Clinical trial NCT02384382
Conditions: Prostate Carcinoma Metastatic to the Bone Castration Resistant Prostate Cancer
Keywords: Cancer of the Prostate
Sponsor: Pfizer
Start date: 2015-11-30; Completion date: 2019-05-03
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate 18F-sodium fluoride positron-emission tomography / computed tomography (18F-NaF PET/CT) imaging as a method for determining treatment response in metastatic bone lesions in patients who are receiving enzalutamide for castration-resistant prostate cancer.

Detailed description:

Arms: arm 1: Enzalutamide (160 mg) administered as four 40-mg capsules by mouth once daily
Interventions: intervention 1: Enzalutamide
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
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Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 6 of 66 
Safety: 
All safety analyses will be based on the safety population, defined as all patients who receive any amount of 
study drug.   
Safety will be evaluated by the incidence of serious adverse events, incidence and severity of adverse events, 
incidence of study drug discontinuation due to adverse events, and incidence of new clinically significant 
changes in clinical laboratory values and vital signs.   
All adverse events will be coded and tabulated by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA).  The number and percentage of patients with 
treatment-emergent adverse events will be presented by MedDRA system organ class and preferred term, 
relationship to study treatment, and severity.  Descriptive statistics will be used.   
Laboratory values will be classified for severity using the National Cancer Institute Common Terminology 
Criteria for Adverse Events, version 4.  Laboratory shift tables of baseline results to each subsequent visit will 
be produced as appropriate.   
Sample Size Considerations:  
The total number of patients to be included in this study is approximately 20 and is based on practical clinical 
considerations.   
 


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Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 9 of 66 
10.6 
Determination of Sample Size .......................................................................................................... 53 
11 
STUDY COMMITTEES AND COMMUNICATIONS .......................................................................... 53 
12 
LABORATORY REQUIREMENTS ....................................................................................................... 53 
13 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ...................................................... 54 
13.1 
Ethics ................................................................................................................................................ 54 
13.1.1 
Institutional Review Board................................................................................................. 54 
13.1.2 
Ethical Conduct of the Study ............................................................................................. 55 
13.1.3 
Patient Information and Informed Consent ........................................................................ 55 
13.1.4 
Maintaining Patient Confidentiality ................................................................................... 55 
13.2 
Data Quality Assurance .................................................................................................................... 55 
13.2.1 
Data Management .............................................................................................................. 55 
13.2.2 
Case Report Forms ............................................................................................................. 56 
13.2.3 
Study Monitoring ............................................................................................................... 56 
13.2.4 
Study Audits ....................................................................................................................... 56 
13.3 
Investigational Product Accountability ............................................................................................ 57 
13.4 
Compensation, Insurance, and Indemnity ........................................................................................ 58 
13.5 
Retention of Records ........................................................................................................................ 58 
13.6 
Study Termination ............................................................................................................................ 58 
14 
USE OF STUDY INFORMATION AND PUBLICATION ................................................................... 59 
15 
REFERENCES ........................................................................................................................................... 61 
16 
INVESTIGATOR SIGNATURE .............................................................................................................. 62 


Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 10 of 66 
LIST OF TABLES 
Table 1: 
Screening Procedures .................................................................................................................... 25 
Table 2: 
Week 1, Day 1 Procedures............................................................................................................. 27 
Table 3: 
Week 5 Procedures ........................................................................................................................ 28 
Table 4: 
Week 13 Procedures ...................................................................................................................... 29 
Table 5: 
Week 21 and Repeating Every 8 Weeks Procedures ..................................................................... 30 
Table 6: 
Time of Third 18F-NaF PET/CT Imaging (NaF-3) ........................................................................ 31 
Table 7: 
Unscheduled Visit Procedures ....................................................................................................... 32 
Table 8: 
Safety Follow-Up Procedures ........................................................................................................ 34 
Table 9: 
Criteria for Serious Adverse Events .............................................................................................. 41 
Table 10: 
Criteria for Determining Causal Relationship to Study Drug ........................................................ 43 
Table 11: 
Criteria for Determining the Severity (Intensity) of an Adverse Event ......................................... 43 
Table 12: 
Clinical Laboratory Safety Tests ................................................................................................... 46 
Table 13: 
ECOG Performance Status Assessments ....................................................................................... 49 
Table 14: 
Definition of Terms for NaF Uptake Measures ............................................................................. 50 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic ............................................................................................................................ 20 
 
LIST OF APPENDICES 
Appendix 1: Brief Pain Inventory (Short Form)................................................................................................. 63 
Appendix 2: Study Schedule of Activities ......................................................................................................... 65 
 


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Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 12 of 66 
Abbreviation 
Definition 
SUVhetero 
Heterogeneity of NaF uptake 
99mTc-MDP 
Technetium Tc 99m medronate 
ULN 
Upper limit of normal 
US 
United States 


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CCI


Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 15 of 66 
adverse reaction leading to treatment discontinuation was seizure, which occurred in 
7 (0.9%) of the enzalutamide-treated patients and none (0%) of the placebo-treated patients.   
In the phase 3 study MDV3100-03 (PREVAIL; N = 1715), enzalutamide was generally well 
tolerated with an overall safety profile consistent with that observed in study CRPC2, with 
a lower seizure rate observed in MDV3100-03 (1 patient [0.1%] each in the enzalutamide 
and placebo treatment groups).  The new adverse drug reactions observed in study 
MDV3100-03, gynecomastia and restless legs syndrome, were uniformly nonserious events 
occurring at low frequency (3.3% and 2.1%, respectively, in enzalutamide-treated patients 
vs 1.3% and 0.4%, respectively, in placebo-treated patients).   
In the phase 2 study 9785-CL-0321, enzalutamide monotherapy was well tolerated.  Most 
common treatment-emergent adverse events were grade 1, and included gynecomastia (36%), 
fatigue (34%), nipple pain (19%), and hot flush (18%).  Five patients had serious adverse 
events; none of the events were assessed as related to enzalutamide treatment.  Mean changes 
from baseline for fasting metabolic variables were +5.0% total cholesterol, +8.9% 
triglycerides, –3.5% hemoglobin A1c, and +19.7% insulin resistance (homeostasis model 
assessment-estimated insulin resistance; HOMA-IR).  Total body bone mineral density was 
maintained (–0.3% from baseline).  Quality of life scores at 1 year demonstrated maintenance 
of global health status, and decreased sexual activity and sexual functioning.   
Additional information on the clinical experience with enzalutamide is provided in the 
Enzalutamide Investigator Brochure.   
1.2.1 
Pharmacokinetics and Drug Metabolism 
In pharmacokinetics (PK) investigations in men with CRPC, enzalutamide was absorbed 
rapidly after oral administration, with the time to maximum plasma concentration (tmax) after 
a single dose typically occurring at 1 hour postdose.  At steady state, enzalutamide showed 
approximately dose proportional PK over the daily dose range of 30 to 360 mg.  Due to the 
long terminal half-life (approximately 5.8 days), it took approximately 1 month to reach 
steady state.  With daily oral administration, enzalutamide accumulation was observed at 
steady state with an 8.3-fold higher exposure (steady-state area under the curve, AUC) 
relative to a single dose.  Based on the mean peak-to-trough ratio, the average difference 
between the peak (maximum plasma concentration, Cmax) and trough (predose plasma 
concentration, Ctrough) concentrations was ≤ 25%.  As a result of the low daily fluctuations, 
plasma profiles at steady state resembled a constant infusion.  The Ctrough values in individual 
patients remained constant beyond day 28 of chronic therapy, suggesting time-linear PK once 
steady state was achieved.  At steady state, plasma concentrations of enzalutamide and the 
active metabolite, N-desmethyl enzalutamide, were approximately the same.   
In a drug-drug interaction study in male patients with CRPC (9785-CL-0007), a single oral 
dose of a substrate for cytochrome P450 (CYP) 2C8, CYP2C9, CYP2C19, or CYP3A4 was 
administered before and concomitantly with enzalutamide (after at least 55 days of dosing at 
160 mg daily).  Enzalutamide at steady state reduced the plasma exposure to midazolam 
(CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate) 
administered orally by 86%, 56%, and 70%, respectively.  Based on the magnitude of the 


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CCI
CCI


Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 17 of 66 
Long-term animal studies have not been conducted to evaluate the carcinogenic potential of 
enzalutamide.   
Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and 
was not genotoxic in either the in vitro cytogenetic assay with mouse lymphoma thymidine 
kinase gene mutation or the in vivo mouse micronucleus assay.   
Based on nonclinical findings in repeat-dose toxicity studies, which were consistent with the 
pharmacologic activity of enzalutamide, male fertility may be impaired by treatment with 
enzalutamide.  In a 26-week study in rats, atrophy of the prostate and seminal vesicles was 
observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC).  In 4-week and 
13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides 
were observed at ≥ 4 mg/kg/day (0.3-times the human exposure based on AUC).   
Additional toxicity studies are ongoing and planned.  Additional information on the 
nonclinical experience with enzalutamide is provided in the Enzalutamide Investigator 
Brochure.   
1.4 
Enzalutamide Benefits and Risks Assessment 
Approximately 5000 subjects and patients have been enrolled worldwide in completed and 
ongoing clinical trials evaluating enzalutamide.  Approximately 3200 have received at least 
1 dose of enzalutamide.  Available data for enzalutamide in men with metastatic prostate 
cancer that has progressed despite therapy with an LHRH analogue or bilateral orchiectomy 
support a positive benefit-risk profile for the use of enzalutamide as an investigational agent 
in this study, which will enroll patients similar to those who participated in MDV3100-03, 
with the caveat that patients must have bone metastatic disease to enter this study.  The 
clinical experience with enzalutamide is discussed briefly in Section 1.2.   
2 STUDY OBJECTIVES 
2.1 
Primary Objective 
• 
Evaluate 18F-NaF PET/CT imaging as a method for determining treatment response in 
metastatic bone lesions at the time of disease progression (PSA, bone or soft tissue, or 
other clinically relevant progression) or at 2 years without progression after treatment 
initiation in patients who are chemotherapy-naïve in the castration-resistant setting 
with progressive bone-metastatic CRPC treated with enzalutamide 
2.2 
Secondary Objective 
• 
Evaluate heterogeneity of response in metastatic bone lesions at the time the primary 
objective is assessed 


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Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 22 of 66 
4.1 
Inclusion Criteria 
Each patient eligible to participate in this study must meet all of the following criteria:   
1. Age 18 years or older and willing and able to provide informed consent.   
2. Histologically or cytologically confirmed adenocarcinoma of the prostate without 
neuroendocrine differentiation, or signet cell or small cell features.   
3. Ability to comply with all study procedures and willingness to remain supine for 
30 minutes during imaging.   
4. Presence of bone metastatic disease as assessed by at least 2 lesions on whole-body 
radionuclide 99mTc-MDP bone scintigraphy.   
5. Throughout the study, ongoing androgen deprivation therapy with an LHRH analogue or 
prior bilateral orchiectomy (medical or surgical castration).   
6. Testosterone ≤ 1.73 nmol/L (≤ 50 ng/dL) at screening.   
7. Progressive disease on androgen deprivation therapy at screening defined as a minimum 
of 2 sequentially rising PSA values (PSA1 < PSA2 < PSA3) assessed by the local 
laboratory with an interval of ≥ 1 week between each determination where PSA3 (the 
screening PSA) is obtained within 4 weeks before planned enrollment.   
8. The screening PSA (PSA3) must be ≥ 2 µg/L (≥ 2 ng/mL).  In the event of prior androgen 
receptor inhibitor use, the screening PSA must be obtained at least 4 weeks after the last 
dose of the androgen receptor inhibitor.   
9. Asymptomatic or minimally symptomatic prostate cancer (Brief Pain Inventory Short 
Form question 3 score < 4) at screening.   
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.   
11. Estimated life expectancy of ≥ 12 months at screening.   
12. Ability to swallow study capsules after a picture to scale of the capsules is shown to the 
patient and to comply with study requirements throughout the study.   
13. Throughout the study, patient and his female partner who is of childbearing potential 
must use 2 acceptable methods of birth control (1 of which must include a condom as 
a barrier method of contraception) from screening through 3 months after last dose of 
study drug.  Two acceptable methods of birth control thus include the following: 
• 
A condom (barrier method of contraception) 
AND 
• 
One of the following is required: 
– Established and ongoing use of oral, injected, or implanted hormonal method of 
contraception by the female partner 
– Placement of an intrauterine device or intrauterine system by the female partner 
– Additional barrier method:  Contraceptive sponge or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the 
female partner 
– Tubal ligation in the female partner performed at least 6 months before screening 
– Vasectomy or other procedure resulting in infertility (eg, bilateral orchiectomy), 
performed at least 6 months before screening 


Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 23 of 66 
14. Throughout the study, the patient must use a condom if having sex with a pregnant 
woman.   
15. Must agree not to donate sperm from first dose of study drug through 3 months after the 
last dose of study drug.   
4.2 
Exclusion Criteria 
Each patient eligible to participate in this study must NOT meet any of the following 
exclusion criteria:   
1. Prior enzalutamide, abiraterone acetate, aminoglutethimide, ketoconazole, radium Ra 223 
dichloride or other bone-targeting radionuclides, or cytotoxic chemotherapy in the CRPC 
setting for the treatment of prostate cancer or participation in a clinical trial of an 
investigational agent that inhibits the androgen receptor or androgen synthesis (unless 
treatment was placebo).   
2. Treatment with hormonal therapy (eg, androgen receptor inhibitors, 5-alpha reductase 
inhibitors) or biologic therapy for prostate cancer (other than LHRH analogue therapy) 
within 4 weeks before day 1.   
3. Initiation of new treatment with denosumab, bisphosphonates, or systemic corticosteroids 
for treatment of prostate cancer within 4 weeks before day 1.   
4. Use of an investigational agent within 4 weeks before the screening visit.  
5. Radiation therapy to bone within 4 weeks before day 1.   
6. Use of opiate analgesics for prostate cancer pain within 4 weeks before day 1.   
7. History of another invasive cancer within 3 years before screening, with the exception of 
fully treated cancers with a remote probability of recurrence.  The medical monitor and 
investigator must agree that the possibility of recurrence is remote for exceptions.   
8. Screening 99mTc-MDP bone scintigraphy showing a superscan.   
9. Visceral (eg, lung, liver) metastatic disease (biopsy not necessary).  Adenopathy is 
allowed.   
10. Absolute neutrophil count < 1500/µL, platelet count < 100,000/µL, or hemoglobin 
< 6.2 mmol/L (< 10 g/dL) at screening.  Patients may not have received growth factors or 
blood transfusions within 7 days, inclusive, before obtaining the screening hematology 
values.   
11. Total bilirubin ≥ 1.5 times the upper limit of normal (ULN) (except patients with 
a diagnosis of Gilbert’s disease), or alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥ 2.5 times ULN at screening.   
12. Creatinine > 177 µmol/L (> 2 mg/dL) at screening.   
13. Albumin < 30 g/L (< 3.0 g/dL) at screening.   
14. Current or previously treated brain metastasis or active leptomeningeal disease.   
15. History of seizure any time in the past for any reason or any condition that may 
predispose to seizures.   
16. History of loss of consciousness or transient ischemic attack within 12 months before 
screening.   


Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 24 of 66 
17. Clinically significant cardiovascular disease, including the following: 
• 
Myocardial infarction within 6 months before screening 
• 
Unstable angina within 3 months before screening 
• 
New York Heart Association class III or IV congestive heart failure, or a history of 
New York Heart Association class III or IV congestive heart failure, unless a 
screening echocardiogram or multigated acquisition scan performed within 3 months 
before screening demonstrates a left ventricular ejection fraction ≥ 50% 
• 
History of clinically significant ventricular arrhythmias (eg, sustained ventricular 
tachycardia, ventricular fibrillation, torsades de pointes) 
• 
History of Mobitz II second-degree or third-degree heart block without a permanent 
pacemaker in place 
• 
Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening 
• 
Bradycardia as indicated by a heart rate < 45 beats per minute on the screening 
electrocardiogram (ECG) and physical examination 
• 
Uncontrolled hypertension as indicated by a systolic blood pressure > 170 mm Hg 
or a diastolic blood pressure > 105 mm Hg at screening 
18. Gastrointestinal disorder affecting absorption.   
19. Major surgery within 4 weeks before screening.   
20. Any concurrent disease, infection, or comorbid condition that interferes with the ability 
of the patient to participate in the trial; places the patient at undue risk; or complicates 
the interpretation of the data, in the opinion of the investigator or medical monitor.   
5 ENROLLMENT AND STUDY PROCEDURES 
Study enrollment and procedures are summarized in the following subsections.  The timing 
of all study procedures is also provided in the schedule of activities (Appendix 2).   
5.1 
Screening Period 
The screening period will be from day -28 through day -1.  Screening procedures are listed in 
Table 1.  Assessments not completed within the appropriate interval must be repeated.   
For the purposes of this study, there will be no day 0.   
5.1.1 
Study Identification Numbers 
After obtaining informed consent, study site personnel will assign a study identification (ID) 
number to a potential study participant.   
For patients who provide informed consent and subsequently do not meet eligibility criteria 
or withdraw consent, study site personnel should document the screen failure in the patient’s 
source documents.  The documentation should include demographics and medical history, 
the reason for screen failure, the eligibility criteria reviewed, and procedures performed.   


Medivation, Inc. 
Enzalutamide 
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5.1.2 
Screening Visit Procedures 
At the screening visit, study site personnel must explain to potential study participants all 
aspects of the study, including all scheduled visits and activities.  Study site personnel must 
obtain signed informed consent before any study-specific procedures are conducted, and 
must document the informed consent process in the patient’s source documents.  Informed 
consent may be obtained before the 28-day screening period.   
Screening procedures are listed in Table 1.  The investigator will assess and confirm the 
eligibility of each patient.  All screening procedure results and relevant medical history must 
be available before eligibility can be determined.  All inclusion criteria must be met and none 
of the exclusion criteria may apply.  No eligibility waivers will be granted.   
After a patient is screened and the investigator determines the patient is eligible, study site 
personnel will complete an Enrollment Authorization Form and fax or email it to the medical 
monitor or designee to approve the enrollment in writing.   
Table 1: Screening Procedures 
Activity / Assessment / Timing 
Comment 
General 
All screening procedures must be performed within the 28-day 
screening period (see below for informed consent).   
Informed consent 
Must obtain informed consent before performing any 
study-specific procedures.  May obtain before the 28-day 
screening period.   
Ensure consent is on the current version of the form approved by 
the IRB.   
Study ID  
Assign study ID number to patient. 
Medical history 
Review any time after obtaining informed consent.   
Eligibility criteria including BPI 
(Short Form) and ECOG 
performance status 
All inclusion criteria must be met and none of the exclusion 
criteria may apply per Section 4.   
Refer to Appendix 1 for BPI and Table 13 for ECOG.   
12-Lead ECG 
Obtain per local practice and read locally to confirm eligibility.   
Technetium Tc 99m 
medronate bone scintigraphy 
→ Perform within 28 days 
before day 1 
Whole-body radionuclide bone scintigraphy to establish the 
presence of bone metastatic disease; read locally.   
Send copy of image to the central imaging vendor for archiving. 
CT or MRI of chest, abdomen, 
and pelvis 
→ Perform within 28 days 
before day 1 
To establish the absence of visceral metastatic disease 
(adenopathy is allowed).   
Complete physical examination 
Measure vital signs (temperature, blood pressure, and heart rate), 
weight, and height.   
Assess systems per standard of care at the study site.   


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Activity / Assessment / Timing 
Comment 
Adverse event review 
Record adverse events (nonserious and serious) occurring during 
screening on the medical history case report form and in the 
patient’s source documents for any patient who subsequently 
meets eligibility criteria and proceeds to enrollment.  If the 
adverse event is serious, also record it on the adverse event case 
report form.   
Collect serious adverse event information from the time of signed 
informed consent and report it per Section 8.3.5.   
Concomitant medications review 
Record all ongoing medications and those discontinued within 
28 days before the visit.   
Enrollment Authorization Form 
Complete, sign, and fax or email the form to the medical monitor 
or designee at least 2 business days before the anticipated day 1 
visit, if possible.   
The patient may proceed to the day 1 visit when the medical 
monitor or designee approves by signed form or email 
correspondence.   
Local Laboratory Evaluations 
 
Serum chemistry, hematology 
Refer to analytes listed in Table 12.   
Testosterone 
 
PSA 
 
 
5.2 
Treatment Period 
Day 1 is the day of the first dose of study drug.  Patients will return to the study site at 
weeks 5, 13, 21, and every 8 weeks thereafter, unless study drug is permanently discontinued 
for reasons outlined in Section 5.3.   
5.2.1 
Visit Windows 
At each specified study visit, procedures will be performed according to the schedule of 
activities (Appendix 2).   
A study visit may be scheduled on any day within a specified study week.  For any given day 
within the study week, the visit window is ±7 days (ie, 7 days before or after the given day) 
except for weeks 5 and 13 (±3 days).  There is no visit window for week 1, day 1.   
Study drug supplies must be taken into account when scheduling visits during windows.  
Procedures for a given visit may be split across the window to allow for drug resupply and 
completion of study procedures.   


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Enzalutamide 
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08 DEC 2016 – FINAL 
 
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5.2.2 
Week 1, Day 1 
Day 1 procedures are listed in Table 2.  Study site personnel should ensure that a medical 
monitor-approved Enrollment Authorization Form is in the patient’s file before proceeding 
with day 1 procedures.   
Table 2: Week 1, Day 1 Procedures 
Activity / Assessment  
Comment 
General Activities 
 
Complete physical examination 
May skip if performed within prior 3 days.   
Measure vital signs (temperature, blood pressure, and heart rate), 
and weight.   
ECOG performance status (Table 13).   
Assess systems per standard of care at the study site.   
Adverse events review 
Record adverse events that occurred during screening on the 
medical history case report form and in the patient’s source 
documents.  Do not record such events on the adverse event case 
report form.   
Concomitant medications review 
Record any new medications or changes in ongoing medications.   
Enzalutamide dispensing 
 
Provide the patient with a 12-week supply.  Provide instructions 
for dosing, storage, and return of all bottles (used and unused) of 
study drug at future visits.   
Local Laboratory Evaluations 
 
Serum chemistry, hematology 
May skip if performed within prior 3 days.   
Refer to analytes listed in Table 12.   
PSA 
 
Central Laboratory/Imaging 
Evaluations 
Refer to laboratory and imaging instruction manuals for sample 
processing and imaging acquisition requirements.   
Circulating tumor cells 
Collect blood sample predose and process per laboratory manual 
instructions.   
18F-NaF PET/CT imaging (NaF-1) 
Perform predose. 
Must perform within 7 days before first dose of enzalutamide.   
Perform a second baseline scan on up to 5 patients at each study 
site to assess reproducibility. 
 
5.2.3 
Week 5 
The visit window is ±3 days.  Drug supply must be taken into account if a window is used 
to schedule the next visit.   
Week 5 procedures are listed in Table 3.   


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Enzalutamide 
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08 DEC 2016 – FINAL 
 
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Table 3: Week 5 Procedures 
Activity / Assessment  
Comment 
General Activities 
 
Brief physical examination 
Measure vital signs (temperature, blood pressure, and heart rate), 
weight, and ECOG performance status (Table 13).   
Perform symptom-directed examination and investigate any new 
abnormalities.   
Adverse events review 
Record any new or ongoing adverse events.   
Concomitant medications review 
Record any new medications or changes in ongoing medications.   
Study drug accountability 
Record study drug returned and remind patient to return all 
bottles (used and unused) at each future visit.   
Local Laboratory Evaluations 
 
Serum chemistry, hematology 
Refer to analytes listed in Table 12.   
 
5.2.4 
Week 13 
The visit window is ±3 days.  Drug supply must be taken into account if a window is used 
to schedule the next visit.   
Week 13 procedures are listed in Table 4.   


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Table 4: Week 13 Procedures 
Activity / Assessment  
Comment 
General Activities 
 
Brief physical examination 
Measure vital signs (temperature, blood pressure, and heart rate), 
weight, and ECOG performance status (Table 13).   
Perform symptom-directed examination and investigate any new 
abnormalities.   
Adverse events review 
Record any new or ongoing adverse events.   
Concomitant medications review 
Record any new medications or changes in ongoing medications.   
Enzalutamide dispensing (if 
applicable) 
As appropriate according to PSA value.  Per PSA assessment 
below, patients with PSA values increased from baseline may 
discontinue study drug and have safety follow-up unless the 
investigator considers continuation of study drug to be beneficial.   
Provide the patient with an 8-week supply.  Provide instructions 
for dosing, storage, and return of all bottles (used and unused) of 
study drug at future visits.   
Study drug accountability  
Record study drug returned and remind patient to return all 
bottles (used and unused) at each future visit.   
Local Laboratory Evaluations 
 
Serum chemistry, hematology 
Refer to analytes listed in Table 12.   
PSA 
Patients with PSA values increased from baseline may 
discontinue study drug and have safety follow-up unless the 
investigator considers continuation of study drug to be beneficial.   
Imaging Evaluations 
Refer to imaging instruction manual for imaging acquisition 
requirements.   
18F-NaF PET/CT imaging (NaF-2) 
 
 
5.2.5 
Week 21 and Repeating Every 8 Weeks 
Visits repeat every 8 weeks (± 7 days) until criteria are met for permanent treatment 
discontinuation (Section 5.3).  Drug supply must be taken into account if a window is used 
to schedule the next visit.  Assessments are performed at every visit or every other visit as 
noted. 
Week 21 procedures are listed in Table 5.   


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Table 5: Week 21 and Repeating Every 8 Weeks Procedures 
Activity / Assessment / Timing 
Comment 
General Activities 
 
Brief physical examination 
→ Perform every 16 weeks 
(± 7 days) 
Measure vital signs (temperature, blood pressure, and heart rate), 
weight, and ECOG performance status (Table 13).   
Perform symptom-directed examination and investigate any new 
abnormalities.   
Adverse events review 
Record any new or ongoing adverse events.   
Concomitant medications review 
Record any new medications or changes in ongoing medications.   
Enzalutamide dispensing 
(if applicable) 
Provide the patient with an 8-week supply.  Provide instructions 
for dosing, storage, and return of all bottles (used and unused) of 
study drug at future visits.   
Study drug accountability  
Record study drug returned and remind patient to return all bottles 
(used and unused) at each future visit.   
Local Laboratory Evaluations 
 
Serum chemistry, hematology 
→ Perform every 16 weeks 
(± 7 days) 
Refer to analytes listed in Table 12.   
PSA 
 
 
5.2.6 
Time of Third 18F-NaF PET/CT Imaging (NaF-3) 
Patients with disease progression (Section 9.1.1.2) and those without progression at 2 years 
after treatment initiation will have a third 18F-NaF PET/CT imaging and other assessments.   
No 99mTc-MDP bone scintigraphy is required if bone disease progression was confirmed 
previously on bone scintigraphy obtained at investigator discretion.  If no bone disease 
progression was seen by 99mTc-MDP bone scintigraphy before NaF-3, 99mTc-MDP bone 
scintigraphy will be required at the time of NaF-3.   
The procedures are listed in Table 6.   


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Enzalutamide 
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Table 6: Time of Third 18F-NaF PET/CT Imaging (NaF-3) 
Activity / Assessment 
Comment 
Central Laboratory/Imaging 
Evaluations 
Refer to laboratory and imaging instruction manuals for sample 
processing and imaging acquisition requirements.   
Circulating tumor cells 
Collect and process blood sample per laboratory manual 
instructions.   
18F-NaF PET/CT imaging (NaF-3) 
Perform at the time of disease progression defined in 
Section 9.1.1.2 and briefly, as follows: 
• PSA progression (increase of at least 25% and an absolute 
increase of at least 2.0 ng/mL above nadir), 
• Radiographic progression (bone or soft tissue), or  
• Other clinically relevant progression.  
Or perform at 2 years after initiation of treatment for patients 
without progression.   
99mTc-MDP bone scintigraphy 
Whole-body radionuclide bone scintigraphy.   
Send copy of image to the central imaging vendor for archiving.  
Not required if bone disease progression was confirmed earlier 
on bone scintigraphy ordered by the investigator.  If no bone 
disease progression was seen by 99mTc-MDP bone scintigraphy 
before NaF-3, 99mTc-MDP bone scintigraphy will be required at 
the time of NaF-3.   
CT or MRI of chest, abdomen, and 
pelvis 
Perform for suspicion of soft tissue disease progression (at 
investigator discretion). 
Local Laboratory Evaluations 
 
PSA 
 
 
5.2.7 
Unscheduled Visits 
Unscheduled visits may be performed any time to assess or follow up adverse events, to 
perform bone scintigraphy, at the patient’s request, or at the investigator’s request.  The date 
and reason for the unscheduled visit must be recorded in the source documents.   
If an unscheduled visit is necessary to assess toxicity or for suspected disease progression, 
then diagnostic tests may be performed based on investigator assessment as appropriate.   
Unscheduled visit procedures are listed in Table 7.   


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Table 7: Unscheduled Visit Procedures 
Activity / Assessment 
Comment 
General Activities  
Perform as needed 
Brief physical examination 
Measure vital signs (temperature, blood pressure, and heart rate), 
weight, and ECOG performance status (Table 13).   
Perform symptom-directed examination and investigate any new 
abnormalities.   
Adverse events review 
Record any new or ongoing adverse events.   
Concomitant medications review 
Record any new medications or changes in ongoing medications.   
Local Laboratory Evaluations 
 
Serum chemistry, hematology 
Refer to analytes listed in Table 12.   
 
5.3 
Permanent Treatment Discontinuation 
Permanent treatment discontinuation is defined as cessation of study drug treatment 
administration.  Safety follow-up will be performed per Section 5.4.   
Temporary treatment interruption is not considered permanent discontinuation.  Regularly 
scheduled study visits will continue for patients based on their enrollment date when their 
treatment is interrupted any time and restarted.   
The reasons that require patients to permanently discontinue study drug treatment are as 
follows: 
• 
Adverse event or intercurrent illness:  Any intolerable adverse event that cannot be 
ameliorated by the use of adequate medical intervention or that in the opinion of the 
investigator or medical monitor would lead to undue risk if study treatment were 
continued.  Refer to Section 8.3.1.   
• 
Gross noncompliance with protocol:  The medical monitor or investigator may 
request permanent treatment discontinuation in the event of a major protocol 
deviation, lack of cooperation, or noncompliance.   
• 
Administration of prohibited concomitant therapy:  Refer to Section 7.2.  NOTE:  
Patients who discontinue due to administration of a prohibited concomitant therapy 
will remain in the study and complete safety follow-up assessments per Section 5.4.   
• 
Laboratory abnormality defined as follows, unless the cause is identified and 
satisfactorily addressed, and the abnormality subsequently improves:   
– Creatinine > 354 µmol/L (> 4.0 mg/dL) 
– AST, ALT, or total bilirubin > 5-times the ULN 
– Absolute neutrophil count ≤ 750/µL 
– Platelet count < 50,000/µL 
• 
Seizure:  Regardless of resolution of any identified etiology.   
• 
Death 


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• 
Loss to follow-up:  Refer to Section 5.5.   
• 
Sponsor discontinuation of study:  The sponsor reserves the right to terminate the 
study any time for any reason as described in Section 13.6.  The sponsor will 
terminate this study following completion of the study objectives, or earlier if deemed 
necessary.   
• 
Patient decision:  Patients may permanently discontinue study drug treatment any 
time for any reason.  Following permanent treatment discontinuation, patients should 
have protocol-required safety follow-up assessments approximately 30 days after the 
last dose of study drug or before initiation of cytotoxic chemotherapy, a lutamide 
(bicalutamide, nilutamide, or flutamide), or a new investigational therapy (whichever 
occurs first), unless the patient specifically declines further follow-up.  Study site 
personnel must document the patient’s decision in the source documents.  The most 
specific reason possible for treatment discontinuation should be recorded on the case 
report form.  “Withdrawal of consent” should be entered only as a last resort.   
5.4 
Safety Follow-Up 
All patients will have safety follow-up after permanent discontinuation of study drug 
(enzalutamide).  Safety follow-up should occur approximately 30 days after the last dose 
of study drug or before initiation of cytotoxic chemotherapy, a lutamide (bicalutamide, 
nilutamide, or flutamide), or a new investigational therapy, whichever occurs first.  In the 
event that one of these treatments is initiated before safety follow-up occurs (eg, a physician 
not associated with protocol MDV3100-18 initiates the treatment, and study site personnel 
are not aware of the treatment until afterward), safety follow-up should be scheduled as soon 
as possible.   
If treatment is discontinued due to an adverse event or serious adverse event, the event(s) 
must be followed up as described in Section 8.3.6.  For patients who refuse further clinic 
study visits, telephone contact should be attempted and documented to review for adverse 
events through approximately 30 days after the last dose of study drug or before initiation of 
cytotoxic chemotherapy, a lutamide (bicalutamide, nilutamide, or flutamide), or a new 
investigational therapy, whichever occurs first.  There is no long-term follow-up phase.   
Safety follow-up procedures are listed in Table 8.   


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Table 8: Safety Follow-Up Procedures 
Activity / Assessment  
Comment 
General Activities 
 
Complete physical examination 
Measure vital signs (temperature, blood pressure, heart rate) and 
weight.   
ECOG performance status (Table 13).   
Assess systems per standard of care at the study site.   
Adverse events review 
Record any new or ongoing adverse events. 
Concomitant medications review 
Record any new medications or changes in ongoing medications. 
Study drug accountability  
Collect all remaining study drug and record study drug returned.   
Local Laboratory Evaluations 
 
Serum chemistry, hematology 
Refer to analytes listed in Table 12.   
PSA 
 
 
5.5 
Loss to Follow-Up 
Every reasonable effort should be made to contact any patient apparently lost to follow-up 
during the course of the study to complete study-related assessments, record outstanding 
data, and retrieve study drug.   
Following unsuccessful telephone contact, an effort to contact the patient by mail using 
a method that provides proof of receipt should be attempted.  Alternate contacts are 
permissible if the patient is not reachable (eg, primary care providers, referring physician, 
relatives).  Such efforts should be documented in the patient’s source documents.   
If all efforts fail to establish contact, the patient will be considered lost to follow-up.   
6 INVESTIGATIONAL PRODUCT INFORMATION 
6.1 
General Information 
The study drug is enzalutamide.  Enzalutamide (Xtandi) is approved in the US and other 
regions to treat men with metastatic CRPC who have previously received docetaxel.   
The sponsor will provide enzalutamide capsules.  Patients who did not have a bilateral 
orchiectomy will receive LHRH analogue therapy per standard of care.   
6.2 
Enzalutamide Product Characteristics 
Enzalutamide, also known as MDV3100, has the chemical name 4-{3-[4-cyano-3-
(trifluoromethyl) phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-
methylbenzamide.  The drug substance is formulated in the surfactant caprylocaproyl 
polyoxylglycerides, or Labrasol.  The product will be supplied as white to off-white gelatin 


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capsules containing 40 mg of enzalutamide.9  The chemical properties and list of excipients 
are presented in the investigator brochure.   
6.2.1 
Packaging of Enzalutamide 
Enzalutamide study drug is packaged in bottles with induction-sealed child-resistant caps 
labeled with the study protocol number, contents, directions for use, storage directions, 
clinical trial statement, and sponsor name.   
6.2.2 
Storage of Enzalutamide 
Enzalutamide study drug should be handled and stored safely and properly in accordance 
with the study drug label.   
6.2.3 
Directions for Administration of Enzalutamide 
The daily dose of enzalutamide is 160 mg/day given in 4 capsules (40 mg each) by mouth.   
Patients should self-administer enzalutamide by mouth once daily, with or without food.  
The capsules should be swallowed whole without chewing, dissolving, or opening them.   
Patients should not make up missed or vomited doses; dosing should resume on the next 
calendar day unless otherwise instructed.   
6.2.4 
Directions for Dose Modification of Enzalutamide 
Patients who experience a grade 3 or higher toxicity that is attributed to enzalutamide and 
cannot be ameliorated by the use of appropriate medical intervention may interrupt treatment 
with enzalutamide for 1 week or until the toxicity grade improves to grade 2 or lower 
severity.  Following consultation with the medical monitor, study drug dosing may be 
restarted at the original dose (160 mg/day) or a reduced dose (80 or 120 mg/day).   
If enzalutamide is coadministered with a strong CYP2C8 inhibitor, the dose of enzalutamide 
should be reduced to 80 mg once daily.  If coadministration of the strong CYP2C8 inhibitor 
is discontinued, the enzalutamide dose should return to the dose used before initiation of the 
strong CYP2C8 inhibitor.   
6.3 
Treatment Compliance 
Accountability for the study drug capsules (enzalutamide) will be performed to document 
compliance with the dosing regimens.  Patients will be asked to bring all used and unused 
study drug bottles to study visits.  Study site personnel must make reasonable efforts to 
obtain used and unused study drug bottles from patients who do not routinely return them at 
study site visits.   
Unreturned capsules will be considered to have been taken.   


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7 PRIOR AND CONCOMITANT THERAPY 
Prior and concomitant medications include all vitamins, herbal remedies, and 
over-the-counter and prescription medications.   
7.1 
Prior Therapy 
Medications taken within 4 weeks before screening and any medications prescribed for 
chronic or intermittent use during the study, or dose adjustments of these medications, must 
be recorded on the case report form and in the patient’s source documents.  The dosage and 
regimen of any chronic permitted concomitant medications should be stable during the 
screening period (≥ 28 days before enrollment) and held constant throughout the study.   
Certain prior medications and therapies for prostate cancer are prohibited.  These include 
enzalutamide, abiraterone acetate, aminoglutethimide, ketoconazole, radium Ra 223 
dichloride or other bone-targeting radionuclides, or cytotoxic chemotherapy in the CRPC 
setting.  Patients who participated in a clinical study of an investigational agent that inhibits 
the androgen receptor or androgen synthesis are also excluded, unless treatment was placebo.   
Investigational agents are prohibited within 4 weeks before the screening visit.   
The following agents are prohibited within 4 weeks (28 days) before day 1:  hormonal 
therapy (eg, androgen receptor inhibitors, 5-alpha reductase inhibitors), biologic therapy for 
prostate cancer (other than LHRH analogue therapy), and opiate analgesics for prostate 
cancer pain.  However, these agents may be washed out (ie, discontinued for 4 weeks) to 
qualify for the study if all other eligibility criteria are met.  Bone radiation therapy to treat 
prostate cancer is also prohibited within 4 weeks before day 1.   
New treatment with denosumab, bisphosphonates, or systemic corticosteroids for prostate 
cancer is prohibited within 4 weeks (28 days) before day 1.   
7.2 
Concomitant Therapy 
Concomitant medications (including LHRH analogue therapy) will be assessed at all clinic 
visits.  All concomitant medications, including analgesic medications and opiates (including 
opioid-containing medications), must be recorded on the appropriate case report form.  If the 
use of any medication during the study is due to an adverse event, the adverse event must be 
recorded on the adverse event case report form and in the patient’s source documents.   
Initiation of bisphosphonates or denosumab for any reason is prohibited following 
enrollment; however, treatment with these agents may continue if initiated at least 4 weeks 
before enrollment.  Standard of care supplementation with calcium and vitamin D is 
encouraged.   
The following are prohibited during this study before NaF-3:   
• 
Initiation of cytotoxic chemotherapy 


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• 
Radium Ra 223 dichloride or other bone-targeting radionuclide therapy 
• 
Other hormonal therapy, including but not limited to commercially available 
enzalutamide (Xtandi), abiraterone acetate, androgen receptor inhibitors, 5-alpha 
reductase inhibitors, or (if for prostate cancer) aminoglutethimide, ketoconazole, or 
systemic corticosteroids for prostate cancer 
• 
Biologic therapy (other than LHRH analogue therapy) 
• 
Radiation therapy to bone 
• 
Participation in another interventional clinical study of an investigational agent 
Another therapy may be used in combination with enzalutamide after NaF-3 with the 
approval of the investigator and sponsor, except for cytotoxic chemotherapy, antiandrogen 
therapy (eg, bicalutamide, nilutamide, or flutamide), or another investigational agent.  Study 
drug treatment must be permanently discontinued and patients will have safety follow-up 
before initiation of one of these prohibited treatments.   
The following treatments are allowed:   
• 
Blood transfusions and growth factor support per standard of care and institutional 
guidelines 
• 
Corticosteroids for indications other than prostate cancer 
• 
Pain therapy per standard of care and institutional guidelines 
Deviation from these guidelines should occur only if it is absolutely necessary for the 
well-being of the patient and does not jeopardize the analysis of the study endpoints, and 
must follow discussion and agreement between the investigator and the medical monitor, 
who will determine the patient’s suitability for continued treatment with study drug.   
7.3 
Potential Interactions Between the Test Products and Concomitant Medications 
7.3.1 
Enzalutamide 
7.3.1.1 
Effects of Enzalutamide on Exposure to Other Drugs 
Clinical data indicate that enzalutamide is a strong inducer of CYP3A4 and a moderate 
inducer of CYP2C9 and CYP2C19 (Section 1.2.1).  Concomitant use of enzalutamide with 
drugs with a narrow therapeutic index that are metabolized by CYP3A4 (eg, alfentanil, 
cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus), CYP2C9 (eg, phenytoin, warfarin), and CYP2C19 (eg, S-mephenytoin) should 
be avoided if possible as enzalutamide may decrease their exposure.  If coadministration with 
warfarin cannot be avoided, additional INR monitoring should be conducted at local 
laboratories.   


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7.3.1.2 
Drugs That May Affect Exposure to Enzalutamide 
7.3.1.2.1 
Drugs That Inhibit or Induce CYP2C8 
Coadministration of a strong CYP2C8 inhibitor (eg, gemfibrozil) increased the composite 
AUC0-∞ of enzalutamide plus its active metabolite in healthy volunteers by 2.2-fold 
(Section 1.2.1); therefore, coadministration of enzalutamide with strong CYP2C8 inhibitors 
should be avoided if possible.  If coadministration of enzalutamide with strong CYP2C8 
inhibitors cannot be avoided, the enzalutamide dose should be reduced to 80 mg once daily.  
If coadministration of the strong inhibitor is discontinued, the enzalutamide dose should be 
returned to the dose used before initiation of the strong CYP2C8 inhibitor.   
The effects of CYP2C8 inducers on the PK of enzalutamide have not been evaluated in vivo.  
Coadministration of enzalutamide with strong or moderate CYP2C8 inducers (eg, rifampin) 
may alter the plasma exposure of enzalutamide and should be avoided if possible.  Selection 
of a concomitant medication with no or minimal CYP2C8 induction potential is 
recommended.   
7.3.1.2.2 
Drugs That Induce CYP3A4 
The effects of CYP3A4 inducers on the PK of enzalutamide have not been evaluated in vivo.  
Coadministration of enzalutamide with strong CYP3A4 inducers (eg, carbamazepine, 
phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure 
of enzalutamide and should be avoided if possible.  Selection of a concomitant medication 
with no or minimal CYP3A4 induction potential is recommended.  Moderate 
CYP3A4 inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin) and 
St. John’s wort may also reduce the plasma exposure of enzalutamide and should be avoided 
if possible.   
7.4 
Precautions Regarding Concomitant Medications 
Refer to the following websites for updated lists of CYP inhibitors, inducers, and substrates: 
• 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ 
DrugInteractionsLabeling/ucm093664.htm#potency  
• 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx   
8 SAFETY CONSIDERATIONS 
Study assessments of safety include adverse events, clinical laboratory tests, physical 
examinations, and vital signs.   
In the following sections, the sponsor’s safety monitoring procedures are described 
(Section 8.1).  Adverse events are discussed in detail in the context of patient management, 
study drug dose modification, and safety reporting requirements, including follow-up 
procedures (Sections 8.2 and 8.3).  Clinical laboratory safety tests are presented 


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(Section 8.4).  The study procedures for physical examinations and vital signs are also 
provided (Section 8.5).   
8.1 
Safety Monitoring 
The sponsor will periodically monitor safety data during the clinical study in addition to 
reviewing individual safety case reports, by examining the incidence and severity of adverse 
events and serious adverse events, changes in laboratory results, and other data (such as 
aggregate analysis of data from other enzalutamide studies).  Any relevant safety concerns 
will be communicated to the investigators and regulatory agencies, as appropriate.   
8.2 
Special Safety Considerations 
8.2.1 
Study Drug Dose Modification Due to Adverse Event 
The instructions for modifying the dose of study drug due to an adverse event are provided 
in Section 6.2.4 for enzalutamide.   
8.2.2 
Overdose Management 
The medical monitor must be contacted in the event of a study drug overdose.   
An overdose is defined as any dose greater than the protocol-specified dose of enzalutamide 
160 mg once daily.  In the event of an overdose, treatment with study drug should be stopped 
and general supportive measures initiated, taking into consideration the half-life is 5.8 days 
for enzalutamide.  Patients may be at increased risk of seizures following an overdose of 
enzalutamide.  There is no known antidote to overdose.   
All overdose events are to be reported as events of special interest within 24 hours of 
awareness by the study site according to Section 8.3.5, whether or not the event meets 
adverse event criteria.   
8.2.3 
Contraception 
A patient must use a condom if having sex with a pregnant woman.  Patients must not donate 
sperm from first dose of study drug through 3 months after the last dose of study drug.   
A patient and his female partner of childbearing potential must use 2 acceptable methods of 
birth control (1 of which must include a condom as a barrier method) from screening through 
3 months after the last dose of study drug.  The 2 acceptable methods of birth control are as 
follows: 
1. A condom (barrier method is required) 
AND 
2. One of the following is required:   


Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 40 of 66 
• 
Established and ongoing use of oral, injected, or implanted hormonal method by the 
female partner 
• 
Placement of an intrauterine device or intrauterine system by the female partner 
• 
Additional barrier method including contraceptive sponge or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository 
by the female partner 
• 
Tubal ligation in the female partner performed at least 6 months before screening 
• 
Vasectomy or other procedure resulting in infertility (eg, bilateral orchiectomy) 
performed at least 6 months before screening 
8.3 
Adverse Event Definitions and Reporting 
8.3.1 
Adverse Event Definitions 
Definitions are provided in this section for adverse events, events of special interest, serious 
adverse events, treatment-emergent adverse events, suspected unexpected serious adverse 
reactions (SUSARs), and unexpected adverse events.   
Adverse events:  An adverse event is 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.   
Examples of adverse events include the following:   
• 
A change, excluding minor fluctuations, in the nature, severity, frequency, or 
duration of a pre-existing condition 
• 
Development of an intercurrent illness during the study 
• 
Development of symptoms that may or may not be related to the use of a concomitant 
medication or investigational product 
• 
Injury or accidents:  if a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as 2 separate 
medical events (eg, for a fall secondary to dizziness, both “dizziness” and “fall” 
should be recorded separately) 
• 
Investigational abnormalities (eg, laboratory parameters, vital signs, ECG data) 
should be defined as adverse events only if the abnormality meets one of the 
following criteria:   
– Induces clinical signs or symptoms 
– Needs active intervention 
– Needs interruption or discontinuation of study medication 
– Abnormality or investigational value is clinically significant in the opinion 
of the investigator 


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An adverse event does not include the following:   
• 
Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, 
transfusion); the condition that leads to the procedure is an adverse event 
• 
Pre-existing diseases or conditions present or detected before the start of study drug 
administration that do not worsen 
• 
Situations where an untoward medical event has not occurred (eg, planned 
hospitalization for an elective procedure as known at the time of informed consent) 
Events of special interest:  Adverse events of special interest are any events identified for 
intensive monitoring during the study.  For MDV3100-18, events of special interest include 
overdose (Section 8.2.2) and pregnancy in the partner (Section 8.3.7).   
Serious adverse events:  Any adverse event that meets any of the criteria in Table 9 as 
determined by the investigator or sponsor.   
Table 9: Criteria for Serious Adverse Events 
Criterion 
Comment 
Results in death 
Death is an outcome, not an adverse event.  The 
primary adverse event resulting in the death 
should be identified.   
Is life threatening (immediate risk of death from 
the adverse event as it occurred) 
Does not include an event that hypothetically 
might have caused death if it were more severe.   
Results in or prolongs an existing inpatient 
hospitalization 
For hospitalizations for surgical or diagnostic 
procedures, the illness leading to the surgical or 
diagnostic procedure will be identified as the 
serious adverse event (not the procedure).   
Results in persistent or significant incapacity or 
substantial disruption of the ability to conduct 
normal life functions 
Permanent or substantial disruption of a person’s 
ability to conduct normal life functions.   
Results in a congenital anomaly/birth defect 
 
Important medical events which jeopardize the 
subject and may require medical or surgical 
intervention to prevent one of the outcomes listed 
above 
Examples include drug-induced bronchospasm 
requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, and 
the development of drug dependency or drug 
abuse.   
Source:  US Code of Federal Regulations:  21 CFR 312.32 [75 FR 59961] 
 
Treatment-emergent adverse events:  Adverse events observed following administration of 
the study drug.   
Suspected unexpected serious adverse reactions (SUSARs):  Adverse events assessed as 
serious, related, and unexpected.   


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Page 42 of 66 
Unexpected adverse events:  Adverse events for which the nature or severity is not consistent 
with the reference safety information.   
8.3.2 
Adverse Event Reporting 
To elicit adverse event reports from patients, the study site personnel should question the 
patient in a general way without suggesting specific symptoms.   
All patients who experience an adverse event will be evaluated at appropriate time intervals 
until the event resolves or stabilizes.  At the conclusion of the study, the investigator and 
medical monitor will assess unresolved adverse events and determine if additional follow-up 
is warranted as described in Section 8.3.6.   
All adverse events, whether or not related to the study drug, must be fully and completely 
documented on the adverse event case report form and in the patient’s clinical record.  
In addition, any adverse event resulting in permanent treatment discontinuation must be 
recorded on the treatment discontinuation case report form as well as documented in the 
patient’s clinical record.  Adverse event terms should include a diagnosis or underlying 
cause, as available, in preference to listing the individual signs and symptoms.  If the 
diagnosis is not known, the investigator should record each sign and symptom as an 
individual adverse event.   
8.3.2.1 
Adverse Event Reporting Periods 
Collection and reporting of adverse event information will begin at the time the patient signs 
informed consent for serious adverse events and from the first dose of study drug for 
nonserious adverse events, and will continue through 30 days after the last dose of study drug 
treatment or before initiation of cytotoxic chemotherapy, a lutamide (bicalutamide, 
nilutamide, or flutamide), or a new investigational therapy, whichever occurs first.  
Additional reporting instructions for serious adverse events and events of special interest are 
provided in Section 8.3.5.   
All adverse events from the time of the first dose of any study drug treatment must be 
documented on the adverse event case report form and in the patient’s clinical record.  Any 
event occurring during screening must be documented on the medical history case report 
form and in the patient’s clinical record for any patient who subsequently meets eligibility 
criteria and proceeds to treatment.   
8.3.3 
Assessment of Causal Relationship 
The investigator will assess the relationship of an adverse event to study drug according to 
the criteria in Table 10 and document the relationship in the patient’s source documents.   
Adverse events considered in the relationship categories of “Possible” or “Probable” should 
be considered “adverse events whose relationship to the study drugs could not be ruled out.”   


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Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 43 of 66 
Table 10: Criteria for Determining Causal Relationship to Study Drug 
Relationship 
Criteria 
Not Related 
A clinical event, including laboratory test abnormality, with a temporal relationship 
to drug administration that makes a causal relationship improbable, and/or in which 
other drugs, chemicals, or underlying disease provide plausible explanations. 
Possible 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, but that could also be explained by 
concurrent disease or other drugs or chemicals.  Information on drug withdrawal 
may be lacking or unclear. 
Probable 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent 
disease or other drugs or chemicals, and that follows a clinically reasonable 
response on re-administration (rechallenge) or withdrawal (dechallenge). 
 
8.3.4 
Assessment of Severity (Intensity) 
Severity describes the intensity of a specific adverse event (mild, moderate, or severe).  The 
particular event may be of relatively minor medical significance (such as severe headache).  
Severity is not the same as “serious,” which is based on patient/event outcome or action 
criteria.   
Investigators will grade the severity of adverse events according to the National Cancer 
Institute Cancer Therapy and Evaluation Program Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.  For terms not specified within the CTCAE, the criteria 
in Table 11 should be used to determine grade.   
Adverse event severity should be recorded in the appropriate section of the adverse event 
case report form and in the patient’s source documents.   
Table 11: Criteria for Determining the Severity (Intensity) of an Adverse Event 
Grade 
Intensity or Severity 
Clinical Description 
1 
Mild 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations only; intervention not indicated 
2 
Moderate 
Minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
3 
Severe or medically 
significant 
Not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care activities of 
daily living 
4 
Life-threatening  
Life-threatening consequences; urgent intervention indicated 
5 
Death 
Death related to adverse event 
Source:  Common Terminology Criteria for Adverse Events v4.0 
 


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08 DEC 2016 – FINAL 
 
Page 45 of 66 
8.3.5.2 
Clarification in Reporting of Deaths 
Death is not an adverse event but is an outcome of an adverse event.  For this protocol, 
reports of death without an adverse event will be managed as expedited reports (SUSARs) 
until the sponsor receives additional information.   
8.3.5.3 
Clarification in Reporting of Disease Progression as an Adverse Event 
Disease progression is not unexpected in this study population and the term “disease 
progression” should not be reported as an adverse event unless a more specific clinical term 
is not defined or available.  When clinical disease progression is identified, the clinical event 
that identifies the disease progression, if known, should be reported as the adverse event.   
8.3.6 
Follow-Up of Serious and Nonserious Adverse Events 
All adverse events reported during the study should be followed at appropriate intervals until 
resolution, or until the event has stabilized, reached a new baseline, or (if enzalutamide is 
discontinued) a new antineoplastic treatment is initiated (all follow-up results are to be 
reported to the sponsor or designee).   
Adverse events that remain unresolved at the conclusion of the study may continue to be 
monitored if warranted based on clinical assessment by the investigator and medical monitor.   
Patients should be contacted by phone and written requests as appropriate for adverse event 
follow-up if they do not come to the clinic for safety follow-up as specified in Section 5.4.   
8.3.7 
Pregnancy Reporting Procedure 
If a study participant impregnates his partner following the first dose of study drug through 
3 months after permanent discontinuation of study drug treatment, the study participant 
should report the pregnancy to the investigator.  The investigator will report the pregnancy to 
the sponsor in the same timeframe as a serious adverse event (Section 8.3.5).  The sponsor 
will provide forms to the investigator for use in reporting.  The expected date of delivery or 
expected date of the end of the pregnancy, last menstruation, estimated conception date, 
pregnancy result, and neonatal data, etc, should be included in this information.   
The investigator will follow the medical status of the mother, as well as the fetus, and will 
report the outcome to the sponsor.   
8.4 
Clinical Laboratory Safety Tests 
Routine clinical laboratory safety tests (hematology, serum chemistry) will be performed 
according to the schedule of activities (Appendix 2), as will PSA and testosterone tests.  
Samples will be stored until the specified analyses are completed and then they will be 
destroyed in accordance with standard laboratory practice and applicable local regulations.   


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Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 46 of 66 
A list of the required routine clinical laboratory safety tests is provided in Table 12.  All 
samples for laboratory analysis must be collected, prepared, labeled, and shipped according 
to laboratory requirements.   
All clinical laboratory safety tests will be performed by the local laboratory specified in 
Form FDA 1572 Section 4.  The local laboratory reference ranges will be used.  Eligibility 
at screening will be based on local laboratory assessments.   
A different clinical laboratory may be used for unscheduled visits or for urgent care.  Such 
laboratory data will not be entered into the study database and these local laboratories will 
not be included on the FDA 1572 form.   
Table 12: Clinical Laboratory Safety Tests 
Hematology 
Chemistry 
Hematocrit  
Hemoglobin 
Mean corpuscular volume 
Platelet count 
Red blood cell count 
White blood cell count with differential 
Albumin  
Alkaline phosphatase  
ALT (alanine aminotransferase) 
AST (aspartate aminotransferase) 
Blood urea nitrogen and creatinine 
Ca++ 
Creatine phosphokinase 
Glucose  
Lactate dehydrogenase 
Magnesium, phosphate 
Na+, K+, total CO2 (bicarbonate), Cl- 
Total bilirubin 
Total protein 
 
8.5 
Physical Examinations, Vital Signs, and Electrocardiograms 
The investigator will perform complete or brief physical examinations according to the 
schedule of activities (Appendix 2).   
Complete physical examinations will be per standard care at the study site and may include 
dermatologic, cardiac, respiratory, lymphatic, gastrointestinal, musculoskeletal, and 
neurologic systems, and other systems if clinically indicated by symptoms.  Weight will be 
measured as part of the examination.  Height will be measured only at screening.   
Brief physical examinations will be directed toward patient-reported symptoms and include 
investigating any new abnormalities.  Weight will be measured as part of the examination.   
Vital sign measurements will include temperature, blood pressure, and heart rate.   
Standard 12-lead ECGs will be obtained and read locally for study eligibility purposes.   


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Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 47 of 66 
9 ASSESSMENT OF EFFICACY AND SAFETY ENDPOINTS 
9.1 
Assessment of Efficacy 
9.1.1 
Assessments for the Primary and Secondary Efficacy Endpoints 
The assessment for the primary and secondary efficacy endpoints will include 
18F-NaF PET/CT imaging and assessment of disease progression.   
9.1.1.1 
18F-NaF PET/CT Imaging 
18F-NaF PET/CT imaging will be performed during the study as follows:   
• 
NaF-1: Following screening, within 7 days before first dose 
• 
NaF-2:  At week 13 
• 
NaF-3: At the time of PSA, radiographic (bone or soft tissue), or other clinically 
 
relevant progression, or at 2 years without progression after treatment 
 
initiation 
Up to 5 patients at each study site will have a second baseline scan to assess reproducibility 
of the scans at each study site.   
18F-NaF PET/CT imaging will be performed according to the procedures detailed in the 
imaging instruction manual and interpreted at the central imaging vendor.   
9.1.1.2 
Assessment of Disease Progression 
The assessment of disease progression will include PSA, radiographic (bone and soft tissue), 
and other clinically relevant events as follows: 
PSA progression triggering NaF-3 will be defined as an increase of at least 25% AND an 
absolute increase of at least 2.0 ng/mL above nadir.   
Bone disease progression will be defined as the appearance of at least 2 new lesions after 
screening assessed by 99mTc-MDP bone scintigraphy.  Progression at week 13 or earlier will 
require a confirmatory 99mTc-MDP bone scintigraphy at least 6 weeks later showing at least 
2 additional new lesions related to prostate cancer (compared with the previous scan).  After 
week 13, no confirmation of progression will be required if at least 2 new lesions related to 
prostate cancer are observed.   
Soft tissue disease will be assessed by CT or MRI obtained at investigator discretion.  
Radiographic progression for soft tissue disease will be defined by RECIST 1.1.7   
Other clinically relevant events of progression will be determined by the investigator and 
may include, but are not limited to, significant bone pain or skeletal-related events.   


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Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 50 of 66 
Table 14: Definition of Terms for NaF Uptake Measures 
Term 
Definition 
SUVtotal 
Total NaF uptake, which represents the tumor burden across all (global) bone lesions or 
in individual lesions reflecting bone-metastatic prostate cancer 
SUVhetero 
Heterogeneity of NaF uptake, which represents heterogeneity of lesion activity 
SUVmean 
Mean NaF uptake, which represents the average activity of all lesions 
SUVmax 
Maximum NaF uptake, which represents the activity of the most aggressive lesion 
N 
Total number of lesions, which represents a numerical sum of all lesions 
VF 
Volume fraction, which represents the fraction of skeletal involvement 
 
10.3.1 Primary Efficacy Endpoint Analysis 
The primary efficacy endpoint is the proportion of patients with at least 1 responding bone 
lesion (defined as a lesion with an SUVtotal less than at baseline) on the third 
18F-NaF PET/CT scan (NaF-3) performed for each patient.  This assessment will be triggered 
by any of the following events:   
• 
PSA progression (an increase of at least 25% AND an absolute increase of at least 
2.0 ng/mL above nadir) 
• 
Bone disease progression (the appearance of at least 2 new lesions after screening 
assessed by 99mTc-MDP bone scintigraphy) 
• 
Soft tissue disease progression defined by RECIST 1.17 
• 
Clinically relevant progression (eg, significant bone pain or a skeletal-related event) 
• 
At 2 years without progression after treatment initiation 
10.3.2 Secondary Efficacy Endpoint Analysis 
The secondary efficacy endpoint is the heterogeneity of response across all bone lesions as 
determined by the global SUVhetero at the time the primary endpoint is determined for each 
patient.  The global SUVhetero score is a measure of the heterogeneity of tumor activity across 
all bone lesions and is defined as follows, where g = global, l = lesion, N = number of bone 
lesions.   
 
In other words, the global SUVhetero score is the sum of the squares of the differences 
between the SUVmean for each bone lesion and the global SUVmean, divided by the number 
of lesions.  Thus, a higher global SUVhetero score reflects more heterogeneity in bone lesion 
activity.   


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Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 53 of 66 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and tabulated by system organ class and by preferred term within each system 
organ class.  Tabular summaries will include the incidence overall (number and percentage 
of patients with treatment-emergent adverse events classified by system organ class and 
preferred term); incidence by intensity (severity graded according to the CTCAE, version 4), 
causality, seriousness, and outcome (eg, leading to discontinuation of study drug); and other 
presentations as appropriate.   
Serious adverse events occurring before study treatment will be tabulated separately if 
considered related to study procedure.   
Patients with the same adverse event reported more than once will be counted once at the 
maximum severity or strongest relationship to study drug.   
Toxicity for laboratory parameters (hematology, serum chemistry) will be graded using the 
CTCAE, version 4 when applicable.  Shift tables will be provided as appropriate for each 
parameter to summarize baseline toxicity grade versus postbaseline toxicity grade.  For each 
laboratory parameter that is not gradable by the CTCAE, a shift table based on the normal 
range (low, normal, and high) will be provided to summarize baseline result versus 
postbaseline result.  For each laboratory parameter, the baseline laboratory value is defined 
as the last laboratory value collected on or before the date of the first dose of study drug.   
10.5 Other Analyses 
Exposure:  The dose and cumulative dose of enzalutamide (mg) will be summarized with 
descriptive statistics:  n, mean, standard deviation, median, and range.   
Treatment compliance:  Will be measured by the number of capsules taken during the entire 
study divided by the expected number of capsules, multiplied by 100%.   
10.6 Determination of Sample Size 
The total number of patients to be included in this study is approximately 20 and is based on 
practical clinical considerations.   
11 STUDY COMMITTEES AND COMMUNICATIONS 
No formal study committees are planned for this study.   
12 LABORATORY REQUIREMENTS 
Clinical laboratory safety samples (hematology, serum chemistry) will be analyzed locally as 
described in Section 8.4, as will the samples for testosterone (screening only) and PSA for 
this study.  These samples should be collected according to local laboratory requirements.   


Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 54 of 66 
13 INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS 
Before initiating the study, the investigator must provide the following documents to the 
sponsor: 
• 
Fully executed and signed Form FDA 1572 
• 
Fully executed clinical trial agreement 
• 
Current curriculum vitae (also applies to all subinvestigators listed on the 
Form FDA 1572) 
• 
Financial disclosure (also applies to all subinvestigators listed on the 
Form FDA 1572) 
• 
Signed protocol signature page 
• 
Signed acknowledgment of receipt of the current Enzalutamide Investigator Brochure 
• 
Institutional review board (IRB) approval letter 
• 
IRB-approved informed consent form 
• 
Additional documents as necessary per local requirements 
If an investigator changes during the course of the study, the sponsor and any local regulatory 
authorities, as applicable, must first approve the change of investigator and the new 
investigator must provide the sponsor all of the documents listed above.   
The sponsor personnel or representatives may visit the study site, if necessary, before 
initiation of the study to review information with study site personnel about protocol 
requirements pertaining to the study drug, case report forms, monitoring, serious adverse 
event reporting, and other relevant information.   
13.1 Ethics 
13.1.1 Institutional Review Board 
Before initiating the study, the investigator will obtain confirmation from the IRB that the 
IRB is properly constituted and compliant with all requirements and local regulations.   
The investigator will provide the IRB with all appropriate material, such as the protocol, 
current Enzalutamide Investigator Brochure, site-specific informed consent form, and other 
written information provided to the patients.  The study will not be initiated until the 
investigator obtains appropriate IRB approval in writing for the protocol and informed 
consent document, and copies are received by the sponsor.   
IRB approval will be obtained for any substantial protocol amendments and informed 
consent revisions before implementing the changes.  The investigator will provide 
appropriate reports on the progress of the study to the IRB, per local requirements, and 
to the sponsor or designee in accordance with applicable local regulations.   


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Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 55 of 66 
13.1.2 Ethical Conduct of the Study 
This study will be conducted under the guiding principles of the World Medical Association 
Declaration of Helsinki, including current Good Clinical Practice (GCP) according to 
International Council for Harmonisation (ICH) guidelines.  Specifically, this study is based 
on adequately performed laboratory and animal experimentation; the study will be conducted 
under a protocol reviewed and approved by an IRB; the study will be conducted by 
scientifically and medically qualified persons; the anticipated benefits of the study are in 
proportion to the risks; the rights and welfare of the patients will be respected; the physicians 
conducting the study do not find the hazards to outweigh the potential benefits; and each 
patient will provide written informed consent before any protocol-specific tests or 
evaluations are performed.   
13.1.3 Patient Information and Informed Consent 
A properly executed, written informed consent, in compliance with the Declaration of 
Helsinki, ICH GCP, US Code of Federal Regulations (CFR) for Protection of Human 
Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), and local 
regulations, will be obtained from each patient before entering the patient in the trial.  The 
investigator or designee will prepare the informed consent form and provide the documents 
to the sponsor or designee for approval before submission to the IRB.  The sponsor and the 
IRB must approve the documents before the investigator implements them.   
The investigator will provide copies of the signed informed consent form to each patient and 
will maintain the signed original document within the patient’s clinical record per local 
requirements.  The investigator will also fully document the informed consent process in the 
patient’s source documents.   
13.1.4 Maintaining Patient Confidentiality 
All reports and patient samples will be identified only by a study ID number and actual 
initials (if permitted) or mock initials and date of birth (month/year only if no date is 
permitted) in order to maintain patient confidentiality.  Additional patient confidentiality 
issues are addressed in the clinical trial agreement and in the informed consent form signed 
by each study participant.   
13.2 Data Quality Assurance 
13.2.1 Data Management 
Clinical data management will be performed by the sponsor or designee according to 
procedures described in a comprehensive data management plan.  The data management plan 
will include procedures for processing the data from this study, and will describe the 
responsibilities of the sponsor and designee when clinical data management is provided by 
an external vendor.  In particular, the data management plan will include a list of the standard 
operating procedures that apply to this study.   


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Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 56 of 66 
Adverse events and medications will be coded using MedDRA and the World Health 
Organization Drug Dictionary (WHO-DD), respectively.  The dictionary versions will 
be named in the data management plan.   
13.2.2 Case Report Forms 
The study will use an electronic data capture system.  All electronic case report forms will 
be designed and provided electronically to the site by the sponsor or designee and electronic 
data capture system vendor.  All case report form books are to be filled out completely, 
reviewed, and signed by the investigator or subinvestigators listed on the Form FDA 1572 or 
other appropriate local health authority documents.   
13.2.3 Study Monitoring 
The sponsor or designee will monitor this study in accordance with current GCP guidelines.  
By signing this protocol, the investigator grants permission to the sponsor or designee and 
appropriate regulatory authorities to conduct onsite monitoring of all appropriate study 
documentation.  To ensure the accuracy of data collected on the case report forms, it is 
mandatory that sponsor representatives (eg, study monitor) have direct access to original 
source documents (eg, paper or electronic patient records, patient charts, and laboratory 
reports) needed to verify the entries on case report forms.  During the review of these 
documents, the anonymity of the patient will be respected with strict adherence to 
professional standards of confidentiality.   
A study monitor will contact and visit the site regularly and will be allowed, on request at 
a mutually acceptable time, to inspect the various original medical records (paper or 
electronic) related to the study.  The study monitor will be responsible for inspecting the case 
report forms at regular intervals throughout the study, to verify the adherence to the protocol 
and the completeness and correctness of all case report form entries.  The investigator agrees 
to cooperate with the study monitor to ensure that any problems detected in the course of 
these monitoring visits are resolved.   
13.2.4 Study Audits 
During the course of the study and after study completion, it is likely that one or more quality 
assurance audits will be undertaken by authorized sponsor representatives.  The purpose of 
the audit is to ensure that the study is (or was) conducted and monitored in compliance with 
the protocol as well as recognized GCP guidelines and regulations.  These audits will also 
increase the likelihood that the study data and all other study documentation can withstand 
a regulatory authority inspection.  If such audits are to occur, they will be arranged for 
a reasonable and agreed upon time.  By signing this protocol, the investigator grants 
permission to the sponsor or designee to conduct onsite audits of all appropriate facilities and 
study documentation.   


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Page 57 of 66 
13.3 Investigational Product Accountability 
The investigator must maintain accurate records (including dates, quantities, and bottle 
identification numbers) of all study drug supplies received.  All records must be made 
available to the sponsor, authorized representatives, and appropriate regulatory agencies, 
upon request.   
Current ICH GCP guidelines require the investigator to ensure that study drug deliveries 
from the sponsor are received by a responsible person (eg, pharmacist), and the following: 
• 
That such deliveries are recorded, for example, on the sponsor’s drug accountability 
log or other sponsor-approved pharmacy log 
• 
That study drug is handled and stored safely and properly in accordance with the label 
and the study protocol 
• 
That study drug is only dispensed to study patients in accordance with the protocol 
• 
That any used or unused drug is returned by the patient at each required visit 
• 
That any unused study drug is returned to the sponsor-designated facility or standard 
procedures for the alternative disposition of unused study drug are followed and only 
after approval by the sponsor representative 
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/pharmacist.  Study drug accountability throughout the study must be 
documented.  The following guidelines are therefore pertinent:   
• 
The investigator agrees not to supply study drug to any persons except the patients 
in this study.   
• 
The investigator/pharmacist will keep the study drugs in a pharmacy or other locked 
and secure storage facility under controlled storage conditions as required by the 
study drug label, accessible only to those authorized by the investigator to dispense 
these study drugs.   
• 
The investigator/pharmacist will maintain a study drug inventory.  The inventory will 
include details of material received and a clear record of when they were dispensed 
and to which patient.   
• 
The investigator/pharmacist agrees to conduct a final drug supply inventory and to 
record the results of this inventory on the drug accountability record at the conclusion 
or termination of this study.  It must be possible to reconcile delivery records with 
those of used and returned study drug.  Any discrepancies must be accounted for.  
Appropriate forms of deliveries and returns must be signed by the person responsible.   
• 
Used or unused study drug may be destroyed at the study site according to standard 
institutional procedures if the sponsor agrees with the procedure, and after drug 
accountability has been conducted by the sponsor or representative, unless otherwise 
approved.  A copy of the standard institutional procedure for destroying 
investigational drugs will be provided to the sponsor or designee upon request for 
review and approval before the first onsite destruction.  Unused study drug not 


Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
 
Page 58 of 66 
destroyed at the site must be returned to the sponsor-designated facility at the end 
of the study or upon expiration.   
13.4 Compensation, Insurance, and Indemnity 
In the event of a side effect or injury, appropriate medical care as determined by the 
investigator or designated alternate will be provided.   
If bodily injury is sustained, resulting directly from the use of the study drug or by required 
study procedures, the sponsor will reimburse for reasonable physician fees and medical 
expenses necessary for treatment of only the bodily injury that is not covered by the patient’s 
medical or hospital insurance, provided that the injury is not due to a negligent or wrongful 
act or omission by the study doctor and study staff.  No other compensation of any type will 
be provided by the sponsor.  Financial compensation for lost wages, disability, or discomfort 
due to the study participation or procedures is not available.   
13.5 Retention of Records 
The investigator must make original study data (paper or electronic) accessible to the study 
monitor, other authorized sponsor representatives, and regulatory agency inspectors 
(eg, US FDA) upon request.  A file for each patient must be maintained that includes the 
signed informed consent form and copies of all source documentation related to that patient.  
The investigator must ensure the reliability and availability of source documents from which 
the information on the case report form was derived.   
Patient identity information recorded will be maintained for at least 15 years on the patient 
confidentiality log or longer if required by local regulations.   
Investigators must maintain all study documentation for at least 2 years following the 
approval of the drug, or until 2 years after the investigational drug program is discontinued, 
or longer if required by local regulations.  Study documentation includes all essential 
documents as defined in ICH E6 Guidelines for Good Clinical Practice.  The sponsor or 
designee will notify the investigator when any records may be discarded, but investigators 
must comply with local regulations.   
13.6 Study Termination 
The sponsor will terminate this study following completion of the study objectives, or earlier 
if deemed necessary.   
The sponsor reserves the right to terminate the study any time for any reason.  When the 
sponsor is aware of information on matters concerning the quality, efficacy, and safety of the 
study drugs, as well as other important information that may affect proper conduct of the 
clinical study, the sponsor may terminate the study and send a written notice of the 
termination along with the reasons to the investigator.   


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Enzalutamide 
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08 DEC 2016 – FINAL 
 
Page 60 of 66 
Investigators in this study agree to have their name listed as an investigator in any 
publication reporting results from this study, whether or not they are an author on the 
publication.   
Professional medical writing support is permissible, and any writing support will be 
acknowledged in each applicable publication, explaining the role the professional writer had 
in the drafting of the publication.  Medical writing and publications support funded by the 
sponsors on behalf of investigator authors will be considered as a transfer of value under the 
reporting requirements of the Patient Protection Affordable Care Act:  Physician Payment 
Sunshine Provision.12  Transfer of value will be allocated to authors following sponsor 
guidelines.   


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08 DEC 2016 – FINAL 
 
Page 61 of 66 
15 REFERENCES 
1. 
Czernin J, Satyamurthy N, Schiepers C. Molecular mechanisms of bone 18F-NaF deposition. 
J Nucl Med. 2010 Dec;51(12);1826-9. 
2. 
Morisson C, Jeraj R, Liu G. Imaging of castration-resistant prostate cancer: development of 
imaging response biomarkers. Curr Opin Urol. 2013 May;23(3):230-6. 
3. 
Kurdziel KA, Shih  JH, Apolo AB, Lindenberg L, Mena E, McKinney YY, et al. The kinetics 
and reproducibility of 18F-sodium fluoride for oncology using current PET camera technology. 
J Nucl Med. 2012 Aug;53(8):1175-84. 
4. 
Alom M, Aleksic I, Ruhle B, Iannotta P, Okeefe C, Mouraviev V, et al. Accuracy of NaF 
PET/CT scan to detect bone metastases in CRPC. Abstract presented at: 2014 Genitourinary 
Cancers Symposium; 2014 Jan 30-Feb 01; San Francisco, CA. (abstract 186). 
5. 
Iagaru A, Young P, Mittra E, Dick DW, Herfkens R, Gambhir SS. Pilot prospective evaluation 
of 99m Tc-MDP scintigraphy, 18F NaF PET/CT, 18F FDG PET/CT and whole-body MRI for 
detection of skeletal metastases. Clin Nucl Med. 2013 Jul;38(7):e290-6. 
6. 
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with 
enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 
2012 Sep 27;367(13):1187-97. 
7. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009 Jan;45(2):228-47. 
8. 
Vanderhoek M, Perlman SB, Jeraj R. Impact of different standardized uptake value measures on 
PET-based quantification of treatment response. J Nucl Med. 2013 Aug;54(8):1188-94. 
9. 
Xtandi (enzalutamide) capsules. Northbrook (IL): Astellas Pharma US, Inc.; 2012 Aug. 
Package insert. 
10. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982 Dec;5(6):649-55.  
11. International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
conduct, reporting, editing, and publication of scholarly work in medical journals [Internet]. 
2013 Aug [cited 2014 Jul 15]. Available from: http://www.icmje.org 
12. 111th Congress. HR 3590 - Patient Protection and Affordable Care Act. Section 6002: Physician 
payment sunshine provision. In: gpo.gov [Internet]. 2010 [cited 2014 Jul 18]. Available from: 
http://www.gpo.gov/fdsys/pkg/BILLS-111hr3590pp/pdf/BILLS-111hr3590pp.pdf  


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16 INVESTIGATOR SIGNATURE 
MEDIVATION, INC. 
A Phase 2, Open-Label, Single-Arm Study of 18F-Sodium Fluoride PET/CT Bone Imaging 
in Enzalutamide-Treated Chemotherapy-Naïve Patients With Bone-Metastatic 
Castration-Resistant Prostate Cancer 
Signature of Agreement for Protocol MDV3100-18, Amendment 2, v3.0, 08 DEC 2016 
I have read this protocol and agree to conduct the study as outlined herein, in accordance 
with Good Clinical Practice and the Declaration of Helsinki, and complying with the 
obligations and requirements of clinical investigators and all other requirements listed 
in 21 CFR Part 312. 
 
 
 
Print Study Site Name 
 
Study Site Number 
Print Investigator Name 
 
 
Investigator Signature 
 
Date 
 


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Appendix 1: Brief Pain Inventory (Short Form) 
 


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Appendix 2: Study Schedule of Activities 
Study Period Screening 
Treatment 
Unsched [1] Safety FUP [2] 
Study Week 
−4 to −1 
1 
5 
13 
21 then q8w 
Varies 
Varies 
Varies 
Study Days 
-28 to -1 
1 
29 
85 
141 then q56d 
na 
na 
na 
Window (Days) [3] 
na 
na 
±3 
±3 
±7 
na 
na 
na 
General Activities 
 
 
 
 
 
 
 
 
Informed consent, study ID number [4] 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Eligibility criteria incl. BPI, ECOG 
X 
 
 
 
 
 
 
 
12-lead electrocardiogram (local read) 
X 
 
 
 
 
 
 
 
99mTc-MDP bone scintigraphy 
X [5] 
 
 
 
 
X [6] 
 
 
CT or MRI of chest/abdomen/pelvis 
X [5] 
 
 
 
 
X [6] 
 
 
Complete physical examination [7] 
X 
X [8] 
 
 
 
 
 
X 
Brief physical examination [9] 
 
 
X 
X 
X [10] 
 
X 
 
Adverse events review [11] 
X 
X 
X 
X 
X 
 
X 
X 
Concomitant medications review 
X 
X 
X 
X 
X 
 
X 
X 
Enzalutamide dispensing 
 
X 
 
X 
X 
 
 
 
Study drug accountability 
 
 
X 
X 
X 
 
 
X 
Enrollment authorization form [12] 
X 
 
 
 
 
 
 
 
Local Lab Evaluations 
 
 
 
 
 
 
 
 
Hematology, serum chemistry  
X 
X [8] 
X 
X 
X [10] 
 
X 
X 
Testosterone 
X 
 
 
 
 
 
 
 
Prostate-specific antigen 
X 
X 
 
X [13] 
X 
X 
 
X 
Central Lab/Imaging Evaluations [14] 
 
 
 
 
 
 
 
 
Circulating tumor cells 
 
X [15] 
 
 
 
X [16] 
 
 
18F-NaF PET/CT imaging 
 
X (F-1) [17] 
 
X (F-2) 
 
X (F-3) [18]  
 
 
[1] 
Any time necessary to assess or follow up adverse events, at the patient’s request, or per investigator decision.   
[2] 
Approximately 30 days after the last dose of study drug (permanent discontinuation) or before initiation of cytotoxic chemotherapy, a lutamide 
(bicalutamide, nilutamide, or flutamide), or a new investigational therapy, whichever occurs first.   
[3] 
Drug supply must be taken into account when scheduling visits during windows.  Visit procedures may be split across the window to allow for drug 
resupply and completion of study procedures.   


Medivation, Inc. 
Enzalutamide 
Protocol MDV3100-18 
08 DEC 2016 – FINAL 
Page 66 of 66 
[4] 
Must be before any study-specific procedures.  May obtain before the screening window.  Ensure consent is on the current version of the form.   
[5] 
Must be within 28 days before day 1.  Send copy of bone scintigraphy image to the central imaging vendor for archiving.   
[6] 
At investigator discretion (eg, significant bone pain or a skeletal-related event for 99mTc-MDP bone scintigraphy; or suspicion of soft tissue disease 
progression for CT or MRI) or (for 99mTc-MDP bone scintigraphy only) to coincide with NaF-3 unless bone disease progression was confirmed earlier.  
Progression at week 13 or earlier will require a confirmatory 99mTc-MDP bone scintigraphy at least 6 weeks later showing at least 2 additional new 
lesions related to prostate cancer (compared with the previous scan).  After week 13, no confirmation of progression will be required if at least 2 new 
lesions related to prostate cancer are observed.  If no bone disease progression was seen by 99mTc-MDP bone scintigraphy before NaF-3, then 
99mTc-MDP bone scintigraphy will be required at the time of NaF-3.  Send copies of bone scintigraphy images to the central imaging vendor for 
archiving.   
[7] 
Includes vital signs (temperature, blood pressure, heart rate), ECOG performance status, weight.  Height at screening only.   
[8] 
May skip if performed within prior 3 days.   
[9] 
Symptom-directed and includes vital signs, ECOG performance status, and weight.   
[10] 
Repeats every 16 weeks ±7 days after week 21.   
[11] 
Collect serious adverse event information from the time of signed informed consent and nonserious adverse event information from the time of first 
dose of study drug through 30 days after the last dose or initiation of cytotoxic chemotherapy, a lutamide (bicalutamide, nilutamide, or flutamide), or a 
new investigational therapy, whichever occurs first.  Phone patients for follow-up if they do not come to the clinic.   
[12] 
Complete, sign, and fax or email the form with requested items to the medical monitor or designee at least 2 business days before the anticipated day 1 
visit, if possible.  Patient may proceed to day 1 visit when medical monitor or designee approves by signed form or email correspondence.   
[13] 
Patients with PSA values increased from baseline may discontinue study drug and have safety follow-up unless the investigator considers continuation 
of study drug to be beneficial.   
[14] 
Refer to laboratory and imaging instruction manuals for sample processing and imaging acquisition requirements.  Interpretation of 18F-NaF PET/CT 
imaging performed at the central imaging vendor.   
[15] 
Collect predose. 
[16] 
At time of NaF-3. 
[17] 
Perform predose.  Must occur within 7 days before first dose of enzalutamide.  Perform a second baseline scan on up to 5 patients at each study site to 
assess reproducibility. 
[18] 
At time of PSA, radiographic (bone or soft tissue), or other clinically relevant progression, or at 2 years without progression after treatment initiation.   
18F-NaF PET, 18F-sodium fluoride positron emission tomography; CT, computed tomography; BPI, Brief Pain Inventory; ECOG, Eastern Cooperative 
Oncology Group; 99mTc-MDP, technetium Tc 99m medronate; (F-1), (F-2), (F-3) designators for sequential 18F-NaF PET/CT imaging; FUP, follow-up; lab, 
laboratory; ID, identification; MRI, magnetic resonance imaging; na, not applicable; q8w, every 8 weeks; unsched, unscheduled.   
 

SAP_001.pdf: 
Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
Page 1
Protocol MDV3100-18
(C3431012)
A Phase 2, Open-Label, Single-Arm Study of 18F-Sodium Fluoride 
PET/CT Bone Imaging in Enzalutamide-Treated Chemotherapy-Naïve 
Patients with Bone-Metastatic Castration-Resistant Prostate Cancer
Statistical Analysis Plan (SAP)
Version:
1.0
Date:
24-SEPT-2018


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION & STUDY DESIGN ...............................................................................5
2.1. Study Objectives........................................................................................................5
2.2. Study Design .............................................................................................................6
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoint.......................................................................................................8
3.2. Secondary Endpoints.................................................................................................9
3.4. Baseline Variables...................................................................................................11
3.5. Safety Endpoints......................................................................................................12
4. ANALYSIS SETS ...............................................................................................................13
4.1. As Treated (AT) ......................................................................................................13
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................13
5.1. Hypotheses and Decision Rules ..............................................................................13
5.2. General Methods .....................................................................................................13
5.2.1. Pooling of Data by Study Site ....................................................................13
5.2.2. Nominal Timepoints...................................................................................13
5.2.3. Definition of Study Day..............................................................................14
5.2.4. Unscheduled Assessments..........................................................................14
5.2.5. Standard Derivations and Reporting Conventions .....................................14
5.2.6. Analyses for Categorical Data ....................................................................14
5.2.7. Analyses for Continuous Data....................................................................14
5.2.8. Analysis of Covariance...............................................................................15
5.2.9. Analysis for Log-Transformed Data...........................................................15
5.3. Methods to Manage Missing Data ..........................................................................16
6. ANALYSES AND SUMMARIES ......................................................................................17
6.1. Primary Endpoint.....................................................................................................17
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6.2. Secondary Endpoint(s) ............................................................................................17
6.4. Subgroup Analyses..................................................................................................23
6.5. Baseline and Other Summaries and Analyses .........................................................23
6.5.1. Baseline Summaries....................................................................................23
6.5.2. Protocol Deviations ....................................................................................24
6.5.3. Study Conduct and Patient Disposition ......................................................24
6.5.4. Prior and Current Therapies........................................................................24
6.5.5. Study Drug Exposure and Treatment Compliance.....................................24
6.5.6. Concomitant Medications and Non-Drug Treatments................................25
6.6. Safety Summaries and Analyses .............................................................................26
6.6.1. Adverse Events ...........................................................................................26
6.6.2. Adverse Events of Special Interest.............................................................27
6.6.3. Deaths .........................................................................................................27
6.6.4. Laboratory Data ..........................................................................................27
6.6.5. Vital Signs...................................................................................................29
6.6.6. Electrocardiogram.......................................................................................29
6.6.7. ECOG .........................................................................................................29
7. INTERIM ANALYSES.......................................................................................................29
8. REFERENCES ....................................................................................................................30
9. APPENDICES .....................................................................................................................31
10. ABBREVIATIONS ...........................................................................................................43
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments................................................5
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Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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LIST OF FIGURES
Figure 1.
Study Schematic .....................................................................................................7
APPENDICES
Appendix 1. Imputation of Missing/Partially Missing Dates ..................................................31
Appendix 2. Sample SAS Code...............................................................................................33
Appendix 3. Analysis Windows for Reporting........................................................................35
Appendix 4. Summary of Efficacy Analyses...........................................................................36


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
Page 5
1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study MDV3100-18 is based on the Protocol
Amendment #2 dated 08-DECEMBER-2016.
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1.0
Not Applicable
Not Applicable
2. INTRODUCTION & STUDY DESIGN
This SAP provides detailed methodology for summary and statistical analyses of the data
collected in study MDV3100-18.  This document may modify the plans outlined in the
protocol; however, any major modifications of the primary endpoint definition or its analysis
will also be reflected in a protocol amendment. Any deviations from this analysis plan will be
described in the Clinical Study Report (CSR).
MDV3100-18 is a phase 2, open-label, single-arm trial of enzalutamide in adult male patients 
who are chemotherapy-naïve, and who have bone-metastatic castration-resistant prostate 
cancer.
In this study, approximately 20 adult male patients (age ≥18 years) will be enrolled across 
3 sites in the United States.  The primary objective is to evaluate F-NaF PET/CT imaging as 
a method for assessing treatment response in metastatic bone lesions either at time of disease 
progression, or after 2 years of treatment, whichever comes first.
The primary analysis will include all data up to a data cutoff date which will be determined 
when all patients have progressed or have otherwise been followed for two year or are no 
longer being followed due to withdrawal of consent, lost to follow-up, or death. All 
summaries and analyses will include all data pertaining to visits/assessments (both planned 
and unplanned) performed up to and including the data cutoff date.
2.1. Study Objectives
Primary Objectives:

To evaluate F-NaF PET/CT imaging as a method for assessing treatment response in 
metastatic bone lesions either at time of disease progression, or after 2 years of 
treatment, whichever comes first.
Secondary Objectives:

To evaluate the heterogeneity of response in metastatic bone lesions at the time the
primary objective is assessed.


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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2.2. Study Design
This is a phase 2, open-label, single-arm trial of enzalutamide in adult male patients who are 
chemotherapy-naïve, and who have bone-metastatic castration-resistant prostate cancer.
In this study approximately 20 adult male patients will be enrolled across 3 sites in the 
United States.  Eligible patients must have bone metastatic disease in at least 2 lesions with a 
PSA ≥2 ng/mL.  Patients must not have received any prior chemotherapy previously.  
Following screening, enrolled patients will have baseline 18F-NaF PET/CT imaging (NaF-1) 
and then begin open-label treatment with enzalutamide. PSA response will be determined at 
week 13 when a second 18F-NaF PET/CT imaging (NaF-2) is obtained. Patients with any 
increase in PSA at week 13 may discontinue treatment and proceed to safety follow-up 
unless the investigator considers continuation of study drug to be beneficial. For all 
continuing patients, PSA will be monitored every 8 weeks after week 13 and other study 
assessments will continue to be obtained. A third 18F-NaF PET/CT imaging (NaF-3) and a 
follow-up 99mTc-MDP bone scintigraphy will be performed when PSA progression (an 
increase of at least 25% AND an absolute increase of at least 2.0 ng/mL above nadir), 
radiographic progression (bone or soft tissue), or other clinically relevant progression (eg, 
significant bone pain or a skeletal-related event) is observed, or at 2 years without 
progression after initiation of treatment. No 99mTc-MDP bone scintigraphy will be required 
at the time the NaF-3 bone scan is obtained if bone disease progression was confirmed earlier 
on bone scintigraphy obtained at investigator discretion. 
Total study duration will be approximately 36 months.
Enzalutamide will be administered one daily at a starting dose of 160mg/day.  Dose 
modifications downwards are possible to either 120 or 80 mg/day, per protocol section 6.2.4.
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Study periods include screening, treatment, and safety follow-up.  Safety follow-up applies to 
patients who are off protocol therapy and continues to the earliest of 1) 30 days after last 
dose, 2) death, 3) lost to follow-up, 4) withdrawal of consent, or 5) enrollment into another 
anti-cancer clinical trial.
The study schematic is provided in Figure 1.
Figure 1.
Study Schematic
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND
CONVENTIONS
Standardized uptake value (SUV) is a unitless measure derived from the imaging PET/CT 
scans as a ratio of image-radioactivity concentration to the whole-body concentration.  SUV 
and its various uptake measures described below will be analyzed at the central vendor and 
provided to the sponsor.
For a particular lesion (n), where n = 1, 2, 3, … N, a 3-dimensional volume of interest (VOI) 
will be analyzed.  Within that VOI for that lesion, there are numerous voxels which 
compromise the volume.  These voxels are 3-dimensional analogs of the 2-dimensional 
pixels.  A particular voxel will be voxel (k), and there are K voxels compromising the entire 
VOI for that lesion, where k = 1, 2, 3, … K.  Let SUVk be the SUV for a voxel (k) within that 
particular lesion.

SUV(total) is the total standardized uptake value.  This measure assesses the total 
tumor burden.  

First, each lesion (n) of interest produces its own SUV(total) by summing 
from k=1 to k=K of SUVk.

Second, the sum from n=1 to n=N of each lesion’s SUV(total) will produce 
the desired SUV(total).


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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
SUV(mean) is the mean standardized uptake value.

First, each lesion (n) of interest produces its own SUV(mean) by summing 
from k=1 to k=K of SUVk and then dividing that sum by K.

Second, the mean from n=1 to n=N of each lesion’s SUV(mean) will produce 
the desired SUV(mean).

SUV(max) is the maximum standardized uptake value.  

First, each lesion (n) of interest produces its own SUV(max) by taking the 
maximum value from k=1 to k=K of SUVk.

Second, the maximum from n=1 to n=N of each lesion’s SUV(max) will 
produce the desired SUV(max).

SUV(hetero) is the heterogeneity measure of tumor activity across all lesions  

First, each lesion (n) of interest produces its own SUV(mean) by summing 
from k=1 to k=K of SUVk and then dividing that sum by K.

Second, that lesion’s mean is subtracted from the SUV(mean) above, and that 
difference is then squared.

Third, those squared differences from n=1 to n=N are then summed, and then 
divided by N to produce the desired SUV(hetero).
3.1. Primary Endpoint
The single primary endpoint is the proportion of patients with ≥1 responding bone lesion 
on the third scheduled F-NaF PET/CT scan for this study.  For clarity going forward, this
scan will be referred to as NaF.  Three such NaF scans are scheduled and are noted below:
Scan identifier
Scheduled to occur at
NaF-1
Screening
NaF-2
Week 13
NaF-3
Time of progression, or at 2 years after 
treatment start, whichever occurs first*
* If progression occurs before Week 13, then NaF-3 will constitute the scan at progression and support the 
primary analysis, even though NaF-2 hadn’t occurred yet.
A lesion is considered responding if the change from baseline in total standardized uptake 
value (SUV(total)) is below the limit of agreement (LOA).  The LOA will be estimated based 
upon test/retest analysis and provided by the vendor.


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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The NaF-3 will be triggered by the earliest of any of the following events:
•
Prostate-specific antigen (PSA) progression:
•
Defined as percentage change from baseline ≥25% and nominal increase 
≥2.0 ng/mL above the nadir (or above the baseline if no decline by week 13).
•
Bone disease progression:
•
Defined as ≥2 new lesions assessed by bone scintigraphy.
•
Soft tissue disease progression:
•
Defined by RECIST v1.1.
•
Clinically relevant progression:
•
Defined by the investigator.
•
Two years after start of therapy.
NaF scans will be interpreted by a central imaging vendor.  
3.2. Secondary Endpoints
There is one secondary endpoint for this study, namely the heterogeneity of response 
across all bone lesions at the time the primary endpoint is assessed, SUV(hetero).  At the 
NaF-3, the observed SUV(hetero) will be assessed.
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3.4. Baseline Variables
The date of first dose (start date) of study treatment is the earliest date of non-zero dosing of
the study drug. The date of last dose of study treatment is the latest date of non-zero dosing 
of the study drug.
No windowing will be applied when defining baseline. Any deviations from the protocol
specified window will be documented as protocol deviations. For efficacy analyses and
baseline characteristics associated with tumor assessments, the last assessment prior to the 
date and time of first study drug will serve as the baseline assessment.
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For safety, the last assessment performed on or prior to date of the first dose of study 
treatment will serve as the baseline assessment.  If there are no observations meeting these 
criteria, then baseline is considered missing.
Post-baseline value is defined as a measurement taken after the first administration of study
drug.  Change from baseline is defined as (post baseline value – baseline value).  Percent 
change from baseline is defined as [(post baseline value – baseline value)/(baseline value)] 
multiplied by 100%. Both date and time of study drug administration and measurement will 
be considered when calculating baseline value. If time is not available, then date only will be
used.
3.5. Safety Endpoints
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment is defined as the period between the first dose of the study drug to the earliest 
of 30 days after the last dose of study drug treatment, the start of cytotoxic chemotherapy, the 
start of a lutamide (bicalutamide, nilutamide, or flutamide), or the start of a new 
investigational therapy. Adverse events occurring on the same day as the first dose of study 
treatment will be considered to have occurred during the on-treatment period.  All other 
assessments which occur on the same day as the firs dose of study treatment will be 
considered baseline assessments. 
Safety data collected outside the on-treatment period as described above will be listed but not 
summarized. 
An adverse event is considered treatment emergent relative to a given treatment if:

the event occurs for the first time during the on-treatment period and was not seen 
prior to the start of treatment, or

the event was seen prior to the start of treatment but increased in severity during the 
on-treatment period.
Adverse events will be coded to preferred term and system organ class using the Medical
Dictionary for Regulatory Activities (MedDRA) and classified by severity using the CTCAE, 
version 4.    
Hematology and chemistry results will be programmatically graded according to the NCI
CTCAE version 4 for relevant parameters.  Parameters which cannot be graded will be
summarized relative to the normal range (ie, normal range high or normal range low).  
Additional details are provided in Section 6.6.


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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4. ANALYSIS SETS
While the protocol notes an intent-to-treat population, the below As Treated population will
be used instead since the study is single-arm and exploratory in nature.  Certain restrictions 
will later be noted where baseline and certain post-baseline measurements are required for 
particular endpoints.
4.1. As Treated (AT)
The As Treated (AT) population is defined as all enrolled patients who receive any amount 
of study treatment.  
5. GENERAL METHODOLOGY AND CONVENTIONS
There is no planned interim analysis.  The final analysis will occur when all patients have 
progressed or have otherwise been followed for two year or are no longer being followed due 
to withdrawal of consent, lost to follow-up, or death.  Since the study is phase 2 and 
exploratory, no adjustments for multiplicity will be made.
5.1. Hypotheses and Decision Rules
The primary purpose of this study is to assess the NaF imaging as a method for evaluating 
treatment response in bone lesions at the time of progression.  The sample size of 20 patients 
was chosen for practical clinical considerations.  
Due to the exploratory nature of this study, there is no formal hypothesis.  Instead, estimation 
will be the primary aim.
5.2. General Methods
Confidence intervals will be done with 95% coverage.  No adjustments to the confidence 
intervals are planned for any multiple testing.
5.2.1. Pooling of Data by Study Site
In order to provide overall estimates, data will be pooled across study sites.  Furthermore, the 
small number of enrolled patients makes an analysis by study site not feasible.  However, 
study site will be used as a factor in the ANCOVA models so as to improve precision of the 
estimates.
5.2.2. Nominal Timepoints
Visit windows will apply per Appendix 3. Analysis Windows for Reporting.
Note that NaF-1 and NaF-2 are scheduled for baseline and week 13, respectively.  NaF-3, 
however, is more fluid and can occur depending on different disease progressions or 2-years 
of therapy, per Section 3.1.  If NaF-3 occurs before the scheduled NaF-2, then that scan will 
be NaF-3, and the pre-planned NaF-2 will not exist.
For endpoints only collected once post-baseline at NaF-3 (eg, circulating tumor cells), the 
NaF-3 slotted value will be the measurement closest to the NaF-3 scan.


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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5.2.3. Definition of Study Day
The study day for assessments occurring on or after the first dose of study treatment (eg, 
adverse event onset, tumor measurement) will be calculated as:
Study day = Date of the assessment/event −start date of study treatment +1. 
The study day for assessments occurring prior to the first dose of study treatment (eg, 
baseline characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event – start date of study treatment.
The study day will be displayed in all relevant data listings.
5.2.4. Unscheduled Assessments
Unscheduled assessments will be used when deriving baseline and worst case on-treatment 
for safety and patient-reported outcome analyses (except where noted for baseline ECGs). 
Additionally, unscheduled assessments will be used for efficacy analyses (eg, defining date 
of PSA progression, date of last contact).
5.2.5. Standard Derivations and Reporting Conventions
The following conversion factors will be used to convert days into weeks, months or years: 
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Percentages will be reported to one decimal place. The rounding will be performed to closest 
integer / first decimal using the common mid-point between the two consecutive values.
Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 to 5.9 will be rounded to an integer 
of 6.
5.2.6. Analyses for Categorical Data
The number and percentage of patients in each category will be provided for categorical 
variables. Unless otherwise specified, the calculation of proportions will include the missing 
category. Therefore counts of missing observations will be included in the denominator and 
presented as a separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of
patients with an assessment at that visit, unless otherwise specified.
If a binary proportion requires a confidence interval, it will be calculated with a 2-sided exact
95% CI using the Clopper-Pearson method (Clopper, C. J.; Pearson, E. S. (1934)).  This 
confidence interval is an exact interval, not relying on any normal approximations.  Sample 
SAS code can be found in Appendix 2. Sample SAS Code.
5.2.7. Analyses for Continuous Data
Descriptive statistics, including the number of observations (N), mean, standard deviation,
median, minimum, 25th quantile, 75th quantile, and maximum values, will be provided for 
continuous variables.


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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In case the analysis refers only to certain visits, descriptive statistics will be based on the 
number of patients with a non-missing assessment at that visit, unless otherwise specified.
5.2.8. Analysis of Covariance
A linear model for analysis of covariance (ANCOVA) will be used to analyze continuous 
data collected at baseline and at particular post-baseline visits.  The dependent variable in the 
ANCOVA model will be the change from baseline at the specified post-baseline windowed 
visit.  The model will include fixed effects terms for:
•
Treatment (as a categorical variable);
•
Baseline value (as a continuous variable);
•
Study site (as a categorical variable).
The observed margins option (OM) will be implemented in assigning categorical weights 
when calculating the least squares means.  There will be no imputation for missing data in 
the analyses.  While there is only one treatment arm in this study, the inclusion of the fixed 
effect for treatment is needed in order to produce the desired least squares mean.
The model-adjusted mean change from baseline will be presented at the specified post-
baseline visit using the least squares mean, its standard error, and its 95% confidence 
interval.  
In the event of convergence problems, then the fixed effect term for study site will be 
removed and the model re-run.
Sample SAS code for the ANCOVA model is found in Appendix 2. Sample SAS Code.
5.2.9. Analysis for Log-Transformed Data
Endpoints that are markedly skewed can be analyzed with log-transformation.  The natural 
log of the baseline and the natural log of post-baseline observed data will be used in the 
ANCOVA analysis from Section 5.2.8.  Nominal change in the log-transformed data 
(log[post-baseline value] minus log[baseline value]) will be analyzed.  The following will 
estimate a percent change from baseline and will be displayed in the tables.
Percent change for treatment = [exp (LSMean) – 1]*100%
Likewise, the confidence intervals for the percent change will be obtained similarly, where 
the above back-transformation is applied to the log-transformed confidence interval for the 
LSMean.  If any values for analysis are zero, then a positive value of 0.0001 will be used 
instead; this will allow the computation of the natural log. 
 
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5.3. Methods to Manage Missing Data
Missing data will not be imputed unless specified elsewhere in the SAP.  Missing dates or
partially missing dates will be imputed conservatively for adverse events and
prior/concomitant medications/procedures.  Specific rules for handling missing or partially 
missing dates for date of birth, adverse events, prior/concomitant medications/procedures,
and diagnosis of cancer are provided in Appendix 1. Imputation of Missing/Partially Missing 
Dates. Any imputations will occur at the analysis dataset level and not the raw dataset level.  
Additionally, in all patient data listings imputed values will be presented and flagged as
imputed.
Missing statistics, eg, when they cannot be calculated, should be presented as ‘ND’ for not 
done, ‘NR’ for not reached or ‘NA’ for not applicable.  For example, if N=1, the measure of 
variability cannot be computed and should be presented as ‘ND’ or ‘NA’.  If too few events 
are observed in the KM analyses, then certain quartiles may not be estimable; hence NR 
should be presented.
Missing toxicity grades for adverse events:
Prior to Study Treatment: If no toxicity grade is available or the grade is reported as 
unknown for an adverse event prior to the first study treatment, then Grade 1 will be 
assumed for purposes of defining a baseline grade for assessing if further occurrences 
are treatment emergent. However, if the patient experiences multiple episodes of the 
same AE prior to study treatment, then the maximum toxicity grade observed prior to 
study treatment will be utilized in assessing if further occurrences are treatment 
emergent. 
During Study Treatment: If no toxicity grade is available or the grade is reported as 
unknown for an adverse event during the study treatment, then the event will be 
considered treatment emergent unless a baseline event was reported as Grade 4. 
In summaries which present maximum toxicity grade, the maximum of non-missing grades 
will be displayed.  Missing grade will only be displayed for cases where a patient reported 
only one event and the grade is missing.
CCI


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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For incomplete day of last dose of study drug, the 15th of the month will be assumed in 
determining the treatment-emergent period.
6. ANALYSES AND SUMMARIES
All efficacy analyses will be based on the AT population. Any confidence intervals 
presented will be 2-sided 95% CI.  No adjustments to the confidence intervals are planned
for any multiple testing.  The start day for time to event analyses will begin at the date of first 
study drug.
Safety analyses (adverse events, laboratory tests, etc.) will be based on the AT population.
A grid-summary of the efficacy analyses can be found in Appendix 4. Summary of Efficacy 
Analyses.
6.1. Primary Endpoint
The primary endpoint is the proportion of patients with ≥1 responding bone lesions at NaF-3.  
A lesion is considered responding if the change from baseline at NaF-3 in total standardized 
uptake value (SUV(total)) is below the limit of agreement (LOA).  
The primary endpoint will be summarized with number and percent of patients with 
≥1 responding bone lesions at NaF-3 along with the 95% CI using the Clopper-Pearson 
method.
This endpoint will be analyzed for all patients in the AT population who also have 
non-missing scans at both NaF-1 and NaF-3.  Patients not having both NaF-1 and NaF-3 will 
be counted as non-evaluable (hence not included in the denominator of the point estimate).
6.2. Secondary Endpoint(s)
The secondary endpoint is the observed heterogeneity of response across all bone lesions, 
SUV(hetero).  This endpoint will be assessed for each patient when their primary endpoint is 
assessed, and is based on the post-baseline scan NaF-3.  This endpoint was analyzed at the 
central vendor and provided to the sponsor.  Summary statistics will be used to describe the 
endpoint.  Graphical displays utilizing histograms will also be produced. 
This endpoint will be analyzed for all patients in the AT population who also have non-
missing scans at both NaF-1 and NaF-3.
 
CCI


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CCI


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CCI


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CCI


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CCI


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CCI


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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6.4. Subgroup Analyses
Not applicable due to the small sample size and exploratory nature of the study.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
The following demographic and baseline characteristics will be summarized for all patients 
in the AT population.
•
Age, race, ethnicity, height (cm), weight (kg), and body mass index (kg/m2).
•
PSA (ng/mL) and Gleason scores.
•
From the medical history prostate cancer CRF page.
•
Primary diagnosis.
•
Continuous summary of time from primary diagnosis to study enrollment (in 
years).
•
ECOG status.
•
Tabulations with n (%) for the different categories.
•
Brief Pain Inventory (Short Form).
•
Yes/No categories will be tabulated with n (%).
•
Categories scaled from 0 to 10, or from 0% to 100%, will be summarized as a 
continuous measure using descriptive statistics.
•
Medical history.
•
Derived from the medical history non-prostate cancer CRF page.
Listings will be provided for these parameters.
CCI


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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6.5.2. Protocol Deviations
Protocol deviations will be compiled prior to database closure and will be summarized by 
category (n(%)) for the AT population.  Categories will be assigned by the study clinician.
6.5.3. Study Conduct and Patient Disposition
Summaries will include the number and percentage of patients in AT population.
The number and percentage of patients who discontinue study drug and the reasons for
discontinuation will be summarized for all patients in the AT population.  Likewise the 
number and percentage of patients who discontinue the study itself will be summarized for 
all patients in the AT population.
6.5.4. Prior and Current Therapies
Prior therapies and current therapies will be summarized separately for patients in the AT 
population:

Radiotherapy for prostate cancer.

Surgical procedures for prostate cancer.
6.5.5. Study Drug Exposure and Treatment Compliance
Study Drug Exposure
Summary statistics will be provided for all patients in the AT population for:

Treatment duration (months): For each patient, treatment duration is defined as (date 
of last dose – date of first dose +1)/30.4375. Treatment duration will be summarized 
both as a continuous measure and a categorical measure (<3 months, 3 to <6 months, 
6 to <12 months, 12 to <24 months, 24 to <36 months, and ≥36 months).

Cumulative dose (mg): For each patient, the cumulative dose is calculated based on 
the Study Drug Dosing CRF page.  The daily total dose (mg) will be summed across 
the study.

Average daily dose (mg/day): The average daily dose is defined as the cumulative
dose divided by the dose exposure.

Dose exposure (days) is defined as the total number of actual days on study
drug during the treatment period.
Treatment Compliance

Percent overall compliance will be summarized both as a continuous measure and a
categorical measure (<80%, ≥80%).


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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Percent overall compliance rate will be defined as the number of capsules taken during the 
study divided by the expected number of capsules, multiplied by 100%, as specified in 
section 10.5 of the protocol.  Capsules not returned will be assumed to have been taken, as 
per section 6.3 of the protocol.  The number of returned capsules is obtained from the Study 
Drug Accountability CRF page. A patient’s expected number of capsules, if no dose 
modifications, will be calculated as [4 (date of last dose – date of first dose of study drug + 
1)].  Adjustments to the expected number of capsules are made if dose adjustments occurred:

If a dose reduction to 120mg, then subtract one capsule from the above formula for 
every day on the 120mg dose.

If a dose reduction to 80mg, then subtract two capsules from the above formula for 
every day on the 80mg dose.

If a dose interruption, then subtract the appropriate number of capsules (4 or 3 or 2) 
from the above formula for every day of interruption.
Dose Interruptions and Reductions
Dose modifications include dose interruptions and/or reductions.  A dose interruption will 
include a missing or a zero dose on the dosing page.  A dose reduction is any dose that is 
lower than the previous dose.  Dosage of enzalutamide may be reduced to either 120 mg/day, 
or 80 mg/day.

Patients with at least 1 dose modification (interruption or reduction) and the reason 
for the dose modifications will be tabulated. 

Patients with at least 1 dose interruption will be tabulated.

Patients with at least 1 dose reduction will be tabulated.
A data listing will be provided to present dose administration, modifications, and the derived
compliance variables.
6.5.6. Concomitant Medications and Non-Drug Treatments
Concomitant medications taken during the study treatment period will be summarized for all
patients in the AT population.  Concomitant medications refer to all medications which 
started prior to first dose of study treatment and continued during the treatment-emergent 
period (earliest of 30 days after the last dose of study drug treatment, the start of cytotoxic 
chemotherapy, the start of a lutamide (bicalutamide, nilutamide, or flutamide), or the start of 
a new investigational therapy (whichever occurs first)) as well as those started during the on-
treatment period.
Concomitant medications will be coded in the WHO Drug coding dictionary and will be 
tabulated by Anatomical Therapeutic Chemical (ATC) Classification level 2 and preferred 
term in descending order of frequency. In case of equal frequency regarding drug class 
(respectively drug name), alphabetical order will be used.  A patient will be counted only 


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times.  Preferred Terms will be reported under each ATC class 
that it is included under within WHO Drug (no primary path is available in WHO Drug).
All concomitant medications and non-drug treatments recorded on the case report form will
also be listed.
6.6. Safety Summaries and Analyses
All patients in the AT population will be used in the safety analyses.
6.6.1. Adverse Events
Adverse events will be coded using MedDRA, in accordance with the version(s) documented
in the data management plan.  Adverse events will be graded by the investigator using the 
CTCAE v4.0.
All analyses will be based on treatment emergent events unless otherwise specified.  
Treatment emergent is defined in Section 3.5.  AEs not considered treatment emergent will be 
flagged in data listings.  Only TEAEs with onset date to the earliest of 30 days after the last 
dose of study drug treatment, the start of cytotoxic chemotherapy, the start of a lutamide
(bicalutamide, nilutamide, or flutamide), or the start of a new investigational therapy 
(whichever occurs first) will be included in the adverse event summaries.
Adverse event incidence will be summarized with frequency and percentage using MedDRA.  
Some summaries are by system organ class (SOC) and preferred term (PT), while others are 
only by PT (see below).  In addition, adverse event incidence will also be summarized by 
severity and relationship to study drug.  The denominator for the adverse event incidence will 
be based on the number of patients in the AT population unless otherwise specified.
Patients with multiple occurrences of events for a given preferred term (even if concurrent), 
system organ class, or overall will only be counted once at the worst severity and strongest 
relationship to study drug for each preferred term, system organ class, and overall, 
respectively.  If relationship to study drug is missing, the adverse event will be counted as
treatment-related. Adverse event listings will show missing relationship as missing.
Tabular summaries including numbers and percentages of the following adverse events will
be provided:

TEAEs;

TEAEs by SOC and PT;

TEAEs by PT and maximum severity;

TEAEs (treatment related);

TEAEs (treatment related) by SOC and PT;


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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
TEAEs (treatment related) by PT and maximum severity;

TEAEs leading to study drug discontinuation by PT;

TEAEs leading to temporary study drug interruptions by PT;

TEAEs leading to dose interruptions or reductions by PT;

Serious TEAEs;

Serious TEAEs by SOC, PT and maximum severity.
6.6.2. Adverse Events of Special Interest
Not applicable.
6.6.3. Deaths
The frequency (number and percentage) of patients in the AT population who died and who 
also died within 30 days after last dose of study treatment as well as the primary reason for 
death will be tabulated.
Date and cause of death will be provided in individual patient data listing together with 
selected dosing information (date of first/last administration, dose).
6.6.4. Laboratory Data
Laboratory data in this study consist of hematology values and chemistry tests. Only data
collected from the central laboratory during the treatment-emergent period will be 
summarized.  Laboratory data collected outside the treatment-emergent period will only be 
listed in the data listings.
Laboratory results will be converted to International System of Units (SI) units which will be 
used for applying toxicity grades and for all summaries. 
Quantitative data will be summarized using simple descriptive statistics (mean, standard 
deviation, median, quartiles, minimum, and maximum) of actual values and change from 
baseline for each nominal visit over time (ie, unscheduled assessments will be excluded).  
The total number of patients for change from baseline will include all patients in the 
treatment arm who have both a baseline and a value at the nominal visit.  
As described in Section 3.4, baseline will defined as the last assessment performed on or 
prior to date of the first dose of study treatment.  If there are multiple assessments that meet 
the baseline definition on the same day without the ability to determine which was truly last, 
then the worst grade will be assigned as the baseline grade.  


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Results collected as strict inequalities (eg, >10, <10) will be converted to numeric values by
subtracting a factor of <0.001>.  Expressions of the form” ≥” or “≤” will be converted to the 
end point.  These numeric values will be evaluated for clinically significant abnormalities, 
but will not be included in calculations of summary statistics.
Additionally, laboratory results will be programmatically classified according to 
NCI-CTCAE version 4.0 grade.  Non-numerical qualifiers will not be taken into 
consideration in the derivation of grade (eg, hypokalemia Grade 1 and Grade 2 are only 
distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). In 
summary statistics the number and percentage of patients corresponding to grades that only 
include non-quantitative criteria will be displayed as a blank or NA (not assessed) rather than 
0.  If there is any overlap between grade criteria (eg, CTCAE grading criteria for Creatinine 
Increased – a value can fall into one range based on comparison to ULN and another range 
based on comparison to baseline), the highest (worst) grade would be assigned to that record. 
Grade 5 is defined in the CTCAE criteria guidance as an event with an outcome of death.
Since laboratory data does not collect an outcome, Grade 5 is not used when 
programmatically grading laboratory data.  Grade 0 or Outside Toxicity Reference (OTR) is 
not defined specifically by in the CTCAE guidance. However, programmatically this is used 
as a category to represent those patients who did not meet any of the Grades 1 to 4 criteria.  If 
the laboratory value is evaluable for CTCAE criteria grading (numeric value is present, valid 
units and ranges are present as required to allow conversion to standard units and grading), 
and does not qualify for any of the Grade 1-4 criteria for a given lab test, then the value is 
assigned as Grade 0 or OTR.
Normal ranges will be implemented to identify values that are outside the normal ranges and 
create the NCI toxicity grade using the CTCAE version 4.0. Parameters that have criteria 
available for both low and high values will be summarized for both criteria (low and high). 
Patients will only be counted once for each criterion. The same patient can be counted for 
both criteria if the patient has laboratory values meeting each criterion.  The change from 
baseline to post baseline value will be calculated for each laboratory parameter where 
available.
For laboratory parameters that are gradable by the CTCAE, a shift table will be provided for 
each parameter to summarize baseline toxicity grade versus worst post baseline toxicity 
grade during the treatment-emergent period.  The number and percentage of patients will be 
provided for each parameter.
For each laboratory parameter that is not able to be graded by the CTCAE, a shift table based 
on the normal range (low, normal, and high) will be provided to summarize the baseline 
result versus both the lowest and the highest post baseline result during the 
treatment-emergent period.
For patients with grade 3 and/or grade 4 laboratory values in the treatment-emergent period, 
a by-patient data listing will be presented to display data including visit label, assessment 
date (day), laboratory value, and normal range flag (low, normal, and high).  The baseline 
value will be flagged in this data listing.


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The number and proportion of patients with liver function test elevations will be presented.  
Liver function test elevations are assessed by using post baseline results in ALT, AST, and 
total bilirubin during the treatment-emergent period based upon the definitions presented 
below:
Categories of Liver Function Test Elevations
Parameter
Elevation
AST
>5 x ULN
ALT
>5 x ULN
Total bilirubin
>5 x ULN
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal
6.6.5. Vital Signs
Systolic and diastolic blood pressure (mmHg), height (cm), and weight (kg) at baseline and at 
all subsequent scheduled time points will be summarized. Changes from baseline value will
be presented for all scheduled time points.  
All recorded vital sign data will be listed.
6.6.6. Electrocardiogram
Echocardiogram findings that were collected during the screening period will be listed by 
patient.
6.6.7. ECOG
Descriptive summaries at baseline and at the safety follow-up will be provided.  These 
include:

Number and percentage of patients for each of the six categories.
The ECOG performance status scores will be listed.
7. INTERIM ANALYSES
Not applicable.


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8. REFERENCES
1.
Brookmeyer R, Crowley JJ. A confidence interval for median survival time. Biometrics. 
1982 Mar;38 (1):29-41. 
2.
Clopper, C. J.; Pearson, E. S. (1934). "The use of confidence or fiducial limits 
illustrated in the case of the binomial". Biometrika. 26: 404–413.
3.
Eisenhauer E, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J. New response evaluation criteria in solid tumors: Revised 
RECIST guideline version 1.1. Eur J Can 45: 228-47, 2009.
4.
Kaplan EL, Meier P.  Nonparametric estimation from incomplete observations. J Am
Stat Assoc 1958; 53:457-481.
5.
National Cancer Institute (NCI). Common Terminology Criteria For Adverse Events
(CTCAE). http://evs.nci.nih.gov/ftp1/CTCAE/About.html


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9. APPENDICES
Appendix 1. Imputation of Missing/Partially Missing Dates
Missing data will not be imputed unless otherwise specified.  Any imputations will occur at 
the analysis dataset level and not the raw dataset level.  Additionally, in all patient data 
listings imputed values will be presented and flagged as imputed.
For safety analyses, incomplete date of last dose of study drug such as missing the day, the 
15th of the month will be used to impute the missing data. When imputing partial last dose
dates, the last assessment date and death date will be taken into consideration. This 
imputation rule will be used to determine the treatment-emergent period.  
Adverse Events
The imputation rule for the safety analyses will be used to address the issues with partial 
dates.  The imputed dates will be used to determine the treatment-emergent period.  For 
adverse events with a partial date, available date parts (year, month, and day) of the partial 
date will be compared with the corresponding date components of the start date and end date
of the treatment-emergent period to determine if the event is treatment emergent. When in
doubt, the adverse event will be considered treatment emergent by default. The following
rules will be applied to impute partial dates for adverse events:
If start date of an adverse event is partially missing, impute as follows:

If both month and day are missing and year = year of treatment start date, then set to
treatment start date.

If both month and day are missing and year ≠year of treatment start date, then set to
January 01.

If day is missing and( month and year) = (month and year) of treatment start date, then
set to treatment start date.

If day is missing and (month and year) ≠(month and year) of treatment start date, then
set to first of the month.

If start date is completely missing, set to treatment start date as long as adverse event
end date is not before treatment start date.
If end date of an adverse event is partially missing, impute as follows:

If both month and day are missing, then set to December 31.

If only day is missing, then set to last day of the month.

If end date is completely missing, do not impute.


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Concomitant Medications
When the start date or end date of a medication is partially missing, the date will be imputed
to determine whether the medication is prior or concomitant (or both).  The following rules 
will be applied to impute partial dates for medications:
If start date of a medication is partially missing, impute as follows:

If both month and day are missing, then set to January 01.

If only day is missing, then set to the first of the month.
If end date of a medication is partially missing, impute as follows:

If both month and day are missing, then set to December 31.

If only day is missing, then set to last day of the month.
If start date or end date of a medication is completely missing, do not impute.
Diagnosis of Primary Cancer
If the diagnosis date of primary cancer is partially missing, the following rules will be 
applied to impute partial dates:

If both month and day are missing and year = year of treatment start date, then set to 
treatment start date.

If both month and day are missing and year ≠ year of treatment start date, then set to 
December 31.

If day is missing and (month and year) = (month and year) of treatment start date, 
then set to treatment start date.

If day is missing and (month and year) ≠ (month and year) of treatment start date, 
then set to the last day of the month.


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Appendix 2. Sample SAS Code
Sample SAS code follows below.  The code is meant for a general start.  Further dialogue 
between the programmer and statistician is encouraged.  
KM quartiles and plot
proc lifetest data=x1 alpha=0.05 conftype=loglog plot=s;
time months*eventn(0);
run;
The variable “months” is a continuous variable representing months of exposure.  The 
variable “eventn” is a binary variable (0=censor, 1=event).
Hazard ratio
proc phreg data=x1;
model months*eventn(0) = group / rl alpha=0.05;
run;
The variable “months” is a continuous variable representing months of exposure.  The 
variable “eventn” is a binary variable (0=censor, 1=event).  The variable “group” is a binary 
variable for median cutpoint (below/above the median change from baseline).
Clopper-Pearson Confidence Interval
proc sort data=y1 out=y2;
by descending response;
proc freq data=y2 order=data;
tables response / binomial(exact) alpha=0.05;
run;
The descending sort is included to ensure that the response modeled is 1 and not 0.  The input 
dataset y1 has a one-record-per-patient format similar to:
PATIENT
RESPONSE
1001
0
1002
1
1003
0
…
…
…
…


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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ANCOVA Analysis
proc mixed data=z1;
class treat studysite;
model efchg = treat efbase studysite;
lsmeans treat / cl alpha=0.05 om;
run;
The variables “efchg” and “efbase” represent change from baseline and baseline values 
respectively.  The OM option is used when the categorical term “studysite” is used in the 
model.  If “studysite” is not included for convergence reasons, then the OM option can be 
removed.
While there is only one treatment arm in this study, the inclusion of the fixed effect for 
“treat” is needed in order to produce the desired least squares mean.


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Appendix 3. Analysis Windows for Reporting
The below applies to certain windowed summaries and analyses (eg, descriptive statistics by 
visit, change from baseline by visit, etc.).  Windows will be based on the patient’s date of 
first dose of study medication; the first day of dosing is Day 1.  
Adverse events, however, do not follow windows.
If there is more than one observation in a specific window, then the one closest to the target 
day will be selected for analysis.  If there are two observations that are equidistant to the 
target day, then the first of these two observations will be selected for analysis.  If there are 
two or more observations on the same selected day within the same analysis window, then 
the mean of these observations will be used.
Week
Target Day
Analysis Window
Week 5
29
Day 2 to Day 57
Week 13
85
Day 58 to Day 113
Week 21
141
Day 114 to Day 169
Week 29
197
Day 170 to Day 225
Week 37
253
Day 226 to Day 281
Week 45
309
Day 282 to Day 337
Week 53
365
Day 338 to Day 393
Week 61
421
Day 394 to Day 449
Week 69
477
Day 450 to Day 505
Week 77
533
Day 506 to Day 561
Week 85
589
Day 562 to Day 617
Week 93
645
Day 618 to Day 673
Week 101
701
Day 674 to Day 729
Week 109
757
Day 730 to Day 785
Week 117
813
Day 786 to Day 841
Week 125
869
Day 842 to Day 897
Week 133
925
Day 898 to Day 953
Week 141
981
Day 954 to Day 1009
Week 149
1037
Day 1010 to Day 1065
Week 157
1093
≥ Day 1066
Additional weeks if needed are derived by adding 8 weeks onto Week, and adding 56 days 
onto Target Day.  Lower and upper bounds are also adjusted by adding 56 days.


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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Appendix 4. Summary of Efficacy Analyses
Endpoint
Classificati
on
Population
Descriptive
analysis
Inferential
analysis
Proportion with 
responding bone 
lesions at NaF-3
Primary
AT*
Number and %
Point estimate and 
CI using Clopper-
Pearson method
Heterogeneity of 
response at NaF-3
Secondary
AT*
Summary stats 
and histograms
CCI


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Endpoint
Classificati
on
Population
Descriptive
analysis
Inferential
analysis
CCI


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Endpoint
Classificati
on
Population
Descriptive
analysis
Inferential
analysis
CCI


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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Endpoint
Classificati
on
Population
Descriptive
analysis
Inferential
analysis
CCI


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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Endpoint
Classificati
on
Population
Descriptive
analysis
Inferential
analysis
CCI


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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Endpoint
Classificati
on
Population
Descriptive
analysis
Inferential
analysis
CCI


Protocol MDV3100-18 (C3431012) (Enzalutamide) Statistical Analysis Plan
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Endpoint
Classificati
on
Population
Descriptive
analysis
Inferential
analysis
Chg: change; bsl: baseline; Obs: observed, LSMean: least-squares mean
* And non-missing scans at NaF-1 and NaF-3.
CCI
CCI


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10. ABBREVIATIONS
AE
Adverse event
ANCOVA
Analysis of covariance
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AT
As treated
BLQ
Below the level of quantification
CI
Confidence interval
CSR
Clinical study report
CTC
Circulating tumor cells
CTCAE
Common terminology criteria for adverse events
EpCAM
Epithelial cell adhesion molecule
GM
Geometric mean
HR
Hazard ratio
KM
Kaplan-Meier
LOA
Limit of agreement
LSMean
Least-squares mean
MedDRA
Medical dictionary for regulatory activities
NCI
National Cancer Institute
OM
Observed margins
PSA
Prostate specific antigen
PT
Preferred term
RECIST
Response evaluation criteria in solid tumors
SAP
Statistical analysis plan
SOC
System organ class
StD
Standard deviation
SUV
Standardized uptake value
TEAE
Treatment emergent adverse event
ULN
Upper limit of normal