Clinical trial NCT01927627
Conditions: Adenocarcinoma of the Prostate
Keywords: Prostate cancer adenocarcinoma of the prostate Enzalutamide
Sponsor: Case Comprehensive Cancer Center
Start date: 2013-11-11; Completion date: 2017-04-26
Enrollment: 42 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to see how long it takes for prostate cancer to come back in patients who have had surgery to remove their prostate gland (radical prostatectomy), while being treated with enzalutamide (formerly known as MDV3100).

Enzalutamide is known as an androgen-receptor signaling inhibitor, which means that it blocks activity of the male hormone, testosterone. Most prostate cancers are dependent on testosterone for growth. In this study, patients will take enzalutamide after surgery to see if it keeps their cancer from coming back.

Detailed description:
This is a pilot phase II study evaluating the clinical activity and safety of Enzalutamide (formerly known as MDV3100) a novel androgen receptor (AR) inhibitor in men with high-risk prostate cancer who have undergone local definitive therapy with radical prostatectomy.

Primary Objectives:

-To evaluate the clinical efficacy of enzalutamide in patients with high-risk prostate cancer with regards to: Time to disease progression defined by biochemical recurrence (BCR)

Secondary Objectives:

-To further evaluate the safety of enzalutamide in patients with high-risk prostate cancer

Patients will receive daily oral therapy with enzalutamide at 160mg (4 capsules) orally once daily (QD). Patients will continue on study until progressive disease, drug intolerability, consent withdrawal or completion of study at 24 months.

Arms: arm 1: Oral therapy with enzalutamide at 160mg (4 capsules) orally once daily (QD).
Interventions: intervention 1: enzalutamide
Intervention descriptions: intervention 1: oral therapy with enzalutamide at 160mg (4 capsules) orally once daily (QD).

Protocol documents:
Prot_SAP_000.pdf: 
CCF- Adjuvant Enzalutamide in High-risk PCa  
 
TITLE:   A Phase 2 Study of Enzalutamide in patients with High-risk Prostate Cancer who have 
undergone local definitive therapy with Radical Prostatectomy 
 
Coordinating Center:  
 
 
Cleveland Clinic 
 
*Principal Investigator: 
Jorge A. Garcia, MD., FACP. 
 
 
 
Taussig Cancer Institute 
 
Cleveland Clinic 
 
9500 Euclid Ave, Cleveland, OH 44195 
 
216-444-7774 
 
216-444-9464 
 
garciaj4@ccf.org 
 
*Co-Principal Investigator: 
Andrew Stephenson, MD 
 
Glickman Urological and Kidney Institute 
 
Cleveland Clinic 
 
216-445-1062 
 
216-636-4492 
 
Stephea2@ccf.org 
 
Co-Investigators: 
 
Eric A. Klein, MD 
 
 
 
 
 
Petros Grivas, MD, PhD 
Chairman 
 
 
 
 
 
Taussig Cancer Institute 
Glickman Urological and Kidney Institute 
 
 
Cleveland Clinic 
Cleveland Clinic 
 
 
 
 
 
216-636-0100 
216-444-5601 
 
 
 
 
 
216-444-9464 
216-636-4492 
 
 
 
 
 
grivasp@ccf.org  
KLEINE@ccf.org 
 
 
Timothy Gilligan, MD 
 
 
 
 
 
Cristina Magi-Galluzzi, MD., PhD.  
Taussig Cancer Institute 
 
 
 
 
 
Pathology Department 
Cleveland Clinic 
 
 
 
 
 
Cleveland Clinic 
216-444-0391 
 
 
 
 
 
216-444-9251 
216-444-9464 
 
 
 
 
 
216-445-6967 
gilligt@ccf.org 
 
 
 
 
 
MAGIC@ccf.org 
 
Responsible Research Nurse:  
 
Responsible Data Manager: 
Allison Tyler, RN, BSN, OCN 
Kimberly Schach 
Taussig Cancer Institute 
Taussig Cancer Institute 
Cleveland Clinic 
Cleveland Clinic 
216-445-0861 
216-636-5628 
216-444-0114 
216-636-5628 
tylera2@ccf.org 
schachk@ccf.org 


CCF- Adjuvant Enzalutamide in High-risk PCa 
Protocol Version # 13:  08JUN2015 
 
ii
Statistician: 
 
 
Study Coordinator: 
Paul Elson, ScD.  
Kimberly Schach 
Taussig Cancer Institute 
Taussig Cancer Institute 
Cleveland Clinic 
Cleveland Clinic 
216-444-7775 
216-636-5628 
216-636-2498 
216-636-5628 
elsonp@ccf.org 
schachk@ccf.org 
 
Protocol Type / Version # / Version Date: 
Amendment / Version # 13 /  08/JUN/2015 
 


CCF- Adjuvant Enzalutamide in High-risk PCa 
Protocol Version # 13:  08JUN2015 
 
iii
SYNOPSIS 
 
This is a pilot phase II study evaluating the clinical activity and safety of Enzalutamide (formerly 
known as MDV3100) a novel androgen receptor (AR) inhibitor in men with high-risk prostate 
cancer who have undergone local definitive therapy with radical prostatectomy. Despite the 
limitations of interpreting PSA outcome in this clinical setting, time to disease progression (TTP) 
(serologic progression) was selected as the primary endpoint of the trial. Traditional secondary 
endpoints in this setting will include tolerability and safety. All eligible patients will receive 
enzalutamide, 160mg orally daily in a 28-day cycle regimen for 24 months or until disease 
progression or drug intolerance. Radiographic assessment will be conducted only if patients 
develop biochemical recurrence.  
 


CCF- Adjuvant Enzalutamide in High-risk PCa 
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iv 
TABLE OF CONTENTS 
 
Page 
1. Objectives .................................................................................................................................. 1 
2. Background ............................................................................................................................... 1 
3. Rationale ................................................................................................................................... 7 
4. Patient Selection ....................................................................................................................... 7 
5. Registration Procedures ............................................................................................................ 9 
6.  Treatment Plan........................................................................................................................ 10 
7. Dose Delays/Modifications ..................................................................................................... 13 
8.  Pharmaceutical Information ................................................................................................... 14 
9. Study Calendar ........................................................................................................................ 16 
10. Study Assessments .................................................................................................................. 17 
11. Measurement of Effect ........................................................................................................... 19 
12. Adverse Events/Data Safety Monitoring Plan ........................................................................ 19 
13. Statistics .................................................................................................................................. 24 
14. References .............................................................................................................................. 25 
 
Appendix I ..................................................................................................................................... 29 
Appendix II .................................................................................................................................... 30 
Appendix III ................................................................................................................................... 31 
Appendix IV ................................................................................................................................... 32 
Appendix V .................................................................................................................................... 34 
Appendix VI ................................................................................................................................... 35 
 
 
 
 
 
 


CCF- Adjuvant Enzalutamide in High-risk PCa 
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1
1. OBJECTIVES 
 
1.1. 
Primary Objectives 
 
1.1.1. To evaluate the clinical efficacy of enzalutamide in patients with high-risk 
prostate cancer with regards to: 
 
1.1.1.1. Time to disease progression defined by biochemical recurrence (BCR) 
 
1.2. 
Secondary Objectives 
 
1.2.1. To further evaluate the safety of enzalutamide in patients with high-risk prostate 
cancer 
 
2. BACKGROUND 
 
2.1 Study Disease 
Prostate cancer is the second-leading cause of cancer death in men in the United States. 
It is expected that more than 241,740 new cases will be diagnosed in 2012. [1] Despite 
the widespread use of prostate-specific antigen (PSA) screening, a significant number of 
patients are diagnosed with high-risk or locally advanced disease.  
 
Existing risk-stratification criteria including more contemporary tools have permitted us 
to define this population at risk for systemic disease. [2, 3] To date, pathological stage, 
Gleason Score (GS) and nodal disease after surgery remain the most common features 
used to determine the risk of recurrence after radical prostatectomy. According to the 
preoperative D’Amico criteria, RP alone in patients with high-risk PCa leads to a cure in 
about 50% of cases. [3] Although quite heterogeneous, recurrence is mostly due to 
distant micrometastases and is often manifested first by a rising PSA. The goal of 
adjuvant therapy is to control and/or treat distant micrometastases, delay/avoid 
progression and ultimately improve survival. Outside of post-operative radiation 
therapy (RT) for those with node negative high-risk disease, no standard adjuvant 
systemic treatments after surgery exist. Existing data using adjuvant androgen 
deprivation therapy (ADT) significantly improves survival in patients with positive lymph 
nodes. [4, 5] The limitation of this data however is the lack of understanding of the 
appropriate timing to initiate ADT and the known long-term complications of 
testosterone suppression.  In the case of negative lymph nodes, the survival advantage 
has not been demonstrated. [6]  
 
Similar data exist with chemotherapy when offered to high-risk patients in the peri-
operative setting. [7, 8] Neoadjuvant chemotherapy has been studied in multiple phase 
2 trials. Despite the heterogeneity in the chemotherapy regimen, the utility of this 
approach is quite limited. Although chemotherapy prior to surgery appears to be safe, 
no pathological complete response (pCR) has been observed. Similarly, time to PSA 


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2
progression and overall survival remained unaffected. [9-13] Two large studies have 
addressed the role of adjuvant therapy for high-risk disease. The first one, TAX305 
unfortunately closed due to pour accrual. [14] This trial randomized patients to either 
observation or treatment. Patients on the treatment arm were randomized to receive 
standard androgen deprivation therapy +/- 6 cycles of docetaxel based chemotherapy. 
Cross over to the treatment arm was allowed at the time of biochemical recurrence 
(BCR) for patients initially randomized to the observation arm. A similar trial, SWOG 
(Southwest Oncology Group) S9921 randomly assigned 983 men with high-risk features 
at prostatectomy to receive adjuvant therapy with androgen deprivation (ADT) alone or 
in combination with mitoxantrone chemotherapy. ADT consisted of goserelin and 
bicalutamide for 2 years. SWOG 9921 was closed to further accrual after three cases of 
acute myelogenous leukemia (AML) were reported of a total of 487 patients in the 
mitoxantrone treatment arm. [15] Although the final primary treatment comparison 
results have not been published, a report by Dorff et al [16] reported the outcome of 
patients receiving ADT-alone (n=485). The estimated 5-year biochemical failure-free 
survival was 92.5% (95% CI, 90 to 95), and 5-year overall survival was 95.9% (95% CI, 
93.9 to 97.9). 
 
Radiotherapy has been another modality commonly employed to treat patients with 
high-risk disease after RP. The rationale for immediate adjuvant RT is to gain local 
control by eradicating residual tumor in patients with undetectable PSA but featuring 
high-risk pathologic features (eg, high Gleason score, extraprostatic extension, seminal 
vesicle invasion [SVI], and positive surgical margins (PSM). Two recent, large, 
randomised trials demonstrated the impact of this approach in this cohort of patients. 
Adjuvant RT decreases biochemical recurrence risk with improved local control, delays 
time to metastases, time to ADT initiation and in the intergroup US trial improvement in 
OS. [17-19] 
 
Despite of the existing data, the management of high-risk patients remains a major 
clinical challenge. There is no convincing evidence that either systemic therapies or local 
adjuvant RT truly impact outcome. As such, most patients in the US elect to undergo 
observation. Understanding the risk of recurrence in this cohort of patients, there is a 
pressing need to develop novel and non toxic therapies that can be utilized in the 
adjuvant setting with the goal of reducing the risk if recurrence and to improve overall 
survival. 
 
2.2 Enzalutamide and Androgen Receptor 
The androgen receptor (AR) is a well-known target in prostate cancer as disease growth 
is initially dependent on androgens. Depleting or blocking androgen action has been a 
mainstay of treatment for over 6 decades in the setting of metastatic disease or when 
prostate cancer recurs following resection and/or radiation. In addition, AR expression 
has been noted in a variety of breast cancers and an emerging body of data suggests 
that tumor growth may be promoted through the AR. Enzalutamide is an androgen 
receptor signaling inhibitor (ARSI) rationally designed to block multiple steps in the AR 


CCF- Adjuvant Enzalutamide in High-risk PCa 
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3
signaling pathway and to be devoid of agonist activity. Enzalutamide inhibits androgen-
induced receptor activation (binding of androgens to ARs in the cytosol), inhibits nuclear 
translocation of activated ARs, and inhibits the association of the activated AR with 
chromatin, even in the setting of AR overexpression and in prostate cancer cells 
resistant to anti-androgens such as bicalutamide. The consequence of enzalutamide AR 
signaling inhibition is decreased growth of prostate cancer cells, induction of cancer cell 
death, and tumor regression. The apoptotic effect of enzalutamide is consistent with AR 
blockade. Enzalutamide induces cleavage of poly (adenosine diphosphate-ribose) 
polymerase (PARP), a marker of apoptosis, in prostate cancer cells while bicalutamide 
treatment has no effect on PARP cleavage. [20] In a mouse xenograft model of 
castration-resistant prostate cancer, enzalutamide dose-dependently reduced tumor 
volume while bicalutamide treatment showed no significant benefit [Investigator’s 
Brochure 2012]. 
 
2.3 Non Clinical and Clinical Data 
2.3.1 Non Clinical 
Safety pharmacology studies in mice, rats, and dogs were performed with enzalutamide 
to assess any acute effects on central nervous system, respiratory, and cardiovascular 
parameters. No enzalutamide-related effects were noted in the central nervous system 
study assessing a functional observation battery and in a respiratory study in rats. 
Enzalutamide inhibits the human ether-a-go-go-related gene (hERG) channel; however, 
the highest free concentrations of enzalutamide expected in patient plasma at a steady-
state dose of 160 mg/day are well below the hERG IC50 value. No enzalutamide -related 
effects on cardiac electrophysiology were noted in a safety pharmacology study in 
conscious, telemetered dogs.  
 
As enzalutamide inhibits the GABA-gated chloride channel, convulsion potential was 
assessed in single- and multiple-dose studies in mice. [21]. Oral enzalutamide daily for 7 
days was associated with convulsions in a dose-dependent manner with doses ≥200 
mg/kg being active. When administered as a single dose of 400 mg/kg enzalutamide 
treatment was also associated with convulsions. At the highest dose at which no 
convulsions occurred (single dose, 100 mg/kg), the maximum plasma concentration 
(Cmax) and area under the curve at 24 hours after dosing (AUC24) were at least 2.5-
times higher than those in patients receiving 160 mg/day. Enzalutamide is metabolized 
primarily to 2 metabolites, M1 (a carboxylic acid derivative) and M2 (N-desmethyl 
enzalutamide). The metabolite M2 has a pharmacology profile similar to that of the 
parent molecule and may contribute to the therapeutic effects of enzalutamide in 
patients. M2 also binds to and inhibits the GABA-gated chloride channel with potency 
similar to that of the parent molecule and may contribute to convulsion risk. Metabolite 
M1 does not have significant pharmacological actions and probably does not contribute 
to the therapeutic effects of enzalutamide. 
 
2.3.2 Clinical 
The pharmacokinetics (PK), tolerability, and antitumor activity of enzalutamide were 


CCF- Adjuvant Enzalutamide in High-risk PCa 
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4
first studied in a multi-center, open-label, first-in-human, dose-escalation study in 140 
patients with castration-resistant prostate cancer (S-3100-1-01) [Scher, 2010]. Patients 
who were chemotherapy-naïve or who had previously failed docetaxel-based 
chemotherapy were treated with enzalutamide at doses of 30 to 600 mg/day until 
disease progression or intolerable side effects developed. Enzalutamide was absorbed 
rapidly after oral administration, with the time to Cmax after a single dose typically 
occurring at 1-hour post dose. No major deviations from dose proportionality were 
observed over the dose range 30 to 600 mg. Due to the long t1/2 (~ 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 AUC) relative to a single dose. Based on the mean peak-to-
trough ratio, the average difference between the peak (Cmax) and trough (Cmin) 
concentrations was ≤ 25%. As a result of the low daily fluctuations, plasma profiles at 
steady-state resembled a constant infusion. The Cmin values in individual patients 
remained constant beyond Day 28 of chronic therapy, suggesting time-linear PK once 
steady state was achieved.  
 
The maximum tolerated dose was determined to be 240 mg daily. Enzalutamide 
demonstrated antitumor activity across endpoints in patients both with and without 
previous exposure to chemotherapy. The antitumor activity endpoints included 
prostate-specific antigen (PSA) reduction from baseline, median time to PSA 
progression, responses on imaging, and circulating tumor cell conversion from favorable 
to unfavorable counts. Three potential enzalutamide-associated toxicities were 
identified in this study: fatigue, rash, and seizure. Three seizures (2 witnessed, 1 
unwitnessed) occurred in this study at doses of 360, 480, and 600 mg/day, and were 
reported between 26 and 48 days after initiation of enzalutamide.  
 
After review of all data available from the S-3100-1-01 study, the optimal dose of 
enzalutamide for evaluation in Phase 3 clinical trials was determined to be 160 mg/day. 
A Phase 3, randomized, double-blind, placebo-controlled efficacy and safety study of 
oral enzalutamide (160mg daily) in patients with progressive castration-resistant 
prostate cancer (CRPC) previously treated with docetaxel-based chemotherapy (CRPC2, 
also known as AFFIRM) was conducted in 1199 men, 800 of whom received treatment 
with enzalutamide. 
 
A formal interim analysis of overall survival was performed at 520 events (80% of the 
650 targeted number of events for final analysis) and demonstrated a statistically-
significant increase in the duration of survival among patients treated with 
enzalutamide compared with patients treated with placebo [hazard ratio = 0.631 (95% 
CI 0.529, 0.752), p < 0.0001]. Median survival was 18.4 months in the enzalutamide arm 
and 13.6 months in the placebo arm (Ä = 4.8 months). The survival benefit was seen in 
all pre-specified patient subgroups defined by age, geographic region, ECOG 
performance status, pain score, Gleason score, number of prior chemotherapy 
regimens, type of disease progression at study entry, baseline level of PSA, baseline 


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5
level of hemoglobin, and baseline level of lactate dehydrogenase (LDH). There were also 
statistically-significant increases in radiographic progression-free survival (assessed by 
CT or MRI and by bone scan); time to first skeletal-related event; time to PSA 
progression; PSA response, and overall objective soft tissue radiographic response 
among patients treated with enzalutamide compared to placebo. In addition, 
statistically-significant differences favoring enzalutamide over placebo in pain palliation 
and pain progression rate at Week 13 were also observed. 
 
2.4 Enzalutamide Key Safety Summary Information 
The safety and tolerability of enzalutamide have been evaluated in 13 studies, including 
2 completed studies (Phase 1), 7 active studies (Phase 1 through 3), and 4 enrolling 
studies (Phase 2 through 3). It is estimated that a total of 124 healthy volunteers, 16 
subjects with hepatic impairment, and approximately 1800 patients with prostate 
cancer have been exposed to enzalutamide in completed, open-label, and ongoing 
blinded studies. In the completed interim analysis of the randomized, double-blind, 
placebo-controlled Phase 3 efficacy and safety study in patients with progressive 
castration-resistant 
prostate 
cancer 
previously 
treated 
with 
docetaxel-based 
chemotherapy (CRPC2), 800 patients received enzalutamide (160 mg daily). The 
duration of enzalutamide exposure in this study ranged from 1 day to 23.3 months 
(median 8.3 months). 
 
 
Safety data are presented from the formal interim analysis of data from the CRPC2 
study, with a data cut-off date of 25 September 2011. Table 1 provides an overview of 
exposure to study drug, adverse events, and deaths. 
 
Table 1 
 
Treated (Safety Population) Enzalutamide 
Enzalutamide 
(n = 800) 
Placebo 
(n = 399) 
Discontinued Treatment 
569 (71.1%) 
380 (95.2%) 
Treatment Duration (median months) 
8.3 
3.0 
Patients with ≥ 1 Treatment Emergent Adverse Event 
785 (98.1%) 
390 (97.7%) 
Patients with ≥ 1 Treatment Emergent Adverse Event 
(Grade 3 or Higher) 
362 (45.3%) 
212 (53.1%) 
Patients with ≥1 Serious Treatment Emergent Adverse 
Event 
268 (33.5%) 
154 (38.6%) 
Patients with an Adverse Event Leading to Death 
23 (2.9%) 
14 (3.5%) 
Patients with Adverse Events Leading to Study Drug 
Discontinuation 
61 (7.6%) 
39 (9.8%) 
SUSARs (all in unique patients) 
10 
6 
Deaths  
308 (38.5%) 
212 (53.1%) 
 
Enzalutamide (160 mg daily) was generally well-tolerated in the placebo-controlled CRPC2 


CCF- Adjuvant Enzalutamide in High-risk PCa 
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6
study of 1199 patients with progressive castration-resistant prostate cancer previously 
treated with docetaxel-based chemotherapy. Adverse events reported by those treated 
with enzalutamide (160 mg daily) with an incidence of at least 5% and by at least 2% greater 
than by those who received placebo included fatigue (33.6% v 29.1%), diarrhea (21.4% v 
17.5%), hot flush (20.3% v 10.3%), musculoskeletal pain (13.6% v 10.0%), headache (11.6% v 
5.5%), insomnia (8.6% v 6.0%), anxiety (6.4% vs. 4.0%), hypertension (6.1% v 2.8%), and 
nasopharyngitis (5.1% v 3.0%). Other adverse events reported less commonly than 5% but 
that may be associated with enzalutamide treatment after careful assessment of the 
adverse events include: falls (4.0% vs. 1.3%), dry skin (3.6% vs. 1.3%), and pruritus (3.5% vs. 
1.3%).  
 
A greater proportion of patients in the enzalutamide -treated group (4.1% vs. 1.8%) 
reporting the following adverse event terms: memory impairment, cognitive disorder, 
amnesia, disturbance of attention, and dementia. In addition, event terms related to 
hallucination (visual hallucination and tactile hallucination) were reported more frequently 
in the enzalutamide -treated group (1.6% vs. 0.3%). Serious adverse events that occurred at 
a ≥ 0.5% absolute difference in event frequency and more frequently in the enzalutamide 
arm than the placebo arm included: spinal cord compression (6.0% vs. 3.8%), bone pain 
(1.5% vs. 1.0%), metastatic pain (1.5% vs. 0.8%), pathological fracture (1.5% vs. 0.5%), 
urinary tract infection (0.9% vs. 0.3%), and cauda equina syndrome (0.8% vs. 0.0%). Seizure 
is a known potential toxicity of enzalutamide. In vitro studies have shown that Enzalutamide 
and its metabolite M2 bind to the GABA-gated chloride channel with IC50 values of 1.2 
ìg/mL and 3.3 ìg/mL, respectively and in a cell-based assay inhibit the channel’s activity with 
IC50 values of 1.4 ìg/mL and 1.07 ìg/mL, respectively. Some compounds that inhibit the 
GABA-gated chloride channel are associated with seizures. [21] In the first clinical study of 
enzalutamide (S-3100-1-01), a dose-escalation study in men with castration-resistant 
prostate cancer with and without prior exposure to chemotherapy, the following doses 
were evaluated: 30, 60, 150, 240, 360, 480 (as 240 mg twice per day [BID]), and 600 (as 300 
mg BID) mg/day. Three patients were reported to have dose-limiting toxicities of seizure, 
one each at doses of 360, 480, and 600 mg/day. The results of this study led to the selection 
of the clinical dose of Enzalutamide of 160 mg/day. 
 
As of the database cut-off date for the respective unblinded or open-label studies reported 
in the Investigator’s Brochure, 7 patients out of a total of 1100 patients (0.6%) exposed to 
enzalutamide at a dose of 160 mg/day have reported a seizure during the enzalutamide 
treatment emergent adverse event reporting period. These include one patient each in 
studies 9785-CL-0007 and 9785-CL-0321, and 5 patients in the CRPC2 study. Two additional 
patients have been identified by the Sponsor to have experienced adverse events that may 
have been seizures, including one case reported by the Investigator as syncope (CRPC2) and 
the other reported as a transient ischemic attack with an abnormal electroencephalogram 
(CRPC-MDA-1). As of the data cut-off date, treatment with enzalutamide at a daily dose of 
160 mg is associated with a 0.6-0.8% risk of seizure in men with late-stage castration-
resistant prostate cancer. Taking into account information from ongoing blinded studies and 
events occurring after the database cut-off date, the range for seizure risk is unchanged. No 


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seizures have been reported in the blinded placebo controlled Phase 3 study PREVAIL with 
over 1300 patients enrolled (randomized 1:1 to enzalutamide 160 mg/day or placebo). One 
additional patient in the CRPC2 study has been reported to have had a seizure after the 
safety data cut-off date, and one additional patient in an ongoing blinded study (9785-CL-
0222) has also reported a seizure. Please see the most current version of the Investigator 
Brochure for additional details. 
 
3 Rationale 
The current standard of care for men with high-risk prostate cancer after radical 
prostatectomy is observation or adjuvant RT. Although RT has demonstrated to impact 
outcome, timing of this technique remains controversial. Similarly, the utility of RT for men 
with high-risk disease with microscopic disease in lymph nodes remains unknown. ADT for 
this patient population also remains controversial due to the long-term complications 
related to early testosterone suppression. The existing clinical data with enzalutamide in the 
castrate-resistant setting is quite robust and provides the support to test this novel AR 
inhibitor in an earlier state of the disease with the goal of improving outcome in patients 
with high-risk disease whom are destined to develop systemic disease. 
 
4 Patient Selection 
4.1 Inclusion Criteria 
4.1.1 Understand and voluntarily sign an informed consent form. 
4.1.2 Age 18 years at the time of signing the informed consent form. 
4.1.3 Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
[Appendix 1] 
4.1.4 Histologically confirmed adenocarcinoma of the prostate. 
4.1.5 Patients must have undergone a Radical Prostatectomy (any surgical technique is 
permitted) within 3 months from study entry and have high-risk disease define 
by any of the following: 
4.1.5.1 Pathological stage T3a, T3b, T4 (any grade or iPSA) 
4.1.5.2 Gleason’ sum > 8 (any stage or iPSA) 
4.1.5.3 Initial Pre-operative PSA > 20ng/mL (any GS or pT stage) 
4.1.5.4 Any stage/PSA/Gleason patients with a 35% or greater chance of biochemical 
failure at 5 years based on Kattan's nomogram [Appendix 2] 
http://nomograms.mskcc.org/Prostate/PostRadicalProstatectomy. 
4.1.5.5 Patients with Lymph node (LN) positive disease, regardless of iPSA, pT stage 
or GS provided their post-operative PSA 6-8 weeks after surgery is < 
0.4ng/mL. (Lymph node dissection is desired but not mandated) 
4.1.6 
Able to swallow the study drug and comply with study requirements. 
4.1.7 
Patients must have normal organ and marrow function as defined below: 
4.1.7.1 Testosterone > 50 ng/dL per laboratory reference range 
4.1.7.2  Baseline Post-RP PSA < 0.4 
4.1.7.3 Hemoglobin ≥ 10.0 g/dL independent of transfusion 
4.1.7.4 Absolute neutrophil count >1,500/mcL 
4.1.7.5 Platelet count ≥100,000/ìL 


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8
4.1.7.6 Serum albumin ≥ 3.5 g/dL 
4.1.7.7 Serum potassium ≥ 3.5 mmol/L 
4.1.7.8 Liver function: serum bilirubin < 1.5 x ULN (except for patients with 
documented Gilbert’s disease) and AST or ALT < 2.5 x ULN 
 
4.2 Exclusion Criteria 
4.2.1 Severe concurrent disease, infection, or co-morbidity that, in the judgment of 
the investigator, would make the patient inappropriate for enrollment 
4.2.2 Prior radiotherapy to the prostate or pelvis (related to prostate cancer).  
Concurrent adjuvant radiation therapy is permitted once patient has been 
enrolled on trial. 
4.2.3 Prior use of Abiraterone acetate or cytotoxic chemotherapy for prostate cancer 
4.2.4 Prior androgen deprivation with LHRH is permitted provided that testosterone 
levels prior to study entry have recovered to normal limits per reference 
laboratory. 
4.2.5 No prior anti-androgen therapy (bicalutamide, flutamide or Nilutamide) is 
permitted 
4.2.6 Prior use of 5-alpha reductase inhibitors is permitted provided such medications 
were stopped 7-14 days prior to enrollment 
4.2.7 Use of herbal products that may have hormonal anti-prostate cancer activity 
and/or are known to decrease PSA levels (e.g., saw palmetto) or systemic 
corticosteroids greater than the equivalent of 10 mg of prednisone per day 
within 2 weeks of enrollment 
4.2.8 Active unresolved infection 
4.2.9 Known history of CNS metastases 
4.2.10 Patients must have no known history of HIV 
4.2.11 Evidence of metastatic disease as evidenced by a CT or MRI of abdomen and 
pelvis and/or whole body bone scan (WBS). To be done prior to treatment start 
and up to 4 months prior to radical prostatectomy date.  
4.2.12 History of seizure or any condition that may predispose to seizure (e.g., prior 
cortical stroke, significant brain trauma). Also, history of loss of consciousness or 
transient ischemic attack within 12 months of enrollment. 
4.2.13 Clinically significant cardiovascular disease including: 
4.2.13.1 
Myocardial infarction within 6 months prior to Screening; 
4.2.13.2 
Uncontrolled angina within 3 months prior to Screening; 
4.2.13.3 
Congestive heart failure New York Heart Association (NYHA) class 3 or 4,  
 or patients with history of congestive heart failure NYHA class 3 or 4 in 
the past, unless a screening echocardiogram (ECHO) or multi-gated 
acquisition scan (MUGA) performed within 3 months results in a left 
ventricular ejection fraction that is ≥ 45% 
4.2.13.4 
History of clinically significant ventricular arrhythmias (e.g., ventricular  
 
 
tachycardia, ventricular fibrillation, torsades de pointes) 
4.2.13.5 
History of Mobitz II second degree or third degree heart block without a  
 
 
permanent pacemaker in place 


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4.2.13.6 
Hypotension as indicated by systolic blood pressure < 86 mmHg at the  
 
 
Screening visit 
4.2.13.7 
Bradycardia as indicated by a heart rate of < 50 beats per minute at the 
screening visit.   
4.2.13.8 
Uncontrolled hypertension as indicated by systolic blood pressure > 170   
 
 
mmHg or diastolic blood pressure > 105 mmHg at the Screening visit 
4.2.14 Gastrointestinal disorder affecting absorption (e.g., Gastrectomy, active peptic 
ulcer disease within last 3 months) 
4.2.15 Any condition or reason that, in the opinion of the Investigator, interferes  
with the ability of the patient to participate in the trial, which places the patient 
at undue risk, or complicates the interpretation of safety data. 
4.2.16 The effects of enzalutamide on the developing human fetus at the 
recommended therapeutic doses are unknown. Thus, men must agree to use 
adequate contraception (barrier method of birth control or abstinence) prior to 
study entry, for the duration of study participation, and for 6 months after the 
usage of enzalutamide. Should the patient's partner become pregnant or suspect 
she is pregnant while the patient is participating in this study, the patient should 
inform his treating physician immediately. 
 
5 
Registration Procedures 
5.1 
General Guidelines 
Eligible patients will be entered on study centrally at the Cleveland Clinic Taussig 
Cancer Institute by the Study Coordinator. Following registration, patients should 
begin protocol treatment within 14 working days. If a patient does not receive 
protocol therapy following registration, the patient’s registration on the study may 
be canceled. The Study Coordinator should be notified of cancellations as soon as 
possible. 
5.2 
Pre-treatment Evaluation: Clinical: required within 14 days before the first cycle “or 
as otherwise indicated” 
5.2.1 History and physical examination, including height, weight, and vital signs 
5.2.2 Performance status evaluation 
5.2.3 Laboratory /Diagnostic: required within 14 days before the first cycle. 
5.2.3.1 CBC, platelet count, and automated differential.  
5.2.3.2 Serum chemistries: includes BUN, Creatinine, ALT, and AST, glucose, alkaline 
phosphatase, total bilirubin and LDH. 
5.2.3.3 Testosterone level 
5.2.3.4 PSA 
5.2.3.5 Baseline correlative studies 
5.2.3.6 Imaging/Diagnostic:  Must be performed prior to treatment start and up to 4 
months prior to radical prostatectomy date.: Baseline imaging studies to 
document the presence or not of measurable disease. (Whole body bone 
scan and MRI or CT scans of abdomen/pelvis).  Pre-operative imaging, done 
within 4 months of surgical date may be used for screening purposes. 
 


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5.3 
Registration Process 
To register a patient, the following documents should be completed by the research 
nurse or data manager and e-mailed to  Kimberly Schach at Schachk@ccf.org [the 
Study Coordinator]: 
 Registration Form  
 Eligibility Worksheet  
 Copy of source documentation (required laboratory tests, radiographic scans, 
physician notes, nursing notes, list of medications, pathology/surgical 
reports, etc.) 
 Signed patient consent form 
 HIPAA authorization form 
 
To complete the registration process, the Coordinator will 
 Verify patient eligibility worksheet is complete 
 Request additional documentation if necessary 
 Assign a patient study number 
 Register the patient on the study using the ONCORE database 
 E-mail a letter of Confirmation of Registration, including the patient study 
number, to the responsible research nurse 
 
6 Treatment Plan 
6.1 Identity of Investigational Product 
Enzalutamide has the chemical name 3-(4-cyano-3-trifluoromethylphenyl)-1-[3-fluoro-4- 
(methylcarbamoyl) phenyl]-5,5-dimethyl-2-thioxoimidazolin-4-one. It is a white to off-
white solid that is insoluble in water and no salt forms are available at ~pH 2 to 10. The 
drug substance is formulated in the surfactant caprylocaproyl polyoxylglycerides, or 
Labrasol®. The product will be supplied as white to off white gelatin capsules containing 
40 mg of enzalutamide.  
 
6.2 Agent Administration 
Treatment will be administered on an outpatient basis and will consist of 28-day cycles.   
A delay of cycle due to holidays, weekends, and bad weather or other unforeseen 
circumstances will be permitted and not counted as a protocol deviation. 
 
6.2.1 Patients will receive daily oral therapy with enzalutamide at 160mg (4 capsules) 
orally once daily (QD). Patients will continue on study until progressive disease, 
drug intolerability, consent withdrawal or completion of study at 24 months. 
 
6.2.2 Enzalutamide tablets should be taken at approximately the same time of day and 
at regular intervals (i.e., approximately every 24 hours). If a patient misses a dose 
of study drug, he may take the missed dose at any time up to 6 hours before the 
next intended dose on that day and should not be taken on a subsequent day. 
Patients will be instructed to notify study site personnel of any missed doses. 


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6.2.3 Enzalutamide can be taken with or without food 
 
6.3 Treatment Compliance 
At all times, when dispensing study drug, research center personnel will review the 
instructions, printed on the packaging, with subjects. Subjects will be asked to maintain 
a diary to record the drug administration. Subjects will be asked to bring any unused 
study drug and empty bottles to the research center at their next visit. Research 
personnel will count and record the number of used and unused study drug capsules at 
each visit.   Regardless of the reason, the maximum time off enzalutamide allowed will 
be 21 consecutive days. 
 
6.4 Dose Reduction/Dose Adjustment 
Patients who experience a Grade (G) 3 or greater toxicity that cannot be ameliorated by 
the use of adequate medical intervention may have their treatment interrupted until 
the toxicity improves to a Grade 2 or lower severity. Patients may subsequently be re-
started on study drug at a reduced dose as per Section 8. 
 
6.5 Management of Overdose 
An overdose is defined as 2 days of study drug taken over the course of a 24 hour 
period. Neither the effects of overdose of enzalutamide nor an antidote to overdose are 
known. In case of overdose of enzalutamide, symptomatic treatment with frequent 
monitoring is recommended. 
 
6.6 General Concomitant Mediations and Supportive Care Guidelines 
Medication taken within 4 weeks prior to enrollment and any medications prescribed 
chronically or intermittently during the study or dose adjustments of these medications 
must be captured on the research nurse notes. Concomitant medications will be 
assessed at screening and all clinic visits. The dosage and regimen of the following 
medications and any chronic permitted concomitant medications should be stabilized 
during the screening period and held constant throughout the study. 
No formal clinical drug-drug interaction studies have been completed with 
enzalutamide.  
In vitro studies show that enzalutamide is an inhibitor of CYP2C8 and CYP2C19 with 
lesser inhibitory effects on CYP2B6 and CYP2C9. Substrates of CYP2B6, CYP2C8, CYP2C9, 
and CYP2C19 that have a narrow therapeutic index should be used with caution. 
 
In vitro studies show that enzalutamide is an inhibitor of the efflux transporter 
permeability glycoprotein (P-gp). Use caution when co-administering P-gp substrates 
during enzalutamide treatment. 
 
In vitro studies show that enzalutamide is an inducer of CYP3A4. Induction of CYP3A 
occurs via activation of the nuclear pregnane X receptor (PXR), which is expected to 
result in co-induction of CYP2C. Co-administration of enzalutamide with CYP3A or CYP2C 


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substrates may reduce oral bioavailability and/or accelerate elimination of the 
substrates. 
In vitro studies show that enzalutamide is metabolized by CYP2C8 and CYP3A4/5. Strong 
inhibitors or inducers of these enzymes may affect enzalutamide exposures. Use caution 
when co-administering strong inhibitors of CYP2C8 or CYP3A4/5 during enzalutamide 
treatment, as enzalutamide concentrations may increase. Use caution when co-
administering strong inducers of CYP2C8 or CYP3A4/5 during enzalutamide treatment, 
as enzalutamide concentrations may decrease. 
 
6.7 Prohibited Medications while on Study Drug 
6.7.1 Cytotoxic chemotherapy 
6.7.2 Hormonal therapies (e.g., anti-androgens, abiraterone, estrogens; testosterone; 
dehydroepiandrosterone [DHEA], etc.) 
6.7.3 Biologics and vaccines (e.g., sipuleucel-T) 
6.7.4 Any other investigational agent. 
6.7.5 Caution is advised when considering the concomitant use of the following 
medications: 
6.7.5.1 Medications known to lower the seizure threshold. These include but are not 
limited to: 
6.7.5.1.1 Aminophylline/theophylline 
6.7.5.1.2 Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, 
ziprasidone) 
6.7.5.1.3 Bupropion  
6.7.5.1.4 Lithium 
6.7.5.1.5 Pethidine 
6.7.5.1.6 Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, 
thioridazine) 
6.7.5.1.7 Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, 
desipramine, doxepin, imipramine, maprotiline, mirtazapine) 
6.7.5.1.8 Substrates of CYP2B6, CYP2C8, CYP2C9, and CYP2C19 that have a 
narrow therapeutic index (e.g., phenytoin, warfarin). Based on in vitro 
data, enzalutamide is an inhibitor of CYP2B6, CYP2C8, CYP2C9, and 
CYP2C19 and may be an inducer of CYP3A4 
6.7.5.1.9 Substrates of CYP3A4/5 that have a narrow therapeutic index. Co-
administration of enzalutamide with CYP3A4/5 substrates may affect 
oral bioavailability and/or elimination of the CYP3A4/5 substrate 
6.7.5.1.10 Strong CYP2C8 inhibitors (e.g., gemfibrozil) or strong CYP3A4/5 
inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, grapefruit, 
grapefruit juice and soft drinks that contain grapefruit juice). In vitro 
studies showed that enzalutamide is metabolized by CYP2C8 and 
CYP3A4/5 
6.7.5.1.11 Sensitive P-gp substrates (e.g., digoxin, fexofenadine). In vitro studies 
show that enzalutamide and metabolite M2 are potential inhibitors of 
P-gp. Co-administration of enzalutamide with P-gp substrates may 


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13
increase the plasma concentrations of the P-gp substrate. 
 
6.8 Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
6.8.1 Disease progression 
6.8.2 Intercurrent illness that prevents further administration of treatment 
6.8.3 Unacceptable adverse event(s) 
6.8.4 Major violation of the study protocol 
6.8.5 Enzalutamide held for greater than 21 days 
6.8.6 Lost to follow up 
6.8.7 Failure to recover from toxicity despite a dosing interruption of up to 21 days  
6.8.8 Patient decides to withdraw from the study 
6.8.9 General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
6.8.10 Study termination by the sponsor, IRB, ethics committee, or regulatory agency.  
6.8.11 Death 
 
6.9 Duration of Follow-up 
Patients will be followed for safety purposes for 4 weeks after removal from study or 
until death, whichever occurs first.  Patients removed from study for unacceptable 
adverse event(s) will be followed until resolution or stabilization of the adverse event.  
Patients will be followed for progression, via phone call or visit, every 3 months for the 
first year after completing therapy, then every 6 months for 2 years, then annually 
thereafter for 5 years. 
 
6.10 
Criteria for Study Discontinuation Treatment 
Patients will be removed from study when any of the criteria listed in Section 7.8 
applies.  The reason for study removal and the date the patient was removed must be 
documented in the medical chart. 
6.10.1 The primary efficacy endpoint is time to disease progression (PSA, radiographic), 
as defined in Section 13 Patients should ordinarily be maintained on study 
treatment until confirmed serologic or radiographic progression. Study 
treatment should be stopped and patients advised regarding available treatment 
options. 
 
7 Dosing Delays/Dose Modifications 
7.1 The NCI Cancer Clinical Trials Common Toxicity Criteria (version 4.0) will be utilized.  
7.2 Toxicity will be evaluated as outlined by the study calendar [Table 2] during the course 
of the study. 
7.3 All toxic events should be managed with optimal supportive care 
7.4 Subjects who experience a Grade 3 or greater adverse event that cannot be ameliorated 
by the use of adequate medical intervention must have enzalutamide interrupted. 
7.5 Enzalutamide may be resumed when the adverse event has improved to a Grade 2 or 


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lower severity. If the adverse event is considered not related to enzalutamide by the 
investigator, enzalutamide may be resumed at the same dose.  
7.6 If the adverse event is considered possibly or probably related to enzalutamide,  
enzalutamide may be resumed either at the same dose or at an initial reduced dose of 
120mg and, if needed, a second reduction to 80 mg once daily, based on the discretion 
of the investigator.  
7.7 Enzalutamide must be permanently discontinued if subject experiences any criteria  
 
listed below: 
7.7.1 Any adverse event that is intolerable to the subject and that cannot be 
ameliorated by the use of adequate medical intervention, or that in the opinion 
of the investigator would lead to undue risk to the subject if dosing continued 
7.7.2 Any seizure 
7.7.3 Creatinine >305 ìmol/L (4.0 mg/dL) 
7.7.4 Absolute neutrophil count of ≤ 750 /ìL 
7.7.5 Platelet count of < 50,000/ìL 
7.7.6 LFTs that meet one of the following 
7.7.7 An ALT or AST value of > 8x ULN 
7.7.8 An ALT or AST value of > 5x ULN for more than 2 weeks 
7.7.9 An ALT or AST value of > 3x ULN and TBL > 2x ULN  
7.7.10 If close monitoring for a subject with moderate (defined in Appendix 6 as ALT or 
AST > 3x ULN or total bilirubin > 2x ULN) hepatic laboratory tests is not possible, 
study drug should be discontinued. 
7.7.11 Subjects who are, in the opinion of the investigator or the medical monitor, 
grossly noncompliant with the protocol’s requirements. 
 
8 Pharmaceutical Information 
8.1 
Description of Study Drug 
8.1.1 Enzalutamide is a white to off white solid. It is insoluble in water and no salts are 
formed from ~ pH 2 to 10. Enzalutamide drug product is formulated in a Labrasol 
solution containing antioxidants (butylated hydroxytoluene and butylated 
hydroxyanisole) and filled into gelatin capsules. Capsules are filled to contain 40 
mg of active pharmaceutical ingredient and are provided in high-density 
polyethylene bottles with child-resistant induction seal closure. 
 
8.1.2 Comparative Drug(s): Not applicable. 
 
8.2 Packaging and Labeling 
 
All medication used in this study will be prepared, packaged, and labeled under the 
responsibility of a qualified person at Astellas US Technologies, Inc. (AUST) in 
accordance with AUST Standard Operating Procedures (SOPs), Good Manufacturing 
Practice (GMP) guidelines, ICH GCP guidelines, and applicable local laws/regulations. 
Enzalutamide soft gelatin capsules will be supplied in bottles according to the study 
design. Subjects will be provided with a 4-week supply at the Day 1 and Week 4 visits, 
respectively. At and after the Week 12 visit, subjects will be provided with a 12-week 


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15
supply to allow for visits to occur every 84 days with a ± 9 day window. Information 
presented on the label for investigational product will comply with applicable local 
regulation. 
Site pharmacist or medically qualified staff will dispense the study treatment to each 
subject in accordance with this protocol. 
 
8.3 Study drug Handling 
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the sponsor are received by a responsible person (e.g. pharmacist), and 
8.3.1 that such deliveries are recorded 
8.3.2 that study drug is handled and stored safely and properly 
8.3.3 that study drug is only dispensed to study subjects in accordance with the 
protocol 
8.3.4 That any unused study drug is returned to the sponsor or standard procedures 
for the alternative disposition of unused study drug are followed. 
8.3.5 Drug inventory and accountability records for the study drugs will be kept by the 
investigator/pharmacist/designee. Study drug accountability throughout the 
study must be documented. The following guidelines are therefore pertinent: 
8.3.5.1 The investigator agrees not to supply study drugs to any persons except the 
subjects in this study. 
8.3.5.2 The investigator/pharmacist/designee will keep the study drugs in a 
pharmacy or other locked and secure storage facility under controlled 
storage conditions, accessible only to those authorized by the investigator to 
dispense these test drugs. 
8.3.5.3 A 
study 
drug 
inventory 
will 
be 
maintained 
by 
the 
investigator/pharmacist/designee. The inventory will include details of 
material received and a clear record of when they were dispensed and to 
which subject. 
8.3.5.4 At 
the 
conclusion 
or 
termination 
of 
this 
study, 
the 
investigator/pharmacist/designee agrees to conduct a final drug supply 
inventory and to record the results of this inventory on the Drug 
Accountability Record. It must be possible to reconcile delivery records with 
those of used and returned medication. Any discrepancies must be 
accounted for. Appropriate forms of deliveries and returns must be signed by 
the person responsible. 
8.3.5.5 Used or unused study drug may be destroyed at the study center according 
to standard institutional procedures after drug accountability has been 
conducted by the Sponsor or representative, only if agreed upon by the 
Sponsor. A copy of the standard institutional procedure for destroying 
investigational drugs will be provided to the Sponsor or designee upon 
request. Unused study drug not destroyed at the site must be returned to 
the Sponsor or designee at the end of the study or upon expiration. 
8.3.5.6 Enzalutamide should be stored in a secure location with limited access at 
77°F (25°C), with excursions permitted to 59°F to 86°F (15°C to 30°C). Bottles 


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16
will be labeled with the study protocol number, medication or bottle 
number, contents, directions for use, storage directions, clinical trial 
statement, and the sponsor.  
8.4 Availability 
Enzalutamide is an investigational agent supplied to investigators by Astellas 
Pharmaceutical. 
 
9 Correlative/Especial Studies;  NONE 
 
10 Study Calendar 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy.  
Imaging studies must be done prior to the start of therapy and up to 4 months prior to 
radical prostatectomy date. Patients will be evaluated on C1D1 of therapy and every 28 
days thereafter for the first 4 cycles. If patients are stable and do not have any major issues 
with AEs, patients will then be evaluated every 3 cycles until the completion of study. 
 
Table 2. Study Calendar- Enzalutamide in High-risk Patients 
 
 
Pre- 
Study 
C1D1 
(+ 3 
days) 
Day 1 of 
Cycle 2-4 
(+ 3 days) 
Day 1 of 
every 3 
cycles 
(+ 7 days) 
End of 
Treatmentd 
(+ 7 days) 
Safetye,f 
follow 
up 
Enzalutamidea 
 
X 
X 
X 
 
 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
Xh 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts 
X 
 
X 
X 
X 
X 
Testosterone 
X 
 
X 
 
X 
 
Serum Chemistry 
including PSA, LDHb 
X 
Xg 
X 
X 
X 
X 
AE evaluation 
 
X 
X 
X 
X 
X 
Radiologic 
Evaluationc 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
a:  Enzalutamide: 160mg  PO daily - continuous dosing 
b: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 


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creatinine, glucose, LDH, potassium, total protein, SGOT [AST], SGPT [ALT], sodium 
c: Baseline scans done pre-operatively may be used, as long as done prior to study 
treatment start and up to 4 months prior to surgical date.  At the time of serologic 
progression, patient will undergo CT Abdomen/Pelvis and Bone scan .  
d:  EOT procedures to be completed at the time of drug discontinuation 
e  Safety follow up visit to be completed within 30 days of last dose of enzalutamide.   
f:  Progression follow up for survival and disease progression [PSA or radiographic], via 
phone call, or some type of clinic visit, will be done every 3 months for the first year after 
completing therapy, then every 6 months for 2 years, then annually for 5 years.  
g:  Laboratory studies drawn at screening may be used as baseline prior to starting 
treatment. 
h:  Physical exam does not need to be repeated on C1 D1 if done within the 7 days prior to 
C1 D1.  
 
11 Study Assessments 
11.1 
Screening Period: The following activities/procedures will be conducted during the 
screening period which may occur over 14 days: 
 
 Medical history including prior prostate cancer therapies, PSA, clinical and 
pathological T stage, and Gleason score at diagnosis 
 Demographics 
 Physical examination, weight, and height with baseline signs and symptoms 
 Vital signs including blood pressure, heart rate, respiratory rate, height and 
weight. 
 Assessment of ECOG Performance Status. Appendix 1 
 Laboratory tests including: CBC/differential and Platelets; CMP (Sodium, 
Potassium, Chloride, CO2, BUN, Creatinine, SGPT [ALT], SGOT [AST], Glucose, 
Alkaline Phosphatase, Total Bilirubin, and LDH); PSA and testosterone. 
 Documentation of all concomitant medications and procedures.  
 Baseline tumor assessment including a CT/MRI of the abdomen/pelvis and a 
whole body scan [To be done prior to study treatment start and up to 4 
months prior to radical prostatectomy date. ].  
 
 
Treatment Period (Cycle 1 Day 1 to end of Study Treatment): 
 
 
Cycle 1 Day 1: 
 
Visit may occur on the same day as the Screening visit provided that all screening 
assessments have been completed and screening results are reviewed prior to the 
commencement of Cycle 1 Day 1 assessments. The following procedures should be 
completed prior to receiving study drug. 
 
 Concomitant Medications listing 


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 Physical exam [if not done within 7 days prior to C1D1] including vital signs 
including blood pressure, heart rate, respiratory rate and weight 
 Assessment of ECOG Performance Status by investigator 
 Laboratory studies from screening can be used as baseline prior to starting 
treatment. 
 
 
Day 1of each subsequent Cycle (2-4): 
 Physical exam including vital signs including blood pressure, heart rate, 
respiratory rate and weight 
 Assessment of ECOG Performance Status  
 Concomitant Medications listing 
 Toxicity evaluation 
 Laboratory tests including: CBC/differential and Platelets; CMP (Sodium, 
Potassium, Chloride, CO2, BUN, Creatinine, SGPT [ALT], SGOT [AST], Glucose, 
Alkaline Phosphatase, Total Bilirubin, and LDH) testosterone, and PSA 
 
Day 1 of every 3 cycles: 
 Physical exam including vital signs including blood pressure, heart rate, 
respiratory rate and weight 
 Assessment of ECOG Performance Status  
 Concomitant Medications listing 
 Toxicity evaluation 
 Laboratory tests including: CBC/differential and Platelets; CMP (Sodium, 
Potassium, Chloride, CO2, BUN, Creatinine, SGPT [ALT], SGOT [AST], Glucose, 
Alkaline Phosphatase, Total Bilirubin, and LDH) and PSA 
 
 
Radiographic evaluation will be completed at baseline and at the time of PSA failure. Earlier 
scans will be performed at the discretion of the treating physician. 
 
 
Treatment Discontinuation 
 
The Treatment Discontinuation Visit can occur at any scheduled or unscheduled visit when 
applicable. At this visit, documentation to confirm progressive disease (serologic or 
radiographic) is required.  If a patient discontinues therapy due to reasons other than PD 
(ie: adverse events), then patient’s PSA will be followed at the discretion of the treating 
physician. 
 
End of Study Treatment Visit 
 
The End of Study Treatment Visit should be scheduled to collect safety assessments at the 
time the patient stops treatment. The following safety assessments should be carried out at 
the End of Treatment Visit after patients discontinue study treatment for any reason: 
 
 Physical exam including vital signs including blood pressure, heart rate, respiratory 


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19
rate and weight 
 Assessment of ECOG Performance Status by investigator 
 Toxicity Evaluation. Treatment-related AEs will be followed until resolved. 
 Documentation of all concomitant medications and procedures.  
 Laboratory tests including: CBC/differential and Platelets; CMP (Sodium, 
Potassium, Chloride, CO2, BUN, Creatinine, SGPT [ALT], SGOT [AST], Glucose, 
Alkaline Phosphatase, Total Bilirubin, and LDH) and PSA. 
 Radiographic tumor assessment (if not done within the last 6 weeks) 
 
 
Safety Visit 
 
The Safety Visit should be scheduled to collect safety assessments within 30 days after the 
patient stops treatment/last dose of study drug. The following safety assessments should be 
carried out: 
 
 Physical exam including vital signs including blood pressure, heart rate, respiratory 
rate and weight 
 Assessment of ECOG Performance Status by investigator 
 Toxicity Evaluation. Treatment-related AEs will be followed until resolved. 
 Documentation of all concomitant medications and procedures.  
 Laboratory tests including: CBC/differential and Platelets; CMP (Sodium, 
Potassium, Chloride, CO2, BUN, Creatinine, SGPT [ALT], SGOT [AST], Glucose, 
Alkaline Phosphatase, Total Bilirubin, and LDH) and PSA. 
 
Follow-up (every 3 months for the first year after completing treatment, then every 6 
months for two years and then yearly thereafter) for 5 years: 
 
 Progression-free survival follow-up can be done by phone contact or clinic visit. 
 Follow treatment-related adverse events until resolved. 
 
12 Measurement of Effect 
12.1 
Progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in 
the case of malignant lymph nodes are used in the RECIST criteria.  
12.2 
PSA progression will be defined by a PSA value > 0.4ng/mL repeated in two 
consecutive occasions at least 2 weeks apart. 
12.3 
Definitions 
12.3.1 Evaluable for Toxicity: All patients will be evaluable for toxicity from the time of 
their first treatment with enzalutamide 
12.3.2 Time to PSA Progression: The start of the time to PSA progression is the day 
treatment is initiated. The end date is the time of PSA progression as defined in 


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section above.  
12.3.2.1 
Radiographic Progression-Free Survival 
 
 
A patient is considered to have progressed by scans if 
12.3.2.2 
The first bone scan with ≥1 new lesions compared to baseline is observed  
12.3.2.3 
The first CT A/P with any new evidence of disease as per RECIST 1.1   
 
 
 
 
 
compared with baseline scans. 
 
13 Adverse Events/Data Safety Monitoring Plan 
13.1 
Definition of Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a subject 
administered a study drug and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a study drug, whether or not related to the study drug. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital 
sign, physical exam) should be defined as an AE only if the abnormality meets one of 
the following criteria: 
1. Induces clinical signs or symptoms 
2. Requires active intervention 
3. Requires interruption or discontinuation of study medication 
4. The abnormality or investigational value is clinically significant in the opinion 
of the investigator. 
 
13.2 
Definition of a Serious Adverse Event (SAEs) 
An adverse event is considered “serious” if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
13.2.1.1 
Results in death 
13.2.1.2 
Is life threatening (an adverse event is considered “life-threatening” if, in 
the view of either the investigator or sponsor, its occurrence places the 
subject at immediate risk of death. It does not include an adverse event that, 
had it occurred in a more severe form, might have caused death) 
13.2.1.3 
Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions 
13.2.1.4 
Results in congenital anomaly, or birth defect 
13.2.1.5 
Requires inpatient hospitalization or leads to prolongation of 
hospitalization 
(hospitalization 
for 
treatment/observation/examination 
caused by AE is to be considered as serious). 
13.2.1.6 
Other medically important events. 
 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed in the definition above. These events, including those that may 


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result in disability/incapacity, should also usually be considered serious. Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. Additionally, Astellas requests 
that all medical events listed in Appendix 3 (Adverse Events Always Considered to be 
Serious), Appendix 4 (Liver Safety Monitoring and Assessment) and Appendix 5 
(Common Serious Adverse Events) be reported by the Investigator as SAEs, even if 
none of the above criteria apply. 
 
13.3 
Criteria for Causal Relationship to the Study Drug 
Adverse events that fall under either "Possible" or "Probable" should be defined as 
"adverse events whose relationship to the study drugs could not be ruled out". 
Table 3.  Adverse Events 
 
Causal relationship to the study drug 
Criteria for causal relationship 
 
Not Related  
 
A clinical event, including laboratory test abnormality, 
with a temporal relationship to drug administration 
which 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 which 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 which follows a 
clinically reasonable response on re- administration 
(rechallenge) or withdrawal (dechallenge). 
 
13.4 
Criteria for Defining the Severity of an Adverse Event 
Severity of adverse events will be graded according to the Cancer Therapy and 
Evaluation Program (CTCAE) Common Terminology Criteria for Adverse Events v. 
4.03. For terms not specified within NCI-CTCAE, the following guideline should be 
used to determine grade: 
 
 
 
 
 
 
 


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Table 4 Criteria for Severity of Adverse Event Terms Not Specified Within 
NCICTCAE 
 
Grade 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms, clinical or 
diagnostic 
observations 
only; 
intervention 
not 
indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention 
indicated; 
limiting 
age 
appropriate 
instrumental 
activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-
threatening; 
hospitalization 
or 
prolongation 
or 
hospitalization indicated; disabling; limiting self 
care activities of daily living 
Grade 4 
Life-threatening consequences; urgent intervention 
indicated. 
Grade 5 
Death related to AE. 
 
13.5 
General Requirements 
13.5.1 Investigators are required by Federal Regulations to report serious adverse 
events as defined in the table below.  Investigators are required to notify the 
Investigational Drug Branch (IDB), Study Chair, and their Institutional Review 
Board if a patient has a reportable serious adverse event (follow guidelines in the 
table below). This study will utilize the Common Toxicity Criteria version 4.0 to 
determine the severity of the reaction for adverse event reporting. 
13.5.2 Reporting requirements and procedures depend upon: (1) whether agents are 
suspected of causing the adverse event, (2) whether the possibility of such an 
adverse event was reported in the protocol, consent form, or manufacturer's 
literature (expected or unexpected adverse event), (3) the severity or grade of 
the adverse event, (4) the phase of the study and attribution (the determination 
of whether an adverse event is related to a medical treatment or procedure).  
13.5.3 All reactions in a "reportable" category must be reported. Reactions attributable 
to a regimen that includes commercial agents must be reported using the FDA 
Form #3500 (MedWatch). 
 
13.6 
Monitoring And Reporting Guidelines 
Data related to these trials are discussed at weekly scheduled study group or site 
committee meetings where the result of each patient’s treatment is discussed. The 
discussion will include for each treatment arm/dose level, the number of patients, 
significant toxicities as described in the protocol, dose adjustments, and responses 
observed. Additionally, the study team will meet quartly to review protocol and 
evaluate accurance of data entered into the OnCore database. Twice yearly, 
summaries will be submitted to the Data Monitoring Committee for review. 
 
13.7 
Review and Oversight Requirements will be communicated to: XTANDI Adverse 
Event Reporting: 800-888-7704 ext. 8224 or email: safety-us@usastellas.com 


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13.7.1 Adverse Event  – Reported By Phone Within 24 Hours 
13.7.2 Adverse events requiring expedited reporting by phone within 24 hours (as 
described in the protocol) will also be reported by phone to the Clinical Research 
Support Services (CRSS) administrator within one working day.  Confirmation 
that all appropriate parties (including the CCF Committee on Human Research) 
were notified will be done at this time.  Hardcopies or electronic versions of FDA 
Form #3500 (MedWatch) and/or any other documentation available at that time 
will also be reviewed by the DMC Committee Chair who will determine if 
immediate action is required. Within ten working days all subsequent SAE 
documentation that is available will be submitted to the DMC Committee Chair 
who will determine if further action is required.  All information will be tracked 
in the Case Comprehensive Cancer Center’s database. 
13.7.3 If the AE occurs on a multiple-institutional clinical trial coordinated by the Case 
Comprehensive Cancer Center, the Principal Investigator will insure that all 
participating sites are notified of the event and resulting action within one 
working day of the determination. 
13.7.4 Adverse Event  – Reported within 10 Days 
13.7.4.1 
Adverse events requiring expedited AE reports in writing within 10 
working days (as described in the protocol) will be sent to the CRSS office. 
Hardcopies or electronic versions of FDA Form #3500 (MedWatch), or other 
required forms will be submitted for review by the DMC Committee Chair to 
determine if further action is required.  This information will be tracked in 
the Case Comprehensive Cancer Center’s database. 
 
13.8 
Study Progress – Quarterly Review 
13.8.1 Principal Investigators are required to submit quarterly study progress reports to 
determine whether accrual projections are being met, to summarize adverse 
reactions reported, and to determine if the trial should be continued based upon 
the likelihood of timely completion.  These quarterly reports are reviewed at 
Data Monitoring Committee meetings.  Failure to submit such reports will result 
in trial suspension. 
13.8.2 An overall assessment of accrual, toxicities as described in the protocol, and 
responses will enable the committee members to assess whether significant 
benefits or risks are occurring that would warrant study closure. This information 
is provided by study committee/site committee meeting minutes, internal data 
quality audits, and annual DMC audits, all of, which is required of all research 
studies at Case Comprehensive Cancer Center.  The committee will also receive 
all external DSMB reports and external data audits and may request further 
information from the Principal Investigator or Site Committee. 
13.8.3 The Data Monitoring Committee recommendations for modifications to the trial 
or corrective actions are forwarded to the Protocol Review Committee and the 
Clinical Research Steering Committee. The Principal Investigator is notified of this 
recommendation in order that he/she may alert all investigators, at the Case 
Comprehensive Cancer Center and at external sites involved in the trial, about 


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the potential action.  At this time the Principal Investigator may submit to the 
Clinical Research Steering Committee additional information that could affect 
the Committee’s decision.  The Clinical Affairs Committee will notify the Principal 
Investigator 
if 
they 
concur 
with 
the 
Data 
Monitoring 
Committee 
recommendations, including suspension or closure.  The DMC Chair will notify all 
investigators involved with the study at Case Comprehensive Cancer Center and 
external sites, the IRB, the sponsor and the funding agency and provide written 
documentation of these notifications to the Clinical Research Steering 
Committee. The Case Comprehensive Cancer Center Clinical Research Steering 
Committee (CRSC), composed of Cancer Center senior leaders oversees these 
activities. 
 
13.9 
Review of Adverse Event Rates 
13.9.1 Once a month, adverse event rates will be monitored utilizing the Case 
Comprehensive Cancer Center Clinical Trials database.  If any study has had two 
or more of the same AE reported in a month or more than six of the same AE in 
six months, the DMC Chair will review the summary of SAEs, discuss events with 
Principal Investigator, and conduct a more detailed review with the Principal 
Investigator or the external DSMB if warranted.  The Committee Chair will 
determine if further action is required. If this occurs on a multiple-institutional 
clinical trial coordinated by the Case Comprehensive Cancer Center, the Safety 
Coordinator will insure that all participating sites are notified of the resulting 
action. 
13.9.2 Astellas instructions for rapid notification of serious adverse events 
13.9.3 The principle investigator has the obligation to report all serious adverse events 
to the FDA, IRB, and XTANDI Adverse Event Reporting: 800-888-7704 ext. 8224 
or email: safety-us@usastellas.com 
13.9.4 All events reported to the FDA by the investigator are to be filed utilizing the 
Form FDA 3500A (MedWatch Form).  
13.9.5 All events must be reported to XTANDI Adverse Event Reporting: 800-888-7704 
ext. 8224 or email: safety-us@usastellas.com within 24 hours of learning of its 
occurrence. This includes serious, related, labeled (expected) and serious, 
related, unlabeled (unexpected) adverse experiences. All deaths during 
treatment or within 30 days following completion of active protocol therapy 
must be reported within 5 working days. 
13.9.6 Any serious adverse event occurring after the patient has initiated study 
treatment dosing and until 4 weeks after the patient has stopped dosing study 
drug must be reported. This includes the period in which the study protocol 
interferes with the standard medical treatment given to a patient (e.g. treatment 
withdrawal during washout period, change in treatment to a fixed dose of 
concomitant medication). 
13.9.7 Serious adverse events occurring more than 4 weeks after last dose of study 
drug need only be reported if a relationship to the Astellas study drug (or 
therapy) is suspected.  


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13.9.8 For Comparator Drugs/Secondary Suspects (Concomitant Medications), all 
serious adverse experiences will be forwarded to the product manufacturer by 
the investigator. 
 
13.10 Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure 
patient safety each pregnancy must also be reported to Astellas within 24 hours of 
learning of its occurrence. The pregnancy should be followed up to determine 
outcome, including spontaneous or voluntary termination, details of birth, and the 
presence or absence of any birth defects, congenital abnormalities or maternal and 
newborn complications. 
 
14 Statistical Considerations 
14.1 
Study Design/Endpoints  
This is a pilot phase II single institutional open label study. The primary endpoint of 
the trial is time to progression, defined by serologic criteria. That is a PSA value > 0.4 
in two separate occasions at least two weeks apart.  
 
Secondary endpoints include safety based on CTCAE version 4.03 criteria.  
 
14.2 
Statistics 
The primary goal of this trial is to assess the efficacy of enzalutamide in high risk 
patients following radical prostatectomy as measured by the biochemical failure-
free (BFF) interval. Historically the 5-year BFF interval in this population is 
approximately 55% (Hernandez et al., Urology, 70:931-935, 2007). Assuming the BF 
interval follows an exponential distribution, accrual will take approximately 24 
months. There will be at least 12 months of additional follow-up once accrual is 
completed. A sample size of 40 eligible and evaluable patients is recommended in 
order to have 80% power to detect a 75% decrease in the risk of biochemical failure 
(based on a 2-sided exponential MLE test that makes use of a Normal 
approximation, and a 5% type I error). To allow for a 5% exclusion rate, a total of 42 
patients will be accrued. A secondary goal of the trial is to assess safety. Adverse 
events will be coded and graded according to CTCAE version 4.03 criteria. With 40 
eligible and evaluable patients the likelihood of a specific type and/or grade of 
adverse event can be estimated using an exact 95% confidence interval that has a 
maximum half-width of 17%. BFF interval will be summarized using the Kaplan-
Meier method; and proportional hazards models will be used to assess the impact of 
factors such as Gleason Score, PSA at diagnosis, seminal vesicle invasion, and nodal 
status. 
 
14.3 
Sample Size/Accrual Rate 
The required sample size will be based upon evaluating the primary study objective. 
A total of 42 patients, 40 of whom are expected to be eligible and evaluable, will be 
entered into the study and treated with enzalutamide. Similar studies in high-risk 


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26
populations previously conducted at our institution have accrued an average of 2-3 
patients per month. Thus it is estimated that 24 months will be required to complete 
total accrual for the clinical trial. 
 
15 References 
1. Siegel R, Naishadham D, Jemal A. Cancer Statistics 2012. CA Cancer J Clin 2012 Jan-
Feb;62(1):10-29. 
 
2. Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogram for disease recurrence 
after radical prostatectomy for prostate cancer. J Clin Oncol. 1999;17(5):1499–507. 
 
3. D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, et al. 
Biochemical outcome after radical prostatectomy, external beam radiation therapy, or 
interstitial radiation therapy for clinically localized prostate cancer. JAMA. 
1998;280(11):969–74. 
 
4. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal 
therapy compared with observation after radical prostatectomy and pelvic 
lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 
1999;341(24):1781–8. 
 
5. Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, et al. Immediate versus 
deferred androgen deprivation treatment in patients with node-positive prostate cancer 
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6. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP. Bicalutamide 150 mg plus 
standard care vs standard care alone for early prostate cancer. BJU Int. 2006;97(2):247–54. 
 
7. Kibel AS, Rosenbaum E, Kattan MW, Picus J, Dreicer R, Klein EA, et al. Adjuvant weekly 
docetaxel for patients with high risk prostate cancer after radical prostatectomy: a multi-
institutional pilot study. J Urol. 2007;177(5):1777–81. 
 
8. Montgomery B, Lavori P, Garzotto M, Lee K, Brophy M, Thaneemit-Chen S, et al. Veterans 
Affairs Cooperative Studies Program study 553: Chemotherapy after prostatectomy, a phase 
III randomized study of prostatectomy versus prostatectomy with adjuvant docetaxel for 
patients with high-risk, localized prostate cancer. Urology. 2008;72(3):474–80. 
 
9. Pettaway CA, Pisters LL, Troncoso P, et al. Neoadjuvant chemotherapy and hormonal 
therapy followed by radical prostatectomy: feasibility and preliminary results. J Clin Oncol 
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10. Febbo PG, Richie JP, George DJ, et al. Neoadjuvant docetaxel before radical prostatectomy 
in patients with highrisk localized prostate cancer. Clin Cancer Res 2005;11: 5233–40. 
 


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11. Prayer-Galetti T, Sacco E, Pagano F, et al. Long-term follow- up of a neoadjuvant 
chemohormonal taxane-based phase II trial before radical prostatectomy in patients with 
non-metastatic high-risk prostate cancer. BJU Int 2007;100:274–80. 
 
12. Kelly WK, Halabi S, Elfiky A, et al., Cancer and Leukemia Group B. Multicenter phase 2 study 
of neoadjuvant paclitaxel, estramustine phosphate, and CBDCA plus androgen deprivation 
before radiation therapy in patients with unfavorable-risk localized prostate cancer: results 
of Cancer and Leukemia Group B 99811. Cancer 2008;113:3137–45. 
 
13. Nakabayashi M, Oh WK. Neoadjuvant and adjuvant chemotherapy for high-risk localized 
prostate cancer. Curr Treat Options Oncol. 2004 Oct;5(5):349-55.  
 
14. Ozen H, Yazici S, Inci K. Management of High-Risk Localised Prostate Cancer. European 
urology supplements. 2009:8:439–47. 
 
15. Flaig TW, Tangen CM, Hussain MH, et al. Randomization reveals unexpected acute 
leukemias in Southwest Oncology Group prostate cancer trial. J Clin Oncol. 2008 Mar 
20;26(9):1532-6. 
 
16. Dorff TB, Flaig TW, Tangen CM,  et al. Adjuvant androgen deprivation for high-risk prostate 
cancer after radical prostatectomy: SWOG S9921 study. J Clin Oncol. 2011 May 
20;29(15):2040-5 
 
17. Bolla M, van Poppel H, Collette L, et al. European Organization for Research and Treatment 
of Cancer. Postoperative radiotherapy after radical prostatectomy: a randomized controlled 
trial (EORTC trial 22911). Lancet 2005;366: 572–8. 
 
18. Thompson Jr IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically 
advanced prostate cancer: a randomized clinical trial. JAMA 2006;296:2329–35. 
 
19. Thompson IM, Tangen CM, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate 
cancer significantly reduces risk of metastases and improves survival: long-term follow-up 
of a randomized clinical trial. J Urol. 2009;181(3):956. 
 
20. Tran C, Ouk S, Clegg NJ, et al. Development of a second generation antiandrogen for 
treatment of advanced prostate cancer. Science. May 2009:324(5928):787-90. 
 
21. Foster WR, Car, BD, Hong S, et al. Drug safety is a barrier to the discovery and development 
of new androgen receptor agonists. The Prostate. 2011:71:480-8. 
 
22. Mocellin S, Keilholz U, Rossi CR, Nitti D. Circulating tumor cells: the ‘leukemic phase’ of solid 
cancers. Trends Mol Med. Mar 2006:12(3):130-9. 
 
23. Hayes DF, Cristofanilli M, Budd GT, et al. Circulating tumor cells at each follow-up time point 


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during therapy of metastatic breast cancer patients predict progression-free and overall 
survival. Clin Cancer Res. Jul 2006:12(14):4218-24. 
 
24. Larson  CJ, Moreno JG, Piento KJ, et al. Apoptosis of circulating tumor cells in prostate 
cancer patients. Cytometry A.Nov 2004:62(1):46-53. 
 
25. Meng S, Tripathy D, Frenkel EP. Circulating tumor cells in patients with breast cancer 
dormancy.  Clin Cancer Res. Dec 2004:10:8152-62. 
 
26. Smirnov DA, Zweitzig DR, Foulk BW, et al. Global gene expression profiling of circulating 
tumor cells. Cancer Res. Jun 2005:65(12):4993-7. 
 
27. Shaffer DR, Leversha MA, Danila DC, et al. Circulating tumor cell analysis in patients with 
progressing castration-resistant prostate cancer. Clin Cancer Res. Apr 2007:13(7):2023-9. 
 
28. Olmos D, Arkenau HT, Ang JE, et al. Circulating tumour cell (CTC) count as intermediate end 
points in castration-resistant prostate cancer (CRPC): a single-centre experience. Ann Oncol. 
Jan 2009:20(1):27-33. 
 
29. Danila DC, Heller G, Gignac GA, et al. Circulating tumor cell number and prognosis in 
progressive castration-resistant prostate cancer. Clin Cancer Res. Dec 2007:13(23):7053-8. 
 
30. Hayashi N, Yamauchi H. Role of circulating tumor cells and disseminated tumor cells in 
primary breast cancer. Breast Cancer. Apr 2012:19(2):110-7. 
 
31. Wong NS, Kahn HJ, Zhang L, et al. Prognostic significance of circulating tumour cells 
enumerated after filtration enrichment in early and metastatic breast cancer patients. 
Breast Cancer Res Treat. Sep 2006:99(1):63-9. 
 
32. Allard WJ, Matera J, Miller MC, et al. Tumor cells circulate in the peripheral blood of all 
major carcinomas but not in healthy subjects or patients with nonmalignant disease. Clin 
Cancer Res. Oct 2004:10(20):6897-904. 
 
33. Hayes DF, Smerage JB. Circulating tumor cells. Prog Mol Biol Transl Sci. 2010:95:95-112. 
 
34. O’Hara SM, Moreno JG, Zweitzig DR, Gross S, Gomella LG, Terstappen LW. Miltigene reverse 
transcription-PCR profiling of circulating tumor cells in hormone-refractory prostate cancer. 
Clin Chem. May 2004:50(5):826-35. 
 
35. Fehm T, Hoffman O, Aktas B, et al. Detection and characterization of circulating tumor cells 
in blood of primary breast cancer patients by RT-PCR and comparison to status of bone 
marrow disseminated cells. Breast Cancer Res. Apr 2009:11(4):R59. 
 
36. Kosaka N, Iquchi H, Ochiya T. Circulating microRNA in body fluid: a new potential biomarker 


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for cancer diagnosis and prognosis. Cancer Sci. Oct 2010:101(10):2087-92. 
 
APPENDIX 1 
 
Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 


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APPENDIX 2 
 
MSKCC Nomogram – Post-RP 
http://nomograms.mskcc.org/Prostate/PostRadicalProstatectomy.aspx 
 
 
 
 
 
 


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APPENDIX III 
 
Adverse Events Always Considered To Be Serious 
 
If any of the following adverse events occur during the study, they should be considered as 
serious adverse events and reported as per protocol. 
 acute liver failure 
 acute renal failure 
 acute respiratory failure 
 agranulocytosis 
 anaphylaxis 
 any new primary malignancy 
 aplastic anemia 
 confirmed or suspected endotoxin shock 
 confirmed or suspected transmission of infectious agent by marketed product 
 congenital anomalies 
 liver necrosis 
 malignant hypertension 
 pulmonary fibrosis 
 pulmonary hypertension 
 sclerosing syndromes 
 seizure 
 torsade de pointes 
 toxic epidermal necrolysis 
 ventricular fibrillation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX IV 
Liver Safety Monitoring and Assessment 
 
If laboratory testing for a subject enrolled in study and receiving study drug reveals an increase 
of serum aminotransferases (AT) to > 3x ULN, or bilirubin > 2x ULN, at least all four of the usual 
serum hepatic measures (ALT, AST, ALP, and TBL) should be repeated. Testing should be 
repeated within 48-72 hours of notification of the test results. If applicable, for studies for 
which a central laboratory is used, alerts will be generated by the central lab regarding 
moderate and marked liver abnormality to inform the investigator, study monitor and study 
team. Subjects should be asked if they have any symptoms suggestive of hepatobiliary 
dysfunction. 
 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and marked where ULN: 
  
 
 
ALT or AST  
 
 
Total Bilirubin 
Moderate  
 
> 3x ULN  
or >  
 
2x ULN 
Marked  
 
> 3x ULN  
and 
 
 > 2x ULN 
 
In addition, the subject should be considered to have marked hepatic abnormalities for any of 
the following: 
 ALT or AST > 8x ULN 
 ALT or AST > 5x ULN for more than 2 weeks 
 ALT or AST > 3x ULN and INR > 1.5 
 ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
 quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or marked abnormalities and require additional monitoring 
and follow-up. Discontinuation of treatment must occur if subject has marked abnormalities. In 
addition, if close monitoring for a subject with moderate hepatic laboratory tests is not 
possible, drug should be discontinued. 
 
Follow-up Procedures 
Confirmed moderate and marked abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. The site should complete the Liver Abnormality Case Report 
Form (LA-CRF) or an appropriate document. Subjects with confirmed abnormal liver function 
testing should be followed as described below.  
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or less 
if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic. 
Marked hepatic liver function abnormalities, in the absence of another etiology, may be 
considered an important medical event and reported as a Serious Adverse Event (SAE). The 
sponsor should be contacted and informed of all subjects for whom marked hepatic liver 


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function abnormalities possibly attributable to study drug are observed.  
 
To further assess abnormal hepatic laboratory findings, the investigator is expected to: 
 Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new onset-diseases should be recorded as ’adverse events’ on the AE page of CRF. 
Illnesses and conditions such as hypotensive events, and decompensated cardiac disease 
that may lead to secondary liver abnormalities should be noted. Non-alcoholic 
steatohepatitis (NASH) is seen in obese hyperlipoproteinemic, and/or diabetic subjects and 
may be associated with fluctuating aminotransferase levels. The investigator should ensure 
that the medical history form captures any illness that pre-dates study enrollment that may 
be relevant in assessing hepatic function. 
 Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page of CRF. Information on alcohol, other substance use, and diet should be 
entered on the LA-CRF or an appropriate document. 
 Obtain a history of exposure to environmental chemical agents 
 Based on the subject’s history, other testing may be appropriate including: 
a. Acute viral hepatitis (A,B, C, D, E or other infectious agents). 
b. ultrasound or other imaging to assess biliary tract disease 
c. other laboratory tests including INR, direct bilirubin 
 Consider gastroenterology or hepatology consultations 
 Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document. 
 
Study Discontinuation 
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or acute 
liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study. The investigator may determine that it is not in the subject’s best 
interest to continue study enrollment. 
 
Discontinuation of treatment must occur if: 
 ALT or AST > 8x ULN 
 ALT or AST > 5x ULN for more than 2 weeks 
 ALT or AST > 3x ULN and TBL > 2x ULN or INR > 1.5 
 
Discontinuation of treatment should be considered if: 
 ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
 In addition, if close monitoring for a subject with moderate hepatic laboratory tests is not 
possible, drug should be discontinued. 
 
 


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Protocol Version # 13:08JUN2015 
 
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APPENDIX V 
Common Serious Adverse Events 
The following list of serious adverse events are considered common for the study population 
defined in this protocol and should be reported by the investigator as described in the protocol. 
 
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting. If aggregate analysis of these events indicates they occur more frequently 
with study drug, an expedited IND safety report may be submitted to FDA 
 
 Anemia 
 Anorexia 
 Asthenia / Fatigue 
 Back pain 
 Bone pain 
 Catheter related infection 
 Dyspnea 
 Hematuria 
 Hydronephrosis 
 Metastases to bone 
 Metastases to central nervous system 
 Nausea 
 Obstructive uropathy 
 Pain 
 Prostate cancer metastatic 
 Renal failure 
 Renal failure acute 
 Spinal compression fracture 
 Spinal cord compression 
 Urinary retention 
 Urinary tract infection 
 Urinary tract obstruction 
 Vomiting 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX VI 
 
Subject Registration Form 
 
Protocol No: 
CASE 12812 
 
Title: 
A Pilot Phase II study of Enzalutamide in men with High-
risk PCa after Radical Prostatectomy 
Date: 
 
___/___/_____ 
 
Subject Demographics 
Study Site: 
 
MRN: 
 
 
Last Name: 
First Name 
MI: 
Gender: 
 
X    Male 
 
Ethnicity: 
 
□    Hispanic 
□    Non-Hispanic 
□    Unknown 
 
  
Race: 
□   American Indian or Alaska Native 
□   Asian 
□   Black or African American 
□   Native Hawaiian or Other Pacific Islander 
□   Unknown 
□   White 
 
Date of Birth: 
 
___/___/_____ 
On Study Date: 
 
___/___/_____ 
Study Patient  No: 
 
Disease Site:     PROSTATE 
 
 
Histology:    PROSTATE 
 
 
Registrar’s Name  
 
 
Registrar’s Signature