Study to Compare Capsule and Liquid Formulations of Enzalutamide After Single Dose Administration Under Fasting Conditions in Prostate Cancer
Phase: PHASE1
Conditions: Prostate Cancer
Sponsor: National Cancer Institute (NCI)

 
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Abbreviated Title: Enzalutamide Formulation PK  
Version Date: 03.11.2020 
 Abbreviated Title: Enzalutamide Formulation PK  
CC Protocol #: 18-C-0070 C 
Version Date:  March 11, 2020 
NCT #: NCT03478904 
 
Title: A Bioequivalence Study to Compare Capsule and Liquid Formulations of Enzalutamide 
After Single Dose Administration Under Fasting Conditions in Prostate Cancer 
 
NCI Principal Investigator:  
William D. Figg, PharmD, MBA  
Clinical Pharmacology Program 
Genitourinary Malignancies Branch (GMB) 
Center for Cancer Research (CCR) 
National Cancer Institute (NCI) 
10 Center Drive 
Building 10, Room 5A01 
Bethesda, MD 20892 
Phone: (240) 760-6179  
Email: figgw@mail.nih.gov 
 
 
 
 
 
 
 
Commercial Agent: Enzalutamide 
 
 
 
 
 
 
 
 
 
 

 
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Abbreviated Title: Enzalutamide Formulation PK  
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PRÉCIS 
Background: 
• Enzalutamide is currently approved for the treatment of patients with mCRPC 
• The marketed (reference) formulation of enzalutamide is a liquid-filled, soft gelatin 
capsule containing 40 mg enzalutamide dissolved in Labrasol; four such capsules are 
required to deliver a 160 mg dose 
• The four-capsule regimen is inconvenient because of the number of capsules that must be 
taken, particularly in light of the fact that cancer patients usually have to take multiple 
drugs.  
• Additionally, some patients may not be able to swallow pills; therefore, alternate methods 
of oral administration are necessary 
Objectives: 
• To evaluate the bioequivalence, safety, and tolerability of two oral formulations of 
enzalutamide following a single 160 mg dose in male subjects with prostate cancer under 
fasting conditions. 
Eligibility: 
• Male subjects with prostate cancer 
Design: 
• Comparative, randomized, open-label, single-dose, 2-way crossover bioavailability, 
safety and tolerability study 
• Subjects will be randomized in Period 1 to one of two sequences: AB or BA. Following a 
minimum 42-day washout period, subjects will be crossed over in Period 2 to receive the 
treatment that they did not receive in Period 1.  
• Treatment A will be the standard capsule (reference) formulation; Treatment B will be 
the liquid formulation (test product) 
• Blood samples will be collected for pharmacokinetic analysis 
 
 

 
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TABLE OF CONTENTS 
PRÉCIS .......................................................................................................................................... 1 
TABLE OF CONTENTS ................................................................................................................ 2 
1 
Introduction ............................................................................................................................. 6 
1.1 
Study Objectives .............................................................................................................. 6 
1.1.1 
Primary Objective ..................................................................................................... 6 
1.1.2 
Secondary Objective ................................................................................................. 6 
1.2 
Background and Rationale ............................................................................................... 6 
1.2.1 
Enzalutamide Background ........................................................................................ 6 
1.2.2 
Pharmacokinetic Studies ........................................................................................... 6 
1.2.3 
Rationale for an Oral Formulation of Enzalutamide ................................................. 8 
1.2.4 
Summary ................................................................................................................... 8 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ......................................................... 8 
2.1 
Eligibility Criteria ............................................................................................................ 8 
2.1.1 
Inclusion Criteria ...................................................................................................... 8 
2.1.2 
Exclusion Criteria ..................................................................................................... 9 
2.1.3 
Recruitment Strategies ............................................................................................ 10 
2.2 
Screening Evaluation...................................................................................................... 10 
2.2.1 
Screening activities performed prior to obtaining informed consent ...................... 10 
2.2.2 
Screening activities performed after a consent for screening has been signed ....... 10 
2.3 
Registration Procedures.................................................................................................. 10 
2.3.1 
Treatment Assignment and Randomization/Stratification Procedures ................... 11 
2.4 
Baseline Evaluation ........................................................................................................ 12 
3 
STUDY IMPLEMENTATION ............................................................................................ 12 
3.1 
Study Design .................................................................................................................. 12 
3.2 
Drug Administration ...................................................................................................... 13 
3.3 
Study Calendar ............................................................................................................... 14 
3.4 
Compensation ................................................................................................................. 15 
3.5 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 15 
3.5.1 
Criteria for removal from protocol therapy ............................................................ 15 
3.5.2 
Off-Study Criteria ................................................................................................... 15 

 
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3.5.3 
Off Protocol Therapy and Off-Study Procedure ..................................................... 16 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 16 
4.1 
General Guidelines ......................................................................................................... 16 
4.2 
Seizure threshold lowering drugs ................................................................................... 16 
4.3 
Cytochrome P450 and P-glycoprotein ........................................................................... 16 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 17 
5.1 
Correlative Studies for Research/Pharmacokinetic Studies ........................................... 17 
5.2 
Sample Processing.......................................................................................................... 17 
5.3 
Sample Storage, Tracking and Disposition .................................................................... 17 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 18 
6.1 
Data Collection ............................................................................................................... 18 
6.2 
Data Sharing Plans ......................................................................................................... 19 
6.2.1 
Human Data Sharing Plan ....................................................................................... 19 
6.3 
Toxicity Criteria ............................................................................................................. 20 
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN .. 20 
7.1 
Definitions ...................................................................................................................... 20 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 20 
7.2.1 
Expedited Reporting ............................................................................................... 20 
7.2.2 
IRB Requirements for PI Reporting at Continuing Review ................................... 20 
7.3 
FDA Requirements ......................................................................................................... 20 
7.4 
NCI Clincial Director Rerporting ................................................................................... 21 
7.5 
NIH Required Data and Safety Monitoring Plan ........................................................... 21 
7.5.1 
Principal Investigator/Research Team .................................................................... 21 
8 
STATISTICAL CONSIDERATIONS.................................................................................. 21 
8.1 
Statistical Hypotheses .................................................................................................... 21 
8.2 
Sample Size Determination ............................................................................................ 21 
8.3 
Populations for Analysis ................................................................................................ 22 
8.4 
Statistical Analyses ........................................................................................................ 22 
8.4.1 
General Approach ................................................................................................... 22 
8.4.2 
Analysis of the Primary Efficiacy Endpoints.......................................................... 22 
8.4.3 
Analysis of the Secondary Efficacy Endpoints ....................................................... 22 

 
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8.4.4 
Safety Analyses ....................................................................................................... 22 
8.4.5 
Baseline Descriptive Statistics ................................................................................ 23 
8.4.6 
Planned Interim Analyses ....................................................................................... 23 
8.4.7 
Subgroup Analyses ................................................................................................. 23 
8.4.8 
Tabulation of Individual Participant Data............................................................... 23 
8.4.9 
Exploratory Analyses .............................................................................................. 23 
9 
HUMAN SUBJECTS PROTECTIONS ............................................................................... 23 
9.1 
Rationale For Subject Selection ..................................................................................... 23 
9.1.1 
Selection Based on Ethnicity, and Race ................................................................. 23 
9.1.2 
Strategies/Procedures for Recruitment ................................................................... 23 
9.2 
Participation of Children ................................................................................................ 23 
9.3 
Participation of Subjects Unable to Give Consent ......................................................... 24 
9.4 
Evaluation of Benefits and Risks/Discomforts .............................................................. 24 
9.4.1 
Alternative Approaches or Treatments ................................................................... 24 
9.4.2 
Procedure for Protecting Against or Minimizing any Potential Risks .................... 24 
9.4.3 
Provisions for Monitoring Data Collection to Ensure Safety of Subjects .............. 24 
9.5 
Risks/Benefits Analysis.................................................................................................. 24 
9.6 
Consent Process and Documentation ............................................................................. 25 
9.6.1 
Request for Waiver of Consent for Screening Activities ........................................ 25 
9.6.2 
Telephone Re-consent ............................................................................................. 25 
10 PHARMACEUTICAL INFORMATION ............................................................................. 25 
10.1 Enzalutamide .................................................................................................................. 26 
10.1.1 Source ..................................................................................................................... 26 
10.1.2 Toxicity ................................................................................................................... 26 
10.1.3 Formulation and Preparation................................................................................... 27 
10.1.4 Stability and Storage ............................................................................................... 28 
10.1.5 Administration Procedures...................................................................................... 28 
10.1.6 Tolerability Assessment .......................................................................................... 28 
11 REFERENCES ..................................................................................................................... 29 
12 APPENDIX A: Performance Status Criteria ........................................................................ 30 
13 APPENDIX B: Tolerability assessment of liquid (test) enzalutamide formulation ............. 31 

 
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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
• To evaluate the bioequivalence of two oral formulations of enzalutamide following a 
single 160 mg dose in male subjects with prostate cancer 
1.1.2 Secondary Objective 
• To evaluate the safety and tolerability of two oral formulations of enzalutamide following 
a single 160 mg dose in male subjects with prostate cancer. 
1.2 
BACKGROUND AND RATIONALE  
It is expected that 26,120 men will die from prostate cancer in the US in 2016 [1]. While some 
men are definitively treated for localized disease, many men will ultimately develop castrate 
resistant prostate cancer (CRPC) and succumb to the disease. Treatment options typically 
involve radical prostatectomy (RP) or radiation therapy in combination with androgen 
deprivation therapy. Following RP upwards of 50% of patients with high-risk disease will 
experience a biochemical recurrence at 5 years [2], and approximately 30% will die of their 
disease in 10-15 years [3]. 
1.2.1 Enzalutamide Background  
Oral enzalutamide (160mg once daily) is currently approved in more than 40 countries for the 
treatment of metastatic castration-resistant prostate cancer (mCRPC). Enzalutamide acts on 
several steps of the androgen receptor (AR) pathway by inhibiting binding of androgen to the 
ligand binding domain of the AR, translocation of AR to the nucleus, and interaction of AR with 
DNA [4]. The efficacy and safety of enzalutamide was assessed in two randomized, placebo-
controlled, multicenter phase III clinical trials (AFFIRM and PREVAIL) [5, 6]. 
Enzalutamide is a Biopharmaceutics Classification System (BCS) class 2 drug substance (low 
solubility, high permeability). It has been previously shown that lipid-based formulations work 
well with this drug class. The commercial product is a liquid-filled, soft gelatin capsule 
containing 40 mg enzalutamide dissolved in caprylocaproyl polyoxylglycerides (Labrasol). 
1.2.2 Pharmacokinetic Studies  
Multiple clinical pharmacokinetic studies of enzalutamide have been conducted [7]. 
Enzalutamide has a half-life of 5.8 days, achieves steady state by day 28, accumulates 8.3-fold 
with once-daily dosing, shows approximate dose proportionality from 30–360 mg/day, and has 
<30 % intersubject variability. It is primarily eliminated by hepatic metabolism, while renal 
excretion is an insignificant elimination pathway for enzalutamide and its active metabolite, N –
desmethyl enzalutamide. Exposure to enzalutamide active moieties is not affected by food or 
baseline mild or moderate hepatic impairment. Enzalutamide has predictable pharmacokinetics, 
with low intersubject variability. Similar efficacy was observed in patients across the 
concentration/exposure range associated with a fixed oral dose of enzalutamide 160 mg/day. 

 
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Study NCT01911715 was a phase I, open-label, one-period, single-dose mass balance and 
biotransformation study in six healthy male subjects [7]. After a single oral dose of enzalutamide 
160 mg (4 x 40 mg capsules), at least 84.2% of the drug was absorbed. The average Cmax, tmax, 
AUCinf, and t1/2 of enzalutamide were 4.5 ug/mL, 1.8 h, 237 ug*h/mL, and 2.9 days, respectively. 
 
A phase I, open-label, randomized, single-dose, parallel design, food-effect study was performed 
in 60 healthy men (n=30 in fasted and fed arms) to determine the effect of a high-fat meal on the 
pharmacokinetics of enzalutamide [7]. The average Cmax and Tmax for the fasted and fed arms 
were 5.3 and 3.7 ug/mL and 1 and 2h post-dose, respectively. The average AUCinf for the fasted 
and fed arms were 292 and 285 ug*h/mL, respectively. In all, the data suggest that consumption 
of a high-fat meal slightly slows the rate of absorption but does not lower exposure of 
enzalutamide. 
 
Gibbons et al. conducted two phase I drug interaction studies: one investigating the effects of 
coadministered drugs on the pharmacokinetics of enzalutamide, and one investigating the effects 
of enzalutamide on the pharmacokinetics of coadministered drugs [8]. Study NCT01913379, 
which used a parallel-treatment design (n=41), studied the effects of a strong CYP2C8 inhibitor 
(p.o. gemfibrozil 600 mg twice daily) and a strong CYP3A4 inhibitor (p.o. itraconazole 200 mg 
once daily) on the pharmacokinetics of enzalutamide after a single dose of enzalutamide (160 
mg). Coadministration of gemfirozil and itraconazole increased the AUCinf of enzalutamide by 
2.2- and 1.3-fold, respectively. Study NCT01911728, which used a single-sequence cross-over 
design (n=14), studied the effects of enzalutamide (160 mg/day) on the pharmacokinetics of a 
single oral dose of sensitive substrates for CYP2C8 (picoglitazine 30 mg), CYP2C9 (warfarin 10 
mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg). The AUCinf of warfarin, 
omeprazole, and midazolam were decreased by 56, 70, and 86%, respectively, after 
coadministration of enzalutamide, suggesting that enzalutamide is a moderate inducer of 
CYP2C9 and CYP2C19 and a strong inducer of CYP3A4. 
 
A randomized, two-period crossover pilot bioequivalence and food effect study was carried out 
in 60 healthy male subjects to compare two enzalutamide formulations [9]. The reference 
formulation, which had previously been used in human clinical trials, was a liquid-filled soft 
gelatin capsule containing 40 mg enzalutamide dissolved in Laprasol. Four capsules were 
necessary to deliver 160 mg enzalutamide. The test formulation was a tablet composed of 160 
mg enzalutamide in a 60%A:hydroxypropyl methylcellulose acetate succinate (HPMCAS)-M 
spray dried dispersion. While cohorts A and B (n=15, each) were fasted, cohorts C and D (n=15, 
each) were fed. Cohorts A and C were given a single dose of 160 mg enzalutamide as a tablet. 
Cohorts B and D were given a single dose of 160 mg enzalutamide as 4x40 mg liquid-filled 
capsules. After a 42-day washout, cohorts A and B, C and D were crossed over. The average 
AUCday1-7 for the tablet and capsule formulations in fasted subjects was 177 and 185 ug*h/mL, 
respectively. The average AUCday1-7 for the tablet and capsule formulations was 191 and 187 
ug*h/mL, respectively. In all, the data suggest that the bioequivalence of the formulations was 
comparable. 

 
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1.2.3 Rationale for an Oral Formulation of Enzalutamide  
The reference formulation is a liquid-filled, soft gelatin capsule containing 40 mg enzalutamide 
dissolved in Labrasol; four such capsules are required to deliver a 160 mg dose. The liquid-filled 
capsule formulation had previously been used in clinical studies in castration-resistant prostate 
cancer and is currently the marketed formulation. The four-capsule regimen is inconvenient 
because of the number of capsules that must be taken per dose, particularly in light of the fact 
that cancer patients often have to take multiple drugs. In addition, some patients may have 
difficulty with swallowing. Therefore, alternate methods of oral administration are necessary. 
1.2.4 Summary 
This is a single-dose randomized, open-label, 2-way crossover pilot bioequivalence study to 
compare two oral formulations of enzalutamide. The reference formulation is a liquid-filled, soft 
gelatin capsule containing 40 mg enzalutamide dissolved in Labrasol; four such capsules are 
required to deliver a 160 mg dose. The test formulation is a liquid enzalutamide formulation 
prepared by extracting the liquid from the gelatin capsule. Patients will be dosed under fasting 
conditions, which involve nothing to eat or drink 2 hours prior to dosing and 2 hours after dosing 
is complete.. The pharmacokinetics of each method of administration will be studied to see if a 
liquid formulation of enzalutamide is a viable alternate to dosing as a capsule. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Patients must have histologically or cytologically confirmed prostate cancer . Note: If 
histopathological documentation is unavailable, a clinical course consistent with 
prostate cancer is acceptable. 
2.1.1.2 ECOG performance status 0 to 2 ( see APPENDIX A) 
2.1.1.3 Patients must have adequate organ and marrow function as defined below: 
− 
Hemoglobin  
 
≥ 9 g/dL 
− 
leukocytes 
 
 
≥ 3,000/mcL 
− 
absolute neutrophil count 
≥ 1,500/mcL 
− 
platelets 
 
 
≥ 150,000/mcL 
− 
total bilirubin  
 
within normal institutional limits 
− 
AST(SGOT)/ALT(SGPT) 
≤3 X institutional upper limit of normal 
− 
creatinine 
 
 
within normal institutional limits 
OR 
− 
creatinine clearance  
≥ 30 mL/min/1.73 m2 for patients with creatinine 
   levels above institutional normal (calculated via   
   Cockcroft-Gault equation) 
2.1.1.4 Patients must not have other concurrent malignancies (within the past 2 years with the 
exception of non-melanoma skin cancer and Rai Stage 0 chronic lymphocytic 
leukemia), in situ carcinoma of any site, or life threatening illnesses, including untreated 

 
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infection (must be at least 1 week off intravenous antibiotic therapy before beginning 
enzalutamide). 
2.1.1.5 Ability of subject to understand and the willingness to sign a written informed consent 
document. 
2.1.1.6 Willingness to travel to NIH for follow-up visits. 
2.1.1.7 Men age > 18 years of age.  Children are excluded because prostate cancer is not 
common in pediatric populations.  Women are not eligible because this disease occurs 
only in men 
2.1.1.8 The effects of enzalutamide on the developing human fetus are unknown. For this 
reason men must agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) throughout the course of the study and for 3 months after the 
last dose. Should a woman become pregnant or suspect she is pregnant while her 
partner is participating in this study, she should inform her treating physician 
immediately. 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients who are receiving any other investigational agents (in the past 28 days) or 
herbal medications (within 7 days). 
2.1.2.2 Patients must not be on enzalutamide within five half-lives before the first planned dose 
of the study drug or anticipating to start enzalutamide within the next 3 months of the 
first planned dose of study drug 
2.1.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to enzalutamide or other agents used in study. 
2.1.2.4 Clinically significant cardiac disease, e.g. New York Heart Association (NYHA) classes 
III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension, 
myocardial infarction in the previous 6 months as confirmed by an electrocardiogram 
(ECG). 
2.1.2.5 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements 
2.1.2.6 Patients who are taking medications that may alter the metabolism of enzalutamide. 
This includes the following: strong or moderate CYP2C8 inhibitors or inducers; strong 
CYP3A4 inhibitors or inducers; or CYP2C9, 2C19 or 3A4 substrates with a narrow 
therapeutic index. For a current table of Substrates, Inhibitors and Inducers please 
access the following website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Drug
InteractionsLabeling/ucm093664.htm 
2.1.2.7 History of seizure, including any febrile seizure, loss of consciousness, or transient 
ischemic attach, or any condition that may pre-dispose to seizure (e.g. prior stroke, 

 
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brain arteriovenous malformation, head trauma with loss of consciousness requiring 
hospitalization). 
2.1.3 Recruitment Strategies 
This protocol may be abstracted into a plain language announcement posted on NIH websites 
and on NIH social media platforms. Participants will be recruited from the current patient 
population at NIH. 
2.2 
SCREENING EVALUATION 
2.2.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
• Email, written, in person or telephone communications with prospective subjects.  
• Review of existing medical records to include H&P, laboratory studies, etc.   
• Review of existing  MRI, x-ray, or CT images. 
• Review of existing photographs or videos. 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes. 
A waiver of consent for these activities has been requested in Section 9.6.1. 
2.2.2 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the subject has signed the consent for this 
study for screening. Assessments performed at outside facilities or on another NIH protocol 
within the timeframes below may also be used to determine eligibility once a patient has signed 
the consent. 
• Pathological confirmation: Patients must have histopathological documentation of 
prostate cancer prior to enrollment. Note: If no pathologic specimen is available, a 
clinical course consistent with prostate cancer is acceptable. 
• Within 8 weeks of study entry: ECG, laboratory tests (CBC with differential and platelet 
count, hepatic panel, acute care panel, mineral panel, PT/PTT, serum PSA), history and 
physical examination with documentation of weight, and ECOG performance status. 
2.3 
REGISTRATION PROCEDURES 
Registration will be a two-part process as patients are screened on this protocol. Authorized staff 
must register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours 
of signing consent. To initially register a subject after the participant has signed the consent, 
complete the top portion the registration Eligibility Checklist from the website 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) indicating that the patient is being 
registered for screening and send via encrypted email to: NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov. Once eligibility is confirmed after completion of 
screening studies, complete the remainder of the form which is the eligibility checklist, 

 
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indicating that the patient is being registered for treatment and email the completed registration 
checklist to the CRO at NCI Central Registration Office  ncicentralregistration-l@mail.nih.gov. 
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents. Verification of Registration will be forwarded electronically via e-mail to 
the research team. A recorder is available during non-working hours.  
Subjects that do not meet screening criteria should be removed from the study following the 
procedure in section 3.5.2. 
 
2.3.1 Treatment Assignment and Randomization/Stratification Procedures 
Cohorts 
Single Cohort study 
Number Name 
Description 
1 
Prostate Cancer   
Patients with Prostate Cancer 
 
Arms 
Letter 
Name 
Description 
A 
Sequence AB 
Enzalutamide capsule (Treatment A) followed by 
enzalutamide liquid (Treatment B) 
B 
Sequence BA 
Enzalutamide liquid (Treatment B) followed by 
enzalutamide capsule (Treatment A) 
 
Randomization and Arm Assignment 
Period 1 
Minimum 42-day 
washout 
Period 2 
Arm A 
Single dose of 4x40 mg 
liquid-filled capsules, fasted 
(n = 6-7) 
Arm B 
Single dose of 4x40 mg 
liquid-filled capsules, fasted 
(n = 6-7) 

 
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Arm B 
Single dose of 160 mg liquid 
formulation, fasted 
(n = 6-7) 
 
Arm A 
Single dose of 160 mg liquid 
formulation, fasted 
(n = 6-7) 
Patients will be randomized on a 1:1 basis between arms A and B.  
The randomization will be performed by the NCI Central Registration Office at the time of 
enrollment.  
2.4 
BASELINE EVALUATION 
• History and physical examination within 17 days of treatment initiation (for medical 
record only). 
• Laboratory studies (Tests completed at screening may be omitted if performed within 17 
days of treatment initiation): CBC with differential and platelet count, PT/PTT, and 
Acute care panel (Serum sodium, Potassium test, Serum chloride, CO2, Creatinine, 
Glucose test, BUN); Mineral panel (Albumin, Calcium, Magnesium, Phosphorous – 
serum); Hepatic Panel (Alkaline phosphatase, ALT, AST, direct and total bilirubin); 
Gamma-GT, LDH, total cholesterol, total protein, Serum PSA, uric acid,  
• Urinalysis 
• Baseline ECG (within 17 days of treatment initiation) 
• Vital signs including weight and height 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is a randomized, open-label, single-dose, 2-way crossover, pilot bioavailability trial 
evaluating two oral formulations of enzalutamide. All men (n=12-14) enrolled in the trial will 
receive oral enzalutamide in two formulations: Treatment A will be the standard liquid-filled, 
soft gelatin capsule (reference) formulation; Treatment B will be the liquid formulation (test 
product). Subjects will be randomized in Period 1 to one of two sequences: AB or BA. Following 
a minimum 42-day washout period, subjects will be crossed over in Period 2 to receive the 
treatment that they did not receive in Period 1. Blood samples will be collected for 
pharmacokinetic analysis. 
Subjects are admitted to the Clinical Center on Day 1 (for the first 24-hours of PK sampling) and 
will take a single 160mg dose of enzalutamide. They are to return to the Clinical Center on Day 
3 for the 48h, on Day 8 for the 168h, and Day 42 for the post-dose blood draws. After an 
appropriate washout period (at least 42 days), subjects will be crossed over in Period 2 to receive 
the treatment that they did not receive in Period 1. Subjects will be re-admitted to the Clinical 
Center to receive the study drug and blood samples will be drawn as described above on Days 1, 
3, 8, and 42.Drug Administration 

 
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3.2 
DRUG ADMINISTRATION 
Enzalutamide will be administered under the following fasting conditions (no caloric intake for  
2 hours before dosing and 2 hours after dosing).  
Subjects will be randomized in Period 1 to one of two sequences: AB or BA. Subjects are 
admitted to the Clinical Center on Day 1 (for the first 24-hours of PK sampling) and will take a 
single 160mg dose of an oral enzalutamide formulation. After an appropriate washout period (at 
least 42 days), subjects will be crossed over in Period 2 to receive the treatment that they did not 
receive in Period 1. Subjects will be re-admitted to the Clinical Center to take another 160mg 
dose of an oral enzalutamide formulation.  
Enzalutamide will be administered at approximately 0800 hours with ambient temperature water 
to a total volume of about 240 mL. When the liquid formulation is administered, the subject will 
administer the liquid directly from the oral syringe into the mouth and will swallow. Following 
administration of the liquid dose, a small volume of water (e.g. 3-7 mLs) may be drawn into the 
syringe and then the contents will be administered orally to the subject. This technique to “rinse” 
the syringe is intended to reduce the residual enzalutamide remaining in the oral syringe to 
ensure the complete dose is administered.  This will be followed by approximately 240 mL 
water. When the capsule formulation is administered, capsules must be swallowed whole without 
breaking, crushing, or chewing with approximately 240 mL water.Subjects are required to refrain 
from drinking beverages other than water  or eating for 2 hours after dosing. Subjects may 
resume their normal meals 2 hours after dosing.  

 
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3.3 
STUDY CALENDAR 
Procedure 
 
 
Screening 
Baseline 
Period 1 
Period 2 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
Day 
42 
Day 
1 
Day 
2 
Day 
3 
Day 
8 
Day 
42 
Confirmation of 
diagnosis 
X 
X 
 
 
 
 
 
 
 
 
 
 
History and PE 
X 
X 
 Xg 
  
  
  
X 
Xd 
  
  
  
X 
Vital signs 
X 
X 
 X 
  
  
 X 
X 
Xd 
  
  
  
X 
Performance 
Score 
X 
X 
  
  
  
  
X 
Xd 
  
  
  
X 
Labs 
Xa 
Xb 
Xf 
X 
Xd 
X 
Urinalysis 
X 
X 
 
 
 
 
X 
Xd 
 
 
 
X 
ECG 
X 
X 
 
 
 
 
X 
Xd 
 
 
 
X 
PKc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
 
 
X 
 
 
X 
X 
Xd 
 
 
X 
X 
Questionnaire 
 
 
Xe 
 
 
 
 
Xe 
 
 
 
 
aFor screening labs see Section 2.2  
bFor baseline labs see Section 2.4;  
cSee Section 5.1 for complete details. 
dWith the exception of PK and adverse events, all assessments and labs on Period 2 Day 1 do not need to be repeated if within 8 days 
of Period 1 Day 42.  
eSubjects will be given a questionnaire (see APPENDIX B) to complete following the administration of the liquid (test) formulation 
to assess the tolerability. The questionnaire is only completed on the day the liquid formulation is administered. It is not necessary to 
complete the quiestionnaire on the day the capsule formulation is administered.  
fLabs do not need to be repeated if they were completed at screening/baseline within 17 days of of period 1 day 1.  
fH&P may be performed within 17 days of treatment initiation.

 
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3.4 
COMPENSATION 
Study participants will be compensated for each blood sample collected for PK analysis as 
follows: 
• $20 for the 1st pre-dose (0 hour) PK sample 
• $20 for the 2nd (30 minutes post dose) PK sample 
• $20 for the 3rd (1 hour post dose) PK sample 
• $20 for the 4th (2 hours post dose) PK sample  
• $20 for the 5th (4 hours post dose) PK sample 
• $20 for the 6th (8 hours post dose) PK sample 
• $20 for the 7th (24 hours post dose) PK sample 
• $20 for the 8th (48 hours post dose) PK sample 
• $20 for the 9th (168 hours post dose) PK sample 
• $20 for the 10th (Day 42 post dose) PK sample 
All remuneration will be directed to be paid to the participant via check through standard 
compensation procedures. These funds are intended to compensate for time away from work that 
is required to participate in this study. As we intend to recruit from the local metropolitan region, 
we will not provide remuneration for meals, lodging or transportation. If a participant withdraws 
from study, no future compensation will be made, but prior compensation will not be revoked. 
Subjects will not receive direct benefit from their study participation in this protocol. 
Subjects will only be compensated if samples are collected solely for research purposes. 
If subjects return to clinic solely for any clinical/non-research reasons, subjects will not be 
reimbursed. 
3.5 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
3.5.1 Criteria for removal from protocol therapy 
• Completion of protocol therapy 
• Participant requests to be withdraw from active therapy 
• Unacceptable Toxicity as determined by the investigator   
• Investigator discretion 
3.5.2 Off-Study Criteria 
• Completed study follow-up period  
• Participant requests to be withdrawn from study 
• Loss of capacity to render informed consent 
• Death 
• Screen failure 

 
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3.5.3 Off Protocol Therapy and Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office  
ncicentralregistration-l@mail.nih.gov. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
Patients may be on concomitant drugs to prevent bone loss, including calcium, vitamin D, 
bisphosphonates and denosumab. 
Other supportive care with blood components, antibiotics, analgesics, general medical therapy, 
etc., will be delivered as required. 
4.1 
GENERAL GUIDELINES 
All medications (other than study drug) and significant non-drug therapies (including physical 
therapy and blood transfusions) taken within 28 days of starting study treatment through the 
follow up visit should be reported on the CRF. 
While patients are on protocol treatment, all medications required for the health of the patient are 
allowed with the following exception: concomitant use of herbal supplements. 
4.2 
SEIZURE THRESHOLD LOWERING DRUGS 
Use caution when coadministering medications which may lower the seizure threshold. 
4.3 
CYTOCHROME P450 AND P-GLYCOPROTEIN  
• Co-administration of enzalutamide with strong or moderate CYP2C8 inducers (e.g., 
rifampin) or inhibitors may alter the plasma exposure of enzalutamide and are not 
allowed while on study. 
• Co-administration of enzalutamide with strong CYP3A4 inducers (e.g., carbamazepine, 
phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) or inhibitor may alter the 
plasma exposure of enzalutamide and are not allow while on study. Selection of a 
concomitant medication with no or minimal CYP3A4 induction potential is 
recommended.  
• Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) 
and St. John’s Wort may also reduce the plasma exposure of enzalutamide and should be 
avoided if possible.  
• Concomitant use of enzalutamide with narrow therapeutic index drugs that are 
metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, 
warfarin), or CYP2C19 (voriconazole) should be avoided, as enzalutamide may decrease 
their exposure.  
• Grapefruit, Seville oranges, and starfruit affect P450 and PgP activity. Concomitant use 
should be avoided. 

 
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5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
The time of enzalutamide dose administration is t = 0 for purposes of pharmacokinetic sample 
collection times. Due to the long t½ of enzalutamide, N-desmethyl enzalutamide, and the 
carboxylic acid metabolite in healthy subjects (approximately 6, 8, and 10 days, respectively [7], 
pharmacokinetic samples will be collected over 42 days. 
With each 160 mg dose of enzalutamide, pharmacokinetic blood samples will be collected in 6-
mL tubes with dipotassium ethylenediaminetetraacetic acid (K2 EDTA) as the anticoagulant. 
Venous blood samples for plasma will be collected at the following times: pre-dose (0 hr) and 
post-dose at 30 minutes; and at 1, 2, 4, and 8 hours (Day 1), 24h (Day 2), 48h (Day 3), 168h 
(Day 8), and Day 42 post-dose. 
Validated bioanalytical methods based on ultra high-performance liquid chromatography with 
tandem mass spectrometry (uHPLC-MS/MS) [10] will be developed by the Clinical 
Pharmacology Program and used to analyze plasma samples for concentrations of enzalutamide 
and the two major human metabolites (e.g. N-desmethyl enzalutamide and carboxylic acid 
enzalutamide). 
Non-compartmental PK analysis of enzalutamide in plasma will be performed using WinNonlin 
5.0 (Pharsight, Inc., Mountain View, CA). PK parameters derived from plasma concentration-
time data may include Cmax, Tmax, AUC, Cl, Cl/F, Vd, and t1/2. 
5.2 
SAMPLE PROCESSING 
All samples will be sent to and stored in Dr. Figg’s Lab at NCI, Bldg 10, Bethesda, MD. Place 
all samples on wet ice. 
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. 
5.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required.  
Any transfer of materials to other NIH or non-NIH investigators will occur following NIH 
Intramural Research Program guidelines. If the subject withdraws consent the participants data 
will be excluded from future distributions, but data that have already been distributed for 
approved research use will not be able to be retrieved. 

 
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Upon arrival in the Clinical Pharmacology Program (CPP), blood samples will be centrifuged 
and the plasma transferred into cryovials for storage at -80° C until the time of analysis.  
All PK samples will be barcoded, with data entered and stored in the LABrador (aka 
LabSamples) utilized by the CPP. This is a secure program, with access to LABrador System 
limited to defined CPP personnel, who are issued individual user accounts. The program creates 
a unique barcode ID for every sample and sample box, which cannot be traced back to patients 
with LABrador access. The data recorded for each sample includes the patient ID, name, trial 
name/protocol number, time drawn, cycle time point, dose, material type, as well as box and 
freezer locations. Patient demographics associated with the clinical center patient number are 
provided in the system. For each sample, there are notes associated with the processing method 
(e.g. delay in sample processing, storage conditions on the ward, etc.). 
Barcoded samples are stored in barcoded boxes in locked freezers at either -20 C or -80 C 
according to stability requirements. These freezers are located onsite in the CPP and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Samples will be stored until 
requested by a researcher named on the protocol.  
All requests are monitored and tracked in LABrador. All researchers are required to sign a form 
stating that the samples are only to be used for research purposes associated with this trial (as per 
IRB approved protocol) and that any unused samples must be returned to the CPP. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB. The PI will record any loss or unanticipated descruction of samples as a deviation. 
Reporting will be per the requirments of Section 7.2.  
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
pharmacokinetic data with these variables.  
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
C3D and LABrador will be used for data collection purposes. The PI will be responsible for 
overseeing entry of data into an in-house password protected electronic system and ensuring data 
accuracy, consistency and timeliness. The principal investigator, associate investigators/research 
nurses and/or a contracted data manager will assist with the data management efforts. All data 
obtained during the conduct of the protocol will be kept in secure network drives or in approved 
alternative sites that comply with NIH security standards. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant. 

 
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All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in Section 7.2.1.  
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
What data will be shared? 
I will share human data generated in this research for future research as follows: 
• Coded, linked data in an NIH-funded or approved public repository.   
• Coded, linked data in BTRIS (automatic for activities in the Clinical Center) 
 
How and where will the data be shared?  
Data will be shared through: 
• An NIH-funded or approved public repository.  Insert name or names:   ClinicalTrials.gov  . 
• BTRIS (automatic for activities in the Clinical Center) 
• Approved outside collaborators under appropriate individual agreements. 
• Publication and/or public presentations. 
 
When will the data be shared?  
• Before publication. 
• At the time of publication or shortly thereafter. 

 
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6.3 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  
7.3 
FDA REQUIREMENTS  
The person conducting the study must retain reserve samples of any test article and reference 
standard used in the study and release the reserve samples to FDA upon request, in accordance 
with, and for the period specified in, 320.38 (at least 5 years following the date of completion of 
the bioavailability study in which the sample from which the reserve sample was obtained was 
used). 
The PI or AI must notify FDA and all participating investigators of any serious adverse event, 
observed during the conduct of the study as soon as possible but in no case later than 15 calendar 
days after becoming aware of its occurrence. Each report must be submitted on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive. Each report must 
bear prominent identification of its contents, i.e., "bioavailability/bioequivalence safety report." 
The person conducting the study must also notify FDA of any fatal or life-threatening adverse 
event from the study as soon as possible but in no case later than 7 calendar days after becoming 
aware of its occurrence. Each notification under this paragraph must be submitted to the 
Director, Office of Generic Drugs in the Center for Drug Evaluation and Research at FDA. 
Relevant followup information to a bioavailability/bioequivalence safety report must be 
submitted as soon as the information is available and must be identified as such, i.e., "Followup 
bioavailability/bioequivalence safety report." Upon request from FDA, the person conducting the 
study must submit to FDA any additional data or information that the agency deems necessary, 
as soon as possible, but in no case later than 15 calendar days after receiving the request.  

 
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7.4 
NCI CLINCIAL DIRECTOR RERPORTING 
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director. A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.5 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis (at least weekly) when patients are being 
actively treated on the trial to discuss each patient. Decisions about dose level enrollment and 
dose escalation if applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
Section 7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8 
STATISTICAL CONSIDERATIONS 
8.1 
STATISTICAL HYPOTHESES 
Primary efficacy endpoints:  
To evaluate the bioequivalence of two oral formulations of enzalutamide following a single 160 
mg dose in male subjects with prostate cancer. 
The primary measure of efficacy will be AUC for the first period of administration obtained 
during blood draws during visits on day 1, 3, 8, and 42 evaluations, and then AUC at a second 
set of  visits at least 42 days after the first administration, for evaluations on days 1, 3, 8 and 42 
relative to the second administration, for the second period evaluations.  
Secondary efficacy endpoints: 
To evaluate the safety and tolerability of two oral formulations of enzalutamide following a 
single 160 mg dose in male subjects with prostate cancer. 
8.2 
SAMPLE SIZE DETERMINATION 
This study will be conducted as a two-period randomized crossover trial design. Patients will be 
randomized to initially receive the standard liquid filled soft gelatin formulation (Arm A) 
followed later by the liquid formulation, or the liquid formulation as the test product (Arm B) 

 
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followed by the liquid filled soft gelatin formulation. A total of 12 evaluable patients will be 
randomized into the two arms. It has been identified that a decrease of approximately 30-40 
ug*h/mL in the AUC (less than a 20% decrease in the AUC for the test version vs. the standard 
formulation) would permit the two formulations to be considered bioequivalent, and it may be 
expected that the actual difference between the formulations may be a decline of approximately 
10% (approximately 20 ug*h/mL). When the sample size in each sequence arm is 6, (a total 
sample size of 12) a crossover design will have 80% power to reject the null hypothesis that the 
Arm B mean minus the Arm A mean is below -40  ug*h/mL and the null hypothesis that the Arm 
B mean minus the Arm A mean is above 0 ug*h/mL, i.e., that the two groups are not equivalent, 
in favor of the alternative hypothesis that the means of the two treatments are equivalent, 
assuming that the expected difference in means is -20 ug*h/mL, the standard deviation of 
differences, sd, is 20 ug*h/mL, and that each test is made at the 5% level.  
It is expected that approximately 1 patient per month may enroll onto this trial. Thus, to enroll 12 
evaluable patients, it is anticipated that one year may be required. To allow for the possibility of 
a small number of patients who do not have full measurements obtained based on both drug 
administrations, the accrual ceiling will be set at 14 patients. 
8.3 
POPULATIONS FOR ANALYSIS 
Modified intention to treat. Only patients who participated in both drug administrations and have 
blood draws on at least 3 of the 4 required dates for each of the two administrations. 
8.4 
STATISTICAL ANALYSES 
8.4.1 General Approach 
The difference in the AUCs will be calculated following a published non-parametric approach 
for analyzing data from two-period cross-over studies: 
Koch GG “The Use of Non-parametric methods in the statistical analysis of the two-period 
change-over design. Biometrics 28: 577-584 (1972). 
8.4.2 Analysis of the Primary Efficiacy Endpoints 
The average of the AUC values at the 4 determinations associated with each of the two drug 
administrations will be determined and the difference assessed for statistical significance at the 
0.05 level using the non-parametric procedures identified in the Koch 1972 paper. 
8.4.3  Analysis of the Secondary Efficacy Endpoints 
The number of episodes of nausea and vomiting, as well as the grades of nausea and vomiting 
will be calculated and reported for each of the two formulations at each time point. The rates of 
grade 3 vomiting will be compared between the two formulations at each time point using 
Fisher’s exact test. 
8.4.4 Safety Analyses 
Toxicity data: tabulated counts. The primary toxicity, nausea and vomiting, will be reported per 
arm at each of the time points when the drugs are administered. 

 
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8.4.5 Baseline Descriptive Statistics 
Demographic and clinical characteristics of patients on both arms will be tabulated. 
8.4.6 Planned Interim Analyses 
No interim analyses are planned; the data will be analyzed at the completion of the trial. 
8.4.7 Subgroup Analyses 
None will be performed; inadequate numbers of subjects to be enrolled for meaningful subgroup 
analyses. 
8.4.8 Tabulation of Individual Participant Data 
None will be provided 
8.4.9 Exploratory Analyses 
There are no exploratory objectives so no exploratory analyses will be undertaken. 
9 
HUMAN SUBJECTS PROTECTIONS  
9.1 
RATIONALE FOR SUBJECT SELECTION 
9.1.1 Selection Based on Ethnicity, and Race 
Subjects from all racial/ethnic groups are eligible for this study if they meet the eligibility 
criteria. To date, there is no information that suggests that differences in drug metabolism or 
disease response would be expected in one group compared with another. Efforts will be made to 
extend accrual to a representative population, but in this preliminary study, a balance must be 
struck between patient safety considerations and limitations on the number of individuals 
exposed to potentially toxic and/or ineffective treatments on one hand and the need to explore 
ethnic aspects of clinical research on the other hand. If differences in outcome that correlate with 
ethnic identity are noted, accrual may be expanded or a follow-up study may be written to 
investigate those differences more fully. Women are not eligible for this protocol as this disease 
occurs only in men. 
9.1.2 Strategies/Procedures for Recruitment  
Patient accrual for this protocol will be facilitated by Web-based recruitment strategies. This 
protocol will be listed on clinicaltrials.gov. 
9.2 
PARTICIPATION OF CHILDREN 
Because no dosing or adverse event data are currently available on the use enzalutamide in 
patients <18 years of age and because prostate cancer is uncommon in pediatric populations, 
children are excluded from this study, but may be eligible for future pediatric trials. 

 
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9.3 
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol because there is no 
prospect of direct benefit. Adults who become incapacitated or cognitively impaired during the 
course of the study will be removed from the study.   
9.4 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
9.4.1 Alternative Approaches or Treatments 
Patients will be consented verbally and in writing regarding the risks and benefits of this trial, the 
treatment requirements, and alternative approaches to entering on this trial. 
9.4.2 Procedure for Protecting Against or Minimizing any Potential Risks 
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity. This study may involve risks to patients, which are currently unforeseeable. All patients 
will have blood tests, examinations and scans as described in the protocol evaluation (Section 
3.3, Study Calendar). Patients will also be required to have a local physician to provide long-
term care and to monitor for complications. If patients suffer any physical injury as a result of the 
participation in this study, immediate medical treatment is available at the Clinical Center, 
National Cancer Institute, Bethesda, Maryland. Although no compensation is available, any 
injury will be evaluated and treated in keeping with the benefits or care to which patients are 
entitled under applicable regulations. 
9.4.3 Provisions for Monitoring Data Collection to Ensure Safety of Subjects 
As information is gathered from this trial, clinical results will be shared with patients as they 
become available. Laboratory and clinical data will be frequently gathered and any new 
significant finding(s) found during the course of the research, which may affect a patient’s 
willingness to participate further, will be explained. Confidentiality of information concerning 
participants will be maintained, including in all publications and presentations results from this 
study. Names of participants and/or material identifying participants will not be released without 
permission, except as such release is required by law. Records at the National Cancer Institute 
are maintained according to current legal requirements, and are made available for review, as 
required by the Food and Drug Administration or other authorized users, only under the 
guidelines established by the Federal Privacy Act. 
9.5 
RISKS/BENEFITS ANALYSIS 
Adult Subjects 
The patient will derive no direct benefit from the procurement of blood or from the enzalutamide 
as administered in this protocol and this will be clearly stated in the protocol consent. 
The risks of blood draw are relatively small and include pain at the needle site, bruising, possible 
dizziness if you stand up quickly, and possible inflammation of the vein or infection at the needle 
site.  
The dose (160mg) and route of administration (oral) of enzalutamide being used in this study has 
been approved by the FDA for the treatment of prostate cancer. However, the safety of 

 
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administering the enzalutamide liquid without the capsule surround has not been evaluated. The 
potential risk of the liquid formulation which may be greater than the capsule formulation 
include local irritation effects and accidental aspiration. 
9.6 
CONSENT PROCESS AND DOCUMENTATION 
The investigational nature and objectives of this trial, the procedures involved, and their 
attendant risks and discomforts, potential benefits, and potential alternative therapies will be 
explained to the patient and a signed informed consent document obtained. Moreover, any 
experimental invasive procedure will require a separate consent form. All associate investigators 
who have clinical privileges listed in this protocol are permitted to obtain informed consent. 
9.6.1 Request for Waiver of Consent for Screening Activities 
Prior to the subject signing the consent for this study pre-screening activities listed in Section 
2.2.1 may be performed.  
We request a waiver of consent for these activities as they involve only minimal risk to the 
subjects.  A waiver will not adversely affect the rights and welfare of the subjects given that the 
activities are only intended to determine suitability for screening for participation in research 
protocols.  These activities could not practicably be carried out without the wavier as central 
recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for 
multiple studies and obtaining consent for each one is beyond their resources.  The subjects will 
be provided with additional pertinent information after participation as they will be informed 
whether or not they are eligible to sign a consent for additional screening. 
9.6.2 Telephone Re-consent 
In the cases where re-consent is needed, re-consent may be obtained via telephone. 
Telephone consent will be obtained and documented per OHSRP/IRBO and CCR policies and 
procedures. 
10 PHARMACEUTICAL INFORMATION 
This study meets the criteria for exemption from IND based on the following criteria listed in 
Title 21 Code of Federal Regulations: 
• 
The investigation is not intended to be reported to FDA as a well-controlled study in 
support of a new indication for use nor intended to be used to support any other 
significant change in the labeling for the drug;  
• 
In the case of a prescription drug, the investigation is not intended to support a significant 
change in the advertising for the drug; 
• 
The investigation does not involve a route of administration or dosage level or use in a 
patient population or other factor that significantly increases the risks (or decreases the 
acceptability of the risks) associated with the use of the drug product;  
• 
The investigation is conducted in compliance with the requirements for review by an IRB 
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50); and 
• 
The investigation is conducted in compliance with the requirements of 312.7  

 
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10.1 ENZALUTAMIDE 
10.1.1 Source  
Enzalutamide will be obtained from commercial sources and dispensed by the institutional 
pharmacy. 
10.1.2 Toxicity  
10.1.2.1 Seizure 
In the randomized clinical trial, 7 of 800 (0.9%) patients treated with enzalutamide 160 mg once 
daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures 
occurred from 31 to 603 days after initiation of enzalutamide. Patients experiencing seizure were 
permanently discontinued from therapy and all seizures resolved. There is no clinical trial 
experience re-administering enzalutamide to patients who experienced seizures. The safety of 
enzalutamide in patients with predisposing factors for seizure is not known because these 
patients were excluded from the trial. These exclusion criteria included a history of seizure, 
underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 
months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use 
of concomitant medications that may lower the seizure threshold. Because of the risk of seizure 
associated with enzalutamide use, patients should be advised of the risk of engaging in any 
activity where sudden loss of consciousness could cause serious harm to themselves or others.  
10.1.2.2 Other adverse events  
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. Grade 3 and higher adverse 
reactions were reported among 47% of enzalutamide-treated patients and 53% of placebo-treated 
patients. Discontinuations due to adverse events were reported for 16% of enzalutamide-treated 
patients and 18% of placebo-treated patients. The most common adverse reaction leading to 
treatment discontinuation was seizure, which occurred in 0.9% of the enzalutamide-treated 
patients compared to none (0%) of the placebo-treated patients. Hypertension was also seen in 
patients who received enzalutamide relative to placebo (6.6% vs. 3.3%). 
  
10.1.2.3 Laboratory Abnormalities 
In the randomized clinical trial, Grade 1-4 neutropenia occurred in 15% of patients on 
enzalutamide (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of 
Grade 1-4 thrombocytopenia was similar in both arms; 0.5% of patients on enzalutamide and 1% 
on placebo experienced Grade 3-4 thrombocytopenia. Grade 1-4 elevations in ALT occurred in 
10% of patients on enzalutamide (0.3% Grade 3-4) and 18% of patients on placebo (0.5% Grade 
3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients on enzalutamide and 2% of 
patients on placebo. 
  

 
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10.1.2.4 Infections  
In the randomized clinical trial, 1.0% of patients treated with enzalutamide compared to 0.3% of 
patients on placebo died from infections or sepsis. Infection-related serious adverse events were 
reported in approximately 6% of the patients on both treatment arms.  
 
10.1.2.5 Falls and Fall-related Injuries 
In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients 
treated with enzalutamide compared to 1.3% of patients on placebo. Falls were not associated 
with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated 
with enzalutamide and included non-pathologic fractures, joint injuries, and hematomas. 
 
10.1.2.6 Hallucinations 
In the randomized clinical trial, 1.6% of patients treated with enzalutamide were reported to have 
Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with 
hallucinations, the majority were on opioid-containing medications at the time of the event. 
Hallucinations were visual, tactile, or undefined. 
10.1.3 Formulation and Preparation  
Enzalutamide (XTANDI ©) 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}z-2-
fluoro-N-methylbenzamide. Enzalutamide is a white crystalline non-hygroscopic solid. It is 
practically insoluble in water.  
10.1.3.1 Standard (reference) Formulation 
Enzalutamide is provided as liquid-filled soft gelatin capsules for oral administration. Each 
capsule contains 40 mg in 0.96 mL of enzalutamide as a solution (unpublished) 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.  
10.1.3.2  Liquid (test) Formulation 
The liquid (test) formulation of enzalutamide is prepared by extracting the liquid from the gelatin 
capsule by pharmacy personnel in a biological safety cabinet or appropriate clean bench. The 
soft gelatin enzalutamide capsule (which contains 40 mg in 0.96 mL) will be cut using a sharp 
object (scissor or similar item). Then, using a needle, the appropriate amount of liquid will be 
extracted from the necessary number of capsules to equal a 160mg dose.  The liquid formulation 
will be stored at room temperature and given a 24 hour expiration from the time of preparation 
and will then be dispensed in a Baxter EXACTAMED oral 10mL amber syringe for oral 
administration. 

 
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10.1.4 Stability and Storage  
Store enzalutamide capsules between 20C to 25C (68F to 77F) in a dry place and keep the 
container tightly closed. Excursions permitted from 15C to 30C (59F to 86F). The expiration 
date for each lot utilized in this study will be obtained from commercial packaging. 
Stability studies have been completed after 24 hours for the liquid enzalutamide after it has been 
extracted from the capsule. The concentration of enzalutamide extracted from the capsule at time 
0 was compared to the concentration of enzalutamide at 24 hours post extraction. During the 24 
hour period, liquid enzalutamide was stored in Baxter EXACTAMED oral 10mL amber 
syringes. The enzalutamide concentration at 24 hours post extraction decreased by 3.04% 
indicating stability at this time point (a concentration +/- 10% from time 0 was concerned 
acceptable). Additional stability studies are ongoing.   
10.1.5 Administration Procedures 
Enzalutamide will be administered under fasting conditions (no caloric intake for 2 hours before 
dosing and 2 hours after dosing) as a liquid formulation (as prepared by extracting the liquid as 
described in Section 10.1.3.2) and liquid-filled, soft gelatin capsules (4 x 40mg capsules, 160mg 
total). When the liquid formulation is administered, the subject will administer the liquid directly 
from the oral syringe into the mouth and swallow. Following administration of the liquid dose, a 
small volume of water (e.g. 3-7 mLs) may be drawn into the syringe and then the contents will 
be administered orally to the subject. This technique to “rinse” the syringe is intended to reduce 
the residual enzalutamide remaining in the oral syringe to ensure the complete dose is 
administered. This will be followed by approximately 240 mL water. When the capsule 
formulation is administered, capsules must be swallowed whole without breaking, crushing, or 
chewing with approximately 240 mL water. 
10.1.6 Tolerability Assessment 
To date, there is no available information on the palatability of the liquid enzalutamide 
preparation. Therefore, a brief tolerability assessment will be completed by each participant. 
Following the administration of the liquid (test) formulation, participants will be asked to 
complete APPENDIX B 

 
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11 REFERENCES 
1. 
Siegel, R.L., K.D. Miller, and A. Jemal, Cancer Statistics, 2016. CA Cancer Journal for 
Clinicians, 2016. 66(1): p. 7-30. 
2. 
Zelefsky, M.J., et al., Metastasis after radical prostatectomy or external beam 
radiotherapy for patients with clinically localized prostate cancer: a comparison of 
clinical cohorts adjusted for case mix. J Clin Oncol, 2010. 28(9): p. 1508-13. 
3. 
Kane, C.J., et al., Changing nature of high risk patients undergoing radical 
prostatectomy. J Urol, 2007. 177(1): p. 113-7. 
4. 
Tran, C., et al., Development of a Second-Generation Antiandrogen for Treatment of 
Advanced Prostate Cancer. Science, 2009. 324(5928): p. 787-790. 
5. 
Scher, H.I., et al., Increased Survival with Enzalutamide in Prostate Cancer after 
Chemotherapy. New England Journal of Medicine, 2012. 367(13): p. 1187-1197. 
6. 
Beer, T.M., et al., Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. 
New England Journal of Medicine, 2014. 371(5): p. 424-433. 
7. 
Gibbons, J.A., et al., Clinical Pharmacokinetic Studies of Enzalutamide. Clinical 
Pharmacokinetics, 2015. 54(10): p. 1043-1055. 
8. 
Gibbons, J.A., et al., Pharmacokinetic Drug Interaction Studies with Enzalutamide. 
Clinical Pharmacokinetics, 2015. 54(10): p. 1057-1069. 
9. 
Lorenz, D.A., et al., Formulations of Enzalutamide. 
10. 
Bennett, D., et al., Validation of a method for quantifying enzalutamide and its major 
metabolites in human plasma by LC-MS/MS. Bioanalysis, 2014. 6(6): p. 737-744. 
 

 
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12 APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 

 
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13 APPENDIX B: TOLERABILITY ASSESSMENT OF LIQUID (TEST) 
ENZALUTAMIDE FORMULATION 
 
The following questions refer to the liquid enzalutamide formulation you took. 
 
1. Did you complete taking the liquid enzalutamide formulation? (circle one) 
 
yes 
 
 
no 
 
If no, why did you not complete taking the medication? 
________________________________________________________________________ 
 
2. Please rate the overall taste of the liquid enzalutamide formulation. (circle one) 
 
bad 
 
almost acceptable 
 
acceptable 
 
good 
 
3. Which of the following best describes the taste of the liquid enzalutamide formulation? 
(circle one) 
 
sweet  
salty 
 
bitter  
other (please describe below) 
                                                                                  __________________________ 
 
4. Did you encounter any problems with the use of this liquid formulation? 
 
yes 
 
 
no 
 
If yes, please describe what problems you encountered:  
________________________________________________________________________ 
 
5. In your opinion, would the liquid formulation be an acceptable way of taking enzalutamide if 
you had difficulty swallowing?  (circle one) 
 
yes 
 
 
no