initials in the "Yes" or "No" box. If you have any questions, please 
talk to your doctor or nurse, or call our research review board at 415-476-1814. No 
matter what you decide to do, it will not affect your care. 
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019


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I allow additional research to be performed on my tissue and blood samples in the 
future. 
YES 
NO 
************************************************************ 
CONSENT
You have been given copies of this consent form and the Experimental Subject's Bill of 
Rights to keep. 
You will be asked to sign a separate form authorizing access, use, creation, or 
disclosure of health information about you. 
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to 
which you are otherwise entitled.
If you wish to participate in this study, you should sign below. 
Date 
Participant's Signature for Consent
Date 
Person Obtaining Consent
Date 
Witness Signature (Only required if the participant is
a non-English speaker)
IRB NUMBER: 15-17292
IRB APPROVAL DATE: 10/23/2018
IRB EXPIRATION DATE: 06/25/2019