Clinical trial NCT02278185
Conditions: Adenocarcinoma of the Prostate Recurrent Prostate Cancer Stage III Prostate Cancer Stage IV Prostate Cancer
Sponsor: University of Colorado, Denver
Start date: 2015-11-11; Completion date: 2024-07-18
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial compares enzalutamide with standard androgen deprivation therapy in reducing incidence of metabolic syndrome in patients with prostate cancer that has spread to other places in the body. Metabolic syndrome is defined as changes in cholesterol, blood pressure, circulating sugar levels, and body weight. Previous studies have shown that patients with prostate cancer, who have been treated with standard medical therapy that lowers testosterone levels, have an increased risk of these changes. Hormone therapy using enzalutamide may fight prostate cancer by blocking the use of testosterone by the tumor cells instead of lowering testosterone levels. It is not yet known whether prostate cancer patients who receive enzalutamide will have reduced incidence of metabolic syndrome than patients who receive standard androgen deprivation therapy.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the incidence of metabolic syndrome within 12 months, as defined by the Adult Treatment Panel III, in patients treated with enzalutamide compared to standard androgen deprivation therapy.

SECONDARY OBJECTIVES:

I. To determine the incidence of metabolic syndrome within 6 months, as defined by the Adult Treatment Panel III, in patients treated with enzalutamide compared to standard androgen deprivation therapy.

II. To assess bone health, as measured by a dual-energy x-ray absorptiometry (DXA) scanner.

III. To assess body composition (sarcopenic obesity), as measured by a DXA scanner.

IV. To assess quality of life (QOL), as measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Sexual Health Inventory in Men (SHIM).

V. To assess time to prostate-specific antigen (PSA) progression and time to radiographic progression.

VI. To assess the incidence of developing individual risk factors, or components, which comprise metabolic syndrome.

VII. To assess the change in high-sensitivity C-reactive protein (hs-CRP) as a marker of inflammation.

VIII. To assess the safety and tolerance of enzalutamide or androgen deprivation therapy (ADT).

IX. To assess the change in physical function as measured by the Short Physical Performance Battery (SPPB).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive enzalutamide orally (PO) once daily (QD) for 12 months in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive standard of care ADT comprising one of the following at the discretion of the treating physician: leuprolide acetate, goserelin acetate, histrelin acetate, triptorelin, or degarelix subcutaneously (SC) or intramuscularly (IM) for 12 months in the absence of disease progression or unacceptable toxicity. Patients may also choose to undergo surgical castration as an alternative form of ADT.

After completion of study treatment, patients are followed up at 30 days.

Arms: arm 1: Patients receive enzalutamide PO QD for 12 months in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive standard of care ADT comprising one of the following at the discretion of the treating physician: leuprolide acetate, goserelin acetate, histrelin acetate, triptorelin, or degarelix SC or IM for 12 months in the absence of disease progression or unacceptable toxicity. Patients may also choose to undergo surgical castration as an alternative form of ADT.
Interventions: intervention 1: Enzalutamide intervention 2: leuprolide acetate intervention 3: goserelin acetate intervention 4: histrelin acetate intervention 5: triptorelin intervention 6: degarelix
Intervention descriptions: intervention 1: Given PO intervention 2: Given SC or IM intervention 3: Given SC or IM intervention 4: Given SC or IM intervention 5: Given SC or IM intervention 6: Given SC or IM

Protocol documents:
Prot_SAP_000.pdf: 
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COMIRB PROTOCOL #: 
14-0909 
PROTOCOL VERSION: 
April 27, 2018 
 
 
 
 
PROTOCOL TITLE: 
An open label, randomized, Phase II trial of Metabolic complications in patients 
treated with enzalutamide vs standard ADT for the treatment of hormone 
sensitive prostate cancer 
 
NCT02278185 
 
 
COORDINATING CENTER: 
University of Colorado Cancer Center 
 
 
LEAD PRINCIPAL INVESTIGATOR: 
Elizabeth Kessler, MD 
University of Colorado Denver, Division of Medical Oncology 
12801 East 17th Avenue, MS 8117 
Aurora, CO 80045 
Phone: 720-848-0402 
Fax: 303-724-3889 
Elizabeth.kessler@ucdenver.edu 
 
 
 
Statistician: 
Dexiang Gao, PhD 


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Protocol Summary 
 
 
An open label, randomized, Phase II trial of Metabolic complications in patients treated with 
enzalutamide vs standard ADT for the treatment of hormone sensitive prostate cancer 
Primary Objective 
To determine the incidence of metabolic syndrome within 12 months, as defined by 
the Adult Treatment Panel III, in patients treated with enzalutamide compared to 
standard androgen deprivation therapy. 
Secondary 
Objectives 
In patients on enzalutamide versus traditional ADT: 
 To determine the incidence of metabolic syndrome within 6 months, as 
defined by the Adult Treatment Panel III, in patients treated with 
enzalutamide compared to standard androgen deprivation therapy. 
 To assess bone health, as measured by a DXA scanner 
 To assess body composition (sarcopenic obesity), as measured by cross 
sectional CT analysis 
 To assess QOL, as measured by the FACT-P and SHIM 
 To assess time to PSA progression and time to radiographic progression. 
Progression will be defined as lack of clinical benefit in the setting of either 
rising PSA, growth of visceral or soft tissue metastasis, or development of 
new bone metastasis as defined per protocol 
 To assess the incidence of developing individual risk factors, or 
components, which comprise metabolic syndrome 
 To assess the safety and tolerance of enzalutamide or ADT 
 To assess the change in hs-CRP as a marker of inflammation 
 To assess the change in physical function as measured by the Short Physical 
Performance Battery 
Study Population 
Patients with biochemically recurrent disease, metastatic disease, and patients 
offered ADT as primary therapy if they are not candidates for local therapy. 
Other Participating 
Site (enrolling 
subjects) 
University of Colorado Health - Poudre Valley Hospital (UCH-North) 
Site Principal Investigator:  Steven Schuster, MD 
STUDY DESIGN 
Multi-center, open label, randomized, phase II trial evaluating the incidence of metabolic syndrome 
within 12 months in patients treated with enzalutamide in comparison with androgen deprivation therapy 
for treatment of advanced prostate cancer. Enzalutamide 160mg orally daily versus standard androgen 
deprivation therapy. Acceptable forms of ADT will be specified and this therapy must result in castrate 
levels of testosterone. Patients will be treated for a 12-month period and assessed for the development of 
metabolic syndrome at 3 month intervals. Patients with continued clinical benefit beyond the 12-month 
endpoint may continue on their assigned treatment through standard of care prescribing methods. 


 
 
 
 
TABLE 1: Schedule of Events 
Screening 
Day 0 
Start of 
Treatment 
Month 1, Day12 
Month 2, 
Day1 
Month 4, 
Day 1 
Month 7, 
Day 1 
Month 10, 
Day 1 
Month 13, Day 
1 
End of 
Treatment 
End of 
study6 
Informed Consent 
X 
VISIT ASSESSMENTS 
Adverse events assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Review medication list 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam and history 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs, including weight, waist circumference 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY STUDIES 
CBC, Comprehensive metabolic panel (fasting for 
glucose) 
X1 
X 
X 
X 
X 
X 
X 
X8 
PSA 
X 
X7 
X 
X 
X 
X 
X 
Lipid Profile (including triglycerides and HDL) 
X 
X 
X 
X 
X 
N-Telopeptide, Bone specific alkaline phosphatase, 
hs-CRP, estradiol 
X 
X 
X 
X 
X 
Testosterone 
X 
X 
X 
X 
X 
X 
25-OH Vitamin D 
X 
X 
X 
IMAGING 
Fill out QOL questionnaires (FACT – P and SHIM) 
X 
X 
X 
X 
X 
Bone densometry (DXA) 
X9 
X 
X9 
CT scan of chest, abdomen, pelvis3, 4 
X 
X 
X 
Nuclear Bone scan3,4 
X 
X 
X 
TREATMENT 
Enzalutamide dosed at 160mg po daily 
X 
X 
X 
X 
X 
GNRH agonist/antagonist (Standard of care) 
X 
X 
X 
X 
X 
Calcium/Vitamin D5 
X 
X 
X 
X 
X 
OTHER 
Short physical performance battery 
X 
X 
X 
X 
X 
Optional biomarker blood testing (3 tubes, see lab 
manual) 
X 
X 
X 
X 
X 
1 May be performed from day -14 to 0.  Screening is day 0. 
2 Day 1 Month 1 must occur with 21 days of screening. Visit days of the remaining months must occur +/- 5 days to date on the calendar. 
3 May be performed Day - 28 - Day 0 
4 Also to be performed during treatment to evaluate a rising PSA. CT chest combined with MRI of the abdomen/pelvis is also accepted. 
5 At least 1000mg of calcium and 800 International Units (IU) of vitamin D 
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6. Safety visit to be performed within 30 days from last study drug dose, or prior to starting a new treatment, whichever is sooner 
7 If screening PSA is within 5 days of Day 1, repeat testing is not necessary 
8 Glucose does not have to be fasting 
9 Please see protocol for windows as DXA and NM bone scan need 14 days of separation if bone scan is performed first 


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Table of Contents 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ......................................................................................... 8 
1. BACKGROUND AND STUDY RATIONALE ........................................................................................................... 10 
1.1 Prostate cancer ..................................................................................................................................................................... 10 
1.2 Androgen deprivation therapy and metabolic syndrome ..................................................................................... 10 
1.3 Metabolic syndrome ........................................................................................................................................................... 10 
1.4 Rationale for study design ................................................................................................................................................ 11 
1.5 Enzalutamide ......................................................................................................................................................................... 11 
1.6 Androgen deprivation therapy ....................................................................................................................................... 12 
1.7 Nonclinical Experience ...................................................................................................................................................... 13 
1.7.1 Drug Metabolism and Pharmacokinetics ............................................................................................................................... 13 
1.8 Toxicology .............................................................................................................................................................................. 13 
1.8.1 Drug-Drug Interaction Risk Assessment ................................................................................................................................ 13 
2. STUDY OBJECTIVES .................................................................................................................................................. 14 
2.1 Primary Objectives .............................................................................................................................................................. 14 
2.2 Secondary Objectives.......................................................................................................................................................... 14 
3. STUDY ENDPOINTS ................................................................................................................................................... 14 
3.1 Primary Endpoints .............................................................................................................................................................. 14 
3.2 Secondary Endpoints .......................................................................................................................................................... 14 
4. STUDY DESIGN ........................................................................................................................................................... 15 
4.1 Overview of Study Design ................................................................................................................................................. 15 
4.2 Duration of Study ................................................................................................................................................................. 15 
4.3 Overview of treatment ....................................................................................................................................................... 16 
4.4 Criteria for Dose Administration.................................................................................................................................... 16 
4.4.1 Study Drug Administration .......................................................................................................................................................... 16 
4.4.2 Clinical Benefit .................................................................................................................................................................................. 16 
4.5 Dose Modification Guidelines .......................................................................................................................................... 17 
4.6 Study specific biomarker collection .............................................................................................................................. 17 
5. STUDY POPULATION ................................................................................................................................................ 17 
5.1 Inclusion Criteria ................................................................................................................................................................. 17 
5.2 Exclusion Criteria ................................................................................................................................................................. 17 
6. STUDY PROCEDURES AND ASSESSMENTS ........................................................................................................ 19 
6.1 Informed Consent ................................................................................................................................................................ 19 
6.2 Randomization ...................................................................................................................................................................... 19 
6.3 Study Visits ............................................................................................................................................................................. 19 
6.3.1 Physical Examination ..................................................................................................................................................................... 19 
6.3.2 Schedule of Events........................................................................................................................................................................... 19 
7. STUDY ASSESSMENTS .............................................................................................................................................. 22 
7.1 Assessment of metabolic syndrome .............................................................................................................................. 22 
7.2 Efficacy Evaluations ............................................................................................................................................................ 22 
7.2.1 PSA ......................................................................................................................................................................................................... 22 
7.2.2 Radiographic evaluation ............................................................................................................................................................... 22 
7.3 Body composition evaluation .......................................................................................................................................... 23 
7.4 Quality of life assessment ................................................................................................................................................. 23 
7.5 Physical function evaluation ............................................................................................................................................ 23 


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7.6 Safety evaluations ................................................................................................................................................................ 23 
7.6.1 Adverse Events ................................................................................................................................................................................. 24 
7.6.2 Clinical Laboratory Evaluations ................................................................................................................................................. 24 
7.7 Concomitant Medication and Therapies...................................................................................................................... 24 
7.8 Completion of Study ............................................................................................................................................................ 25 
7.9 Study Compliance................................................................................................................................................................. 25 
8. INVESTIGATIONAL AGENTS................................................................................................................................... 26 
8.1 Precautions and Restrictions .......................................................................................................................................... 26 
8.2 Description of Investigational Agents .......................................................................................................................... 26 
8.2.1 Enzalutamide ..................................................................................................................................................................................... 26 
8.2.2 Androgen deprivation therapy................................................................................................................................................... 26 
8.3 Preparation, Reconstitution, and Dispensation........................................................................................................ 26 
8.4 Storage, Handling, Accountability .................................................................................................................................. 26 
8.4.1 Enzalutamide ..................................................................................................................................................................................... 26 
8.4.2 Handling and Accountability ....................................................................................................................................................... 27 
9. STUDY CONDUCT ....................................................................................................................................................... 27 
9.1 Oversight of multiple participating sites ..................................................................................................................... 27 
Study will be conducted at multiple sites with the University of Colorado Anschutz Campus as the 
coordinating site. Dr. Kessler, as the Lead PI, will work with the Site PI(s) to insure proper training and 
conduct ........................................................................................................................................................................................... 27 
9.2 Arrangements for Recruitment of Patients ................................................................................................................ 27 
9.3 Treatment Group Assignments ....................................................................................................................................... 28 
10. STATISTICAL AND QUANTITATIVE ANALYSES ............................................................................................ 28 
10.1 Statistical Methods ............................................................................................................................................................ 28 
10.1.1 Endpoint Analysis ......................................................................................................................................................................... 28 
10.1.2 Accrual ............................................................................................................................................................................................... 29 
10.2 Safety population ............................................................................................................................................................... 29 
10.3 Metabolic syndrome population .................................................................................................................................. 29 
10.4 Secondary endpoint population ................................................................................................................................... 29 
11. Safety Analysis ........................................................................................................................................................ 29 
11.1 Oversight and Monitoring .............................................................................................................................................. 30 
12. ADVERSE EVENTS ................................................................................................................................................... 31 
12.1 Definitions............................................................................................................................................................................ 31 
12.2 Maintenance of Safety Information............................................................................................................................. 33 
12.2.1 Product Quality Complaints ...................................................................................................................................................... 33 
12.2.2 Reconciliation of SAEs ................................................................................................................................................................. 33 
12.3 Dissemination of Safety Information from Astellas, Inc. to Principal Investigator ................................... 33 
12.4 Monitoring of Adverse Events and Period of Observation ................................................................................. 33 
13. ADMINISTRATIVE REQUIREMENTS ................................................................................................................. 34 
13.1 Data Quality Assurance ................................................................................................................................................... 34 
13.2 Study Monitoring ............................................................................................................................................................... 34 
13.3 Ethical Considerations ..................................................................................................................................................... 34 
13.4 Patient Information and Informed Consent ............................................................................................................ 34 
13.5 Patient Confidentiality .................................................................................................................................................... 35 
13.6 Investigator Compliance ................................................................................................................................................. 35 
13.7 On-site Audits ..................................................................................................................................................................... 35 
13.8 Investigator and Site Responsibility for Drug Accountability ........................................................................... 35 


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13.9 Closure of the Study .......................................................................................................................................................... 35 
13.10 Record Retention ............................................................................................................................................................ 35 
14. USE OF INFORMATION .......................................................................................................................................... 36 
15. REFERENCES............................................................................................................................................................. 37 
16. APPENDICES ............................................................................................................................................................. 41 
16.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status .............................................. 41 
16.2 Correlative lab sample collection ................................................................................................................................ 42 
16.3 Short Physical Performance Battery .......................................................................................................................... 42 
16.4 FACT-P questionnaire ...................................................................................................................................................... 43 
16.5 SHIM questionnaire .......................................................................................................................................................... 46 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
 
Abbreviation 
Term 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
AUC 
Area under the plasma concentration versus time curve 
AUC0-inf 
Area under the plasma concentration versus time curve zero to infinity 
CRPC 
Castrate resistant prostate cancer 
CBC 
Complete blood count 
CI 
Confidence interval 
hs-CRP 
C-reactive protein 
CrCL 
Creatinine clearance 
CL/F 
Apparent oral clearance 
Cmax 
Maximum plasma concentration 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction 
DNA 
Deoxyribonucleic acid 
DXA 
Dual-energy x-ray absorptiometry scan 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
End of study 
FACT-P 
Functional assessment of cancer therapy-prostate 
FDA 
Food and Drug Administration 
FPG 
Fasting plasma glucose 
FSH 
Follicle stimulating hormone 
GABA 
Gamma-aminobutyric acid 
GnRH 
Gonadotropin releasing hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
HDL 
High density lipoprotein 
HIPAA 
Health insurance portability and accountability act 
HR 
Hazard ratio 


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Abbreviation 
Term 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational new drug 
IRB 
Institutional Review Board 
IU 
International units 
LDL 
Low density lipoprotein 
LH 
Leutinizing hormone 
LHRH 
Leutinizing hormone releasing hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common  Terminology Criteria for     Adverse 
NYHA 
New York Heart Association 
PI 
Principal investigator 
PD 
Progressive disease 
PFS 
Progression-free survival 
PSA 
Prostate specific antigen 
PCWG2 
Prostate Cancer Working Group 2 
QOL 
Quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SPPB 
Short physical performance battery 
SRE 
Skeletal related event 
SUSAR 
Serious Unexpected Suspect Adverse Reaction 
SHIM 
Sexual Health Inventory in Men 
T1/2 
Terminal half life 
UCH-North 
University of Colorado Health – Poudre Valley Hospital 
ULN 
Upper limit of the normal range 
V/F 
Volume of distribution 
WHO 
World Health Organization 


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1. 
BACKGROUND AND STUDY RATIONALE 
 
1.1 
Prostate cancer 
Prostate cancer is the most common non-cutaneous cancer in men in the United States, and the second 
leading cause of cancer death in US men1. As many as three-quarters of prostate cancer patients 
present with localized disease yet a good proportion have recurrent or metastatic disease requiring 
systemic treatment with androgen deprivation therapy (ADT). 
 
1.2 
Androgen deprivation therapy and metabolic syndrome 
While many new agents have been developed for the treatment of prostate cancer, these focus on 
treatment in the metastatic, castrate-resistant setting. Patients requiring systemic therapy for prostate 
cancer continue to be initially treated with traditional gonadotropin hormone analogues, despite 
advances in therapeutic development. The treatment is very effective with survival results mainly 
impacted by disease state at initiation. The average time from biochemical recurrence, or prostate 
specific antigen (PSA) relapse, to development of metastatic disease is approximately 8 years 2 and 
survival for patients with metastatic disease on ADT is approximately 30 months. The median time 
of response for patients with biochemically relapsed disease treated with ADT is 10.8 months 3. 
Thereafter, patients remain on ADT in combination with other therapies for the duration of their anti- 
cancer therapy, which may be years. Men treated with ADT experience long-term adverse effects 
such as fatigue, loss of muscle mass (i.e. sarcopenia), loss of bone density, increased adiposity, 
development of metabolic syndrome, depression, sexual dysfunction and poor quality of life (QOL)4- 
13. Men treated with ADT had lower levels of self-reported physical function and QOL in comparison 
to age-matched controls 8,10,14-17. These effects are profound for any patients but may be felt to a larger 
degree in the standard older patient population afflicted with prostate cancer, already dealing with the 
changes of decreasing functional reserve. 
 
1.3 
Metabolic syndrome 
One of the long term sequelae of ADT is the development of metabolic syndrome. While many 
definitions exist, “metabolic syndrome” broadly encompasses reduced insulin sensitivity and 
increasing body mass. The syndrome itself imposes a higher risk of cardiovascular disease and 
diabetes which subsequently impact mortality risk 18. Metabolic syndrome is a common health 
problem in the United States with a distant evaluation of the prevalence estimated at over 40% for 
persons over the age of 60 with more recent updates suggesting that the incidence is increasing 19. 
This is the same age group most likely to be affected by prostate cancer. A long term hypogonadal 
state, such as is induced by prostate cancer therapy, has been shown to independently predict the 
development of metabolic syndrome, and patients with metabolic syndrome have a 3 times greater 
risk of death from cardiovascular disease than healthy counterparts 20,21. There are data supporting the 
role of hypogonadism in independently increasing the risk of many of the components of metabolic 
syndrome such as dyslipidemia, hypertension, alterations in body mass and glucose intolerance, and 
that these parameters may change as early as 3-6 months after the initiation of therapy 7,22-25. 
Population-based analyses have shown a higher incidence of diabetes and coronary disease in patients 
treated with ADT 26,27. Cross sectional studies have shown that men with prostate cancer treated with 
ADT are twice as likely to meet the criteria for metabolic syndrome in comparison to matched prostate 
cancer patients or healthy controls7. Unlike many cancer treatments, patients remain on ADT for 
years, allowing for the development of long-term sequelae, which impact a patient’s global health and 
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1.4 
Rationale for study design 
Improved understanding of the biology of prostate cancer has allowed for the development of agents, 
which more effectively manipulate the androgen axis even under castrate conditions. Not only 
reduction in circulating testosterone, but also improved blockade of the androgen receptor has led to 
an improvement in survival for patients with metastatic castrate resistant prostate cancer (CRPC). The 
development of a new generation of agents, such as enzalutamide, that preserve circulating 
testosterone levels while acting on the androgen receptor, provide new therapeutic opportunities for 
an active single agent with the potential for a reduction of the long term effects associated with ADT. 
Single agent data of enzalutamide reveals an excellent PSA response and tolerance profile28 
Preservation of these hormone levels may delay the adverse effects associated with long term ADT 
that contribute to development of metabolic syndrome. 
 
The influence of the adverse events associated with newer agents on a patient’s QOL is increasingly 
used to guide cancer care 29, and understanding the comparative effectiveness of agents is important. 
Men with prostate cancer have higher rates of noncancerous mortality than men in the general 
population, perhaps due to the contribution of the hypogonadal state in worsening common causes of 
death such as heart disease and diabetes. The clustering of cardiovascular risk factors, which occurs 
with ADT, may not be found in patients treated with enzalutamide due to its preservation of systemic 
testosterone levels. There has not been a longitudinal analysis of the development of metabolic 
syndrome in patients on ADT, nor a structured evaluation of the development of metabolic syndrome, 
or metabolic changes in patients treated with enzalutamide. This protocol will evaluate the effect of 
androgen blockade via enzalutamide versus traditional ADT on development of metabolic syndrome, 
changes in body composition, changes in quality of life, and changes in physical function in patients 
with advanced prostate cancer. 
 
1.5 
Enzalutamide 
Enzalutamide is a non-steroidal anti-androgen that blocks the ability of testosterone to signal through 
the androgen receptor. Enzalutamide has no known agonistic properties even when the androgen 
receptor is overexpressed as supported in preclinical models of CRPC. Enzalutamide is currently 
approved by the FDA for treatment of men with metastatic prostate cancer that have previously been 
treated with docetaxel chemotherapy. In the AFFIRM trial, which led to this approval, patients 
received enzalutamide 160mg/day orally or placebo 30. The study showed a survival advantage for 
patients treated with enzalutamide of 18.4 months in comparison to 13.6-months (hazard ratio (HR) 
0.631 [95% CI: 0.529-0.752], p< 0.0001).  Other endpoints of radiographic progression free survival 
(PFS), 8.3 versus (vs) 2.9 months; hazard ratio (HR) 0.40, p< 0.001 and PSA response 54% vs 2%, p< 
0.001were also significantly improved in those receiving enzalutamide. The AFFIRM trial also 
supported an improved QOL in the enzalutamide treated group as well as improvement in time to first 
skeletal-related event (SRE) (16.7 vs 13.3 months; HR 0.69, p< 0.001). In addition, the PREVAIL 
trial is studying enzalutamide versus placebo in men with metastatic castrate resistant prostate cancer 
that have not yet been treated with chemotherapy and has reported promising results that will likely 
lead to its approval 31. 
 
Ongoing studies of enzalutamide are evaluating its efficacy earlier in the treatment spectrum. The 
Phase II, STRIVE trial is evaluating the efficacy of enzalutamide for patients that may have castrate 
resistant disease with metastatic and non-metastatic CRPC (NCT01664923). In addition, there was a 
relatively small phase II trial evaluating the use of enzalutamide prior to the initiation of traditional 
testosterone-lowering agents 32. This single agent trial was conducted in 67 men without previous 
exposure to ADT with a primary endpoint of PSA response defined as an 80% decline from baseline. 
Monotherapy with enzalutamide was highly effective, with a median PSA decrease of    99.6% seen, 


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and 92.5% of patients achieving the primary endpoint at week 25. The trial enrolled patients with and 
without metastatic disease at baseline. 
 
In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had 
previously received docetaxel, 1200 patients were enrolled. The most common adverse drug reactions 
(≥ 5%) reported in patients receiving enzalutamide in the randomized clinical trial were 
asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, 
headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory 
infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and 
hypertension 33. Severe, grade >3 adverse events, were reported in 47% patients receiving 
enzalutamide and 53% of patients receiving placebo. The most common adverse reaction leading to 
treatment discontinuation in the enzalutamide treated group was seizure, which occurred in 0.9% of 
the enzalutamide-treated patients compared to none (0%) of the placebo-treated patients. In the Phase 
III trial, 7 of 800 patients treated with enzalutamide experienced a seizure in comparison to 0 events 
in the placebo arm. The seizures occurred days 31-603 after drug initiation. No further seizures 
occurred after patients discontinued enzalutamide. Patients were never readministered enzalutamide 
while on study, and patients with a history of seizure have been excluded in additional studies. It is 
thought that the mechanism of seizure may be the inhibition of the GABA-gated chloride channel. It 
is suggested that enzalutamide may lower the seizure threshold but not directly contribute to these 
events. This trial will exclude patients with a predisposition to seizure, as the exclusion of this subset 
of patients should not have a known impact on altering the incidence of metabolic syndrome. Another 
notable adverse event associated with the enzalutamide treatment arm is fall and fall-related injuries. 
This occurred in 4.6% of patients enrolled in the randomized trial and assigned to the enzalutamide 
treatment group in comparison to 1.3% of patients treated with placebo. The mechanism of fall is not 
clear.  Fall-related injuries are described as joint injuries, non-pathologic fractures, and hematomas. 
 
Very few laboratory abnormalities were seen in patients treated with enzalutamide. Neutropenia of 
all grades occurred in 15% of patients on enzalutamide (1% Grade 3-4). The incidence of 
thrombocytopenia was similar in the treatment and placebo arms (0.5% on enzalutamide v 1% on 
placebo). Elevation in transaminases occurred in 10% of patients on enzalutamide (0.3% Grade 3-4) 
and 18% of patients on placebo (0.5% Grade 3-4), with elevations in bilirubin occurring in 3% v 2 % 
on placebo. 
 
1.6 
Androgen deprivation therapy 
Standard androgen deprivation therapy is a broad term encompassing any agent, or method, which 
invokes a castrate state for the treatment of prostate cancer. Medical therapy generally includes a 
gonadotropin releasing hormone (GnRH) analogue (agonist or antagonist) with a lowering of 
testosterone to castrate levels as the primary result of treatment. The agonists bind to the GnRH 
receptors in the pituitary to alter release of luteinizing and follicle stimulating hormones (LH and FSH) 
and eventually alter the feedback loop. A GnRH antagonist suppresses testosterone while avoiding 
the initial flare in testosterone seen with the administration of GnRH agonist. Examples of currently 
available formulations include: degarelix, goserelin, leuprolide, triptorelin, and histerelin. Surgical 
castration by means of an orchiectomy also reduces overall testosterone production. Hormone therapy 
is palliative in nature but has been shown to have a significant effect on the morbidity and mortality 
of prostate cancer. Notable side effects include sexual dysfunction, osteoporosis, sarcopenic obesity, 
increase in cardiovascular risk factors and diabetes, vasomotor symptoms, fatigue and alterations in 
cognition. 


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1.7 
Nonclinical Experience 
1.7.1 
Drug Metabolism and Pharmacokinetics 
Enzalutamide alters the functioning of the androgen receptor-signaling pathway. Enzalutamide has 
been shown to competitively inhibit androgen binding to androgen receptors and to inhibit the 
translocation of the receptor to the nucleus and subsequent DNA binding. The phase I, first-in-human 
trial of enzalutamide (or MDV3100) enrolled 140 patients with CRPC 34. Dosing ranged from 30 to 
600 milligrams (mg)/day with the maximum tolerated dose (MTD) determined as 240 mg orally per 
day.  The recommended phase II dose was 160 mg/day. 
 
The major active metabolite of enzalutamide is N-desmethyl enzalutamide. The pharmacokinetics of 
enzalutamide and this metabolite have been evaluated in healthy male volunteers or men with castrate- 
resistant metastatic prostate cancer 33. A linear two-compartment model with first-order absorption 
adequately described. Following oral administration, the median time to reach maximum plasma 
enzalutamide concentrations (Cmax) is 1 hour. The mean steady state Cmax values are 16.6 μg/mL for 
enzalutamide and 12.7 μg/mL for N-desmethyl enzalutamide.  The mean predose trough values    are 
11.4 μg/mL and 13.0 μg/mL, respectively. With the approved dosing schedule, steady state is reached 
in 28 days due to the long half-life ( t1/2) of 5.8 days. At steady state, enzalutamide showed 
approximately dose proportional pharmacokinetics. The mean apparent volume of distribution (V/F) 
of enzalutamide in patients after a single oral dose is 110 L. Enzalutamide is 98% bound to plasma 
proteins.  N-desmethyl enzalutamide is 95% bound to plasma proteins. 
 
Plasma samples were analyzed after a single oral administration of 160mg of carbon-labeled 
enzalutamide. Enzalutamide, N-desmethyl enzalutamide, and an inactive carboxylic acid metabolite 
accounted for 30%, 49%, and 10%, respectively, of the total AUC. Based on in vivo and in vitro data, 
CYP2C8 is primarily responsible for the formation of N-desmethyl enzalutamide, but in vitro data 
suggests the CYP3A4 is partially responsible for metabolism. 
 
Enzalutamide is primarily eliminated by hepatic metabolism. The majority of elimination is through 
the urine (71% from one study) with 14% through feces. The mean apparent clearance (CL/F) of 
enzalutamide in patients after a single oral dose is 0.56 L/hour. 
 
Based on limited data, the apparent clearance of enzalutamide is similar in patients with pre-existing 
mild and moderate renal impairment (CrCL 30 to < 90 mL/minute) compared to patients and 
volunteers with normal renal function. There are insufficient data to describe the potential effect of 
more severely impaired renal function on the clearance of enzalutamide. Hepatic function 
abnormalities of mild or moderate grade do not affect the area under the curve (AUC) of enzalutamide 
or its active metabolite. 
 
1.8 
Toxicology 
1.8.1 
Drug-Drug Interaction Risk Assessment 
In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of enzalutamide was 
administered alone or after multiple oral doses of a strong CYP2C8 inhibitor and the AUC was 
increased 2.2 times with minimal effect on Cmax. When administered with a single dose of a strong 
CYP3A4 inhibitor, the AUC0-inf increased by 1.3 times 33. 


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2. 
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
To determine the incidence of metabolic syndrome within 12 months, as defined by the Adult 
Treatment Panel III, in patients treated with enzalutamide compared to standard androgen deprivation 
therapy. 
 
2.2 
Secondary Objectives 
In patients treated with enzalutamide versus traditional ADT: 
 To determine the incidence of metabolic syndrome within 6 months, as defined by the Adult 
Treatment Panel III, in patients treated with enzalutamide compared to standard androgen 
deprivation therapy 
 To assess bone health, as measured by a DXA scanner 
 To assess body composition (sarcopenic obesity), as measured by measurements of fat on CT 
 To assess QOL, as measured by the FACT-P and SHIM 
 To assess time to PSA progression and time to radiographic progression. Progression will be 
defined as lack of clinical benefit in the setting of either rising PSA, growth of visceral or soft 
tissue metastasis, or development of new bone metastasis as defined per protocol 
 To assess the incidence of developing individual risk factors, or components, which comprise 
metabolic syndrome 
 To assess the change in hs-CRP as a marker of inflammation 
 To assess the safety and tolerance of enzalutamide or ADT 
 To assess the change in physical function as measured by the Short Physical Performance 
Battery (SPPB) 
 
3. 
STUDY ENDPOINTS 
 
3.1 
Primary Endpoints 
Incidence of metabolic syndrome within 12 months as defined by the ATP III, in patients treated with 
enzalutamide versus patients treated with standard testosterone-lowering ADT. 
 
3.2 
Secondary Endpoints 
 Incidence of metabolic syndrome within 6 months, as defined by the ATP III, in patients 
treated with enzalutamide versus patients treated with standard testosterone-lowering ADT 
 Change in bone density, as measured by a DXA scanner 
 Change in bone turnover as measured by bone-specific alkaline phosphatase and N- 
telopeptide 
 Change in body composition (fat distribution as measured on CT) 
 Change in QOL, as measured by the FACT-P and SHIM 
 Time to PSA progression and time to radiographic progression. Progression will be defined 
as lack of clinical benefit in the setting of either rising PSA, growth of visceral or soft tissue 
metastasis, or development of new bone metastasis as defined per protocol 
 Incidence of developing individual risk factors, or components, which comprise metabolic 
syndrome 
 Change in inflammatory markers as measured by serum hs-CRP 


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 Safety and tolerability as assessed by regular recording of toxicities via physical exam and 
laboratory analysis using the CTCAE v4.1 guidelines 
 Change in physical function as measured by the Short Physical Performance Battery 
 
4. 
STUDY DESIGN 
 
4.1 
Overview of Study Design 
This study is a multi-center, open label, randomized, phase II trial of the incidence of metabolic 
syndrome within 12 months in patients treated with enzalutamide in comparison with androgen 
deprivation therapy for treatment of advanced prostate cancer. This will include patients with 
biochemically recurrent disease, metastatic disease, and patients offered ADT as primary therapy if 
they are not candidates for local therapy. Fifty-six patients will be 1:1 randomized to one of two 
treatment arms with metastasis as a stratification factor. Patients will be treated for a 12-month period 
continuously and assessed for the development of metabolic syndrome at 3-month intervals. 
 
Treatment will be administered for a 12-month period. Enzalutamide will be taken orally on each day 
of the cycle. Androgen deprivation therapy will be administered according to standard of care; 
however, there will be no intermittent dosing of this treatment. Acceptable forms of ADT must result 
in castrate levels of testosterone (<50ng/dL), and may include: leuprolide, goserelin, histerelin, 
triptorelin, degarelix, and surgical castration. Toxicity will be evaluated according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.1 35. Metabolic 
syndrome will be diagnosed by assessing a patient’s blood pressure, waist circumference, fasting 
glucose, high density lipoprotein (HDL), and triglyceride level and determined according to the Adult 
Treatment Panel III criteria 36. 
 
Analysis of bone turnover will include measurement of urinary N-telopeptide and serum bone-specific 
alkaline phosphatase. A dual-energy x-ray absorptiometry scan (DXA) will also be performed at 
enrollment, month 3 and EOT. This scan will provide information on bone density changes induced 
by treatment. 
 
Quality of life questionnaires will be administered at each study visit. Physical function changes will 
be assessed via the Short Physical Performance Battery; the SPPB incorporates 3 validated portions 
to assess a patient’s balance and mobility. Changes in systemic inflammation will be assessed via 
circulating hs-CRP levels. Additional collection of complete blood counts and chemistries will 
provide safety information.  This testing will occur in the clinic setting every 3 months as well. 
 
Adverse events (AEs) will be assessed; and laboratory values, vital signs, and physical exam will be 
obtained in order to evaluate the development of metabolic syndrome in patients treated with either 
enzalutamide or standard androgen deprivation therapy. In addition, we will obtain a PSA every 3 
months and radiographic imaging at baseline, 6 months, and 12 months. Patients may remain on study 
as long as they are deriving clinical benefit, until there is clear progression of disease (per protocol), 
unacceptable toxicity, or withdrawal of consent. 
 
4.2 
Duration of Study 
Patients will continue therapy until disease progression, development of unacceptable toxicities, non- 
compliance, intercurrent illness that prevents treatment continuation, withdrawal of consent, or change 
in subject condition that render the subject unacceptable for further treatment.  If a patient   develops 


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metabolic syndrome, but the patient has at least stable disease and ongoing clinical benefit, then the 
patient may be allowed to continue on their assigned treatment. The End of Study (9) visit will occur 
within 30 days after the last dose of study drug, or prior to the start of subsequent anti-cancer therapy. 
Patients will be assessed for metabolic syndrome over a 12-month period of treatment, as this allows 
adequate time in which to see the emergence of the metabolic syndrome parameters as well as time 
for patients to derive a potential clinical benefit from the respective treatment agent. Patients with 
continued clinical benefit beyond the 12-month endpoint will have the option of remaining on their 
current therapy with additional follow up visits every 3 months for safety and tolerability assessment. 
Patients receiving enzalutamide will no longer receive this as a study medication beyond the 12-month 
time point but may potentially obtain the medication through standard prescribing methods. It is 
estimated this trial will take 36 months to complete. 
 
4.3 
Overview of treatment 
During the trial, patients will be assigned to treatment with either enzalutamide or standard of care 
ADT. For patients randomized to the ADT arm, the choice of type of ADT will be at the discretion  
of the treating provider. Patients that are in the enzalutamide arm may not also be treated with ADT. 
In addition, patients on the ADT arm may not also be treated with an androgen-receptor blocker. Anti- 
androgen therapy may be administered as a single agent <14 days prior to and 14 days following 
medical castration with a GnRH agonist in order to cover the potential testosterone surge. Intermittent 
dosing of ADT is not acceptable. Enzalutamide will be dosed at the approved dose of 160mg orally 
daily. ADT will be administered according to the standard prescribing information for the agent. All 
subjects should also take at least 1000mg of calcium and 800 International Units (IU) of vitamin D. 
This treatment will allow protection against bone density loss caused by metastasis or ADT. All 
subjects will receive this treatment to avoid confounding data, as it is a non-toxic, non-prescription 
supplement. 
 
4.4 
Criteria for Dose Administration 
4.4.1 
Study Drug Administration 
All protocol-specific criteria for administration of study drug must be met and documented prior to 
drug administration. Enzalutamide or ADT will be administered only to eligible patients under the 
supervision of the investigator or identified sub-investigator(s). 
 
Patients should be instructed to take their study medication at approximately the same time each day. 
Enzalutamide can be taken with or without food, patients must swallow capsules whole without 
chewing, opening or dissolving the capsule. If a patient misses a dose, then they should take it as soon 
as they remember. If they forget an entire day’s dose, they should take their normal dose the next day. 
They should not take more than their prescribed dose per day. 
 
For any depot-injections of ADT, the site of injection and name of the agent will be recorded. Patients 
on depot-injections may only be treated with formulations given every 4, 8, or 12 weeks. 
 
4.4.2 
Clinical Benefit 
Continuation on the trial is dependent on toxicities, as well as evidence of clinical benefit. Patients 
must not have evidence of radiographic or PSA disease progression as per protocol section 7. Efficacy 
assessments will be performed via provider assessment. Imaging studies will be obtained every 6 
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months, or sooner at the discretion of the treating provider. Patients with progressive disease per 
section 7 will be ineligible to receive further study treatment. 
 
4.5 
Dose Modification Guidelines 
Patients will be assessed for toxicities at each study visit, every 3 months. Patients may be evaluated 
more frequently at the discretion of the treating provider. Toxicities are to be assessed according to 
the NCI CTCAE, version 4.1. Each AE should be assessed for potential contribution by the study 
drug. If a patient experiences a grade>3 toxicity on enzalutamide or an intolerable side effect, withhold 
dosing for one week or until symptoms improve to grade<2. Dosing may resume at the same, or a 
reduced dose, (per treating physician discretion) for a maximum dose reduction to 80mg daily. Once 
a dose reduction has occurred, the patient may not re-escalate to a higher dose. 
 
There are no dose modifications for ADT. As stated, this therapy must be dosed continuously and 
may not be given on an intermittent basis. 
 
4.6 
Study specific biomarker collection 
Plasma samples will be obtained and stored for future correlative analysis regarding potential 
identified biomarkers important in the development of metabolic syndrome or prostate cancer 
progression. Approximately 3 7mL tubes of blood will be drawn. De-identified tubes will be 
processed and stored for future analysis. See lab manual for processing instructions. 
 
5. 
STUDY POPULATION 
 
5.1 
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Histologically or cytologically proven adenocarcinoma of the prostate. If pathology is 
unavailable, the PI may also make a determination of prostate cancer based on unequivocal 
clinic data. 
2. Patients with advanced prostate cancer suitable for systemic treatment defined as: having 
metastatic disease, a biochemical relapse after primary therapy, or patients in whom primary 
therapy is not appropriate or feasible. Patients without metastatic disease will need evaluation 
for local therapy and deemed inappropriate or have refused this treatment option 
3. ECOG 0-2 
4. Age > 18 years old 
5. Must use a condom if having sex with a pregnant woman 
6. A male patient and his female partner who is of childbearing potential must use 2 acceptable 
methods of birth control (one of which must include a condom as a barrier method of 
contraception) starting at screening and continuing throughout the study period and for 3 
months after final study drug administration 
7. Life expectancy estimated at >12 months 
8. Ability to understand and willingness to provide written informed consent document 
 
5.2 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
1. A history of androgen deprivation therapy. 


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a. Patients receiving hormonal therapy in the adjuvant and/or neoadjuvant setting 
must have discontinued therapy at least 6 months prior to day 1 of treatment 
b. AND have a serum testosterone level >50ng/dL 
c. AND cannot have received more than 18 months of previous ADT. 
2. A history of orchiectomy 
3. Previous androgen blockade (e.g. antiandrogens) given for greater than 2 weeks in the 
last 3 months. Anti-androgens used during the initiation of ADT to avoid a flare 
phenomenon are acceptable for up to 4 weeks. 
4. Patients already meeting the criteria for metabolic syndrome as defined by the Adult 
Treatment Panel III Criteria which requires 3/5 parameters below.. Patients with 2 of the 
parameters at baseline will be allowed enrollment provided that one of those risk factors 
is hypertension (≥130/≥85 mm Hg). 
a. Abdominal obesity, defined as a waist circumference >102 cm (>40 in) 
b. Serum triglycerides ≥150 mg/dL (1.7 mmol/L) or drug treatment for elevated 
triglycerides 
c. Serum HDL cholesterol <40 mg/dL (1 mmol/L) or drug treatment for low HDL 
d. Blood pressure ≥130/≥85 mmHg or drug treatment for elevated blood pressure 
e. Fasting plasma glucose (FPG) ≥100 mg/dL (5.6 mmol/L) or drug treatment for 
elevated blood glucose 
5. Baseline hypogonadism as defined as a testosterone <50 ng/dL 
6. PSA <0.5ng/dL 
7. Serum Vitamin D 25, OH <12 ng/mL 
8. Active Hepatitis C virus 
9. Use of corticosteroids as defined by a daily dose of prednisone (or equivalent) of 5mg or 
greater for more than 1 month continuously within 3 months of screening 
10. Corrected calcium >10.6 mg/dL 
11. Absolute neutrophil count <1500/uL; platelet count <100, 000/uL, hemoglobin <9g/dL 
12. Total bilirubin >1.5xULN (unless documented Gilbert’s); alanine aminotransferase or 
aspartate aminotransferase > 2.5xULN 
13. Creatinine >2mg/dL 
14. Clinically significant cardiovascular disease as evidenced by: Myocardial infarction 
within 6 months of screening; uncontrolled angina within 3 months of screening; New 
York Heart Association (NYHA) class 3 or 4 congestive heart failure; clinically 
significant ventricular arrhythmia; Mobitz II/2nd degree/or 3rd  degree heart block without 
a pacemaker in place; uncontrolled HTN (systolic >180mmHg or diastolic >105mmHg at 
screening) 
15. Previous exposure to enzalutamide 
16. Use of an investigational therapeutic within 30 days 
17. History of gastrointestinal disorders (medical disorders or extensive surgery) that may 
interfere with the absorption of the study agent 
18. Known or suspected brain metastasis or active leptomeningeal disease 
19. History of seizure or any condition that may predispose to seizure (e.g., prior cortical 
stroke, significant brain trauma) at any time in the past. Also, history of loss of 
consciousness or transient ischemic attack within 12 months of Day 1 visit 
20. Have any condition that, in the opinion of the investigator, would compromise the well- 
being of the subject or the study or prevent the subject from meeting or performing study 
requirements 


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6. 
STUDY PROCEDURES AND ASSESSMENTS 
The schedule of assessments is summarized in Table 1 
6.1 
Informed Consent 
Enrollment in the study requires that all inclusion and exclusion criteria have been met. A patient may 
be enrolled into the study when the written informed consent has been obtained and the patient’s 
eligibility per all inclusion and exclusion criteria has been confirmed. 
 
6.2 
Randomization 
Randomization will occur using the GraphPad QuickCalcs randomization service. 
 
6.3 
Study Visits 
Patients will be evaluated at scheduled visits over the following study periods: Screening, Treatment, 
and end of study (EOS). Tests and procedures should be performed on schedule for all visits during 
Cycle 1. During all subsequent cycles, occasional changes are allowable (± 5 days) with permission 
for holidays and other administrative reasons. If extenuating circumstances prevent a patient from 
completing a scheduled procedure or assessment within this time, the patient may continue the study 
only with the permission of the Principal Investigator (PI). All EOS evaluations should occur within 
30 days after the last dose of study drug, or prior to the start of subsequent anti-cancer therapy. 
 
6.3.1 
Physical Examination 
A complete physical examination will be performed before dosing on Day 1 of each cycle and at the 
end of treatment. Vital signs (temperature, blood pressure, pulse rate, respiratory rate, weight, waist 
circumference) will be performed at each visit. ECOG performance status will be evaluated at day 1 
of each cycle and end of study.  Clinically significant AEs will be captured as well. 
 
6.3.2 
Schedule of Events 
Screening/Baseline Day -21 - 0 
 Informed consent and HIPAA release 
 Study eligibility per inclusion/exclusion criteria 
 Medical history/baseline conditions 
 Physical examination 
 Vital signs, including height and weight, waist circumference 
 ECOG performance status 
 Blood samples for hematology, comprehensive metabolic panel (fasting), lipid profile 
 Serum Testosterone 
 Serum PSA 
 25-OH Vitamin D 
 CT scan and assessment of tumor burden, may use imaging study within 28 days of day 1 
 Bone scan, may use imaging study within 28 days of day 1 
 Collection of concomitant medications 
 Collection of adverse events 
 
Month 1 Day 1 


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 Physical examination 
 Vital signs, including weight and waist circumference 
 ECOG performance status 
 Blood samples for CBC, Comprehensive metabolic panel (fasting), PSA, N-telopeptide, bone 
specific alkaline phosphatase, estradiol, hs-CRP 
 Optional tubes of blood for future biomarker testing 
 FACT-P, SHIM completed 
 DXA scan (+/-14 Days of Day 1 Dosing); note that there must be a 14 
day separation of bone scan and a DXA scan 
 Short Physical Performance Battery 
 Collection of concomitant medications 
 Collection of adverse events 
 Dosing of medication, or documentation of continued dosing 
 Verification of calcium/vitamin D administration 
 
Month 2 Day 1 +/- 5 days 
 Physical examination 
 Vital signs, including weight and waist circumference 
 ECOG performance status 
 Blood samples for CBC, Comprehensive metabolic panel (fasting), PSA, testosterone 
 Collection of concomitant medications 
 Collection of adverse events 
 Dosing of medication, or documentation of continued dosing 
 Verification of calcium/vitamin D administration 
 
Month 4 Day 1+/- 5 days 
 Physical examination 
 Vital signs, including weight and waist circumference 
 ECOG performance status 
 Blood samples for CBC, Comprehensive metabolic panel (fasting), testosterone, PSA, N- 
telopeptide, bone specific alkaline phosphatase, lipid profile, estradiol, hs-CRP 
 Optional tube of blood for future biomarker testing 
 FACT-P, SHIM completed 
 DXA scan (+/-14 Days of Day 1 Dosing); note that there must be a 14 
day separation of bone scan and a DXA scan 
 Short Physical Performance Battery 
 Collection of concomitant medications 
 Collection of adverse events 
 Dosing of medication, or documentation of continued dosing 
 Verification of calcium/vitamin D administration 
 
Month 7 Day 1+/- 5 days 
 Physical examination 
 Vital signs, including weight and waist circumference 
 ECOG performance status 


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 Blood samples for CBC, Comprehensive metabolic panel (fasting), testosterone, PSA, N- 
telopeptide, bone specific alkaline phosphatase, lipid profile, estradiol, hs-CRP, 25-OH 
Vitamin D 
 Optional tubes of blood for future biomarker testing 
 FACT-P, SHIM completed 
 CT scan and assessment of tumor burden +/- 5 days 
 Bone scan +/- 5 days 
 Short Physical Performance Battery 
 Collection of concomitant medications 
 Collection of adverse events 
 Dosing of medication, or documentation of continued dosing 
 Verification of calcium/vitamin D administration 
 
Month 10 Day 1+/- 5 days 
 Physical examination 
 Vital signs, including weight and waist circumference 
 ECOG performance status 
 Blood samples for CBC, Comprehensive metabolic panel (fasting), testosterone, PSA, N- 
telopeptide, bone specific alkaline phosphatase, lipid profile, estradiol, hs-CRP 
 Optional tube of blood for future biomarker testing 
 FACT-P, SHIM completed 
 Short Physical Performance Battery 
 Collection of concomitant medications 
 Collection of adverse events 
 Dosing of medication, or documentation of continued dosing 
 Verification of calcium/vitamin D administration 
 
Month 13 Day 1 or End of Treatment (+/- 5 days) 
 Physical examination 
 Vital signs, including weight and waist circumference 
 ECOG performance status 
 Blood samples for CBC, Comprehensive metabolic panel (fasting), testosterone, PSA, N- 
telopeptide, bone specific alkaline phosphatase, lipid profile, estradiol, hs-CRP, 25-OH 
Vitamin D 
 Optional tubes of blood for future biomarker testing 
 FACT-P, SHIM completed 
 DXA scan (+/-14 Days of Day 1 Dosing); note that there must be a 14 day separation of bone 
scan and a DXA scan 
 CT scan and assessment of tumor burden +/- 5 days 
 Bone scan +/- 5 days 
 Short Physical Performance Battery 
 Collection of concomitant medications 
 Collection of adverse events 
 
End of Study (EOS) safety visit 
 Physical examination 
 Vital signs, including weight and waist circumference 


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 ECOG performance status 
 Blood samples for CBC, Comprehensive metabolic panel 
 Collection of concomitant medications 
 Collection of adverse events 
 
7. 
STUDY ASSESSMENTS 
 
7.1 
Assessment of metabolic syndrome 
The primary endpoint is the determination of the incidence of metabolic syndrome in patients with 
advanced prostate cancer treated with either enzalutamide or standard ADT. Metabolic syndrome will 
be assessed every 3 months and defined by the presence of 3 of the following five traits 36: 
• 
Abdominal obesity, defined as a waist circumference >102 cm (>40 in) 
• 
Serum triglycerides ≥150 mg/dL (1.7 mmol/L) or drug treatment for elevated 
triglycerides 
• 
Serum HDL cholesterol <40 mg/dL (1 mmol/L) or drug treatment for low HDL 
• 
Blood pressure ≥130/≥85 mmHg or drug treatment for elevated blood pressure 
• 
Fasting plasma glucose (FPG) ≥100 mg/dL (5.6 mmol/L) or drug treatment for elevated 
blood glucose 
 
Patients may continue on treatment even upon development of metabolic syndrome at the discretion 
of the PI. 
 
7.2 
Efficacy Evaluations 
 
7.2.1 
PSA 
Patients will be monitored for clinical efficacy while on study. Serum PSA will be obtained every 3 
months. PSA rise is allowable at the discretion of the investigator. However, patients must 
discontinue treatment if there is evidence of PSA progression as defined by an increase in >50% from 
nadir and an absolute increase of at least 2 ng/mL above the nadir, occurring at least 12 weeks after 
start of therapy that is confirmed by two consecutive increases taken at least 2 weeks apart. The date 
of first recorded increase will serve as the date of progression. 
 
7.2.2 
Radiographic evaluation 
Patients will be removed from study if they have evidence of radiographic disease progression as 
defined below. Radiographic analysis via CT scan (and/or MRI), and bone scan will occur at baseline, 
6 months, and 12 months. For the purposes of this study, investigators should utilize the protocol- 
specified tumor assessment criteria, defined as assessment of evaluable soft tissue disease sites 
according to RECIST v1.1, and/or assessment of bone disease according to the PCWG2 criteria. Soft 
tissue disease will be assessed on CT (or MRI) and defined by RECIST v1.1. Bone disease will be 
assessed on bone scan and progression will be defined as the development of two or more new bone 
lesions from baseline confirmed with an additional lesion on bone scan 6 weeks later. New bone 
lesions noted after the 6-month radiographic assessment do not require a confirmatory bone scan. 
Increase in intensity of known bone lesions will not constitute progression. The date of progression 
will be recorded as the date the first scan shows change. 


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7.3 
Body composition evaluation 
The change in bone health will be assessed via urine N-telopeptide and serum bone specific alkaline 
phosphatase measurements. Bone density will be assessed via a DXA scan. The density of the 
posterior-anterior lumbar spine, total hip, femoral neck, and total body bone mineral density will be 
analyzed. Additional body composition analysis of lean body mass and total body mass will be 
analyzed via cross sectional CT image analysis. Changes in body composition can be seen as early as 
3 months in studies of testosterone supplementation 39 or ADT 40 causing an increase in adipose tissue 
and decrease in lean muscle. 
 
7.4 
Quality of life assessment 
The Functional Assessment of Cancer Therapy – Prostate (FACT-P) questionnaire will provide data 
on how patients perceive their QOL while on enzalutamide or ADT. The FACT-P tests five subscales: 
physical, social, emotional, functional wellbeing and additional concerns specific to men with prostate 
cancer 41. The FACT-P scales have been widely used to evaluate quality of life in clinical trials for 
prostate cancer treatments. Internal consistency of the FACT-P (version 4) subscales ranges from 0.85 
to 0.89. Concurrent, construct and discriminant validity has been documented (41). The FACT-P will 
be used descriptively. The questionnaire must be administered at each study visit unless the patient 
refuses. It is permissible to assist the patient with the completion of the questionnaire. The study staff 
must review the questionnaire at each visit in order to ensure that all items were answered. Patients 
should be given the option to complete any unmarked questions, but it is not required. 
 
The Sexual Health Inventory for Men (SHIM) will also be used to evaluate alterations in sexual health 
as a result of treatment with enzalutamide or ADT. The SHIM is a scale used widely to assess the 
presence and severity of erectile dysfunction. The scale is used regularly in clinical practice as well 
as in the research setting. The SHIM will be used descriptively. The questionnaire must be 
administered at each study visit unless the patient refuses. It is permissible to assist the patient with 
the completion of the questionnaire. The study staff must review the questionnaire at each visit in 
order to ensure that all items were answered. Patients should be given the option to complete any 
unmarked questions, but it is not required. 
 
7.5 
Physical function evaluation 
The Short Physical Performance Battery (SPPB) will be used for physical function evaluation. This 
battery of tests evaluates physical function and mobility. The test includes assessment of a patient’s 
ability to perform a chair rise, standing balance, and a 8 foot walk. This battery has a clear scoring 
system and a validated score above which patients are identified as at-risk of physical decline. Change 
in score of 1 is clinically significant. The SPPB will be modified to include a 10-time chair rise. The 
coordinator will record the time it takes the subject to perform both 5 and 10 rises from the chair. This 
modification has been made to increase the sensitivity of the exam in identifying small changes in 
function given the generally fit population seen in the clinic. 
 
7.6 
Safety evaluations 
The principal investigator will oversee the care and safety of all subjects enrolled in the trial. Study 
visits will include monitoring and recording all adverse events and serious adverse events; regular 
monitoring of hematology, blood chemistry, hepatic function; regular measurement of vital signs, 
physical examination including weight and performance status. Safety and tolerability will be 
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7.6.1 
Adverse Events 
Monitoring of AEs will be conducted throughout the study. AEs will be reported from the date written 
informed consent is obtained and through 30 days post-last dose of study drug. Serious pretreatment 
events and serious adverse events (SAE) will be reported to the Astellas, Inc. designee. All SAEs will 
be monitored until they are resolved or are clearly determined to be due to a patient’s stable or chronic 
condition or intercurrent illness (es). 
 
7.6.2 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed locally. Chemistry and hematology results must be 
drawn and reviewed within 24 hours prior to each cycle of dosing. 
 
7.7 
Concomitant Medication and Therapies 
Concomitant Strong CYP2C8 Inhibitors 
The concomitant use of strong CYP2C8 inhibitors (i.e. gemfibrozil) should be avoided if possible as 
this increases the plasma AUC of enzalutamide and its active metabolite. If patients must be co- 
administered a strong CYP2C8 inhibitor, reduce the enzalutamide dose to 80 mg once daily. The 
enzalutamide dose should be readjusted if the inhibitor is discontinued. 
 
The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated in 
vivo. Co-administration of enzalutamide with strong or moderate CYP2C8 inducers (e.g., rifampin) 
may alter the plasma exposure of enzalutamide and should be avoided if possible. 
 
Drugs that Inhibit or Induce CYP3A4 
Co-administration of a strong CYP3A4 inhibitor increased the AUC of enzalutamide and its active 
metabolite by 1.3 times. 
 
Co-administration of enzalutamide with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of enzalutamide and 
should be avoided if possible. Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, 
modafinil, nafcillin) and St. John’s Wort may also reduce the plasma exposure of enzalutamide and 
should be avoided if possible. 
 
The following medications and procedures are PROHIBITED during the study: 
• 
Any anti-cancer therapies other than enzalutamide or single agent ADT. Anti-androgens 
used during the initiation of ADT to avoid a flare phenomenon are acceptable for up to 4 
weeks. 
• 
Patients not on osteoclast inhibitors at study enrollment may not begin this treatment while 
on trial. 
 
The following medications and procedures are ALLOWED during the study: 
• 
Any supportive medications to treat the symptoms of enzalutamide or ADT are allowed 
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• 
Palliative radiotherapy, for treatment of the patient’s malignancy. Patients with a fracture 
in an area of pre-existing metastasis without clear progression, the patient may remain on 
trial if approved by the PI. 
• 
Anti-androgens used during the initiation of ADT to avoid a flare phenomenon are 
acceptable for up to 4 weeks. 
 
7.8 
Completion of Study 
Patients will be considered to have completed the study if they (1) have received at least 1 cycle of 
treatment, AND (2) experienced progressive disease OR (3) experienced unacceptable toxicity. In the 
absence of progressive disease or unacceptable toxicity, and in the setting of continued clinical benefit, 
patients may be permitted to remain on therapy upon discussion with the PI. Patients wishing to 
continue therapy beyond cycle 12 may continue on their current therapy at the discretion of their 
treating provider.Patients receiving enzalutamide will no longer receive this as a study medication 
beyond the 12-month timepoint but may be able to obtain the medication through standard prescribing 
methods. 
 
Withdrawal of Patients from Study 
Patients will be informed that they have the right to withdraw from study treatment at any time for any 
reason, without prejudice to their medical care. A patient may be withdrawn from study treatment for 
any of the following reasons: 
• 
Adverse Event 
• 
Protocol Violation 
• 
Radiographic Progressive Disease as defined in section 7.2 
• 
Serologic progressive disease as defined in section 7.2 
• 
Symptomatic Deterioration 
• 
Study Terminated by the University of Colorado Cancer Center 
• 
Withdrawal by Subject 
• 
Lost to Follow-up 
• 
Other 
 
At the time of study drug discontinuation, all study procedures outlined for the EOS visit should be 
completed within 30 days after the last dose of study drug. The primary reason for a patient’s 
withdrawal from the study is to be recorded. 
 
The consequence of withdrawal of consent by a patient will be that no new information will be 
collected from that patient and added to the existing data or any database. However, every effort will 
be made to follow all patients for safety. 
 
7.9 
Study Compliance 
Study drug will be dispensed only to eligible patients under the supervision of the investigator or 
identified sub-investigator(s). The appropriate study personnel will maintain records of study drug 
receipt and dispensing, including the following: applicable lot numbers and total drug administered 
in milligrams. Any discrepancy regarding the dose administered and the reason for the discrepancy 
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Patients will receive a sufficient quantity of enzalutamide for each treatment cycle. The study center 
staff will check the returned pill bottles at each study visit to ensure proper compliance with dosing. 
Patients who are not compliant with the dosing schedule may be withdrawn from the study. 
 
8. 
INVESTIGATIONAL AGENTS 
 
8.1 
Precautions and Restrictions 
Patients should be instructed to consult with the investigator before taking any new medications, 
including over-the-counter and herbal products. Patients should be instructed to limit the use of 
alcohol while enrolled in this study. 
 
8.2 
Description of Investigational Agents 
8.2.1 
Enzalutamide 
Enzalutamide 40 mg capsules are white to off-white oblong soft gelatin capsules imprinted in black 
ink with MDV. Enzalutamide is provided as liquid-filled soft gelatin capsules for oral administration. 
Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The 
inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated 
hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and 
black iron oxide. Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3-4-cyano- 
3-(trifluoromethyl) 
phenyl-5, 
5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl-2-fluoro-N- 
methylbenzamide. Enzalutamide is a white crystalline non-hygroscopic solid. It is practically 
insoluble in water. 
 
8.2.2 
Androgen deprivation therapy 
ADT includes agents such as degarelix, goserelin, leuprolide, triptorelin, and histerelin. These agents 
are long-acting analogues of the GnRH peptide and alter the feedback loop of FSH and LH production 
to subsequently reduce circulating testosterone levels. These agents are FDA approved and may be 
used for the purposes of ADT in this study. These agents are generally administered as a subcutaneous 
or intramuscular injection and should be administered according to manufacturer instruction. Please 
refer to the FDA package insert for information. 
 
8.3 
Preparation, Reconstitution, and Dispensation 
The University of Colorado Cancer Center clinical trials team and the PI will assign each patient who 
signs a consent form a patient number. Patients will be dispensed bottles of study drug containing an 
appropriate number of capsules in order to achieve the assigned doses. Patients may be dispensed a 
maximum of 3 complete cycle’s capsules. 
Patients will be asked to bring back all remaining study drug at each visit. All unused study drug and 
the amount of study drug returned will be recorded on the drug accountability form. Patients will be 
instructed to store the enzalutamide capsules only in the bottles dispensed. 
 
8.4 
Storage, Handling, Accountability 
8.4.1 
Enzalutamide 
Enzalutamide capsules are available in bottles of 120 capsules.  These should be stored at 20°Celsius 
(C) to 25°C in a dry place with the container tightly closed. 


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8.4.2 
Handling and Accountability 
All clinical drug supplies must be kept in an appropriate, limited-access, secure place until used or 
destroyed. The investigator must maintain 100% accountability for all study medication received and 
dispensed.  Proper drug accountability includes, but is not limited to: 
 Frequently verifying that actual inventory matches documented inventory 
 Verifying that the log is completed for the drug lot used to prepare each dose 
 Verifying that all containers used are documented accurately on the log 
 Verifying that required fields are completed accurately and legibly 
 
If any dispensing errors or discrepancies are discovered, the PI must be notified immediately. 
 
The investigator must maintain a current inventory of all study medication delivered to the site, 
inventory at the site, and records of patient use. This log must accurately reflect the drug 
accountability of the study medication at all times. The following information will be recorded at a 
minimum: protocol number and title, name of investigator, site identifier and number, description of 
study medication, expiration date, date and amount dispensed, and the date and amount returned to the 
site by the patient, including the initials of the person dispensing and receiving the study medication. 
The log should include all required information as a separate entry for each patient to whom study 
medication is dispensed. 
 
Before site closure, or at appropriate intervals, a representative from the PI or its designee will perform 
clinical study material accountability and reconciliation before clinical study materials are destroyed. 
The investigator will retain the original documentation regarding clinical study material accountability 
and destruction. 
 
The investigator will monitor any expiration date and subsequently segregate and destroy expired 
clinical study drug. 
 
9. 
STUDY CONDUCT 
This trial will be conducted in compliance with the protocol, good clinical practice (GCP), applicable 
regulatory requirements, and International Conference on Harmonisation (ICH) guidelines. 
 
9.1 
Oversight of multiple participating sites 
Study will be conducted at multiple sites with the University of Colorado Anschutz Campus as the 
coordinating site. Dr. Kessler, as the Lead PI, will work with the Site PI(s) to insure proper training 
and conduct. 
 
A PI oversight plan has been drafted to outline the procedures for maintaining oversight, 
data monitoring and study auditing. All study sites involved will follow the process outlined 
in the document in order to ensure safe and accurate conduct. 
 
9.2 
Arrangements for Recruitment of Patients 
Recruitment and enrollment strategies for this study may include recruitment from the investigator’s 
local practice or referrals from other physicians. If advertisements become part of the recruitment 
strategy, they will be reviewed by the institutional review board (IRB)/independent ethics committee 


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(IEC). It is not envisioned that prisoners (or other populations that might be subject to coercion or 
exploitation) will be enrolled into this study. 
 
The study will aim to enroll at least 1 patient per month to the trial. 
 
9.3 
Treatment Group Assignments 
Patients will be assigned through the randomization process with a 1:1 ratio of patients in each 
treatment group. Randomization will occur centrally through a non-clinical project manager at the 
coordinating site. Participating sites will contact this central manager for randomization assignment 
during regular business hours (M-F 8-5pm). 
 
10. 
STATISTICAL AND QUANTITATIVE ANALYSES 
 
10.1 
Statistical Methods 
We estimate a 7% (2 patients) and 32% (9 patients) incidence of metabolic syndrome for enzalutamide 
and ADT treated patients based on historic data 7. Historical cross-sectional data would suggest that 
almost 50% of patients on ADT will develop metabolic syndrome, however, the trial population 
proposed will be pre-selected. Twenty-eight (28) patients in each of the two groups will provide 80% 
power to detect the 25% difference using a one-sided chi-square test with a significance level of 0.05 
(actual alpha=0.054). 
 
10.1.1 
Endpoint Analysis 
Primary endpoint 
Metabolic syndrome incidence will be summarized by the proportion of patients with at least 3 of the 
5 pre-specified criteria within the first 12 months of therapy. 
 
Secondary endpoint 
The secondary endpoints will be presented as follows: 
Metabolic syndrome incidence will be summarized by the proportion of patients acquiring with at least 
3 of the 5 pre-specified criteria within the first 6 months of therapy. 
 
The change in bone turnover markers from baseline will be assessed for each treatment group. 
Measurements will be taken at day 1 of each cycle and reported as a continuous variable. A paired t- 
test will test within an arm as to whether the change from baseline to each time point is significantly 
different from zero. 
 
The change in bone density, free fat mass, and fat mass will be measured at baseline, 3 months and 
12 months and assessed for each treatment group. A paired t-test will test within an arm as to 
whether the change from baseline to each time point is significantly different from zero. 
 
The change in QOL scores as measured by the FACT-P and SHIM at each visit, will be assessed in 
each treatment group. 
 
Median time to PSA progression as defined in section 7.2. Time to PSA progression is defined as the 
time from randomization to the earliest objective evidence of PSA progression as defined per 


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protocol.  If a patient has had a decline in PSA while on study, the PSA progression date is defined 
as the time from documented PSA nadir to an increase in PSA with confirmation as defined by 
protocol. Time to radiographic progression is defined as the time from randomization to the earliest 
objective evidence of radiographic progression as defined per protocol. Patients will be monitored at 
regular intervals for PSA change and radiographic change. Log rank test will be used to compare the 
distributions of above variables between the group treated with enzalutamide to the group on 
standard ADT. 
 
The change in markers of inflammation as measured by circulating hs-CRPwill be obtained at the 
beginning of each cycle. 
 
Adverse events data will be summarized using tables and descriptive statistics. 
 
The change in SPPB from baseline to 12 months will be measured as a continuous outcome. A 
clinically relevant change is a change in total score of 1, with a standard deviation at baseline of 1.5 
42. 
 
Mean, standard deviation, median, and range will be reported for each outcome at each time point, 
and the mean and standard deviation of the changes, will be calculated. One-group t-test will be used 
to estimate effect size of each outcome measure and test if the change is significant at 0.05 significance 
level. Pearson or Spearman correlation coefficients will be used to assess the association between 
continuous variables. 
 
10.1.2 
Accrual 
The study center treats approximately 6-7 patients monthly who would be eligible for enrollment in 
the trial.  We estimate that 3-4 patients will enroll a month. 
 
10.2 
Safety population 
The safety population is defined as all patients who receive at least 1 dose of either enzalutamide or 
ADT.  This population will be used for all safety analyses as well as efficacy analyses. 
 
10.3 
Metabolic syndrome population 
The metabolic syndrome population is defined as patients who have received at least 1 dose of either 
drug, have baseline values and at least 1 post-baseline assessment. 
 
10.4 
Secondary endpoint population 
Defined as patients who have received at least 1 dose of either drug, have baseline values and at least 
1 post-baseline assessment. 
 
 
11. 
SAFETY ANALYSIS 
The safety population will be used for the analysis of the toxicities and AEs. Individual toxicities will 
be summarized by their frequency and intensity for each treatment group. Safety will be evaluated by 
the incidence of AEs, severity and type of AEs, and by changes from baseline in the patient’s vital 


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signs, weight, and clinical laboratory results using the safety population. Exposure to study drug and 
reasons for discontinuation will be tabulated. 
Treatment related AEs that occur after administration of the first dose of study drug and through 30 
days after the last dose of study drug will be tabulated. AEs will be tabulated according to the Medical 
Dictionary for Regulatory Activities (MedDRA) and will include the following categories: 
• 
Drug-related AEs 
• 
Grade 3 or higher AEs 
• 
Grade 3 or higher drug-related AEs 
• 
The most commonly reported treatment-emergent AEs (i.e., those events reported by 
≥ 10% of all patients) 
• 
SAEs 
 
A listing of AEs resulting in study discontinuation will be provided. 
 
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over time. 
 
All concomitant medications collected from screening through the study period will be classified to 
preferred terms according to the World Health Organization (WHO) drug dictionary. 
 
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of enzalutamide and ADT. 
 
11.1 
Oversight and Monitoring 
The Lead Principal Investigator (PI) will be responsible for monitoring the trial per the trial monitoring 
plan, in addition to overseeing the safety and efficacy of the trial, executing the DSM plan, and 
complying with all reporting requirements to local and federal authorities. This oversight will be 
accomplished through additional oversight from the Data and Safety Monitoring Committee (DSMC) 
at the University of Colorado Cancer Center (CU Cancer Center). The DSMC is responsible for 
ensuring data quality and patient safety for all clinical studies at the CU Cancer Center. A summary 
of the DSMC’s activities is as follows: 
 
• 
Conduct of internal audits 
• 
Ongoing review of all serious adverse events (SAEs), unanticipated problems (UAPs) and 
reportable adverse events (AEs) 
• 
Has the authority to close and/or suspend trials for safety or trial conduct issues 
• 
May submit recommendations for corrective actions to the CU Cancer Center’s Executive 
Committee 
 
Per the CU Cancer Center Institutional DSM Plan, SAEs, UAPs and reportable AEs are reported to 
the DSMC, IRB and the sponsor per study protocol. All SAEs, UAPs and reportable AEs are to be 
reported to the DSMC within 5 business days of receiving notification of the occurrence. 
 
Each subject’s treatment outcomes will be discussed by the Site PI(s) and appropriate staff at regularly 
scheduled disease-oriented working group meetings. Data regarding number of subjects, significant 
toxicities, dose modifications, and treatment responses will be discussed and documented in the 
meeting’s minutes. 


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The Lead PI in this multi-site trial is responsible for organizing and conducting monthly 
teleconferences with all participating sites. The Lead PI will also be responsible for including data 
from all of the participating sites to include the minutes from these regularly scheduled teleconferences 
between the Lead PI and the sites within the overall trial’s six-month DSM report. 
 
The Lead PI will provide a DSM report to the CU Cancer Center DSMC on a six-month basis. The 
DSM report will include a protocol summary; current enrollment numbers; summary of toxicity data 
to include specific SAEs, UAPs and AEs; any dose modifications; all protocol deviations; and protocol 
amendments. The DSM report to the DSMC will also include, if applicable, the results of any efficacy 
data analysis conducted, as well as any internal DSMB reports. Results and recommendations from 
the review of this six-month report by the DSMC will then need to be submitted by the site to the IRB 
of record at the time of continuing review. 
 
12. 
ADVERSE EVENTS 
12.1 
Definitions 
 
Definition of Adverse Events (AEs) 
An adverse event (AE) is defined as any untoward medical occurrence in a subject administered a 
study drug and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a study drug, whether or not related to the 
study drug. 
 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, 
physical exam) should be defined as an AE only if the abnormality meets one of the following criteria: 
• 
Induces clinical signs or symptoms. 
• 
Requires active intervention. 
• 
Requires interruption or discontinuation of study medication. 
• 
The abnormality or investigational value is clinically significant in the opinion of the 
investigator. 
 
All adverse events, whether or not related to the study drug, must be fully and completely documented. 
 
Definition of Serious Adverse Events (SAEs) 
An AE is considered “serious” if, in the view of either the investigator or sponsor, is unexpected and 
is potentially related to study participation and it results in any of the following outcomes: 
• 
Results in death, 
• 
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It does 
not include an AE that, had it occurred in a more severe form, might have caused death.), 
• 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions, 
• 
Results in congenital anomaly, or birth defect, 


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• 
Requires inpatient hospitalization or leads to prolongation of hospitalization (hospitalization 
for treatment/observation/examination caused by AE is to be considered as serious), 
• 
Other medically important events. 
 
Serious Adverse Event Reporting 
For patients on enzalutamide therapy, within 48 hours of awareness of a serious adverse event, 
whether or not related to enzalutamide, the Investigator will complete and submit a Medwatch 
3500A Form, containing all required information (reference 21 CFR 312.32). The Investigator will 
submit a copy of this MedWatch 3500A form to FDA and Astellas by either e-mail or fax, within the 
same timeframe if subject is on enzalutamide. If submission of this SAE to FDA or Astellas or is not 
possible within 48 hours, the Investigator’s local drug safety contact (IRB, etc.) should be informed 
by phone. 
 
The SAE documentation, including the Medwatch 3500A Form and available source records should 
be emailed or faxed to: 
 
Astellas Pharma Global Development – United States 
Email: 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 
 
Follow-up information for the event should be sent within promptly (within 7 days) as necessary. 
 
All SAEs , regardless of treatment arm, will be reported to the University of Colorado DSMC within 
48 hours of awareness of the event.  
 
 
Procedure in Case of Pregnancy 
The effect of enzalutamide in pregnant and lactating women is not known, and the exposure of a fetus 
or nursing infant is considered a potential risk. Enzalutamide can cause fetal harm when administered 
to a pregnant woman based on its mechanism of action. Subjects receiving enzalutamide are advised 
to use 2 acceptable methods of birth control (one of which must include a condom as a barrier method 
of contraception) starting at the time of screening for an enzalutamide study and continuing throughout 
the course of treatment and for at least three months after enzalutamide is discontinued. 
 
If during the conduct of the clinical trial, a male subject impregnates his partner, the subject should 
report the pregnancy to the Investigator. The Investigator should report the pregnancy to the Sponsor 
as an SAE within 24 hours of awareness of the event. The expected date of delivery or expected date 
of the end of the pregnancy, last menstruation, estimated fertility date, pregnancy result and neonatal 
data etc., should be included in this information. 
 
The Investigator should report the outcome of the pregnancy (independent of outcome, eg. full term 
delivery, pre-term delivery, spontaneous abortion, induced abortion, stillbirth, death of newborn, 


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congenital anomaly [including anomaly in a miscarried fetus, etc] in accordance with the same 
reporting procedure as for SAEs. The date of outcome of the pregnancy, gestational age, date of birth 
and neonatal data etc., should be included in this information. 


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12.2 
Maintenance of Safety Information 
Safety information will be maintained in a clinical database/repository in a retrievable format. At a 
minimum, at the end of the treatment phase (=”last patient off treatment”) as well as the end of the 
follow-up phase (=”last patient out”) of the Study, the Principal Investigator shall provide all adverse 
events, both serious and non-serious, in report format. However, in certain circumstances more 
frequent review of the safety data may be necessary, e/g/ to fulfill a regulatory request, and as such 
the data shall be made available within a reasonable timeframe at Astellas, Inc.’s request. 
 
 
12.2.1 
Product Quality Complaints 
Any product quality complaint, with or without an AE, (including reports of suspicion of 
counterfeiting, diversion, or tampering, and suspected transmission of pathogens) will be transmitted 
by the Principal Investigator within 24 hours of becoming aware of the event(s). 
 
 
 
 
12.3 
Monitoring of Adverse Events and Period of Observation 
AEs, both non-serious and serious (which include all deaths), will be monitored throughout the study 
as follows: 
• 
AEs will be reported from the time of consent through 30 days after administration of the last 
dose of study drug and recorded. 
• 
Serious pretreatment events will be reported to Astellas, Inc. from the time of the signing of 
the informed consent form (ICF) up to first dose of study drug. 
• 
SAEs will be reported to Astellas, Inc. from the time of consent through 30 days after 
administration of the last dose of study drug and recorded. All SAEs should be monitored 
until they are resolved or are clearly determined to be due to a patient’s stable or chronic 


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condition or intercurrent illness (es). If an SAE occurs in the follow-up period and is thought 
to be possibly related to study drug, it must be reported. 
 
13. 
ADMINISTRATIVE REQUIREMENTS 
This is an investigator-initiated trial and thus major trial decisions and document design will occur 
with the PI and supporting institution, the University of Colorado Cancer Center. Astellas Inc. is 
providing study support and thus will have access to trial data and patient safety information. 
 
13.1 
Data Quality Assurance 
The investigator is required to prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each study patient. Study monitors 
will discuss instances of missing or uninterpretable data with the investigator for resolution. Any 
changes to study data will be monitored via an audit trail. 
 
13.2 
Study Monitoring 
Monitoring for this study will be performed by CU Cancer Center Clinical Monitor in accordance with 
the clinical monitoring plan (CMP), incorporated herein by reference. The CMP describes in detail 
who will conduct the monitoring, at what frequency monitoring will be done, at what level of detail 
monitoring will be performed, and the distribution of the monitoring reports. 
 
The CMP will be approved by the PI and will be followed to comply with GCP guidelines. All study 
records must be consistent with the patient’s source documentation. During the course of the study, 
the study monitor will make study site visits to review protocol compliance, verify study record against 
source documentation, assess drug accountability, and ensure that the study is being conducted 
according to pertinent regulatory requirements. The review of medical records will be performed in a 
manner that ensures that patient confidentiality is maintained. 
 
Independent audits will be conducted by the CU Cancer Center DSMC to ensure monitoring practices 
are performed consistently across all participating sites, if applicable, and that monitors are following 
the CMP. 
 
13.3 
Ethical Considerations 
The study will be conducted in accordance with applicable regulatory requirement(s) and will adhere 
to GCP standards. The IRB/IEC will review all appropriate study documentation to safeguard the 
rights, safety, and well-being of the patients. The protocol, Investigator Brochure (IB), ICF, 
advertisements (if applicable), written information given to the patients (including diary cards), safety 
updates, annual progress reports, and any revisions to these documents will be provided to the IRB/IEC 
by the investigator, as allowed by local regulations. 
 
13.4 
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from either the 
patient or his/her guardian or legal representative before study participation. The method of obtaining 
and documenting the informed consent and the contents of the consent must comply with the ICH- 
GCP and all applicable regulatory requirements. 


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13.5 
Patient Confidentiality 
To maintain patient privacy, study drug accountability records, study reports, and communications 
will identify the patient by initials where permitted and/or by the assigned patient number. The 
patient’s confidentiality will be maintained and will not be made publicly available to the extent 
permitted by the applicable laws and regulations. 
 
13.6 
Investigator Compliance 
Changes to the protocol will require written IRB/IEC approval/favorable opinion before 
implementation, except when the modification is needed to eliminate an immediate hazard or hazards 
to patients. When immediate deviation from the protocol is required to eliminate an immediate hazard 
or hazards to patients, the investigator will contact Astellas, Inc., or a designee, if circumstances 
permit, to discuss the planned course of action. Any departures from the protocol must be documented. 
 
13.7 
On-site Audits 
Regulatory authorities, the IRB, and/or Astellas, Inc. may request access to all source documents, and 
any study documentation for on-site audit or inspection. Direct access to these documents must be 
guaranteed by the investigator, who must provide support at all times for these activities. 
 
13.8 
Investigator and Site Responsibility for Drug Accountability 
Accountability for the study drug at the trial site is the responsibility of the investigator. Please see 
section 8.4.2 for details. 
 
All material containing study drug will be treated and disposed of in accordance with governing 
regulations. 
 
13.9 
Closure of the Study 
Study participation may be prematurely terminated if, in the opinion of the investigator or Astellas, 
Inc., there is sufficient reasonable cause. Written notification documenting the reason for study 
termination will be provided by the terminating party. 
 
Circumstances that may warrant termination include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to patients 
• 
Failure to enter patients at an acceptable rate 
• 
Insufficient adherence to protocol requirements 
• 
Insufficient, incomplete, and/or unevaluable data 
 
13.10 
Record Retention 
The investigator will maintain all study records according to the ICH-GCP and applicable regulatory 
requirement(s). Records will be retained for at least 3 years after the last patient is removed from trial 
or according to applicable regulatory requirement(s). If the investigator withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person willing to accept 
the responsibility. 


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14. 
USE OF INFORMATION 
Upon completion of the clinical study and evaluation of results by the hospital or institution and/or 
investigator may publish or disclose the clinical trial results pursuant to the terms contained in the 
applicable Clinical Trial Agreement. 


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15. 
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