A Phase II Trial of Androgen Deprivation, Docetaxel and Enzalutamide in Patients With Metastatic Hormone Sensitive Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer, Prostate Adenocarcinoma
Sponsor: Wake Forest University Health Sciences

Protocol Number: LCI-GU-PRO-ADDE-001 
Version 3: March 14, 2022 
 
 
TITLE:  A PHASE II TRIAL OF ANDROGEN DEPRIVATION, DOCETAXEL AND 
ENZALUTAMIDE IN PATIENTS WITH METASTATIC HORMONE SENSITIVE 
PROSTATE CANCER. 
 
LAY TITLE: ANDROGEN DEPRIVATION, DOCETAXEL AND ENZALUTAMIDE IN 
ADVANCED HORMONE SENSITIVE PROSTATE CANCER 
 
Coordinating Center: 
Levine Cancer Institute 
Carolinas Medical Center 
1021 Morehead Medical Drive 
 
Charlotte, NC 28204 
 
 
Sponsor-Investigator: 
 
Earle Burgess, MD 
Levine Cancer Institute 
1021 Morehead Medical Drive 
Charlotte, NC 28204 
Telephone: (980) 442-9347 
Email: earle.burgess@atriumhealth.org 
 
Statistician: 
James Symanowski, Ph.D. 
Levine Cancer Institute 
1100 Blythe Boulevard 
Charlotte, NC 28203 
Telephone: (980) 442-2371 
Email: James.Symanowski@atriumhealth.org  
 
 
 

Protocol Number: LCI-GU-PRO-ADDE-001 
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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
 
ADT 
 
 
 
Androgen deprivation therapy 
AE  
 
 
 
Adverse event 
ALT  
 
 
 
Alanine transaminase 
AST  
 
 
 
Aspartate transaminase 
AR  
 
 
 
Androgen receptor 
ARV7  
 
 
Androgen receptor splice variant 7 
BUN   
 
 
Blood urea nitrogen 
CBCD   
 
 
Complete blood count with differential 
CMP   
 
 
Complete metabolic profile 
CT  
 
 
 
Computed tomography 
CTC 
 
 
 
Circulating tumor cell 
CTCAE  
 
 
Common terminology criteria for adverse events 
CTMS   
 
 
Clinical trial management system 
DNA    
 
 
Deoxyribonucleic acid 
DSMC   
 
 
Data and safety monitoring committee 
ECOG    
 
 
Eastern Cooperative Oncology Group 
ECRF   
 
 
Electronic case report form 
FN   
 
 
 
Febrile neutropenia 
IB   
 
 
 
Investigator brochure 
IDS                                                Investigational drug Services  
IRB  
 
 
 
Institutional review board 
LCI  
 
 
 
Levine Cancer Institute 
LHRH   
 
 
Luteinizing hormone-releasing hormone 
MCRPC  
 
 
Metastatic castrate resistant prostate cancer 
OS 
 
 
 
Overall survival 
PCWG2 
 
 
Prostate cancer working group 2 
PD 
 
 
 
Progressive disease 
PRES    
 
 
Posterior reversible encephalopathy syndrome 
PSA 
 
 
 
Prostate specific antigen   
RECIST    
 
 
Response evaluation criteria in solid tumors 
RPFS  
 
 
Radiographic progression free survival  
SAE    
 
 
Serious adverse event 
SAR  
 
 
 
Suspected adverse reaction 
SPFS  
 
 
Serologic Progression Free Survival 
UAP   
 
 
Unanticipated problem 
ULN    
 
 
Upper limit of normal 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
SCHEMA……………………………………………………………………..………………………………………..2 
LIST OF ABBREVIATIONS………………………………………………..……………………………………3 
TABLE OF CONTENTS…………………………………………………………..………………………………4 
 
 
1. 
Objectives ......................................................................................................................................... 8 
1.1 
Primary Objective .................................................................................................................. 8 
1.2 
Secondary Objectives ........................................................................................................... 8 
1.3 
Exploratory Objectives ........................................................................................................ 8 
2. 
Background and Rationale ......................................................................................................... 8 
2.1 
Prostate Cancer ...................................................................................................................... 8 
2.2 
Enzalutamide and Prostate Cancer ................................................................................ 9 
2.3 
Biomarkers in Advanced Prostate Cancer ................................................................ 10 
2.3.1 
Circulating Tumor Cells ........................................................................................... 10 
2.3.2 
Androgen Receptor Splice Variant 7 .................................................................. 10 
2.4 
Rationale for Proposed Study ........................................................................................ 11 
3. 
Overall Study Design and Plan .............................................................................................. 11 
4. 
Subject Selection ......................................................................................................................... 12 
4.1 
Inclusion Criteria ................................................................................................................ 12 
4.2 
Exclusion Criteria ............................................................................................................... 13 
5. 
Investigational Plan ................................................................................................................... 14 
5.1 
Milestone Date Definitions ............................................................................................. 14 
5.2 
Registration and Enrollment.......................................................................................... 15 
5.3 
Pre-treatment Screening Period ................................................................................... 15 
5.3.1 
Clinical Assessments................................................................................................. 15 
5.3.2 
Radiologic Assessments .......................................................................................... 16 
5.3.3 
Laboratory Assessments ......................................................................................... 17 
5.4 
Treatment Period ............................................................................................................... 17 
5.4.1 
Treatment Assessments .......................................................................................... 17 
5.5 
Treatment Discontinuation ............................................................................................ 19 
5.6 
End of Treatment Period ................................................................................................. 20 
5.7 
Follow up Period ................................................................................................................. 20 
5.8 
Off Study ................................................................................................................................. 21 

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6. 
Study Calendars .......................................................................................................................... 23 
6.1 
Docetaxel and Castrate Sensitive Enzalutamide Treatment Phases............... 23 
6.2 
Castrate Resistant Treatment Phase and End of Treatment ............................. 25 
7. 
Study Treatment ......................................................................................................................... 26 
7.1 
Treatment .............................................................................................................................. 26 
7.1.1 
Androgen Deprivation Therapy ........................................................................... 26 
7.1.2 
Docetaxel ....................................................................................................................... 27 
7.1.3 
Enzalutamide ............................................................................................................... 28 
7.2 
Concomitant Therapy ....................................................................................................... 30 
7.2.1 
Medications .................................................................................................................. 30 
7.2.2 
Radiotherapy ............................................................................................................... 30 
7.2.3 
Surgery ........................................................................................................................... 31 
7.3 
Treatment Compliance ..................................................................................................... 31 
7.4 
Drug Accountability ........................................................................................................... 31 
7.5 
Destruction ........................................................................................................................... 32 
8. 
Treatment-Related Adverse Events .................................................................................... 32 
8.1 
Reproductive Risks ............................................................................................................ 32 
8.2 
Dose Modifications for Androgen Deprivation Therapy ..................................... 32 
8.3 
Dose Modifications for Docetaxel................................................................................. 33 
8.3.1 
Dose Levels ................................................................................................................... 33 
8.3.2 
Myelosuppression ..................................................................................................... 33 
8.3.3 
Hepatic Dysfunction ................................................................................................. 34 
8.3.4 
Peripheral Neuropathy ............................................................................................ 34 
8.4 
Dose Modifications for Enzalutamide ........................................................................ 34 
8.4.1 
Dose Levels ................................................................................................................... 34 
8.4.2 
Seizures ......................................................................................................................... 35 
8.4.3 
Posterior Reversible Encephalopathy Syndrome ......................................... 35 
8.4.4 
Hypersensitivity ......................................................................................................... 35 
8.4.5 
Ischemic Heart Disease ........................................................................................... 36 
8.4.6 
Falls and Fractures .................................................................................................... 36 
8.4.7 
Embryo-Fetal Toxicity ............................................................................................. 36 
9. 
Data and Safety Monitoring Plan .......................................................................................... 36 
9.1 
Communication Between Investigational Sites ...................................................... 37 
10. 
Safety Data Collection, Recording and Reporting ...................................................... 37 

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10.1 
Adverse Event Definitions .......................................................................................... 37 
10.1.1 Unanticipated Problem (UAP) Definition ......................................................... 37 
10.1.2 Adverse Event (AE) Definition ............................................................................. 38 
10.1.3 Adverse Event Attribution ..................................................................................... 39 
10.1.4 Adverse Event Reporting ........................................................................................ 40 
10.1.5 Suspected Adverse Reaction (SAR) Definition ............................................... 40 
10.1.6 “Unexpected” Definition .......................................................................................... 40 
10.1.7 Serious Adverse Event (SAE) Definition ........................................................... 40 
10.2 
Expedited Safety Reporting........................................................................................ 41 
10.2.1 Expedited Safety Reporting to the Sponsor-Investigator .......................... 41 
10.2.2 Expedited Safety Reporting to the IRB .............................................................. 41 
10.2.3 Expedited Safety Reporting to Astellas ............................................................. 42 
11. 
Measurement of Effect .......................................................................................................... 42 
11.1 
Serologic Assessment ................................................................................................... 42 
11.1.1 PSA Response .............................................................................................................. 42 
11.2 
Radiographic Assessment ........................................................................................... 43 
11.2.1 RECIST............................................................................................................................ 43 
11.2.2 Evaluation of Skeletal Lesions .............................................................................. 47 
12. 
Statistical Considerations .................................................................................................... 47 
12.1 
Sample Size ....................................................................................................................... 47 
12.2 
Endpoint Definitions ..................................................................................................... 48 
12.2.1 Serologic ........................................................................................................................ 48 
12.2.2 Radiographic ............................................................................................................... 49 
12.2.3 Overall Survival .......................................................................................................... 50 
12.2.4 Safety Endpoints ........................................................................................................ 50 
12.3 
Analysis Populations ..................................................................................................... 51 
12.4 
Analysis Methods ........................................................................................................... 51 
12.4.1 Timing of Analysis ..................................................................................................... 51 
12.4.2 Subject Disposition ................................................................................................... 51 
12.4.3 Baseline Subject and Disease Characteristics ................................................. 52 
12.4.4 Efficacy Analysis ......................................................................................................... 52 
12.5 
Interim Analyses............................................................................................................. 54 
13. 
Biomarker Analysis ................................................................................................................ 54 
13.1 
Circulating Tumor Cells ............................................................................................... 54 

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14. 
Study Completion ................................................................................................................... 54 
14.1 
Completion ....................................................................................................................... 54 
14.2 
Termination ..................................................................................................................... 54 
14.3 
Retention of Records .................................................................................................... 55 
15. 
Ethical and Legal Issues ....................................................................................................... 55 
15.1 
Study Conduct ................................................................................................................. 55 
15.2 
Confidentiality ................................................................................................................. 56 
15.3 
Publication ........................................................................................................................ 56 
16. 
References ................................................................................................................................. 57 
 
 
 

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1. Objectives 
 
1.1 Primary Objective 
 
To assess the 52-week prostate specific antigen (PSA) complete response 
rate in subjects with metastatic hormone sensitive prostate cancer 
treated with the combination of androgen deprivation therapy (ADT), 
docetaxel and enzalutamide. 
 
1.2 Secondary Objectives 
 
To assess PSA and radiographic response rates, time to castrate 
resistance, serologic progression-free survival (sPFS), radiographic 
progression free-survival (rPFS), time to treatment failure, overall 
survival (OS) and the safety and toxicity profile of this regimen. 
 
1.3 Exploratory Objectives 
 
To assess and correlate baseline circulating tumor cell levels and 
androgen receptor splice variant 7 (ARv7) protein expression with 
primary and secondary objectives. 
 
2. Background and Rationale 
 
2.1 Prostate Cancer 
  
Prostate cancer is the most common malignancy in men with over twenty 
seven thousand deaths anticipated in the United States in 2015.1  
Management of patients with advanced disease remains focused on 
improving tumor related morbidity and mortality, as no curative 
therapies currently exist.  The role of androgen signaling in this disease 
has long been recognized and underlies current treatment strategies.2  
Although inhibition of the androgen axis through suppression of 
testosterone levels induces high initial response rates in men with 
metastatic disease, overall survival remains generally poor and cancer 
related morbidity is common, underscoring the need for more effective 
therapies.3 
 
Until recently, men with metastatic prostate cancer were initially 
managed with primary ADT alone, though seminal results of two large 
randomized trials have recently demonstrated a marked survival 
improvement and delay in the development of castrate resistance by the 
addition of docetaxel.4,5  Results from a large cooperative group study 
reported by Sweeney et al.  demonstrated that the addition of docetaxel 
to ADT in the treatment naïve setting improved overall survival by 13.6 
months (p<0.001) and delayed the time to castrate resistance from 11.7 

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months to 20.2 months (p<0.001).  Although the improvement in overall 
survival was more pronounced in the men with “high volume” metastatic 
disease, the benefit was statistically significant for the entire study 
population.  The PSA complete response rate (<0.2 ng/mL) at 12 months 
was also improved in the chemohormonal therapy arm (27.7% vs 16.8%, 
p<0.001).4  Preliminary results from another large randomized trial 
comparing the addition of docetaxel to ADT alone in men with metastatic 
disease show similar findings with an OS improvement noted in the 
chemohormonal therapy arm,5 thus providing confirmation that 
docetaxel provides marked synergistic benefit when combined with ADT 
in men with metastatic castrate sensitive prostate cancer. 
 
On the basis of these trials, the use of chemohormonal therapy has 
become the standard of care in fit patients presenting with metastatic 
disease.  Although the survival improvement gained by the addition of 
docetaxel to ADT represents an important advancement in the field, 
median survival for this population remains less than five years,4 
particularly in patients with high volume disease, highlighting the need 
for more effective therapeutic strategies. 
 
2.2 Enzalutamide and Prostate Cancer 
 
In the metastatic setting, resistance to androgen suppression inevitably 
develops due in part to tumor cell upregulation of the androgen receptor 
(AR) and persistence of intratumoral androgens.6,7 
 
Enzalutamide is a potent androgen receptor inhibitor that binds the AR 
ligand binding domain, impairing nuclear translocation and DNA 
binding.8  In patients with metastatic castrate resistant prostate cancer 
(mCRPC), enzalutamide improves overall survival in the pre-9 and post-
docetaxel10 settings, which underscores the critical role of continued AR 
signaling despite castrate androgen levels. 
 
Enzalutamide has also been studied in less advanced clinical settings.  In 
a small pilot study of patients with treatment naïve prostate cancer and 
non-castrate androgen levels, enzalutamide monotherapy led to a PSA 
decline of at least 80% after six months of therapy in 93% of patients.11  
It is therefore anticipated that more stringent blockade of the androgen 
axis using the non-cross resistant mechanisms of action of enzalutamide 
in combination with primary ADT may improve clinical outcomes in men 
with hormone sensitive metastatic disease and is the subject of ongoing 
clinical trials (NCT02446405, NCT02058706).   
 
In patients with mCRPC, both enzalutamide9,10 and docetaxel12 improve 
survival as single agents when given with ADT.  In preclinical prostate 
cancer models, enzalutamide inhibits the drug efflux pump ABCB1 and 

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restores sensitivity to docetaxel, suggesting potential clinical synergy 
with the combination of these two agents.13 In humans, the combination 
of enzalutamide and docetaxel has been studied in the phase I setting and 
appears safe at standard doses.  Of note, enzalutamide induces CYP3A4, 
which is responsible for the metabolism of docetaxel; however, docetaxel 
pharmacokinetics do not appear to be significantly impacted by the 
addition of enzalutamide.14  Further study of the efficacy of this 
combination at standard doses is ongoing in the castrate resistant setting 
(NCT02453009). 
 
2.3 Biomarkers in Advanced Prostate Cancer 
 
2.3.1 Circulating Tumor Cells 
 
Available biomarkers to guide therapeutic decisions in patients with 
metastatic prostate cancer are limited.  Enumeration of circulating tumor 
cells (CTCs) from the peripheral blood of metastatic prostate cancer 
patients has demonstrated prognostic value in the castrate resistant and 
castrate sensitive settings.15-17 Although early studies are based on a 
platform utilizing an immunoaffinity cell capture methodology, 
comparison of immunoaffinity versus size filtration-based CTC 
enrichment suggests that immunoaffinity-based strategies may be less 
sensitive and lack the ability to capture cytokeratin negative CTCs or CTC 
clusters, which may have additional prognostic value.18,19 Despite the 
established prognostic value in patients with advanced prostate cancer, 
how best to utilize CTC enumeration in the clinical setting remains poorly 
defined as an established role for prediction of treatment response is 
lacking. 
 
2.3.2 Androgen Receptor Splice Variant 7 
 
Although second generation AR antagonists improve the outcome of 
patients with mCRPC, resistance to these agents inevitably develops.  
Recently described AR genomic aberrations including mutations20 and 
mRNA splice variants21,22 appear to play a critical role mediating 
resistance to agents such as enzalutamide.  Androgen receptor splice 
variant 7 (ARv7) is a mRNA splice variant lacking the canonical ligand 
binding domain and is frequently detected in patients with mCRPC.22   
 
Antonarakis et al.  elegantly demonstrated that patients with detectable 
ARv7 in CTCs do not respond as well to enzalutamide or abiraterone,23 
suggesting this may be a key mechanism of resistance for AR targeted 
therapies.  However, ARv7 expression does not appear predictive for 
taxane resistance24,25 and may actually decline following taxane-based 
therapy.26  These observations raise the possibility that chemotherapy 
may potentially sensitize patients to AR targeted agents when ARv7 

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expression emerges.  Whether concurrent taxane-based therapy with 
second generation AR targeted therapies influences the timing and 
expression level of the ARv7 aberration is unknown and warrants further 
investigation. 
 
2.4 Rationale for Proposed Study 
 
Two large randomized trials have recently shown that the addition of 
docetaxel to ADT in men with metastatic treatment naïve prostate cancer 
significantly improves patient survival and clinical outcomes and has 
become the standard of care in appropriately fit patients.  Docetaxel also 
improves survival in the castrate resistant setting; however, the 
magnitude of synergism between docetaxel and ADT is clearly greater in 
the androgen dependent tumor setting. 
 
In patients with more advanced mCRPC, the AR antagonist enzalutamide 
also improves survival.  The combination of enzalutamide and docetaxel 
may enhance antitumoral efficacy over monotherapy with either agent 
based on preclinical observations that enzalutamide may potentially 
enhance the cytotoxic effect of docetaxel through inhibition of the ABCB1 
drug efflux pump.  Furthermore, docetaxel may eradicate tumor clones 
with ARv7 splice variant expression and prolong sensitivity to 
enzalutamide.  This combination is currently being studied in patients 
with mCRPC, though whether this regimen improves outcomes in the 
hormone sensitive setting is unknown.  It is therefore hypothesized that 
the addition of enzalutamide to the standard combination of ADT and 
docetaxel may be well tolerated and demonstrate improved antitumoral 
efficacy compared to ADT and docetaxel alone in patients with metastatic 
castrate sensitive prostate cancer.  Enumeration of CTCs and detection of 
ARv7 expression may also predict clinical outcomes in this setting.   
 
3. Overall Study Design and Plan 
 
This is a single center, single arm, phase II trial designed to evaluate the 
52-week PSA complete response rate in subjects with metastatic 
hormone sensitive prostate cancer treated with ADT, docetaxel and 
enzalutamide.  
 
Patients with metastatic (M1) adenocarcinoma of the prostate who are 
previously untreated or have received ADT for 16 weeks or less without 
development of castrate resistance will be eligible.  Subjects will be 
stratified by the presence of high or low volume disease, as defined in 
Section 5.2.  Based on a total of 39 subjects, the study will restrict 
enrollment to 13 subjects with low volume disease and 26 subjects with 
high volume disease in an effort to enroll a subject population similar to a 

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contemporary control study, which serves as the basis for the present 
study.4 
 
Subjects will receive continuous androgen deprivation for the study 
duration to maintain castrate androgen levels.  Additionally, all subjects 
will receive docetaxel 75mg/m2 IV over 1 hour every 21 days for a 
maximum of 6 cycles and enzalutamide 160mg orally with or without 
food daily until the development of clinical or radiographic progression 
utilizing RECIST 1.1 and PCWG2 criteria.27  Subjects who develop 
serologic progression only will be encouraged to remain on study 
therapy until radiographic or clinical progression.   
 
Disease response rates will be assessed serologically by measuring 
serum prostate specific antigen (PSA) every 3 weeks during docetaxel 
therapy followed by every 8 weeks once docetaxel is completed.  After 
the development of castrate resistance as determined by PSA 
progression using PCWG2 criteria, serum PSA will be monitored every 28 
days until the end of study treatment.  Radiographic imaging will include 
chest imaging, a computed tomography scan of the abdomen and pelvis, 
and radionuclide bone scan at baseline, at the development of castrate 
resistance, and every 12 weeks following castrate resistance until the 
end of study treatment.  
 
The primary endpoint of this study will be 52-week PSA complete 
response rate, which will be assessed against a contemporary historical 
control rate for the combination of ADT and docetaxel alone in the 
metastatic hormone naïve setting.4  
 
The study will be conducted at all participating sites across North and 
South Carolina within the Levine Cancer Institute network.  Enrollment is 
anticipated to be completed in approximately 24 months. 
 
4. Subject Selection 
 
Following informed consent and registration, subjects will undergo study 
eligibility screening.  Each of the criteria in the following section must be 
met for a subject to be eligible for study participation. 
 
4.1 Inclusion Criteria 
 
1. Histologically or cytologically confirmed adenocarcinoma of the 
prostate without evidence of small cell carcinoma or greater than 
50% neuroendocrine differentiation.  Metastatic disease must be 
present including soft tissue, and/or bone metastases OR non-
regional lymph node involvement prior to study enrollment.  If the 
subject has regional lymph node involvement, there must be at 

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least one additional site of disease including visceral, non-regional 
nodal or skeletal metastases. 
2. ADT with surgical castration with bilateral orchiectomy or 
medical castration with LHRH agonist or LHRH antagonist therapy 
may have been initiated no greater than 112 days (16 weeks) 
prior to enrollment date.  Subjects who initiated ADT prior to 
consent, are not eligible if PSA has risen ≥ 25% and ≥ 2 ng/ml 
above nadir value since initiation of ADT prior to consent. 
3. At least one PSA level of ≥ 5 ng/ml within 90 days prior to 
consent.   
4. Prior ADT for non-metastatic disease with LHRH agonist or LHRH 
antagonist therapy in the neoadjuvant/adjuvant setting is 
permitted if: 
a. Total duration of therapy did not exceed 36 months 
b. 6 months have elapsed since completion of therapy prior 
to consent.  
c. Serum testosterone > 50 ng/dl within 28 days prior to re-
initiation of ADT for metastatic disease.  
d. Prior ADT for non-metastatic disease must have 
accompanied definitive local therapy for curative intent. 
5. Age ≥ 18 years. 
6. ECOG performance status 0-2. 
7. Adequate liver function: AST and ALT <1.5x upper limit of normal, 
total bilirubin < 1x upper limit of normal. 
8. Adequate bone marrow function: Platelets >100,000 cells/mm3, 
Hemoglobin > 8.0g/dL and ANC > 1,500 cells/mm3. 
9. Adequate renal function with a creatinine clearance (based on 
Cockcroft-Gault formula) ≥ 30 mL/min. 
10. Ability to understand and the willingness to sign a written 
informed consent document. 
11. Able to swallow and retain oral medication. 
 
4.2 Exclusion Criteria 
 
1. Personal history of seizure. 
2. Personal history of conditions that may predispose to seizure 
activity including cortical cerebrovascular accident or brain 
trauma.     
3. Known central nervous system metastases, including involvement 
of brain parenchyma and leptomeninges.     
4. Personal history of any condition that may impair absorption of 
enzalutamide. 
5. Prior or current therapy with ketoconazole, abiraterone, 
enzalutamide, apalutamide (ARN-509, JNJ-56021927), 
darolutamide (ODM-201, BAY1841788) or cytotoxic 
chemotherapy such as docetaxel, cabazitaxel, cyclophosphamide. 

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6. Prior therapy with bicalutamide, nilutamide or flutamide within 
14 days of enrollment. 
7. Within 28 days of major surgery and/or lack of recovery from 
prior surgical procedure or 14 days of palliative radiation prior to 
enrollment. 
8. Prior or current therapy with an investigational agent for 
metastatic prostate cancer.   
9. Known hypersensitivity to drugs formulated with polysorbate 80. 
10. Personal history of posterior reversible encephalopathy 
syndrome. 
11. CTCAE version 4.0 grade 2-4 peripheral sensory neuropathy. 
12. Human immunodeficiency virus infection or active hepatitis B or C 
infection. 
13. Uncontrolled and current illness including, but not limited to, 
ongoing or active infection, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study 
requirements in the opinion of the Investigator.  
14. Presence of any of the following within the previous 3 months 
prior to enrollment: myocardial infarction, severe/unstable 
angina, coronary/peripheral artery bypass graft, congestive heart 
failure, or cerebrovascular accident including transient ischemic 
attack. 
15. History of an additional active malignancy within 12 months prior 
to the date of consent (except non-melanoma skin cancer). 
16. Current use of strong CYP2C8 inhibitors, CYP3A4 inducers or 
CYP3A4, CYP2C9 or CYP2C19 substrates with a narrow therapeutic 
range as listed in Section 7.2.1. 
17. Any condition that requires the use of prednisone > 10mg daily, or 
equivalent daily glucocorticoid dose, for greater than 14 days. 
 
5. Investigational Plan 
 
5.1 Milestone Date Definitions 
 
Registration Date: the date subject signs study consent. 
 
Enrollment (On Study) Date: the date of initiation of docetaxel and 
enzalutamide treatment. 
 
Treatment Discontinuation Date: the date the Investigator decides to 
discontinue the subject from enzalutamide treatment (see Section 5.5). 
 
Castrate Resistance Date: the date of serologic progression as defined 
in Section 11.1.1 or radiographic progression as defined in Section 11.2, 
whichever occurs first. 

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5.2 Registration and Enrollment 
 
Potentially eligible and interested patients will be presented with the 
study consent and complete the treatment eligibility checks.  A Study ID 
number will then be sequentially assigned by the Sponsor.  The Study ID 
will be a four digit number, where 1001 will be the Study ID assigned to 
the first registered subject.  Those confirmed eligible subjects will be 
enrolled on the date of initiation of docetaxel and enzalutamide 
treatment.  Registration will also be documented in the subject research 
chart.  
 
Note: A subject who, for any reason (e.g.  failure to satisfy the selection 
criteria or withdraws consent), terminates participation in the study 
before receiving first dose of study treatment is regarded as a “screen 
failure”.  All screen failures will be tracked. 
 
Subjects will be stratified by the presence of high or low volume 
disease, as defined below: 
 
High volume: presence of visceral metastases or 4 or more bone lesions 
detectable by radionuclide bone scan with 1 or more outside of the pelvis 
and vertebral bodies. 
 
Low volume: absence of visceral metastases and up to 3 bone lesions or 
4 or more bone lesions detectable by radionuclide bone scan with no 
lesions outside of the pelvis and vertebral bodies. 
 
Based on a total of 39 subjects, the study will restrict enrollment to 13 
 
subjects with low volume disease and 26 subjects with high volume 
disease. 
 
5.3 Pre-treatment Screening Period  
 
No protocol-related assessments may be performed prior to obtaining 
written informed consent.  Subjects will be counseled regarding risk of 
teratogenicity and the need to use contraception throughout the course of 
the study and for 90 days after completion of enzalutamide 
administration. 
 
5.3.1 Clinical Assessments 
 
• Demographics and Medical History 
A complete medical history should be obtained, including 
documentation of any clinically significant pre-existing 

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condition.  Medical history is to be completed within 28 days 
prior to the first dose of study medication.  
 
• Prostate Cancer History 
 
Whether a subject presented with metastatic disease at the 
diagnosis of prostate cancer or a prior history of local prostate 
cancer and associated treatment should be documented.  In 
subjects who presented with metastatic disease at diagnosis, a 
Gleason score should be documented from a diagnostic biopsy 
if possible.   
 
In subjects with a prior history of local prostate cancer, the 
following information should be documented: Gleason score 
from original diagnostic biopsy and/or surgical specimen, type 
of prior local therapy, and duration of prior ADT used in the 
curative setting if applicable.  
 
• Physical Examination 
Evaluation by body system, height (at screening only), weight, 
and body surface area (BSA) should be documented.  Vital 
signs will be recorded and should include temperature, pulse 
rate, blood pressure, respiratory rate, and oxygen saturation.  
ECOG performance status should be documented at baseline. 
 
• Concomitant Medications 
Any medications taken up to 14 calendar days prior to signing 
of the informed consent will be considered a concomitant 
medication.  Dose, route, frequency, administration and 
start/stop dates will be documented.  Concomitant 
medications include but are not limited to over the counter 
medications, supplements, and vitamins. 
Date and dose of administration of all prior LHRH agonist or 
antagonist agents and anti-androgens (bicalutamide, 
nilutamide, flutamide) will be documented. 
 
• Symptoms and Toxicities 
Baseline adverse events at the time of first dose of study 
treatment will be documented. 
 
5.3.2 Radiologic Assessments 
 

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The following tests are required prior to enrollment: 
• Computed tomography (CT) scan of the abdomen and pelvis.  
The use of intravenous contrast is recommended though not 
required. 
• Radionuclide bone scan.  
• CT scan of the chest with or without intravenous contrast or 
chest x-ray (CT preferred). 
 
5.3.3 Laboratory Assessments 
 
The following tests are required prior to enrollment: 
• Complete blood count with differential (CBCD) 
• Complete metabolic panel (CMP) (including sodium, 
potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
calcium, albumin, total protein, total bilirubin, AST, ALT, 
alkaline phosphatase) 
• Serum Testosterone 
• PSA 
 
For subjects who initiated ADT prior to study registration, maximum 
pre-ADT (defined as the maximum PSA associated with the diagnosis 
of metastatic disease) and all post-ADT PSA values and dates of 
measurement will be documented. 
 
5.4 Treatment Period 
 
Treatment will be administered on an outpatient basis.  Reported adverse 
events and potential risks are described in Section 8.  No investigational 
or commercial agents or therapies other than those described below may 
be administered with the intent to treat the subject’s malignancy. 
 
 
Subjects will receive treatment as described in Section 7.   
 
5.4.1 Treatment Assessments 
 
5.4.1.1 
Docetaxel Treatment Phase 
 
The docetaxel treatment phase will consist of the time from the 
Enrollment date until the Castrate Sensitive Enzalutamide Treatment 
Phase.  The required clinical assessments include: 
  
 
• Physical exam 
• Documentation of symptoms and toxicities 
• Documentation of concomitant medications 
• Laboratory assessments include a CBCD, CMP and PSA 

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• Specimen for CTC analysis will be collected on the Enrollment 
date (i.e.  C1D1) only  
 
Radiologic assessments are not required during this phase. 
 
During this phase, subjects who develop a rising PSA value ≥ 25% and 
≥ 2 ng/ml above nadir value since initiation of ADT across two 
consecutive increasing values obtained (as defined in Section 11.1.1), 
must have a serum testosterone level checked within 14 days of the 
second consecutive rising PSA value.  If castration (serum 
testosterone < 50 ng/dl) is confirmed, docetaxel should be 
discontinued, and the subject will transition to the Castrate Resistant 
Treatment phase per Section 5.4.1.3.  If serum testosterone > 50 
ng/dl, the subject may remain on study pending approval from the 
Sponsor-Investigator.  Serum testosterone should be repeated in 21 
days (+/- 7 days), and the subject should be withdrawn from the 
study if serum testosterone remains > 50 ng/dl at the subsequent 
assessment.  
 
5.4.1.2 
Castrate Sensitive Enzalutamide Treatment Phase 
 
The Castrate Sensitive Enzalutamide Treatment Phase will consist of 
the time 28 days (+/- 3 days) from the docetaxel treatment 
discontinuation date until the castrate resistance date as defined in 
Section 5.1. 
 
The required clinical assessments include: 
• Physical exam 
• Documentation of symptoms and toxicities 
• Documentation of concomitant medications  
• Laboratory assessments to include a CBCD, CMP and PSA 
• A specimen for CTC analysis will be collected on the first date 
of this phase  
 
Additional laboratory visits to obtain a PSA only should be 
performed 26 and 52 weeks (+/- 1 week) from the enrollment 
date if subject has not developed castrate resistance as defined in 
Section 5.1 prior to this date.    
 
Radiologic assessments are not required during this phase. 
 
5.4.1.3 
Castrate Resistant Treatment Phase 
 

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The Castrate Resistant Treatment Phase will consist of the time from 
the castrate resistance date as defined in Section 5.1 until the end of 
all study treatment. 
 
The required clinical assessments include:  
• Physical exam  
• Documentation of symptoms and toxicities 
• Documentation of concomitant medications  
• Serum testosterone  
• Laboratory assessments to include CBCD, CMP and PSA   
• A specimen for CTC analysis will be collected on the first date 
of this phase 
• Radiologic assessments consist of the studies obtained at 
screening and should be obtained within 28 days of the 
castrate resistant date and at the frequency defined in the 
Study Calendar (Section 6.2) including: 
o Computed tomography (CT) scan of the abdomen and 
pelvis.  The use of intravenous contrast is recommended 
though not required. 
o Radionuclide bone scan  
o CT scan of the chest with or without intravenous 
contrast or chest x ray.  The same chest imaging 
modality used at screening should be used throughout 
the duration of the study. 
 
If radionuclide bone scan shows the development of two or more new 
lesions, a confirmatory bone scan must be performed a minimum of 6 
weeks later and show development of two additional new lesions to 
be considered radiographic progression per Section 11.2. 
 
 
5.5 Treatment Discontinuation 
Study treatment will continue until one of the following criteria applies: 
• Evidence of progressive disease as defined per treatment phase 
below: 
o Docetaxel: Evidence of confirmed serologic progression per 
Section 11.1.1. Subjects will discontinue docetaxel but 
remain on study treatment and move into the Castrate 
Resistant Treatment Phase. 
o Enzalutamide: Evidence of radiographic or clinical 
progressive disease per Section 11.2.  Investigators are 
encouraged to continue enzalutamide after serologic 
progression until the development of radiographic or 
clinical progression as defined in Section 11.2 
• Unacceptable toxicity 

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• Withdrawal of consent for treatment only   
• Deterioration of ECOG performance status to 4. 
• Use of illicit drugs or other substances that may, in the opinion of 
the Investigator, have a reasonable chance of contributing to 
toxicity or otherwise skewing trial result. 
• Severe allergic reaction to docetaxel or enzalutamide (Grade 3 or 4 
hypersensitivity reaction). Subjects with Grade 3 or 4 
hypersensitivity to docetaxel will remain on study treatment and 
move into the Castrate Sensitive Enzalutamide Treatment Phase. 
• Development of an additional malignancy.  
• Any other reason, at the Investigator’s discretion with prospective 
notification of the Sponsor Investigator (e.g. non-compliance with 
study treatment or procedures, development of an intercurrent 
illness which would significantly affect assessments of clinical 
status and trial endpoints). 
• Enzalutamide is held for greater than 21 days (for any reason) 
 
Note: In the event the criteria for the final analysis are met, and there are 
subjects who have not yet been discontinued from study treatment, they 
will continue to receive therapy beyond the date the criteria for the study 
final analysis are met and until one of the above criteria applies. 
 
5.6 End of Treatment Period 
 
Every subject will undergo an end-of-treatment evaluation at the time it 
is determined that he is no longer eligible to receive both docetaxel and 
enzalutamide per Section 5.5.  If enzalutamide is held at the 
Investigator’s discretion for greater than 21 days, subject withdrawal 
from study treatment is required.   
 
End of treatment evaluations will include:  
• Physical examination 
• Documentation of symptoms and toxicities  
• Documentation of concomitant medications   
• Laboratory evaluation to include a CBCD, CMP, and PSA if these 
laboratory studies have not been obtained within the prior 14 
days 
 
5.7 Follow up Period 
 
Subjects will be tracked for at least 30 days following cessation of study 
treatment to monitor for adverse events, serious adverse reactions, and 
any other unanticipated problems.  If the end of treatment visit occurs 
prior to 30 days from last dose of study treatment, subjects will be 

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contacted by telephone on day 31 or next business day if possible for 
monitoring; no later than by day 50.   
 
If the subject cannot be contacted following three attempted telephone 
calls over a period of 10 business days, subject will be contacted in 
writing.  Following this period, subjects will be contacted every 6 months 
+/- 30  days from treatment discontinuation by telephone, in writing, or 
during clinic visits after treatment discontinuation for collection of 
follow-up data until death, lost to follow-up, withdrawal, or until the 
criteria defined for the final analysis are met (Section 12.4.1).  Note: in 
the event the criteria for the final analysis are met, and there are subjects 
who have not yet been discontinued from study treatment, subjects in 
follow-up will continue to be followed until all subjects have 
discontinued study treatment (see Section 7.4) and completed the 
required 30 day safety monitoring period (see above).  Follow-up clinical 
information may also be obtained through chart reviews or other data 
sources (e.g.  death registries).  Lost to follow-up is defined as four 
consecutive unsuccessful documented attempts (telephone and written) 
to contact the subject. 
 
All subjects, regardless of when they discontinue treatment, will be 
followed per standard of care procedures until all treatment-related 
toxicities have resolved, returned to baseline, stabilized, or are deemed 
irreversible. 
 
5.8 Off Study 
 
Subjects will be considered off-study when the following criteria are met: 
• Death  
• Lost to follow-up (as defined in Section 5.7).   
• Consent withdrawal 
• Withdrawn from study participation by the Investigator  
 
Off-study subjects will not receive study treatment or participate in any 
study procedures, including data collection.  Subjects may also be 
withdrawn from study treatment at the Investigator’s discretion per 
Section 5.5. though continue to participate in study procedures and data 
collection if subject does not withdraw consent for study participation.  
 
Any subject who goes off study will remain under medical supervision 
until discharge or transfer is medically acceptable. 
 
In all cases, the reason for study withdrawal must be documented in the 
subject's medical records and/or research chart and in the CTMS.  
Withdrawn subjects are considered to be off-study. 

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Details for the premature termination of the study as a whole (or 
components thereof [e.g.  investigational sites, treatment arms, dose 
steps]) are provided in Section 14.2. 
 
 
 
 
 
 
 
 

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6. Study Calendars 
6.1 Docetaxel and Castrate Sensitive Enzalutamide Treatment Phases 
 
 
Required 
Procedures 
Screening 
Docetaxel Treatment 
Phasea 
Castrate Sensitive Enzalutamide 
Treatment Phaseb 
  
  
Cycle 1 
Cycles 2-6 
Cycle 
1c 
Cycles ≥ 2 
 
  
Within 28 
days prior 
to 
enrollment 
date 
Day 
1o 
Day 
2 
Day 
1 
(+/-  
3 days) 
Day 
2 
Day 1 
 
Day 1  
(+/- 7 days) 
Week 
26 
(+/- 7 days) 
Week 
52 
(+/- 7 days) 
Informed 
Consent 
X 
 
 
Demographics 
X 
 
 
Medical and 
Treatment 
History 
X 
 
 
 
 
 
 
 
 
Symptoms and 
Toxicities 
X 
X 
X 
X 
X 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
 
 
Physical Examl 
X 
X 
X 
X 
X 
 
 
Radiology and 
Tumor 
Measurements 
Xd 
 
 
 
 
 
 
 
 
Laboratory 
Tests  
Xe 
Xf 
Xf 
Xf 
Xf 
 
 
PSAn 
X 
X 
 
X 
 
X 
X 
Xg 
Xg 
Docetaxel 
Administrationh 
X 
X 
 
 
Enzalutamide 
Administrationi 
X 
X 
X 
X 
X 
X 
 
 
Myeloid Growth 
Factor 
Administationj 
 
 
X 
 
X 
 
 
 
 
Medical or 
Surgical 
Castration 
 
May have been initiated no greater than 16 weeks prior to enrollment date; continuously 
throughout treatment period k 
Circulating 
Tumor Cell 
Blood 
Collectionm 
 
X 
 
 
 
X 
 
 
 
a. Docetaxel Treatment Phase cycle length = 21 days. 

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b. Castrate Sensitive Enzalutamide Treatment Phase cycle length = 
56 days (8 weeks). 
c. Castrate Sensitive Enzalutamide Treatment Phase cycle 1 day 1 
should occur 28 days (+/- 3 days) from the last date of docetaxel 
administration. 
d. Including a CT of the abdomen and pelvis (the use of IV contrast is 
recommended although not required), radionuclide bone scan and 
chest imaging (Chest x-ray or CT Chest with or without IV contrast 
(CT preferred).  Required within 70 days prior to enrollment. 
e. Including: CBC with differential, CMP, serum testosterone. 
f. Including: CBC with differential, CMP.  Laboratory assessment may 
occur up to 3 days prior to Day 1 of each cycle.   
g. An additional laboratory visit to obtain a PSA only should be 
performed at 26 and 52 weeks (+/- 1 week) from the date of study 
enrollment if subject has not demonstrated progression as defined 
in Section 11 prior to this date. 
h. Every 21 days (+/- 3 days) for a total of up to 6 cycles. 
i. Enzalutamide administration should be continuous throughout the 
study period. 
j. Pegfilgrastim or equivalent may be used at the Investigator’s 
discretion.  Administer on Day 2 (or up to+ 4 days from Day 2).  
Refer to Section 7.1.2.3 for guidelines regarding long acting 
prophylactic myeloid growth factor use. 
k. Surgical castration with bilateral orchiectomy prior to study 
enrollment or medical castration with continuous use of a LHRH 
agonist or antagonist is required throughout the study period. 
Surgical castration or initiation of LHRH agonist/antagonist 
therapy must not have occurred greater than 16 weeks prior to 
enrollment date. 
l. Including evaluation by body system, height (at screening only), 
weight, BSA calculation and ECOG performance status.  Vital signs 
should include temperature, pulse rate, blood pressure, 
respiratory rate and oxygen saturation.  Perform within 3 days 
prior to Day 1 of each cycle. 
m. Whole blood samples (10 ml) in Streck cell-free DNA preservative 
tubes should be collected up to 3 days prior to Cycle 1 Day 1 and 
after completion of docetaxel 
n. Perform at screening and within 3 days prior to Day 1 of each 
cycle 
o. C1D1 pre-treatment procedures do not need to be repeated if the 
screening procedures were performed within 7 days prior to C1D1 
 
 

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6.2 Castrate Resistant Treatment Phase and End of Treatment 
 
Required 
Procedures 
Castrate Resistant 
Treatment Phasep 
End of Treatment 
Cycle 1 
Cycle ≥ 2 
End of Treatment 
 Follow-up 
 
Day 1q 
 
Day 1 
(+/- 
3 days) 
Within 30 days after 
the last dose of study 
medication unless 
otherwise specified 
Every 6 months +/- 
30 days after End of 
Treatment visit until 
criteria in Section 5.7 
are met 
Symptoms and 
Toxicities 
X 
X 
Xr 
 
Concomitant 
Medications 
X 
X 
Xr 
Physical Examaa 
X 
X 
Xr 
Radiology and 
Tumor 
Measurementss 
X 
Every 12 weeks 
(+/- 7 days) 
until 
radiographic 
progression 
Xz 
Laboratory Tests  
Xt 
Xu 
Xv,r 
Enzalutamide 
Administrationw 
X 
X 
 
 
Medical or Surgical 
Castration 
Continuously throughout 
treatment periodx 
 
 
Circulating Tumor 
Cell Collection 
Xy 
Survival Analysis 
X 
 
p. Castrate Resistant Treatment Phase cycle length = 28 days. 
q. Castrate Resistant Treatment Phase cycle 1 day 1 defined by   
within 28 days of the castrate resistance date (see Section 5.1 for 
castrate resistance date definition). 
r. If not obtained within 14 days of the End of Treatment Visit. 
s. Including a CT of the abdomen and pelvis (the use of IV contrast is 
recommended although not required), radionuclide bone scan and 
chest imaging (Chest x-ray or CT Chest with or without IV 
contrast) (CT Chest preferred).  Imaging should occur within 28 
days of the castrate resistance date and every 12 weeks from 
Castrate Resistant Treatment Phase C1D1 (+/- 7 days) thereafter 
until radiographic progression.  
If bone scan shows the development of 2 or more new lesions, a 
confirmatory bone scan must be performed a minimum of 6 weeks 

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later and show development of 2 additional new lesions to be 
considered radiographic progression per Section 11.2.2. 
t. Serum testosterone only. 
u. Including CBC with differential, CMP, PSA.  Laboratory assessment 
may occur up to 3 days prior to Day 1 of each cycle.   
v. Including CBC with differential, CMP, PSA if not obtained within 14 
days. 
w. Enzalutamide administration should be continuous throughout the 
study period and should be discontinued at the time of study 
completion. 
x. Surgical castration with bilateral orchiectomy prior to study 
enrollment or medical castration with continuous use of a LHRH 
agonist or antagonist is required throughout the study period. 
y. Whole blood samples should be collected (10 ml) in Streck cell-
free DNA preservative tubes.  Collect up to 3 days prior to Cycle 1 
day 1 
z. For subjects who discontinue study treatment and who have not 
yet had disease progression or started new anti-cancer therapy, 
every effort should be made to continue radiographic disease 
assessments at a frequency as determined by the Investigator 
aa. Including evaluation by body system, weight, and ECOG 
performance status.  Vital signs should include temperature, pulse 
rate, blood pressure, respiratory rate and oxygen saturation.  
Perform within 3 days of Day 1 of each cycle. 
 
7. Study Treatment 
 
7.1 Treatment 
 
No investigational or commercial agents or therapies other than 
enzalutamide, docetaxel and ADT may be administered with the intent to 
treat the subject's malignancy.  The study drugs will be exclusively used 
for the investigation specified in this protocol. 
 
7.1.1 Androgen Deprivation Therapy 
 
ADT with surgical castration (bilateral orchiectomy) or medical 
castration with LHRH agonist or LHRH antagonist therapy for metastatic 
disease may have been initiated no greater than 112 days (16 weeks) 
prior to the enrollment date.  Subjects who have not initiated ADT prior 
to enrollment must begin ADT on C1D1.  ADT should be administered 
continuously for the study duration in subjects who have not undergone 
surgical castration.   

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Prior combined androgen blockade therapy with anti-androgens other 
than enzalutamide (bicalutamide, nilutamide or flutamide) to permit 
tumor flare with initiation of LHRH agonist therapy is permitted; 
however, anti-androgen agents must have been discontinued at least 14 
days prior to subject enrollment date. 
 
The agents used for medical androgen deprivation therapy are 
commercially available and will be sourced locally.  Refer to the 
individual agent’s current Prescribing Information for further details on 
available formulations, preparation, administration and storage 
conditions. 
 
7.1.2 Docetaxel 
 
7.1.2.1 
Premedication 
 
Premedication is required to lower the risk of infusion related 
anaphylactoid reactions to docetaxel.  Dexamethasone 8mg orally 
should be administered approximately 12 and 3 hours prior to 
docetaxel infusion.  Additionally, dexamethasone 8mg should be 
administered orally or intravenously approximately 1 hour prior to 
docetaxel infusion.  Antihistamine premedications may be used at the 
Investigator’s discretion. 
 
The use of concurrent daily prednisone with docetaxel is not permitted 
due to potential CYP3A4-mediated drug interactions with enzalutamide. 
 
7.1.2.2 
Dosage and Administration 
 
Starting on the day of the enrollment visit, docetaxel should be 
administered intravenously over one hour at a dose of 75 mg/m2 on 
day 1 every 21 days for up to six cycles during the Docetaxel 
Treatment Phase as defined in Section 5.4.1.1.  Potential adverse 
events and dose modifications are described in Section 8.  
 
Docetaxel is commercially available and will be sourced locally.  Refer 
to current Prescribing Information for further details on available 
formulations, preparation and storage conditions  
 
7.1.2.3 
Myeloid Growth Factor Support 
 
The incidence of neutropenic fever with the use of ADT and docetaxel 
is approximately 6-12%.4,5  Prophylactic myeloid growth factor 
support may be used at the Investigator’s discretion.  If a subject 
experiences febrile neutropenia (FN), prophylactic myeloid growth 

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factor support is recommended with remaining docetaxel cycles.  The 
incidence of FN with the study regimen will be continuously 
monitored during conduct of the study.  If the incidence of FN exceeds 
the predetermined threshold defined in Section 12.4.4.3, the use of 
prophylactic myeloid growth factors will be required for subsequent 
enrolled subjects. 
 
7.1.3 Enzalutamide 
 
7.1.3.1 
Dosage and Administration 
 
Enzalutamide will be started on the day of the enrollment visit, 
concurrent with administration of the first docetaxel cycle.  
Enzalutamide is administered orally at 160mg once daily.  Subjects 
will swallow four 40mg enzalutamide tablets whole with or without 
food at approximately the same time each day.  Tablets should not be 
broken, chewed or crushed. 
  
If a dose is missed, subject should take it as soon as possible unless 
the next dose is due within 12 hours.  If vomiting occurs after taking a 
dose of study drug, an extra dose should not be taken.  The subject 
should take the next dose at the regular time.   
 
Treatment will be administered orally on an outpatient basis.  
Potential adverse events and dose modifications are described in 
Section 8.   
 
Treatment monitoring during the Docetaxel Treatment Phase is 
defined in Section 5.4.1.1.   
 
Treatment monitoring during the Castrate Sensitive Enzalutamide 
Treatment Phase is defined in Section 5.4.1.2.   
 
Treatment monitoring during the Castrate Resistant Treatment Phase 
is defined in Section 5.4.1.3. 
 
7.1.3.2 
Drug Supply 
 
Enzalutamide tablets for oral administration are formulated as yellow, 
round, film-coated  tablets embossed with E 40.  Enzalutamide will be 
supplied by Astellas.  To request enzalutamide from Astellas, the 
requesting pharmacy will use the drug order forms available on the 
Astellas Portal.  Drug inventory levels should be able to provide 
subjects with enzalutamide for up to eight weeks while waiting for 
additional ordered supplies. 
 

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The requesting pharmacy will receive enzalutamide 40mg tablets in 
study drug bottles containing 120 tablets each.  The study drug bottles 
will have a label affixed containing study identification, product 
identification and quantity of tablets.  Once the drug has been 
received, it must be kept in a secure, dry location.  Study drug must be 
stored in its original study drug bottle at room temperature 20° to 
25°C (68° to 77°F).  Temperature excursions between 15° to 30°C 
(59° to 86°F) are permitted. 
 
Study drug bottles dispensed to subjects will be labeled as an 
investigational treatment and subjects will be instructed to 
comply with the following directions: 
 
• Store tablets in the original study drug bottle. 
• Take tablets at the same time once daily, with or without food. 
• Swallow tablets whole. 
• If a dose is missed, it should be taken as soon as possible.  Unless it 
is close to the next dose (within 12 hours), in which case the 
normal dose should be taken at the usual time. 
• If vomiting occurs after taking a dose, an additional dose should 
not be taken.  The next dose should be taken when due. 
• Men should use adequate contraceptive methods (per Section 8.1) 
while taking study medication and for at least 90 days after 
completing therapy. 
 
7.1.3.3 
Discontinuation 
 
Criteria for treatment discontinuation is defined in Section 5.5. 
 
If a subject is discontinued from docetaxel treatment prior to 
completion of six cycles for reasons other than serologic progression 
of disease or withdrawal of consent for treatment, he may continue 
enzalutamide at the Investigator’s discretion. 
 
Because the interval between serologic (rising PSA) and radiographic 
progression may be clinically significant,9 Investigators are 
encouraged to continue enzalutamide after serologic progression until 
the development of radiographic or clinical progression as defined in 
Section 11.2.  Once serologic progression is established, treatment 
monitoring should occur during the Castrate Resistant Treatment 
Phase as defined in Section 5.4.1.3. 
 
Subjects who discontinue both docetaxel and enzalutamide or require 
enzalutamide to be held at the Investigator’s discretion for greater 

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than 21 days are considered to be off-treatment and should undergo 
end of treatment evaluation as defined in Section 5.5. 
 
7.2 Concomitant Therapy 
 
7.2.1 Medications 
 
Anticancer therapy with agents other than enzalutamide, docetaxel and 
ADT is not permitted.  Medication that is considered necessary for the 
subject’s welfare, and which is not expected to interfere with the study 
treatment, may be given at the discretion of the Investigator.   
 
Enzalutamide is metabolized by CYP2C8 and CYP3A4 in vivo.  Specific 
caution should be taken when considering administration of a 
concomitant medication that is metabolized by these cytochrome 
enzymes.  Such concomitant medication should be avoided if possible.  
 
Avoid concomitant use of enzalutamide with strong CYP2C8 inhibitors, 
CYP3A4 inducers or CYP3A4, CYP2C9 or CYP2C19 substrates with a 
narrow therapeutic range.   
 
Example medications are listed below; however, an updated list may be 
found at: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 
Strong inhibitors of CYP2C8 include but are not limited to: gemfibrozil.   
 
Strong inducers of CYP3A4 include but are not limited to: carbamazepine, 
efavirenz, modafinil, nevirapine, oxcarbazepine, phenobarbital, 
phenytoin, pioglitazone, rifabutin, rifampin, St. John’s Wort and 
troglitazone. 
CYP3A4, CYP2C9 or CYP2C19 substrates with a narrow therapeutic range 
include but are not limited to: alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus and warfarin.  
Co-administration with warfarin is permitted if it cannot be avoided; 
however, subjects are required to conduct additional INR 
monitoring. 
Glucocorticoids may induce CYP3A4.  The use of glucocorticoid agents 
equivalent to prednisone 10mg or greater daily for longer than 14 days is 
not permitted.  
7.2.2 Radiotherapy 

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The development of a new symptomatic disease site requiring palliative 
radiotherapy constitutes subjective disease progression as defined in 
Section 11.2.1.2.2 and requires subject withdrawal from study treatment.  
Palliative radiotherapy may begin at least one day after enzalutamide 
treatment is stopped. 
 
7.2.3 Surgery 
 
The impact of enzalutamide on wound healing is not known.  If surgical 
intervention is necessary during study participation, enzalutamide should 
be stopped 48 hours before surgery and resumed no sooner than 48 
hours after surgery. 
 
If surgery is necessary during the Docetaxel Treatment Phase, 
management of docetaxel-induced cytopenias will be at the Investigator’s 
discretion. 
 
7.3 Treatment Compliance  
 
Enzalutamide will be dispensed to subjects, and the study drug pill 
bottles returned to LCI Clinical Trials staff or delegate according to LCI 
standard operating procedures.  Study drug bottles will be returned to 
the dispensing pharmacy.  Tablets will be counted by pharmacy staff or 
delegate and reported to the applicable research designee.  The number 
of tablets taken by the subject per cycle will be determined by these 
tablet counts. 
 
Subject compliance with the treatment and protocol includes willingness 
to comply with all aspects of the protocol.  Subjects will be asked to 
return used study drug bottles.  Compliance with study treatment will be 
assessed at the end of each cycle.   
 
At the discretion of the Sponsor-Investigator or the subject’s Physician 
Investigator, a subject may be discontinued from the protocol for non-
compliance with study visits or study drug.  
 
 
7.4 Drug Accountability 
 
Study drug will be stored at the investigational site in accordance with all 
applicable federal, state and local laws, rules, regulations, product 
labeling, Good Clinical Practice (GCP) and Good Manufacturing Practices 
(GMP) requirements and will be inaccessible to unauthorized personnel. 
 

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The study bottles will be returned to the pharmacy from which it was 
dispensed.  Pharmacy staff or a delegate will count the number of pills 
and communicate that to the applicable research designee. 
 
An adequate record of receipt, distribution, and destruction of all study 
drugs must be kept in the form of a Drug Accountability Form.  The 
Investigator, or responsible party designated by the Investigator, will 
maintain a careful record of the inventory using the Drug Accountability 
Form.  
 
7.5 Destruction 
 
At the end of the study, unused supplies of enzalutamide will be 
destroyed according to LCI IDS Pharmacy policies.  Destruction will be 
documented by the LCI IDS or dispensing pharmacy in the Study Closure 
Form provided by Astellas certifying that all remaining drug was 
destroyed.  
 
8. Treatment-Related Adverse Events 
 
Based on prior clinical studies with docetaxel and enzalutamide, the 
Investigator should anticipate that any of the following AEs could occur with 
the use of this medication.   
 
The occurrence of AEs and SAEs should prompt immediate notification of the 
appropriate groups as outlined in Section 10.  NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be used for grading 
treatment related-related adverse events. 
 
8.1 Reproductive Risks 
 
Enzalutamide and docetaxel can cause harm to the developing human 
fetus.  For this reason, men with female partners of reproductive 
potential must agree to use adequate contraception (e.g., prior surgical 
sterilization, hormonal or barrier method of birth control; abstinence) 
prior to study entry, the duration of study participation and for at least 
90 days after completion of study treatment.   
 
Women who are pregnant or breast-feeding should not handle 
enzalutamide. 
 
8.2 Dose Modifications for Androgen Deprivation Therapy 
 
Dose modifications for ADT are not permitted.  Subjects must remain on 
continuous ADT for the duration of study participation. 
 

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8.3 Dose Modifications for Docetaxel 
 
8.3.1 Dose Levels 
 
Dose modifications will follow pre-defined dose levels below.  Unless 
otherwise stated below, subjects with Grade 1 or 2 docetaxel-related 
toxicities should be treated symptomatically and continued at the same 
docetaxel dose level.  For subjects with Grade 3 or 4 docetaxel-related 
toxicities (other than anemia), docetaxel should be withheld until 
improvement to grade 0-1 (or baseline if greater than grade 1) and 
resumed at one dose level reduction.  If greater than two dose reductions 
are required or greater than 21 days is required for resolution of toxicity 
to less than grade 2, docetaxel should be discontinued.  If docetaxel is 
held for toxicity, enzalutamide and ADT should continue.     
 
 
Table 1: Docetaxel Dose Levels 
 
Dose Level 
Docetaxel 
0 
75 mg/m2 
-1 
65 mg/m2 
-2 
55 mg/m2 
 
8.3.2 Myelosuppression 
 
Dose modifications for neutropenia or thrombocytopenia on day 1 of 
each docetaxel cycle are listed below.  
 
Table 2: Docetaxel Dose Modification for Hematologic Toxicities  
 
Docetaxel 
Granulocytes/mm3 
Platelets/mm3 
No dose adjustment 
≥ 1500 
≥ 100,000 
Reduce one dose level 
1000-1499 
75,000-99,999 
Delay dosing one week and reduce one dose 
levela 
< 1000 
< 75,000 
 
aDelay resumption of docetaxel at one dose level reduction until recovery 
of granulocyte count ≥ 1500/mm3 and platelet count ≥ 100,000/mm3.  If 
docetaxel is held for 3 consecutive weeks due to prolonged neutropenia 
or thrombocytopenia, discontinue docetaxel and continue ADT and 
enzalutamide alone.  The use of prophylactic myeloid growth factors 
should be considered according to Section 7.1.2.3. 
 

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Dose reductions that are necessary for subjects who receive prophylactic 
myeloid growth factor support following the prior docetaxel cycle will be 
permanent.  
For subjects who are started on prophylactic myeloid growth factor 
support following dose reduction for neutropenia, escalation to prior 
docetaxel dose level is permitted at the Investigator’s discretion with 
subsequent docetaxel cycles if granulocyte count ≥ 1500/mm3 on day one 
of the following cycle. 
 
Dose reductions that are necessary for thrombocytopenia will be 
permanent. 
 
8.3.3 Hepatic Dysfunction 
 
Table 3: Docetaxel Dose Modification for Hepatic Toxicities 
 
Docetaxel 
Bilirubin 
AST/ALT 
Delay dosing one week and reduce one dose 
levela 
> ULN 
or 
> 1.5x ULN 
with 
concomitant 
alkaline 
phosphatase 
> 2.5x ULN 
 
aDelay resumption of docetaxel at one dose level reduction until recovery 
of bilirubin to ≤ ULN and/or AST/ALT to ≤ 1.5 times ULN if alkaline 
phosphatase > 2.5x ULN.  If docetaxel is held for 3 consecutive weeks due 
to prolonged hepatic dysfunction, discontinue docetaxel and continue 
ADT and enzalutamide alone.   
 
8.3.4 Peripheral Neuropathy 
 
If grade 3-4 peripheral neuropathy occurs, subject should discontinue 
docetaxel and continue ADT and enzalutamide alone.   
 
If grade 2 peripheral neuropathy occurs, docetaxel should be held until 
resolution to < grade 2 and resumed at one dose level reduction.  If 
docetaxel is held > 21 days or > 2 dose reductions are required, subject 
should discontinue docetaxel and continue ADT and enzalutamide alone.  
 
8.4 Dose Modifications for Enzalutamide 
 
8.4.1 Dose Levels 
 

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Dose modifications will follow pre-defined dose levels below.  Unless 
otherwise stated below, subjects with Grade 1 or 2 enzalutamide-related 
toxicities should be treated symptomatically and continued at the same 
enzalutamide dose level.  For subjects with Grade 3 or 4 enzalutamide-
related toxicities, enzalutamide should be withheld for one week or until 
symptoms improve to grade 0-2 and resume at one dose level reduction.  
If greater than two dose reductions are required or greater than 21 days 
is required for resolution of toxicity to less than grade 3, enzalutamide 
should be discontinued.  Subjects who discontinue enzalutamide are 
considered to be off-treatment and should undergo end of treatment 
evaluation as defined in Section 5.6.  
 
Table 4: Enzalutamide Dose Levels 
 
Dose Level 
Enzalutamide 
0 
160 mg 
-1 
120 mg 
-2 
80 mg 
 
8.4.2 Seizures 
 
Enzalutamide should be discontinued in any subject who experiences 
seizure activity.  Subjects who discontinue enzalutamide are considered 
to be off-treatment and should undergo end of treatment evaluation as 
defined in Section 5.6. 
 
 
8.4.3 Posterior Reversible Encephalopathy Syndrome 
 
Posterior Reversible Encephalopathy Syndrome (PRES) is a neurologic 
disorder that can manifest as headache, confusion, seizure, visual 
disturbances and lethargy.  Diagnosis requires confirmation by brain 
imaging.  Enzalutamide should be discontinued in any subject who is 
diagnosed with PRES.  Subjects who discontinue enzalutamide are 
considered to be off-treatment and should undergo end of treatment 
evaluation as defined in Section 5.6. 
 
 
8.4.4 Hypersensitivity 
 
Hypersensitivity reactions, including edema of the face, tongue, or lip 
have been observed with enzalutamide.  Pharyngeal edema has been 
reported in post-marketing cases.  Advise subjects who experience any 
symptoms of hypersensitivity to temporarily discontinue enzalutamide 

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and promptly seek medical care.  Permanently discontinue enzalutamide 
for serious hypersensitivity reactions.   
 
8.4.5 Ischemic Heart Disease 
 
In the combined data of previous clinical studies, ischemic heart disease 
occurred more commonly in patients taking enzalutamide when 
compared to patients on placebo.  Some ischemic events led to death in 
more patients taking enzalutamide then patients on placebo.  Subjects 
should be monitored for signs and symptoms of ischemic heart disease.  
Manage cardiovascular risk factors, such as hypertension, diabetes, or 
dyslipidemia.  Permanently discontinue enzalutamide for Grade 3-4 
ischemic heart disease. 
 
8.4.6 Falls and Fractures 
 
Falls and fractures occurred in patients receiving enzalutamide.  Evaluate 
subjects for fracture and fall risk.  Monitor and manage subjects at risk for 
fractures according to established treatment guidelines and consider use 
of bone-targeted agents. 
 
8.4.7 Embryo-Fetal Toxicity 
 
The safety and efficacy of enzalutamide have not been established in 
females.  Based on animal reproductive studies and mechanism of action, 
enzalutamide can cause fetal harm and loss of pregnancy when 
administered to a pregnant female.  Advise males with female partners of 
reproductive potential to use effective contraception during treatment 
with enzalutamide and for 3 months after the last dose of enzalutamide.  
Enzalutamide should not be handled by females who are or may become 
pregnant. 
 
9. Data and Safety Monitoring Plan 
 
 
 
Data will be collected in electronic case report forms (eCRFs). Study 
personnel will be trained on data entry by the sponsor and provided 
protocol-specific eCRF guidelines. 
 
This protocol will be monitored according to the processes in effect for all 
LCI investigator-initiated studies and the protocol-specific monitoring plan 
and will abide by applicable regulations and guidelines (e.g. Good Clinical 
Practice [GCP]).  It is the responsibility of the Sponsor-Investigator to 
monitor the safety data for this study.  The Sponsor-Investigator and other 
sponsor-level team members will meet regularly to monitor subject consents, 

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enrollment and retention, safety data, and timeliness/validity/integrity of 
the data. Documentation of these meetings will be kept with study records. 
The Sponsor-Investigator will submit reports to the LCI Data and Safety 
Monitoring Committee according to the institutional Data and Safety 
Monitoring Plan. 
 
This study will be monitored to ensure the study is conducted in compliance 
with the study protocol, SOPs of the LCI and Atrium Health Office of Clinical 
and Translational Research (and/or other participating institutional SOPs), 
the FDA, and other applicable regulations and guidelines (e.g. GCP).  
 
Investigators and/or their delegated study personnel will be required to be 
available during the monitoring visits. 
 
9.1 Communication Between Investigational Sites 
 
Investigational sites will be required to report SAEs, protocol and subject 
level deviations, and any other problem that could affect the 
validity/integrity of the study data to the Sponsor-Investigator.  All 
investigational sites will record AEs using the eCRFs and report SAEs to the 
Sponsor.  SAEs will be reported within 1 business day of the Investigator 
learning of the event (immediately if the event is fatal or life-threatening). 
Protocol deviations should be reported to the Sponsor-Investigator 
promptly. 
 
10. Safety Data Collection, Recording and Reporting 
 
All subjects who receive at least one dose of study treatment will be 
evaluable for the safety analysis.  All observations pertinent to the safety of 
the study treatment will be recorded and included in the final report. 
 
Safety variables include the following: AEs and SAEs (whether related to 
investigational therapy or not), treatment administration, and, in some 
instances, changes in radiographic images, as ordered per the Investigator’s 
discretion (e.g., for evaluation for pneumonitis).  These assessments should 
be performed according to study protocol except for adverse events, which 
will be evaluated continuously throughout the study.  Safety and tolerability, 
relationship to treatment and intensity will be assessed according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  All 
adverse events (Grades 1 – 5) will be determined by the Investigator and 
documented in subject study charts. 
 
10.1 Adverse Event Definitions 
 
10.1.1 Unanticipated Problem (UAP) Definition 
 

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An UAP is any incidence, experience or outcome that is unexpected, given 
the information provided in research-related documentation (e.g.  
Investigator’s brochure, protocol, informed consent) and the study 
population characteristics that is related or possibly related to 
participation in the research study and places the participant at an 
increased risk.   
 
10.1.2 Adverse Event (AE) Definition 
 
An adverse event or adverse experience is any untoward medical 
occurrence in a study subject who is administered a study drug that does 
not necessarily have a causal relationship with this treatment.  An 
adverse event can therefore be any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of the study 
drug, whether or not considered related to the study drug.  Pre-existing 
conditions that increase in frequency or severity or change in nature 
during or as a consequence of use of a drug in human clinical trials are 
also considered adverse events.  Adverse events may also include pre or 
post-treatment complications that occur as a result of protocol-mandated 
procedures (e.g., invasive procedures such as biopsies). 
 
Any continuing medical condition or clinically significant laboratory 
abnormality with an onset date before the first date of study drug 
administration should be considered pre-existing and should be 
documented in the subject’s medical records and/or in the study chart. 
 
An AE does not include: 
• relapse or progression of the underlying malignant disease; however, 
the associated signs, symptoms, or diagnoses should be recorded as 
adverse events (e.g., “jaundice” due to new or increasing liver 
metastases, or “tumor pain” or “bone pain” due to progressive 
disease); 
• medical or surgical procedures (e.g., surgery, endoscopy, tooth 
extraction, transfusion).  The condition that leads to the procedure is 
the adverse event; 
• situations where an untoward medical occurrence has not occurred 
(e.g., hospitalization for elective surgery, social and/or convenience 
admissions); 
• overdose of either study drug or concomitant medication without any 
signs or symptoms unless the subject is hospitalized for observation   
 
Laboratory abnormalities are usually not recorded as adverse events; 
however, signs and/or symptoms that are associated with laboratory 
findings requiring study withdrawal, dose modification, or medical 
intervention (e.g., anemia requiring transfusions or hyperglycemia 

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requiring treatment) or other abnormal assessments (e.g., ECG, 
radiographs, vital signs) must be recorded as adverse events if they meet 
the definition of an adverse event.  In addition, laboratory abnormalities 
marked as clinically significant by the Investigator should also be 
recorded as adverse events on the eCRF.  The Investigator will record the 
most severe grade of the clinically significant laboratory abnormality and 
will evaluate its relationship to the study drug and clinical condition 
if/when a clinically significant laboratory abnormality occurs.   
 
All adverse events (including event name, grade, start/stop date and 
attribution) will be documented in the medical record and/or research 
chart. 
 
The Investigator is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for 
each event for all subjects enrolled on the trial. 
 
10.1.3 Adverse Event Attribution 
 
Descriptions and grading scales listed in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for all AE reporting.  Each AE will be assigned an attribution to 
one of the following categories: 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE is possibly related to the study treatment. 
• 
Unlikely – The AE is doubtfully related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
For the purposes of statistical analyses, the relationship to study drugs 
will be further dichotomized into the following categories: 
 
“Not Related”:  This includes events that are considered unlikely or 
unrelated to study drug(s).  In the Investigator’s opinion, the AE has an 
etiology other than the study drug(s) (e.g., pre-existing condition, 
underlying disease, intercurrent illness, or concomitant medication).   
 
“Related”:  This includes events that are considered possibly, probably, or 
definitely related to study drug(s).  A temporal relationship exists 
between the event onset and administration of the study drug(s).  It 
cannot be readily explained by the subject’s clinical state, intercurrent 
illness, or concomitant therapies.  In the case of cessation or reduction of 
the dose, the event abates or resolves and reappears upon rechallenge.  
Ineffective study drug treatment should not be considered as causally 
related in the context of AE reporting.   
 

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10.1.4 Adverse Event Reporting 
 
All AEs from the time of enrollment until 30 days after last dose of study 
treatment (including event name, grade, start/stop date and attribution) 
will be captured.  
 
10.1.5 Suspected Adverse Reaction (SAR) Definition 
 
A SAR is an adverse event in which there is reasonable possibility that the 
study drug(s) caused the adverse event as defined by 21 CFR 312.32.  The 
Investigator is responsible for judging whether it is a reasonable 
possibility that the study drug caused the adverse event. 
 
10.1.6 “Unexpected” Definition 
 
An AE or SAR is to be considered unexpected if the event is not listed in 
the current version of the Investigator Brochure (IB), package insert or is 
not listed in the severity or specificity observed.  Investigators should 
refer to the Safety Information section of the current IB and/or 
prescribing information for docetaxel and/or enzalutamide, including the 
DCSI (development core safety information), for the expected side effects 
of docetaxel and/or enzalutamide.  As with any agent, there is always the 
potential for unexpected AEs, including hypersensitivity reactions.  
 
10.1.7  Serious Adverse Event (SAE) Definition 
 
 
An AE or SAR is to be considered serious if the Investigator deems it as 
such and the event results in any of the following outcomes: 
• Death; 
• Life-threatening situation (subject is at immediate risk of death); 
• Inpatient hospitalization or prolongation of an existing hospitalization 
(excluding those for study drug administration, protocol-related 
procedures, palliative or hospice care, or placement of an indwelling 
catheter, unless associated with other serious events); 
• Persistent or significant disability/incapacity; 
• Congenital anomaly/birth defect in the offspring of a subject who 
received study drug; 
• Other:  Important medical events that may not result in death, be 
immediately life-threatening, or require hospitalization, may be 
considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
Examples of such events are: 

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o Intensive treatment in an emergency room or at home for 
allergic bronchospasm; 
o Blood dyscrasias or convulsions that do not result in 
hospitalization; 
o Development of drug dependency or drug abuse. 
 
Planned hospitalizations: 
Elective surgeries that have been planned prior to subject enrollment in 
the study or for conditions existing prior to study enrollment do not need 
to be captured as SAEs, unless complications occur or the conditions are 
worse than the subject’s baseline.  If there are complications, they should 
be clearly documented.  
 
 
10.2 Expedited Safety Reporting 
 
10.2.1 Expedited Safety Reporting to the Sponsor-Investigator 
 
SAEs must be reported to the Sponsor-Investigator within 1 business day.  
 
SAEs will be captured from the time of enrollment through 30 days after 
the date of the last study drug administration.  SAEs will be followed until 
clinical recovery is complete and laboratory tests have returned to 
baseline, until progression has been stabilized, or until there has been 
acceptable resolution of the event.  This may at times cause the follow-up 
period for SAEs to be greater than 30 days.  The above referenced 30-day 
time period applies even if the subject is removed from study treatment 
and begins new anti-cancer therapy during this time period.  Similarly, 
the Sponsor-Investigator is responsible for following the subject during 
the required follow-up period even if the subject lives elsewhere or has 
been released from his or her care and is being treated under another 
provider. 
 
SAEs that are determined to be related to study treatment or study 
procedures are reportable throughout the duration of the subject’s 
participation (informed consent through off study).  
 
10.2.2 Expedited Safety Reporting to the IRB 
 
All events occurring during the conduct of a protocol and meeting the 
definition of an UAP or SAE will be reported to the IRB per their reporting 
requirements. 
 
Protocol deviations that, in the Investigator’s judgment, potentially 
caused harm to participants or others or indicates that the participants or 
others are at an increased risk of harm, or has adversely impacted data 

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integrity will be reported promptly to the IRB per IRB reporting 
requirements. 
 
10.2.3 Expedited Safety Reporting to Astellas 
 
Within 24 hours of awareness of a serious adverse event, whether or not 
related to the study treatment, the Sponsor-Investigator will submit a 
completed Medwatch 3500A Form, containing all required information to 
Astellas by either e-mail or fax.   
 
The SAE documentation, including the Medwatch 3500A Form should be 
emailed or faxed to: 
 
 Astellas Pharma Global Pharmacovigilance  – United States 
 Email: Safety-us@us.astellas.com 
 Fax number: (847) 317-1241 
 
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(s) 
 
Follow-up information for the event should be sent promptly (within 7 
days of Sponsor-Investigator awareness) as necessary. 
 
11. Measurement of Effect 
 
11.1 Serologic Assessment 
 
11.1.1 PSA Response 
 
Serum PSA levels will be assessed as defined in the Study Calendar 
(Section 6).  Subjects will be assigned a PSA response based on the 
following criteria: 
 
• Serologic Complete Response – PSA level less than 0.2 ng/ml for 
two consecutive measurements at least 3 weeks apart. 
 

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• Serologic Partial Response (50) – PSA level decline of greater 
than or equal to 50% reduction of the maximal pre-ADT level for 
two consecutive measurements at least 3 weeks apart. 
 
• Serologic Partial Response (90) – PSA level decline of greater 
than or equal to 90% reduction of the maximal pre-ADT level for 
two consecutive measurements at least 3 weeks apart. 
 
• Serologic Progression – PSA increase ≥ 25% and ≥ 2 ng/ml above 
nadir value since initiation of ADT.  Once serum PSA has increased 
above this threshold, an additional PSA measurement should be 
obtained at least 1 week later, confirming the initial value is above 
the defined threshold.  If the second PSA measurement does not 
confirm the PSA increase ≥ 25% and ≥ 2 ng/ml above nadir value, 
then additional PSA values should be obtained at least one week 
apart until the initial PSA value above this defined threshold is 
confirmed.  The date of the first recorded elevated PSA above the 
defined threshold will be deemed the date of progression.  For 
subjects without a PSA decline following enrollment, progression 
will be defined by a PSA increase ≥ 25% and ≥ 2 ng/ml after 12 
weeks following enrollment. 
 
11.2 Radiographic Assessment 
 
To evaluate objective response, it is necessary to determine tumor 
burden at baseline for comparison of subsequent assessments.  The same 
method of assessment and technique should be utilized to define lesions 
identified at baseline and follow-up imaging.   
 
Soft tissue lesion response and progression will be evaluated in this 
study using the Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline version 1.1.28  Skeletal lesion response and progression will be 
evaluated in this study using the Prostate Cancer Clinical Trials Working 
Group 2 (PCWG2) criteria.27 
 
Only those subjects who have measurable disease present at baseline and 
have received at least one dose of study therapy will be considered 
evaluable for overall response.   
 
11.2.1 RECIST  
 
11.2.1.1 Measurable Disease 
 
At baseline, all soft tissue tumor lesions should be defined as 
measurable or non-measurable. 

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Measurable: 
• Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded), with a minimum size of 10 mm 
by CT scan or caliper measurement by clinical exam. 
• Malignant lymph nodes must be measured by shortest diameter, 
with a minimum size of 15 mm. 
• Lesions growing within a previously irradiated field may be 
considered measurable if enlargement has occurred following 
prior radiation treatment. 
 
Non-measurable: 
• All other lesions (<10 mm by long axis or malignant lymph nodes < 
15 mm by short axis). 
• Leptomeningeal disease, ascites, pleural or pericardial effusions. 
 
Note: Bone lesions will not be evaluated per RECIST criteria.  
Please refer to Section 11.2.2 for evaluation of bone lesions. 
 
11.2.1.2 Response Criteria 
 
11.2.1.2.1 Target Lesions 
 
All lesions up to a maximum of five lesions total (and a maximum 
of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and 
measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated 
measurements.  
 
Pathological lymph nodes, which are defined as measurable and 
may be identified as target lesions must meet the criterion of a 
short axis of ≥ 15 mm by CT scan.  
 
A sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  The baseline sum 
diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the 
disease. 
 
Non-target lesions: All other lesions including pathological lymph 
nodes should be identified as non-target lesions and should also be 

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followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’. 
 
11.2.1.2.2 Definitions of Response 
 
Complete Response (CR):  
• Target lesion: Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm. 
• Non-target lesion: Disappearance of all non-target lesions.  All 
lymph nodes must be non-pathological in size (<10 mm short 
axis). 
 
When nodal disease is included in the sum of target lesions and 
the nodes decrease to ‘normal’ size (<10 mm), they may still have 
a measurement reported on scans.  This measurement should be 
recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the 
nodes.  This means that subjects with CR may not have a total sum 
of the diameters of ‘zero’. 
 
Partial Response (PR): 
• Target lesion: At least a 30% decrease in the sum of diameters 
of target, taking as reference the baseline sum diameters. 
• Non-target lesion: Not applicable 
 
Stable Disease (SD): 
• Target lesion: Neither sufficient shrinkage to qualify for a 
partial response, nor sufficient increase to qualify for 
progressive disease, taking as reference the smallest sum 
diameters while on study. 
• Non-target lesion: Not applicable. 
 
Progressive Disease: 
• Target lesion: At least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study).  
In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered 
progression). 
• Non-target lesion: Unequivocal progression (as described in 
RECIST version 1.1) of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered 

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progression).  Skeletal lesion response and progression will be 
evaluated using the PCWG2 criteria per section 11.2.2.2. 
 
Non-Complete Response / Non-Progressive Disease: 
• Target lesion: Not applicable 
• Non-target lesion: Persistence of one or more non-target 
lesion(s) 
 
 
Table 5: Summary of RECIST 1.1 (Subjects with measurable disease) 
 
Table 6: Summary of RECIST 1.1 (Subjects with non-measurable disease only) 
 
 
Symptomatic Deterioration 
• Subjects with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as ‘symptomatic 
deterioration’.  Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy.  It is 
Target 
Lesions 
Non-target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category also requires 
CR 
CR 
No 
CR 
Documented at least once 
≥ 4 weeks from baseline 
CR 
Non-CR/Non-PD 
No 
PR 
Documented at least once 
≥ 4 weeks from baseline 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
Documented at least once 
≥ 4 weeks from baseline 
Not all 
evaluated 
Non-PD 
No 
NE 
N/A 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, and  
NE = Inevaluable 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/ Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 

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included as part of the criteria for determination of Progression 
Free Survival.  The objective response status of such subjects is to 
be determined by evaluation of target and non-target disease. 
• The development of pain or alternate symptoms requiring 
palliative radiotherapy constitutes subjective clinical disease 
progression, and study treatment should be stopped.   
 
11.2.2 Evaluation of Skeletal Lesions 
 
Skeletal lesion response and progression will be evaluated using the 
PCWG2 criteria.27  Radionuclide bone scans should be utilized for 
characterization of skeletal lesions. 
 
11.2.2.1 Baseline Assessment 
 
The anatomic location and number of skeletal lesions detected on 
baseline radionuclide bone scan should be defined at baseline for 
subjects with one to three lesions.  When four or more bone lesions 
are identified at baseline, subjects should only be classified as having 
“four or greater” lesions and whether or not all lesions are confined to 
the pelvis and vertebral bodies. 
 
11.2.2.2 Definition of Progression 
 
Progression of skeletal disease is defined as the appearance of two or 
more new lesions on follow up radionuclide bone scan followed by a 
confirmatory bone scan performed six or more weeks later that shows 
development of at least two additional new lesions.  The date of 
progression is defined as the date of the first scan showing new bone 
lesions. 
 
12. Statistical Considerations 
 
12.1 Sample Size 
 
The primary endpoint is 52-week PSA complete response, which will be 
determined as a binary variable for each subject indicating whether or 
not the PSA level at 52 weeks (+/- 1 week) is below 0.2 ng/ml.  The 12-
month PSA complete response rate with ADT plus docetaxel is 27.7%.4  
We estimate that the corresponding lower limit of the 95% confidence 
interval is 23.4%.  Therefore, this design will be used to test the null 
hypothesis that the 52 week PSA complete response rate (<0.2 ng/mL) 
for a cohort of subjects treated with study therapy is less than or equal to 
25%.  Thirty-nine (39) subjects will be enrolled, and if 14 of 39 subjects 
achieve a 52-week PSA complete response then the null hypothesis will 
be rejected.  The design will provide 90% power with a 1-sided alpha = 

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0.10 significance level, assuming the true 52-week PSA complete 
response rate is 45%.  An improvement from 25% to 45% in 52-week 
PSA complete response rate is considered clinically relevant.  
 
12.2 Endpoint Definitions 
 
12.2.1 Serologic 
 
12.2.1.1 52-week PSA Complete Response 
 
52-week PSA Complete Response will be determined for each subject 
as a binary variable indicating whether or not the subject achieved a 
PSA complete response (CR) at 52-weeks (+/- 1 week) (52-week 
window) from enrollment date as determined by PSA response 
criteria in Section 11.1.1.  
 
In subjects with missed PSA assessments at 52 (+/- 1) weeks: 
 
• If a confirmed CR is achieved and at least one PSA assessment 
occurs beyond the 52-week window shows serologic complete 
response (providing the subject did not earlier experience 
confirmed progressive disease), the subject achieves 52-week PSA 
Complete Response.  
• If confirmed-CR is achieved before the 52-week window and the 
first assessment after the 52-week window is not a CR, the subject 
did not achieve a 52-week PSA Complete Response.  
  
 
12.2.1.2 PSA Response 
 
PSA response will be determined for each subject as a binary variable 
indicating whether or not the subject achieved a best overall response 
of serologic CR or PR (50 or 90) as determined by PSA response 
criteria in Section 11.1.1. 
 
12.2.1.3 Serologic Progression-Free Survival (sPFS) 
 
sPFS is defined as the duration of time from enrollment to the study to 
first occurrence of either PSA progression or death.  Disease 
progression can be objectively determined as per Section 11.1.1 or 
progression can be subjective as determined by the Investigator.  
Evidence for subjective progression must be documented in the 
medical records.  For objective disease progression, the date of 
progressive disease (PD) is the date of the serologic assessment that 
identified PSA progressive disease as defined in Section 11.1.1.  For 

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subjective disease progression, the date of PD is the date that the 
clinician makes the determination of PSA progression.  If the subject 
died without documented disease progression, the date of 
progression will be the date of death.  For surviving subjects who do 
not have documented disease progression, sPFS will be censored at 
the date of last serologic assessment.  For subjects who receive 
subsequent anti-cancer therapy prior to documented disease 
progression, sPFS will be censored at the date of last serologic 
assessment prior to the commencement of subsequent therapy.  
Subjects who have an initial sPFS event immediately following 2 or 
more consecutive missed assessments will be censored at the date of 
the last assessment prior to those missed assessments.  For 
participants with only one missed assessment, the documented 
progressive disease status and assessment date will be used.  
 
12.2.1.4 Time to Castrate Resistance 
 
Time to Castrate Resistance is defined as the duration from the date of 
enrollment to the date of castrate resistance or death from any cause.  
Date of castrate resistance is defined as the date of serologic 
progression as defined in Section 11.1.1 or the date of radiographic 
progression as defined in Section 11.2, whichever occurs first.  If the 
subject died without documented castrate resistance, the date of 
castrate resistance will be the date of death.  For surviving subjects 
who do not have documented castrate resistance, time to castrate 
resistance will be censored at the date of last serologic or radiologic 
assessment, whichever occurs last.  Other aspects of the censoring 
mechanism will be the same as described for sPFS.  
 
12.2.1.5 Time to Treatment Failure 
 
Time to Treatment Failure is defined as the duration from the date of 
enrollment to the date of discontinuation of all study therapies, or 
death from any cause (whichever occurs first).  For surviving subjects 
who do not discontinue all study therapies, time to treatment failure 
will be censored at the date of last study visit.  Other aspects of the 
censoring mechanism will be the same as described for sPFS. 
 
12.2.2 Radiographic 
 
12.2.2.1 Objective Response 
 
Objective response of soft tissue lesions will be determined for 
each subject as a binary variable indicating whether or not the 
subject achieved a best overall response of CR or PR of soft 

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tissue lesions as determined by RECIST in Section 11.2.1.2.2, 
provided there is an absence of progression of skeletal lesions.  
 
 
12.2.2.2 Radiographic Progression-Free Survival 
 
rPFS is defined as the duration of time from enrollment to the 
study to first occurrence of either radiographic progressive 
disease or death.  Disease progression can be objectively 
determined as soft tissue lesion progression per RECIST in 
Section 11.2.1.2.2, skeletal lesion progression as defined by 
PCWG2 criteria in Section 11.2.2.2, or progression can be 
subjective as determined by the Investigator.  Evidence for 
subjective progression must be documented in the medical 
records.  For objective disease progression, the date of PD is 
the date of the radiographic assessment that identified 
radiologic progressive disease.  For subjective disease 
progression, the date of PD is the date that the clinician makes 
the determination of disease progression.  If the subject died 
without documented disease progression, the date of 
progression will be the date of death.  For surviving subjects 
who do not have documented disease progression, rPFS will be 
censored at the date of last radiologic assessment.  For subjects 
who receive subsequent anti-cancer therapy prior to 
documented disease progression, rPFS will be censored at the 
date of last radiologic assessment prior to the commencement 
of subsequent therapy.  Subjects who have an initial rPFS event 
immediately following 2 or more consecutive missed 
assessments will be censored at the date of the last assessment 
prior to those missed assessments.  For participants with only 
one missed assessment, the documented progressive disease 
status and assessment date will be used.  
 
12.2.3 Overall Survival 
 
Overall survival is defined as the duration from enrollment date to the 
date of death from any cause.  Subjects who are alive or lost to follow-up 
at the time of the analysis will be censored at the last known date they 
were alive. 
 
12.2.4 Safety Endpoints 
 
Treatment administration 
 
Treatment administration will be collected for each subject in terms of 
cumulative dose administered, dose intensity, intended dose intensity, 

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and relative dose intensity.  These calculations will be done separately for 
enzalutamide and docetaxel.  
 
Adverse events 
Adverse events will be collected for each subject using NCI CTCAE v. 4.0 
criteria.  This will be done in terms of treatment-emergent adverse 
events, defined as follows: 
• 
An AE that occurs after treatment start that was not present at the 
time of treatment start; OR 
• 
An AE that increases in severity after treatment start if the event 
was present at the time of treatment start. 
 
SAEs (including deaths while on study treatment) will also be collected 
for each subject. 
12.3 Analysis Populations 
 
Safety and efficacy analyses will be conducted on the population of 
subjects who begin study treatment.  The date of initiation of study 
treatment will be the enrollment date.  Analysis of objective response will 
be conducted on those subjects in the efficacy population with 
measurable disease present at baseline.  The evaluable population for the 
primary analysis will include subjects who begin study treatment, do not 
discontinue enzalutamide prior to the development of castrate resistance 
for reasons other than can be attributed to study treatment, and are not 
censored according to the criteria in Section 12.2.1.1.  Enrollment will 
continue until the targeted sample size described in Section 12.1 is 
achieved for the evaluable population. 
 
12.4 Analysis Methods 
 
12.4.1 Timing of Analysis 
 
The primary analysis will occur after 52-week PSA complete response has 
been determined for all patients.  Updated analyses will be conducted 
after the overall sPFS or rPFS censoring rate reaches 20% or when all 
surviving subjects have been on study for at least 3 years, whichever 
occurs first, or have become lost to follow up or taken off study.  A final 
analysis will be conducted after the overall survival censoring rate 
reaches 20% or after all surviving subjects have been on study for at least 
7 years, whichever occurs first, or have become lost to follow up or taken 
off study. 
 
12.4.2 Subject Disposition 

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An accounting of all consenting subjects will be provided at the end of the 
study.  This will include a breakdown of subjects who consented, were 
treated, discontinued treatment, died, and were lost to follow-up or 
withdrew consent. 
 
12.4.3 Baseline Subject and Disease Characteristics  
 
A summary of subject demographics and disease-related characteristics 
will be completed and clinically-significant subject medical history will be 
assessed.  
 
12.4.4 Efficacy Analysis 
 
12.4.4.1 Primary Analysis 
 
The frequency and proportion of patients experiencing 52-week PSA 
complete response will be calculated.  A corresponding 95% 
confidence interval will be estimated using the Clopper-Pearson 
method.  A one-sided test for binomial proportions using the rejection 
regions described in Section 12.1 will be carried out, testing the null 
hypothesis that the 52-week PSA complete response rate is less than 
25%.  Based on the design and corresponding sample size calculations 
described in Section 12.1, if there are at least 14 52-week PSA 
complete responders the null hypothesis can be rejected. 
 
Logistic regression techniques will be used to correlate 52-week PSA 
complete response rate to low- versus high-volume disease.  This will 
include multiple regression models incorporating key baseline subject 
and disease characteristics.  
 
12.4.4.2 Secondary Analyses 
 
The frequencies and proportions of PSA best overall response and 
radiographic response rate in soft lesions will be calculated.  
Corresponding 95% confidence intervals will be estimated using the 
Clopper-Pearson method. 
 
Overall, serologic progression-free survival, radiologic progression-
free survival, time to castrate resistance, and time to treatment failure 
will be analyzed using Kaplan Meier techniques.  Medians, 25th, and 
75th percentiles will be estimated.  Selected landmarks for OS 
(survival rates for every 6 months from 6 months to 84 months), sPFS 
(sPFS rates for every 6 months from 6 months to 60 months), rPFS 
(rPFS rates for every 6 months from 6 months to 84 months), time to 
castrate resistance, and time to treatment failure will be estimated 

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form the Kaplan Meier curves.  Cox proportional hazards models will 
be used to correlate OS, sPFS, rPFS, time to castrate resistance, and 
time to treatment failure to disease volume.  This will include multiple 
regression models incorporating key baseline subjects and disease 
characteristics. 
 
Safety Analyses 
The cumulative dose, dose intensity, and relative dose intensity will 
be summarized quantitatively.  Incident rates for TEAEs, AEs leading 
to study drug discontinuation, SAEs and deaths while on study 
therapy will be summarized including Clopper-Pearson 95% 
confidence intervals.  The incidence of TEAEs will be analyzed in term 
of maximum grade severity experienced for each subject.  
It has been reported that the incidence of neutropenic fever with the 
use of ADT and docetaxel is approximately 6-12%.  Prophylactic 
myeloid growth factor support may be used at the Investigator’s 
discretion.  If it becomes evident that the rate of neutropenic fever (in 
patients who do not receive prophylactic myeloid growth factor) with 
the addition of enzalutamide treatment convincingly exceeds 0.20, 
study procedure will mandate the use of prophylactic myeloid growth 
factor.  This rule will hold if the posterior probability of the rate of 
neutropenic fever exceeding 0.20 is 50% or higher.  The prior for this 
monitoring rule is beta (3,22).  This means that our prior assumption 
regarding the proportion of neutropenic fever in patients not 
receiving myeloid growth factor is 12% (the high end of estimates of 
incidence of neutropenic fever with use of ADT and docetaxel), and 
there is 90% probability that his proportion is between 3.50% and 
23.98%.  The operating characteristics of the stopping rule are given 
in the following table and are based on 5000 simulations.  
 
Neutropenic fever events 
observed 
Maximum number of 
enrolled subjects for 
mandating myeloid growth 
factor 
Posterior probability: 
Pr(Risk>0.20|Data) 
4 
9 
0.501 
5 
13 
0.524 
6 
19 
0.503 
7 
24 
0.509 
8 
29 
0.510 
9 
34 
0.502 
 
12.4.4.3 Exploratory Analyses 
 
Cox proportional hazards models and logistic regression will be used 
to assess the correlations between baseline circulating tumor cell 
levels and androgen receptor splice variant 7 (Arv7) protein 
expression with clinical outcomes.  

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12.5 Interim Analyses 
 
No interim analyses are planned. 
 
13. Biomarker Analysis 
 
13.1 Circulating Tumor Cells 
 
In attempt to identify molecular markers predictive of response to 
therapy, additional molecular testing will include enumeration of CTCs 
and characterization of CTC ARv7 protein expression by 
immunofluorescence at the following time points in each subject: 
• Prior to docetaxel 
• After completion of docetaxel 
• Following development of castrate resistance 
 
14. Study Completion 
 
14.1 Completion 
 
The study will be considered complete when one or more of the 
following conditions is met: 
• All subjects are dead and/or withdrawn from the study. 
• All subjects have discontinued from the study. 
• The IRB, LCI DSMC, Sponsor-Investigator or Astellas discontinues the 
study because of safety considerations. 
• The Sponsor-Investigator defines an administrative or clinical cut-off 
date. 
 
14.2 Termination 
 
The study will be terminated when one or more of the following 
conditions occur: 
 
If risk-benefit ratio becomes unacceptable owing to, for example: 
• Safety findings from this study (e.g. SAEs) 
• Results of any interim analysis 
• Results of parallel clinical studies 
• Results of parallel animal studies (e.g. toxicity, teratogenicity, 
carcinogenicity or reproduction toxicity). 
• If the study conduct (e.g. recruitment rate; screen failure rate; 
withdrawal rate; data quality; protocol compliance) does not suggest 
a proper completion of the trial within a reasonable time frame. 
 

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The Sponsor-Investigator has the right to close the trial at any site and at 
any time. 
 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved 
parties. 
• All affected institutions must be informed as applicable according to 
local law.   
• In case of a partial study closure, ongoing subjects, including those in 
follow-up, must be taken care of in an ethical manner. 
 
 
Details for individual subject's withdrawal can be found in Section 5.8.3.  
 
14.3 Retention of Records 
 
Essential documentation (e.g.  adverse events, records of study drug receipt 
and dispensation), including all IRB correspondence, will be retained for at 
least 2 years after the investigation is completed.  Documentation will be 
readily available upon request. 
 
15. Ethical and Legal Issues 
 
15.1 Study Conduct 
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, 
and documentation of this study, are designed to ensure that the Investigator 
abides by Good Clinical Practice (GCP) guidelines and under the guiding 
principles detailed in the Declaration of Helsinki.  The study will also be 
carried out in keeping with applicable local law(s) and regulation(s). 
 
Documented approval from appropriate agencies (e.g.  IRB) will be obtained 
for all participating centers before start of the study, according to GCP, local 
laws, regulations and organizations.  When necessary, an extension, 
amendment or renewal of IRB approval must be obtained and forwarded to 
Astellas. 
 
Strict adherence to all specifications laid down in this protocol is required for 
all aspects of study conduct.  The Investigators may not modify or alter the 
procedures described in this protocol.   
 
Modifications to the study protocol will not be implemented by the Sponsor-
Investigator without discussion and agreement by Astellas.  However, the 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to the trial subjects without prior approval 
from applicable agencies.  As soon as possible, the implemented deviation or 

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change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the appropriate agencies.  Any deviations 
from the protocol must be explained and documented by the Investigator. 
 
The Sponsor-Investigator is responsible for the conduct of the clinical trial at 
the sites in accordance with Title 21 of the Code of Federal Regulations 
and/or the Declaration of Helsinki.  The Sponsor-Investigator is responsible 
for personally overseeing the treatment of all study subjects.  The Sponsor-
Investigator must assure that all study site personnel, including sub-
Investigators and other study staff members, adhere to the study protocol 
and all applicable regulations and guidelines regarding clinical trials both 
during and after study completion. 
 
The Sponsor-Investigator will be responsible for assuring that all the 
required data will be collected and properly documented. 
 
15.2 Confidentiality 
 
All records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made 
publicly available. 
 
15.3 Publication 
 
At least thirty (30) days prior to submission for publication, presentation or 
use, the Sponsor-Investigator must submit any proposal, oral or written to 
Astellas for review and comment.  
 
The Sponsor-Investigator will ensure that the information regarding the 
study be publicly available on the internet at www.clinicaltrials.gov.  
 
 

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