Enzalutamide With External Beam Radiation for Intermediate Risk Prostate Cancer: A Phase II Study
Phase: PHASE2
Conditions: Intermediate Risk Prostate Cancer
Sponsor: Dana-Farber Cancer Institute

 
 
Title: Enzalutamide with External Beam Radiation for Intermediate Risk Prostate Cancer: A Phase II Study 
 NCT Number: NCT02028988 
 IRB Approval Date: Version 13.0 Protocol Version Date 01/09/2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  

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         Version 13.0 Protocol Version Date: 1/09/2015  
  
 
NCI Protocol #: N/A  
  
Dana Farber Harvard Cancer Center IRB Protocol #: 13-444  
  
  
Study Title: Enzalutamide with External Beam Radiation for Intermediate Risk  
Prostate Cancer: A Phase II Study  
  
Principal Investigator: Glenn Bubley, MD (BIDMC)   
  
Site Responsible Principal Investigator(s):   
• Peter Orio, DO (DFCI-South Shore/DFCI-Milford)  
• Paul Nguyen, MD (DFCI/BWH)  
  
Agent(s): Enzalutamide - Medivation     
  
   

 
 
  
Version 13.0 Protocol Version Date: 1/09/2015  
  
  
  
2  
  
SCHEMA  
  
  
Disease:  
Patients with Intermediate 
Risk Prostate Cancer:  
  
  
  
  
Treatment:  
6 months of enzalutamide.  
EBRT*** beginning 7-10 
weeks after initiating 
enzalutamide.  
7560-7920 cGy in 180cGy 
fractions  
  
Endpoints:  
Primary-PSA level at 
completion of therapy 
compared to historical 
controls with LH-RH 
agonists  
Secondary:  
1) Quality of Life   
2) Hormonal levels   
3) Body fat measurements  
  
  
Timeline  
  
  
Reg        Start enzalutamide                     6 X 28 day cycles****       End enzalutamide    F/u 3 
month  
                                             Start XRT**         End XRT     
│30 day max │_______|________|_____________|__________________│______________│  
                                Fiducial*                                       
  
* Fiducial placement and biopsy 3-7  weeks after initiating enzalutamide    ** 
Radiation initiated 7-10 weeks after initiating enzalutamide.    
*** Patients that are unable to complete enzalutamide therapy will still be treated with EBRT per  
SOC  
**** 28 day cycle allows for +/- 3 day window 

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TABLE OF CONTENTS  
  
1. OBJECTIVES       
 1  
1.1 Study Design  
 1  
1.2 Primary Objectives  
 2  
1.3 Secondary Objectives  
 2  
1.4 Correlative objective  
 2  
2. BACKGROUND  
 
 
 
 
 
 
 
 
2  
2.1 Enzalutamide   
 
 
 
 
 
 
 
 
2  
2.2 Study Disease  
 
 
 
 
 
 
 
 
5  
2.3 Rationale    
 
 
 
 
 
 
 
 
6  
2.4 Correlative Studies Background  
 
 
 
 
 
 
6  
3. PARTICIPANT SELECTION  
 
 
 
 
 
 
7  
3.1 Inclusion Criteria  
 
 
 
 
 
 
 
 
7  
3.2 Exclusion Criteria  
 
 
 
 
 
 
 
 
8  
3.3 Inclusion of Women, Minorities and Other Underrepresented Populations   
 
9  
4. REGISTRATION PROCEDURES  
 
 
 
 
 
 
9  
4.1 General Guidelines for DF/HCC and DF/PCC Institutions  
 
 
 
9  
4.2 Registration Process for DF/HCC and DF/PCC Institutions  
 
 
 
9  
5. TREATMENT PLAN  
 
 
 
 
 
 
 
10  
5.1 Pretreatment criteria   
 
 
 
 
 
 
 
10  
5.2 Agent Administration  
 
 
 
 
 
 
 
10  
5.3 General Concomitant Medication and Supportive Care Guidelines   
 
 
14  
5.4 Duration of Therapy   
 
 
 
 
 
 
 
15  
5.5 Duration of Follow-up  
 
 
 
 
 
 
 
15  

 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE  
MODIFICATIONS   
 15  
6.1 Fiducial placement for prostate tracking during external beam +/- biopsy  
 
 
15  
6.2 Toxicity Management  
 
 
 
 
 
 
 
17  
6.3 Dose Modification /Delays  
 
 
 
 
 
 
 
17  
  
7. CORRELATIVE/SPECIAL STUDIES  
 
 
 
 
 
18 
8. 
STUDY CALENDAR  
 
 
 
 
 
 
 
18  
9. MEASUREMENT OF EFFECT  
 
 
 
 
 
 
19  
9.1 Primary Endpoint  
 
 
 
 
 
 
 
 
19  
9.2 Secondary Endpoints  
 
 
 
 
 
 
 
20  
9.3 Correlative Endpoints  
 
 
 
 
 
 
 
20  
10. ADVERSE EVENT REPORTING REQUIREMENTS   
 
 
 
21  
10.1 Definitions   
 
 
 
 
 
 
 
 
20  
10.2 Procedures for AE and SAE Recording and Reporting  
 
 
 
 
22  
10.3 Reporting Requirements  
 
 
 
 
 
 
 
23  
10.4 Reporting to the Study Sponsor  
 
 
 
 
 
 
23  
10.5 Reporting to the Institutional Review Board (IRB)  
 
 
 
 
24  
10.6 Reporting to Hospital Risk Management  
 
 
 
 
 
25  
10.7 Monitoring of Adverse Events and Period of Observation  
 
 
 
25  
10.8 Reporting to Hospital Risk Management  
 
 
 
 
 
25  
11. DATA AND SAFETY MONITORING  
 
 
 
 
 
26  
11.1 Data Reporting  
 
 
 
 
 
 
 
 
26  
11.2 Safety Meetings  
 
 
 
 
 
 
 
 
26  
11.3 Ongoing Monitoring of Protocol Compliance  
 
 
 
 
 
27  
12. REGULATORY CONSIDERATIONS  
 
 
 
 
 
27  
12.1 Protocol Review and Amendments  
 
 
 
 
 
 
27  
12.2 Informed Consent  
 
 
 
 
 
 
 
 
27  
12.3 Ethics and Good Clinical Practice (GCP)  
 
 
 
 
 
28  
12.4 Study Documentation  
 
 
 
 
 
 
 
28  

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12.5 Records Retention  
 
 
 
 
 
 
 
 
29  
13. STATISTICAL CONSIDERATIONS   
 
 
 
 
 
29  
 
1431 Sample Size/Accrual Rate  
    29  
 
13.2 Analysis of Secondary Endpoints  
    30  
 
13.3 Analysis of Correlative Endpoints  
    30  
14. REFERENCES   
 
 
 
 
 
 
 
 
31  
15. APPENDICES   
 
 
 
 
 
 
 
 
32  

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1. OBJECTIVES  
  
1.1  
Study Design  
The goal of this exploratory study is to assess efficacy of adding enzalutamide in the neoadjuvant 
and adjuvant setting in combination with external beam radiation therapy (EBRT). The 
population will be prostate cancer patients with intermediate risk prostate cancer, choosing 
radiation therapy as their primary form of therapy.  This is a phase II single arm trial that has as 
its primary objective to estimate the proportion of patients with PSA ≤0.2 ng/ml at the 
completion of therapy. This endpoint has been shown to be predictive of long term response in a 
similar risk-group of patients treated with radiation therapy and LHRH agonists.(1)  Secondary 
endpoints include measurement of serum hormone levels, health-related quality of life (HRQoL) 
and body fat measurements. It is expected that enzalutamide therapy in contrast to LHRH 
agonists has a much better profile for these secondary outcomes. Correlative studies will center 
on understanding enzalutamide’s mechanism of action. Data from this trial, if convincing, would 
lead to a Phase III randomized trial comparing LHRH agonists to enzalutamide as neoadjuvant 
and adjuvant therapy in combination with EBRT.    
  
On this study patients will be treated with 6 months of Xtandi (enzalutamide). Approximately 
one-third of the way through this treatment they will receive EBRT. Starting on Day 1, all 
patients will ingest enzalutamide 160 mg/day at the same time each day without breaks (except 
as outlined for toxicity), with or without food, for 6 (28 day +/-3 days) cycles. Dose reduction of 
enzalutamide to 120 mg/day is allowed with the approval of the Medical Monitor, Dr. Glenn 
Bubley (Section 6.2.2.3). Patients will be instructed to return all unused capsules at each study 
visit to assess compliance and will receive study drug every 28 days (+/-3 days) for 6 cycles (24 
weeks).   
  
1.2  
Primary Objectives  
        1. Estimate the proportion of patients whose PSA level at the end of six (28 day +/-3 days) 
cycles of enzalutamide and EBRT is < 0.2 ng/ml.  
  
1.3  
Secondary Objectives  
1. Assessment of the effect of treatment on health-related quality of life including fatigue, 
sleep quality, as well as urinary, bowel, sexual and hormonal functioning.  
2. Assessment of the effect of treatment on serum sex hormones including androgens and 
estrogens.  
3. Assessment of the effect of treatment on body fat distribution and muscle mass.  
4. Assessment of safety and tolerability according to adverse event reporting during the 
trial.   
5. Assessment of the effect of treatment on bone metabolism.   

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1.4      Correlative Objective   
 1. Assessment of cellular location of androgen receptor expression using              
immunohistochemistry on prostate tissue samples obtained during fiducial placement.   
  
2. BACKGROUND  
  
2.1  
Enzalutamide  
Please refer to the Investigator’s Brochure for further information on the pharmacology of 
enzalutamide.  
  
Enzalutamide (enzalutamide) is a potent androgen receptor signaling inhibitor that blocks several 
steps in the androgen receptor signaling pathway. Enzalutamide competitively binds to the 
androgen receptor with an IC50 of 36 nM, compared to 160 nM for bicalutamide (an androgen 
receptor antagonist commonly used for ADT [2, 3]). In addition, enzalutamide inhibits nuclear 
translocation of activated receptors and inhibits the association of the activated androgen 
receptor with DNA, even in the setting of androgen receptor overexpression and in prostate 
cancer cells resistant to anti-androgens. Enzalutamide treatment decreases the growth of prostate 
cancer cells and can induce cancer cell death and tumor regression. Effective inhibition of 
androgen receptor signaling by enzalutamide (observed in vitro) blocks the oncogenic effects of 
androgen metabolism by tumor cells and the up regulation of the androgen receptor. In addition, 
enzalutamide induces immediate prostate cancer apoptosis, an effect not seen with antiandrogens 
(e.g., bicalutamide) (3) Furthermore, enzalutamide has no known agonist activity when the 
androgen receptor is overexpressed.  
  
Enzalutamide treatment in a prostate cancer xenograft model resulted in a dose-dependent 
reduction in tumor volume: 1/7 tumors in the low-dose group (1 mg/kg/day) and 3/7 tumors in 
the high-dose group (50 mg/kg/day) became unmeasurable. In contrast, bicalutamide had little 
effect on tumor growth.  
  
Enzalutamide was non-mutagenic/clastogenic in in vitro genotoxicity assays (reverse mutation 
and mouse lymphoma). Repeat-dose oral toxicology studies were conducted with durations of up 
to 6 months in rats and 3 months in dogs. The most prominent effects of enzalutamide in these 
species were reductions in prostate, epididymis, and/or seminal vesicle weight, all of which are 
consistent with the expected antiandrogen pharmacology of enzalutamide. These decreases were 
accompanied by corresponding histopathological findings of prostatic and seminal vesicle 
secretory depletion and/or atrophy, with epididymal atrophy in dogs only. Hypospermatogenesis 
and degeneration of seminiferous tubules in testes have been observed in dogs, but not in rats. 
The enzalutamide-related male sex organ findings reversed, or tended to reverse, after at least 8 
weeks of recovery.  Reversible hepatocellular hypertrophy, associated with liver weight 
increases, was a consistent finding of enzalutamide in rats, but not in dogs. Several additional 
histopathological findings (mostly in endocrine tissues) definitively related to enzalutamide 
treatment in the 26-week study in rats included hypertrophy/hyperplasia in adrenals, pituitary, 
and thyroid; atrophy in male mammary gland; gland/lumen dilatation and lobular hyperplasia in 

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female mammary gland; and luminal dilatation in the uterus. In a short-term reversibility study 
in male dogs, enzalutamide treatment did not result in detectable permanent effects to male 
reproductive organs.  
  
Cardiovascular safety was evaluated in vitro in patch-clamped mammalian cells expressing the 
hERG channel. The results showed that enzalutamide inhibited the hERG current with an IC50 
of 16.2 μM (7.29 μg/mL). The highest free concentration of enzalutamide expected in patient 
plasma at a steady-state dose of 160 mg/day is well below the hERG IC50 value. The major 
active metabolite of enzalutamide (M2) was also shown to weakly inhibit the hERG channel 
with an IC50 of 18.6 μM (8.38 μg/mL).  
  
In mice, rats, and dogs, orally administered enzalutamide had a half-life (t1/2) of approximately 
0.25 to 3 days. The t1/2 did not appear to be affected by the dose size; however, bioavailability 
appeared to decrease with increasing dose size. Plasma protein binding of enzalutamide in 
human plasma ranged from 97% to 98% and was similar in mice, rats, rabbits, and dogs.  
  
Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area 
under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl 
enzalutamide in healthy volunteers. Co-administration of enzalutamide with strong CYP2C8 
inhibitors should be avoided (see Appendix F).  
  
The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been 
evaluated in vivo. Co-administration of enzalutamide with strong CYP2C8 inducers (e.g., 
rifampin) may alter the plasma exposure of enzalutamide and should be avoided (see 
APPENDIX F).   
  
The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been 
evaluated in vivo. Co-administration of enzalutamide with strong CYP3A4 inducers (e.g., 
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the 
plasma exposure of enzalutamide and should be avoided. (see APPENDIX F)  Moderate 
CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s 
Wort may also reduce the plasma exposure of enzalutamide and should be avoided.    
  
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in 
humans. At steady state, enzalutamide reduced the plasma exposure to midazolam (CYP3A4 
substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate).   
  
Concomitant use of enzalutamide with narrow therapeutic index drugs that are metabolized by 
CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fetanyl, pimozide, 
quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin), pentobarbital, 
ketoconazole, sertaraline, digitoxin, haloperidol, ketamine, doxocycline, isoniazid, ciprofloxacin 
and CYP2C19 (e.g., S-mephenytoin) should be avoided if possible, as enzalutamide may 

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decrease their exposure. If co-administration with warfarin cannot be avoided, conduct 
additional INR monitoring   
  
Additional nonclinical information can be found in the Investigator’s Brochure.  
  
2.1.1 Previous Human Experience  
The tolerability, pharmacokinetics (PK), and antitumor activity of enzalutamide were studied in 
a multicenter, open-label, dose-escalation study of enzalutamide in 140 patients with advanced 
prostate cancer. Patients were treated with enzalutamide at doses of 30 to 600 mg/day until 
disease progression or intolerable side effects developed.  
  
In this study, enzalutamide was absorbed rapidly after oral administration, with the median 
time to maximum plasma concentration (Cmax) after a single dose occurring at 1.00 hour (range 
0.42 to 4.00 hours postdose). The PK of enzalutamide was essentially linear with no major 
deviations from dose proportionality in Cmax or area under the curve values in the dose range of 
30 to 600 mg. The terminal t1/2 for enzalutamide after a single dose was approximately  
6 days (range 3 to 10 days) and did not appear to be affected by the dose size. In accordance with 
the long t1/2, it took approximately 1 month after the start of a daily dose regimen to reach steady 
state. On achievement of steady state, the mean trough concentrations (Cmin) in individual 
patients remained constant for several months, suggesting time-linear PK. With daily oral 
administration of 150 mg/day, the mean accumulation index for enzalutamide was approximately 
11, reflecting the long t1/2 relative to the dosing interval. Due to its slow clearance from plasma, 
the daily fluctuation in steady-state enzalutamide concentrations was low. The mean peak-to-
trough ratios (Cmax/Cmin) was 1.2 (range 1.14 to 1.3), indicating that variability in steady-state 
Cmax, Cmin, and area under the curve values was low (≤ 30% CV).At 160 mg/day, the mean 
steady-state Cmin is expected to be approximately 12 ± 4 μg/mL. Full PK profiles were linear 
and consistent over the dose range studied.  
  
Fatigue was the most frequently reported adverse event, with dose-dependent increases of Grade 
3 fatigue (0% at 150 mg/day, 9% at 240 mg/day, 15% at 360 mg/day, and 20% at 480 mg/day). 
The dose of 240 mg/day was defined as the maximum tolerated dose. At doses of 240 mg and 
above, an increasing proportion of patients needed dose reductions for fatigue. Dose reductions 
were needed in 1 of 29 patients (3%) that received 240 mg/day, 3 of28 patients (11%) that 
received 360 mg/day, and 5 of 22 patients (23%) that received 480 mg/day, and 0 of 58 patients 
that received 30, 60, or 150 mg/day. After dose reductions, the symptoms resolved. Only 1 
patient discontinued treatment due to fatigue with an onset coinciding with prostate specific 
antigen (PSA) rise. Overall, the most common mild (grade 2) adverse events were fatigue (n = 
38 [27.1%]), nausea (n = 12 [8.6%]), dyspnea (n = 11 [7.9%]), anorexia (n = 8 [5.7%]), and back 
pain (n = 8 [5.7%]). Fatigue, nausea, and anorexia were the only mild adverse events with an 
increasing incidence as the dose of enzalutamide was increased. None of the grade 2 events 
required dose modification or the discontinuation of treatment, apart from 1 patient treated at 
480 mg/day who had nausea at baseline and stopped therapy after 7 weeks.  
  
  

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In the randomized clinical trial, 7 of 800 (0.9%) patients treated with enzalutamide160 mg once 
daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures 
occurred from 31 to 603 days after initiation of enzalutamide. Patients experiencing seizure were 
permanently discontinued from therapy and all seizures resolved. There is no clinical trial 
experience re-administering enzalutamide to patients who experienced seizures.  
  
The safety of enzalutamide in patients with predisposing factors for seizure is not known because 
these patients were excluded from the trial. These exclusion criteria included a history of seizure, 
underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 
months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the 
use of concomitant medications that may lower the seizure threshold.   
  
The antitumor activity of enzalutamide was assessed by post-therapy changes in PSA, soft tissue 
and osseous disease, and circulating tumor cell count. Prostate specific antigen declines of ≥ 
50% from baseline were observed in 62% of patients. Radiographic evidence of disease control 
(i.e., no progression) was also observed in the majority of patients (3).  
  
Based on these results, 2 placebo-controlled, randomized Phase 3 studies (AFFIRM and 
PREVAIL) were initiated to evaluate the efficacy and safety of enzalutamide in patients with 
advanced prostate cancer. The AFFIRM study evaluated the safety and efficacy of enzalutamide 
in 1199 patients who progressed on docetaxel (4) This study showed a survival benefit in favor 
of enzalutamide (hazard ratio 0.631 p < 0.0001, median overall survival of 18.4 versus 13.6 
months for enzalutamide and placebo, respectively (4). The PREVAIL study was designed to 
evaluate the safety and efficacy of enzalutamide in patients who have not yet received 
chemotherapy for their metastatic disease; this study is ongoing. The AFFIRM study, however, 
lead to the approval of this drug for the indication for CRPC with metastatic disease following 
docetaxel in September 2012.   
  
2.2  
Study Disease  
Prostate cancer is the most commonly diagnosed non-cutaneous cancer diagnosed in the US male 
population and the second leading cause of cancer death.  In 2008, 214 633 new cases were 
diagnosed and 28,411 men died of prostate cancer. Standard options for men with early stage 
prostate cancer can include active surveillance, prostatectomy, external beam or brachytherapy 
radiation and hormonal therapy.  Treatment recommendation depends on extent of local disease 
and other issues such as age of the patient, pre-existing medical condition.  Often patients have 
several management options.  Including in this decision making process are the risks and 
toxicities associated with each treatment approach. Both retrospective reports and prospective 
trials have shown the usefulness of categorizing patients with prostate cancer using 
multimodality staging. By combining the presenting tumor stage (AJCC- T stage), the finding on 
rectal exam and the pre-treatment serum PSA level, patients fall into a low, intermediate or risk 
category.   
  

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Definitive treatment is generally recommended for men with a good life expectancy without 
potentially life shortening co-morbidities with Intermediate Risk prostate cancer. The addition of 
hormonal treatments (therapies that reduce testosterone) has been shown to be efficacious to 
external beam in several prospective randomized trials. The reason for this beneficial effect is 
not understood.  One explanation for this effect is the cytoreductive effects of hormonal therapy 
which increases the probability of local tumor control with external beam radiotherapy.  These 
trials where initiated in the era when the total dose external beam dose was low by contemporary 
standards.  In fact, the RTOG is revisiting the role for androgen ablation with high dose 
radiotherapy in the intermediate risk prostate cancer patient (RTOG 0815).  
  
A barrier to treatment with androgen ablation with external radiotherapy are the toxicities 
associated with low serum testosterone levels.  These include loss of libido, erectile dysfunction, 
hot flashes and weight gain.   Since serum testosterone levels are not affected by the androgen 
receptor blockade of bicalutamide, hot flashes, loss of libido and sexual side effects are less 
common.  As stated above, these are nearly universal side effects of LH-RH agonist therapies 
that low serum testosterone to castrate levels. However bicalutamide is a partial agonist of the 
androgen receptor and there is concern regarding its efficacy as monotherapy, particularly at the 
50 mg per day dose (the currently approved dose). D’Amico et al has shown that PSA nadir after 
external beam and 6 months of LH-RH agonist therapy with bicalutamide is predictive of disease 
free survival and metastasis free survival (1).  If the PSA nadir is 0.2 ng/ml or lower, there is 
improvement in outcome. Potentially with longer follow-up in this study, there will be improved 
survival if these low PSA levels can be achieved.  Therefore, PSA nadir at the end of external 
beam and 6 months of hormonal therapy is a surrogate endpoint for disease free survival and 
metastasis free survival.  
  
2.3 Rationale  
Presently most patients with intermediate risk prostate cancer receive neoadjuvant, concurrent 
and adjuvant hormonal therapy with external beam irradiation.  Multiple studies have shown that 
the addition of HT improves survival to external beam radiation (5,6) However androgen 
deprivation  induced by LH-RH agonists consistently results in hot flashes, loss of libido, loss of 
sexual functioning, weight gain, changes in metabolism, loss of muscle mass and fatigue (7, 8) .    
  
In contrast, treatment with the anti-androgens bicalutamide or flutamide has minimal side 
effects, likely related to the fact that these agents do not suppress serum testosterone.  
Enzalutamide has the potential to have similar anti-tumor effects as LH-RH agonist without the 
toxicity associated with castrate testosterone levels. If it were shown that enzalutamide 
(enzalutamide) could be used as an effective adjuvant treatment for prostate cancer without 
androgen deprivation it would have dramatic and significant impact, including expanding its use 
to those patients who may have more intermediate risk and/or are unable to tolerate the toxicities 
associated with androgen deprivation  
  
We have chosen as the primary endpoint the assessment of the proportion of patients whose PSA 
level is <0.2 ng/ml at the conclusion of therapy.  This endpoint was chosen because patients that 

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achieve this value after treatment with LHRH analogs in combination with EBRT have an 
excellent prognosis compared to patients that demonstrate higher PSA levels (1, 9). Furthermore, 
demonstration of PSA levels of ≤0.2ng/ml in a significant number of patients treated on this 
study would be strong motivation to perform a phase III randomized trial comparing 
enzalutamide to LHRH analog therapy in the same setting.  
2.4 Correlative Studies Background  
Patients on this trial will, of necessity, have placement of fiducials that are used to guide the 
radiation treatment. These are placed in the outpatient setting and require exactly the same 
efforts as does a prostate biopsy (pre-treatment antibiotic therapy, ultrasound guidance, patient 
positioning etc.). Fiducials are routinely placed 3-7 weeks after initiating enzalutamide. At this 
juncture patients that consent will undergo two additional core samples to be obtained from the 
prostate, likely in the position of previous disease as documented in the core biopsy diagnostic 
report. The aim of obtaining these samples will be for analysis of localization of the androgen 
receptor by immunohistochemistry. As discussed, data suggest that one of the mechanisms 
behind enzalutamide’s’ effectiveness is to trap the AR in the cytoplasm and block its access to 
the nucleus where it can act as a transcription factor.(3).  The pattern of expression from these 
samples can be compared to the pattern of AR localization in the patient’s pre-treatment core 
biopsies and from patient samples available to us from our tumor bank. The latter patients have 
been treated with or without LHRH analogs, both of which would be important controls.  

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3. PARTICIPANT SELECTION  
  
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study:  
  
3.1  
Inclusion Criteria  
Study population: Participants must have histologically confirmed malignancy and are 
candidates for external beam radiation therapy. Patients eligible for this study must have 
intermediate risk disease defined as PSA values between 10-20 ng/ml and/or T2b-c and/or  
Gleason grade 7.  If all three are present, less than 50% of the core biopsies can be positive.    
  
Patients previously diagnosed with low risk (Gleason score < 6, clinical stage < T2a, and PSA< 
10) prostate cancer undergoing active surveillance who are re-biopsied and found to have 
intermediate risk disease according to the protocol criteria are eligible for enrollment within 180 
days of the repeat biopsy procedure.  
  
3.1.1 Age 18 years or more.   
  
3.1.2 Life expectancy of greater than 1 year.  
  
3.1.3 ECOG performance status <2 (see Appendix D).  
   
3.1.4 Participants must have normal organ and marrow function as defined below:  
• 
Leukocytes > 3,000/mcL  
• 
Platelets > 80,000/mcL  
• 
Total bilirubin < 2X institutional upper limit   
• 
AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal  
• 
Creatinine < 2x institutional limits                  .  
3.1.5 The effects of enzalutamide on the developing human fetus are unknown. For this 
reason and because enzalutamide may be teratogenic, men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) 
prior to study entry and for the duration of study participation.    
3.1.6 Ability to understand and the willingness to sign a written informed consent 
document.  
  
  

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3.2  
Exclusion Criteria  
  
Patients must NOT meet any of the following exclusion criteria    
3.2.1      Received an investigational agent within 4 weeks prior to enrollment (see section 5.3.12).  
3.2.2      Stage T4 prostate cancer by clinical examination or radiologic evaluation.  
3.2.3      Hypogonadism or severe androgen deficiency as defined by screening serum              
 
 
  testosterone less than 50 ng/dL below the normal range for the institution.  
3.2.4     Prior androgen deprivation, chemotherapy, surgery, or radiation for prostate cancer.  
3.2.5    Receiving concurrent androgens, anti-androgens, estrogens, or progestational agents, or   
received any of these agents within the 6 months prior to enrollment or having taken finasteride or 
dutasteride within 30 days of registration.  
3.2.6    History of another active malignancy within the previous 5 years other than curatively 
treated nonmelanomatous skin cancer and superficial bladder cancer. Participants treated for 
malignancy with no relapse within two years are eligible to participate in the study.  
3.2.7    Uncontrolled intercurrent illness including, but not limited to, ongoing or    
  
 
active infection.   
3.2.8    Severe concurrent disease, infection, or co-morbidity that, in the judgment of the 
Investigator, would make the patient inappropriate for enrollment.  
3.2.9     Unwilling to use contraceptives while on study if relevant to patient.  
3.2.10   History of seizure or any condition or concurrent medication that may predispose to 
seizure.  
3.2.11   History of loss of consciousness or transient ischemic attack within 12 months prior to 
enrollment.  
3.2.12   Clinically significant cardiovascular disease, including:  
• Myocardial infarction within 3 months of enrollment;  
• Uncontrolled angina within 3 months of enrollment;  
• Congestive heart failure New York Heart Association (NYHA) class 3 or 4, 
or history of congestive heart failure NYHA class 3 or 4 in the past, unless a 
screening echocardiogram or multi-gated acquisition scan performed within 3 
months results in a left ventricular ejection fraction ≥ 45%;  
• History of clinically significant ventricular arrhythmias (e.g., ventricular 
tachycardia, ventricular fibrillation, torsades de pointes);  
• History of Mobitz II second degree or third degree heart block without a 
permanent pacemaker in place;  
• Hypotension as indicated by systolic blood pressure < 86 mmHg on 2 
consecutive measurements at the Screening visit;  
• Bradycardia as indicated by a heart rate < 50 beats per minute at the  
Screening visit;  
• Uncontrolled hypertension as indicated by systolic blood pressure > 170 
mmHg or diastolic blood pressure > 105 mmHg on 2 consecutive 
measurements at the screening visit;  
•EKG demonstrating equal to or greater than grade III toxicity according the   

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NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0   
3.2.13  History of gastrointestinal disorders (medical disorders or extensive surgery) that may 
interfere with the absorption of oral study drug(s) within 3 months of enrollment.  
3.2.14   Major surgery within 4 weeks of registration.  
3.2.15   Previous use, or participation in a clinical trial, of an investigational agent that blocks 
androgen synthesis (e.g., abiraterone acetate, TAK-700, TAK-683, TAK-448) or targets the 
androgen receptor (e.g., enzalutamide, BMS 641988); ketoconazole.   
3.2.16    Any condition or reason that, in the opinion of the Investigator, interferes with the ability 
of the patient to participate in the trial, places the patient at undue risk, or complicates the 
interpretation of safety data.  
3.2.17    Need for any of the medications on the list of drugs to be used with caution or to be 
avoided (see APPENDIX F).   
3.2.18   Use of herbal or alternative remedies that may affect hormonal status such as Prostasol or 
PC-SPES.  
3.3  
Inclusion of Women, Minorities and Other Underrepresented Populations  
Women are not affected by prostate cancer and therefore are not eligible. Efforts will be made to 
enroll patients that are minorities.  African Americans have a higher incidence of prostate cancer 
and effort will be made to recruit these men to this study.   
4. REGISTRATION PROCEDURES  
    
4.1  
General Guidelines for DF/HCC and DF/PCC Institutions  
  
Institutions will register eligible participants with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. Registration must occur 
prior to the initiation of therapy. Any participant not registered to the protocol before 
treatment begins will be considered ineligible and registration will be denied.   
  
A member of the study team will confirm eligibility criteria and complete the protocol-
specific eligibility checklist.  
   
Following registration, participants may begin protocol treatment. Issues that would 
cause treatment delays should be discussed with the Principal Investigator. If a 
participant does not receive protocol therapy following registration, the participant’s 
protocol status must be changed. Notify the QACT Registrar of participant status 
changes as soon as possible.  
  
4.2 Registration Process for DF/HCC and DF/PCC Institutions  
  
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to  
5:00 PM Eastern Standard Time. In emergency situations when a participant must 
begin  

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treatment during off-hours or holidays, call the QACT registration line at 617-632-3761 
and follow the instructions for registering participants after hours.  
    
The registration procedures are as follows:  
  
1. 
Obtain written informed consent from the participant prior to the performance of 
any study related procedures or assessments.  
  
2. 
Complete the protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical/research record. To be 
eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist.  
   
Reminder: Confirm eligibility for ancillary studies at the same time as 
eligibility for the treatment study. Registration to both treatment and ancillary 
studies will not be completed if eligibility requirements are not met for all 
studies.  
   
3. 
Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT 
at 617-632-2295.  
   
  
4. 
The QACT Registrar will (a) validate eligibility, (b) register the participant on 
the study, and (c) enroll the participant when applicable.  
   
5. 
The QACT Registrar will send an email confirmation of the registration and/or 
enrollment to the person initiating the registration immediately following the 
registration and/or enrollment.  
   
5.  
TREATMENT PLAN   
  
5.1 Pretreatment criteria: Patients with biopsy confirmed prostate cancer who meet eligibility 
criteria as defined in section 3.  
  
5.2 Agent Administration  
  
5.2.1 Treatment will be administered on an outpatient basis. Expected toxicities and potential 
risks as well as dose modifications for enzalutamide are described in Section 6 (Expected 
Toxicities and Dosing Delays/Dose Modification). No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the 
participant’s malignancy.  
  

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5.2.2 Patients will be treated in 6 (28 +/-3 days) cycles. EBRT will be initiated 7-10 weeks 
into enzalutamide therapy. Patients will be seen every 28 (+/-3 days) days for history and 
physical, adverse event and concomitant medication assessment. At these visits routine 
laboratory parameters will be obtained and a subset of these must be reviewed prior to 
dispensing the investigational agent. The routine laboratories at the beginning of each cycle 
should be completed per the Study Calendar in section 8.   
The criteria to treat at the beginning of each cycle are:  
• ANC greater than 1,000mm3  
•  Hgb greater than 8.0 g/dL  
•   Platelets greater than or equal to 50,000  
•  ALT less than 3.5x upper limit normal  
•  AST less than 3.5x upper limit normal  
   
  
Any grade (3 or greater) non-hematologic adverse event (such as fatigue, etc.) must be 
resolved to (grade 1 or less) in order to continue therapy. The Medical Monitor should be 
notified of any adverse events that require holding, stopping or dose modifications of study 
drug.   
  
 5.2.2.1 Identity of Investigational Product  
The study drug, enzalutamide, has the chemical name 3-(4-cyano-3-trifluoromethylphenyl)-1- 
[3-fluoro-4-(methylcarbamoyl) phenyl]-5,5-dimethyl-2-thioxoimidazolin-4-one. The drug 
substance has no chiral centers and no salt forms are available at ~ pH 2 to 10. It is essentially 
insoluble in water, but partially soluble in lipid-based solutions.  
  
Enzalutamide inhibits androgen receptor signaling with a novel mechanism.  Enzalutamide binds 
to the androgen receptor and is inhibited from translocation into the nuclease thereby blocking 
androgen receptor interaction with the chromatin and androgen inducible effects.  Enzalutamide 
with LH-RH agonists have been shown to improve survival in castrate resistant prostate cancer 
(4).  In an unpublished recently completed study, enzalutamide was shown to be safe in 
hormone-naïve prostate cancer patients with minimal toxicity.  Effects on serum PSA levels and 
clinical outcome in this population are presently unavailable.\  
  
5.2.2.2 Product Characteristics  
The drug substance is formulated in the surfactant Labrasol. The drug product is provided as 40 
mg soft gelatin capsules in 124-count bottles with induction-sealed, child-resistant caps.  
  
5.2.2.3 Directions for Administration Enzalutamide  
  
Study participants will self-administer the total daily dose (160 mg) of enzalutamide as a 
single dose, once daily. Enzalutamide can be taken with or without food. Enzalutamide may be 
taken at any time during the day, but should be taken at the same time each day. A missed dose 
should be taken as soon it is remembered. If twelve or more hours have lapsed since their 
regularly scheduled time, patients should not take the missed dose; rather the patient should 

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resume dosing at the next scheduled dose. Patients should not double up or take more than 1 
dose of enzalutamide per day. Vomited doses should not be made up. Enzalutamide should not 
be crushed.  
  
5.2.2.4 Storage and Labeling  
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 will be labeled with the study 
protocol number, medication or bottle number, contents, directions for use, storage directions, 
clinical trial statement, and Medivation Inc. as supplier. Patients will be instructed to store 
bottles containing enzalutamide capsules at room temperature  
  
5.2.3 External Beam Radiation  
  
  
5.2.3.1 Dose Specifications: 3D Conformal Radiotherapy (3DCRT) or IMRT  
Dose will be normalized such that exactly 98% of the PTV (planned target volume) receives the 
prescription dose and will be scored as per protocol. The maximum allowable dose within the 
PTV is 107% of the prescribed dose to a volume that is at least 0.03 cc. The minimum allowable 
dose within the PTV is >95% of the prescribed dose to a volume that is at least 0.03 cc.  
  
EBRT shall receive prescription doses to the PTV 75.6- 79.2 Gy delivered in 1.8 Gy fractions.  
All attempts should be made to deliver the  
PTV dose with the above heterogeneity constraints with adherence to the critical structure 
parameters listed below:  
  
Normal organ 
Limit *  
No more than 15% 
volume receives 
dose that exceeds  
No more than 25% 
volume receives 
dose that exceeds  
No more than 35% 
volume receives 
dose that exceeds  
No more than 50% 
volume receives 
dose that exceeds  
Bladder  
Constraint  
80 Gy  
75 Gy  
70 Gy  
65 Gy  
Rectum  
 Constraint  
75 Gy  
70 Gy  
66 Gy  
60 Gy  
  
5.2.3.2 Technical Factors  
    RT will be delivered with megavoltage equipment at energies ≥6 MV.  
  
  5.2.3.3 EBRT Localization, Simulation, and Immobilization  
Simulation will be CT-based in all cases. The use of urethral contrast at the time of simulation 
is recommended but not required. The degree of bladder fullness should be made to duplicate 
that which is anticipated for daily treatment, i.e., if the patient is instructed to maintain a full 
bladder for treatment, he should be simulated as such (CT images should be acquired at a 
slice thickness of ≤3 mm from the top of the iliac crests superiorly to the perineum inferiorly. 
Target volumes and normal critical structures will be defined in the slices in which they are 

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visualized. The 3DCRT cases must utilize “beam’s eye view” representations to define final 
beam aperture.  
  
5.2.3.4 Fiducial Placement:  
Fiducial markers placed within the prostate are required for this protocol. This procedure is 
routinely performed to permit pre-treatment imaging and position corrections to improve the 
precision of the external beam delivery (Image Guided Radiation Therapy).  The placement of 
the three gold markers is performed by a Urologist.  The fiducials are placed under transrectal 
ultrasound guidance.  The fiducials are placed in the prostate so they do not overlap in the 
anterior and lateral x-ray projection.  
  
Patients will be asked to participate in a procedure for correlative studies.  This is not 
mandatory for participation.  Two routine transrectal ultrasound guided biopsies will be taken 
in the location of previously identified disease on the diagnostic core biopsy report.   These 
tissues samples will be stored for correlative tissue analysis.    
  
  
5.2.3.5 Treatment Planning/Target Volumes  
  The definition of volumes will be in accordance with the ICRU Report #50: Prescribing, 
Recording, and Reporting Photon Beam Therapy. The Gross Tumor Volume (GTV) is 
defined by the physician as all known disease as defined by the planning CT, urethrogram, 
and clinical information. If a urethrogram is used, the GTV will encompass a volume 
inferiorly 5 mm superior to the tip of the dye and no less than the entire prostate. Prostate 
dimensions should be defined as visualized on CT scan.  
  
  
The Clinical Target Volume (CTV) is the GTV plus areas considered to contain microscopic 
disease, delineated by the treating physician, and is defined as follows:  
CTV is the GTV (prostate) plus areas at risk for microscopic disease extension plus the 
proximal bilateral seminal vesicles. Only the proximal 1.0 cm of seminal vesicle tissue 
adjacent to the prostate shall be included in the clinical target volume. This 1.0 cm of seminal 
vesicles refers to both radial (in plane) and superior (out of plane) extent. If both prostate and 
seminal vesicle are visualized in the same CT slice, this seminal vesicle tissue will contribute 
to the 1.0 cm of tissue. The Planning Target Volume (PTV) will provide a margin around the 
CTV to compensate for the variability of treatment set up and internal organ motion. A range 
of 5-10 mm around the CTV is required to define each respective PTV. Superior and inferior 
margins (capping)should be 5-8 mm depending on the thickness and spacing of the planning 
CT scan. Careful consideration should be made when defining the 5-8 mm margin in 3 
dimensions. The ICRU Reference Points are to be located in the central part of the PTV and, 
secondly, on or near the central axis of the beams. Typically these points should be located on 
the beam axes or at the intersection of the beam axes.  
Normal Critical Structures to be defined on the treatment planning CT scan will include the 
following: bladder, rectum (from its origin at the rectosigmoid flexure superiorly or the 
bottom of the SI joints, whichever is more inferior to the inferior-most extent of the ischial 
tuberosities), bilateral femora (to the level of ischial tuberosity), penile bulb and skin. Any 

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small bowel within the primary beam aperture should be defined as well. All structures will 
be contoured in their entirety as solid organs.   
Superior and inferior margins (capping) should be 5-10 mm depending on the thickness and 
spacing of the planning CT scan.  
Careful consideration should be made when defining the 5-10 mm margin in 3 Dimensions. 
The PTV forms the entire target as described. No extension of fields to specifically treat 
regional lymph nodes is permitted. 3D conformal beams will be shaped to include the entire 
PTV and minimize dose to surrounding critical structures as described. Intensity modulated 
radiotherapy (IMRT) using inverse planning is permitted with constraints placed to adhere to 
critical structure dose limitations as defined above.  
  
  
5.2.3.6 Critical Structures   
Every effort should be made to deliver prescription doses to the PTV as specified while 
adhering to these constraints, it is recognized that certain anatomical factors may prevent this.   
  
For purposes of compliance, up to a 5% absolute increase in the volume of critical structure 
receiving greater than the specified dose will be considered” variation acceptable,” e.g. up to 
20% of the rectum may receive a dose of > 75.6 Gy without a protocol deviation. Any 
increase in critical structure volume greater than 5% receiving more than the specified dose 
will be considered a “deviation unacceptable". The prescription dose should be the maximum 
deliverable up to 79.2 Gy while respecting the critical normal structure constraints. Of note, 
the penile bulb constraint is to be regarded as a guideline, and adherence to this should not, in 
any way, result in a reduction of the prescription dose or compromised dose coverage of the 
target volume.  
     5.2.3.7 Treatment Verification  
First day port films or portal images of each field along with orthogonal isocenter verification 
films (or images) must be obtained. If modifications are made in field shaping or design, a 
port film of each modified field along with orthogonal isocenter verification films (or images) 
is required on the first day’s treatment of that field. Thereafter, weekly verification films or 
images of orthogonal isocenter views (anterior to posterior and lateral projection) are 
required. The intensity profiles of each beam must be independently verified and compared to 
the planned field intensity. Portal films are not required for IMRT but orthogonal verification 
films are required. Daily on-line target localization (kV or MV imaging with fiducials) should 
be performed.  
  
    5.2.3.8 Quality Assurance   Documentation 
Requirements:  
The institution will archive treatment prescription and verification images for later review by 
the study chair if requested. At least one port film or pretreatment alignment film per field 
along with the digital reconstructed radiographs (DRRs) from the treatment planning program 
or, alternatively, a simulation verification radiograph shall be acquired and kept for evaluation 
if requested except where geometrically impractical  
  

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    5.2.3.9 Compliance Criteria  
The minimum allowable dose within the PTV is >95% of the prescribed dose to a volume that 
is at least 0.03cc. Cases in which this small volume of at least 0.03cc receives a minimum 
dose that is <95% but >93% or a maximum dose that is >107% and <110% of the prescribed 
dose will be scored as a variation acceptable. Cases in which such a small volume receives 
less than 93% or >110% of the prescribed dose will be scored as a deviation and 
unacceptable. Acceptable dose heterogeneity will be as follows: This maximum dose 
volume of the PTV must not be shared by a normal critical structure. The maximum 
point dose to normal critical structures outside the PTV should not exceed the prescription 
dose.  
  The treating physician must carefully consider the tolerance dose/volume to each critical 
normal structure and unspecified tissue.  
  
5.3  
General Concomitant Medication and Supportive Care Guidelines  
5.3.1 Prior and Concomitant Therapy  
5.3.1.1 Medications taken within 14 days prior to the first dose of study drug will be 
documented on the appropriate case report form as a prior medication. Medications taken 
after the first dose of study medication and until 30 days following the last dose of any study 
drug (enzalutamide) will be documented on the appropriate case report form as concomitant 
medication. All concomitant medication(s) must be reported on the appropriate case report 
form. Prior and concomitant medications include all vitamins, herbal remedies, over the 
counter, and prescription medications. If an intermittent or as needed use of any medication 
during the study is due to an adverse event, then the adverse event must also be recorded on 
the adverse event case report form.  
5.3.1.2 The following medications are prohibited within 4 weeks of first study drug 
administration and throughout time on study, unless otherwise indicated below:  
Androgens (e.g., testosterone, dihydroepiandrosterone), estrogens, or progestational 
agents Ketoconazole, diethylstilbestrol, PC-SPES, and other preparations such as saw 
palmetto thought to have endocrine effects on prostate cancer:  
o Radiopharmaceuticals such as strontium (89Sr) or samarium (153Sm), radium 223 o 
Aldactone, Spironol (spironolactone), eplerenone;   
o Herbal medications, such as Prostasol and PC-SPES, St. Jon’s Wort; o Cancer 
Vaccine therapy;  
o Non-cytotoxic, non-investigational anti-tumor treatment;  
o Use of an investigational agent, unless prior approval by the PI, Glenn Bubley, MD, 
for a shorter washout period, provided the patient has adequately recovered from any 
ongoing adverse events.  
o Any alternative remedy that may affect hormonal status.  

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o Caution is advised for patients taking drugs metabolized through either CYP3A4 or 
CYP2C8 pathways. Please see Appendix F.   
5.4  
Duration of Therapy    
5.4.1 Enzalutamide - 6 (28 +/-3 days) cycles-expected  
5.4.2 External beam radiation up to 11 weeks-expected  
5.4.3 Treatment will continue for 6 (28 day) cycles or until one of the following criteria 
applies:  
• 
Disease progression;  
• 
Intercurrent illness that prevents further administration of treatment;  
• 
Unacceptable adverse event(s);  
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements;  
• 
Participant decides to withdraw from the study; or  
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator.  
  
5.5  
Duration of Follow-up  
5.5.1 Patients will be followed on study for 3 months after treatment (cessation of 
enzalutamide).  Additional follow-up to assess the status of the cancer will be 
conducted at the discretion of the treating physicians  
5.5.2 In the event a patient discontinues enzalutamide due to a related adverse event, 
follow up will continue until adequate resolution of the adverse event, the 
physician deems the adverse event to be stable, the patient initiates another 
systemic antineoplastic drug or an investigational drug, or the patient withdraws 
consent from the study.   
  
  
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
6.1.1 Fiducial placement for prostate tracking during external beam +/- biopsy  
 
Likely:  
• 
Discomfort from the placement of needles into the prostate for fiducial placement 
and biopsy  
• 
Minor Rectal bleeding  

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  Rare: 
• Significant bleeding requiring transfusion and/or hospitalization  Infection  
  
  
  Extremely Rare: 
• 
Massive bleeding  
• 
Death  
  
  
         6.1.2 External Beam Radiation  
  
6.1.2.1Acute Reaction  
 Common  
• 
Urinary frequency  
• 
Dysuria  
• 
Increase bowel frequency  
• 
Exacerbation of hemorrhoids  
  
 Uncommon  
• 
Significant fatigue  
  
  Rare  
• Diarrhea  
• Rectal bleeding  
• Skin erythema  
• Urinary obstruction  
  
6.1.2.2 Late Reaction  
  
Common  
• 
Dry ejaculation  
• 
Erectile dysfunction  
• 
Sterility  
  
Uncommon  
• 
Rectal mucous discharge  
• 
Rectal bleeding  
  
Rare  
• 
Gross hematuria  
• 
Chronic diarrhea  

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• 
Rectal bleeding requiring management  
  
Extremely Rare  
• 
Significant rectal bleeding requiring transfusion  
• 
Radiation induced damage of normal tissues requiring surgery  
• 
Second cancers  
• 
Death  
  
6.1.3  Enzalutamide    
Common  
• 
Peripheral Edema  
• 
Flushing  
• 
Diarrhea  
• 
Neutropenia  
• 
Arthralgia  
• 
Musculoskeletal pain  
• 
Fatigue  
• 
Gynecomastia  
  
Serious  
• 
Seizure  
• 
Spinal cord compression  
• 
Infectious disease  
  
Rare  
• 
Rash  
• 
Neutropenia (grade 3 and 4)  
• 
Short term memory loss   
Evidence of seizure will result in cessation of enzalutamide and withdrawal from the 
study. Other Grade 3 or 4 possibly-related non-hematologic toxicity, including fatigue, 
may result in dose reduction. Based upon experience from Phase 3 studies enzalutamide 
is generally well tolerated. The most common adverse events related to enzalutamide 
include fatigue and nausea. Any dose reduction of enzalutamide requires consultation 
with the Medical Monitor. Instructions on dose reduction for various toxicities are 
provided below (section 6.2):  
  
  
6.2 TOXICITY MANAGEMENT  
  
6.2.1 Management of Radiation Toxicity  
  
6.2.1.1 Urinary   

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6.2.1.1.1 Symptomatic urinary medicines, such alpha blockers for decreased urinary flow  
6.2.1.1.2 NSAIDS for dysuria if no contraindication.  
  
    6.2.1.2 Rectal  
 
   
6.2.1.2.1 Low fiber diet  
 
   
6.2.1.2.2 Loperamide at the discretion of the treating physician.  
    
   6.2.1.3 Management of gynecomastia  
   At the discretion of the treating physician, at any time before or during treatment patients   
are permitted to receive radiation therapy to the breasts to prevent or treat gynecomastia 
Treatments such as tamoxifen are not permitted for gynecomastia.   
  
   6.2.2 Management of enzalutamide toxicity  
  
6.2.2.1 If Grade 1–2 toxicities occur, give supportive care per institutional guidelines. No 
enzalutamide dose reduction should occur. However, at the discretion of the treating 
physician, an investigator can hold enzalutamide for intolerable Grade 2 toxicity for a 
maximum of 14 days. Participants should resume enzalutamide at the original dose (160 
mg/day). If the participant is not able to resume study medication after being held for 14 
days, the participant must be permanently removed from the study.    
  
6.2.2.2 If Grade 3 fatigue occurs, hold enzalutamide and contact the medical monitor for 
appropriate instructions on dose reduction.  
  
6.2.2.3 If Grade 3 or higher toxicities occur that are considered potentially related to 
enzalutamide including headache (that interferes with activities of daily living [ADL]), 
nausea (requiring total parenteral nutrition or intravenous fluids), vomiting (> 6 
episodes/24 hours requiring total parenteral nutrition or intravenous fluids), diarrhea 
(requiring intravenous fluids or hospitalization, or resulting in hemodynamic collapse), or 
any other toxicity where patient safety is jeopardized, hold enzalutamide. When the 
toxicity has resolved to ≤ Grade 1, resume study medication at the full dose. Prophylactic 
medications should be considered as appropriate. If toxicity recurs, hold study medication 
and adjust or add medications to mitigate the toxicity. When the recurrent toxicity has 
resolved to ≤ Grade 1, resume enzalutamide at 120 mg/day (3 pills /day). This should be 
done with the approval of the PI and the medical monitor.  
  
  
6.3 Dose Modification /Delays  
6.3.1 Dose delays and modifications will be made using the following recommendations.  
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
for  

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Toxicity assessments will be done using the CTEP Active Version of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) which is identified and located on the CTEP 
website at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
  
If possible, symptoms should be managed symptomatically. However, if a seizure occurs, stop 
medication immediately. Patients will be removed from study, and medical monitor will be 
contacted. In the case of toxicity, appropriate medical treatment should be used (including 
antiemetics, anti-diarrheals, etc.).  
  
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible.  
  
If a patient misses study medication for a total of 14 days, they should be discontinued from the 
study.  
  
Discontinuing or temporally stopping EBRT is at the discretion of the treating physician.  
Treatment with radiation should be temporarily or permanently stopped due to excessive bowel 
and/or bladder symptoms not ameliorated with medications or other supportive measures.  
Temporary stopping the EBRT is not a protocol violation as long as the radiation is completed in 
nine and half weeks (ten missed weekday treatments during EBRT).  
  
   
  
7.0 CORRELATIVE/SPECIAL STUDIES  
 7.1 Pharmacokinetics-N/A  
 7.2 Pharmacodynamics-N/A   
  7.3 Assessment of AR localization by IHC. (See section 10.5)  
  
  
  

 
 
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27  
  
8.0 STUDY CALENDAR  
  
Screening 
(4 week 
period)  
Baseline 
(Day  
One  
Cycle 
1)5+/- 3 
day   
At  
fiducial 
placement 
(3-7 weeks) 
(Study) (+/- 
3 day)  
Cycle  
2,  
Day  
One  
(+/- 3 
day)  
Cycle  
3,  
Day  
One  
(+/- 3 
day)  
Cycle  
4,  
Day  
One  
(+/- 3 
day)   
Cycle  
5, Day  
One  
(+/- 3 
day)  
Cycle  
6,  
Day  
One  
(+/- 3 
day)  
  
End  
of 
cycle 6 
(+/- 3 
day)  
36 months after 
completion of cycle 
6  
  
Hx/PE  
X  
X  
  
X  
X  
X  
X  
X  
X  
X  
Vital signs  
X  
X  
  
X  
X  
X  
X  
X  
X  
X  
Height/weight3  
  
X  
  
X  
X  
X  
x  
x  
x  
  
CBC with diff  
X  
X  
  
X  
X  
X  
X  
X  
X  
X  
Chemistry/LFTs 9  
X  
X  
  
X  
X  
X  
X  
X  
X  
X  
Bone Metabolism  
markers1,5  
  
X  
  
  
  
  
  
  
X  
X  
PSA  
X  
X  
  
X  
X  
X  
X  
X  
X  
X 
Hormonal  
measurements2, 5   
X11  
X  
  
  
  
  
X  
  
X  
  
Anthropomorphic 
measurements3 and 
waist circumference  
  
X  
  
  
  
  
  
  
X 
  
Prostate tissue samples 
(optional)  
  
  
X  
  
  
  
  
  
  
  
Q of L assessment4  
  
X  
  
  
X  
  
X  
  
X  
X  
Dispense med/Pill diary  
  
X  
  
X  
X  
X  
X  
X  
X7 
  
Adverse event and con 
med  
  
X  
  
X  
X  
X  
X  
X  
X  
  
EBRT  
  
  
  
X8 
X8  
  
  
  
  
  
Sign Informed Consent  
X  
  
  
  
  
  
  
  
  
  
EKG   
X  
  
  
  
  
  
  
  
  
  
Assessment of breast  
enlargement10  
  
X  
  
*  
*  
X  
*  
*  
X  
  

Version 13.0 Protocol Version Date: 1/09/2015  
 
 
• 
1 -bone specific alk phos, serum C-teleopeptide, serum N terminal propeptide of type I collagen (fasting)  
• 
2- DHEA sulfate, estrogen (estradiol), free testosterone, total testosterone, estrone, androstenedione. These should be 
done while fasting.                                                                                                                                                      
• 
3 -Triceps skin fold, biceps (mid-upper arm circumference), shoulder blade and waist.  Height will only be necessary at 
the baseline visit.                                                         
• 
4- EPIC-26, PROMIS, PSQI  
• 
5 -Any time between Day -7 to day 1  
• 
6-  +/- 7 days  
• 
7- Collect pill diary and unused drug  
• 
8 - EBRT 7-10 weeks after initiating enzalutamide. This could fall on cycle 2 or 3.   
• 
9 -Chemistries includes: creatinine, BUN, potassium, sodium, bicarbonate LFT’s include AST, ALT, total bilirubin and 
alkaline phosphatase.  
• 
10- Assessment will be done with calipers. The maximum diameter of the larger breast (if there is asymmetry) at Baseline  
• (Day One Cycle 1), Cycle 4/day 1, End of Cycle 6 and assess it according to these parameters: grade 1 (<=2cm), grade 2 
(>2-<=4cm), grade 3 (>4-6cm), and grade 4 (>6cm).  
• 
11- At screening visit, the only hormonal test required is total testosterone which will not require morning collection or 
fasting.* We will ask you to answer a yes or no about breast tenderness and/or enlargement at every study visit.  
  
CONFIDENTIAL  
This document is confidential. Do not disclose or use except as authorized.  
  

  
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9.  MEASUREMENT OF EFFECT  
       9.1 Primary endpoint:    
The primary endpoint is measured by PSA level. Patients achieving a PSA level <0.2 ng/ml at the end of six cycles 
of enzalutamide and EBRT treatment are considered successes.  
  
9.2 Secondary endpoints   
  
9.2.1. Safety and Tolerability  
Safety and tolerability will be documented throughout the study by assessment of adverse events, vital signs and 
laboratory assessments as defined in the Schedule of Activities (Section 8). Adverse events will be graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03 
(NCICTCAE v4.03). Only toxicity with attribution of possibly, probably or definitely (‘treatment-related’) will be 
reported. Adverse events will be monitored and recorded until the safety follow-up visit (3 months after the 
completion of the drug therapy). Any glucose tests collected under previous protocol amendments will not be 
assessed for adverse events.   
  
9.2.2. Health-Related Quality of Life  
HRQoL will be assessed at baseline, at the beginning of cycles 3 day 1, cycle 5 day 1, end of cycle 6 and 3 months 
after completion of study.   
  
Bone   
Collagen type IC teleopeptide, procollagen Type I Intact N-terminal peptide, bone specific alkaline phosphatase. 
Should be done while fasting. Please see study calendar.   
  
The Expanded-Prostate Index Composite – 26 (EPIC 26)   
EPIC-26 evaluates patient’s urinary incontinence (4 items), urinary irritation/obstruction (4 items), bowel (6 
items), and vitality/hormonal function (5 items).  All domains are reported on a scale of 0 – 100. EPIC is a robust 
prostate cancer HRQoL instrument that measures a broad spectrum of symptoms and has 50 items; however, to 
decrease patient burden only the domains most pertinent to this study will be used as represented in the EPIC-26. 
EPIC-26 has been validated in men with localized prostate cancer who underwent surgery, external beam 
radiation, or brachytherapy with or without the use of hormonal adjuvants. Further information on EPIC can be 
found at the University of Michigan website: http://www.med.umich.edu/urology/research/epic.html.  
  
Patient-Reported Outcome Measurement Information System (PROMIS)-Fatigue Short Form   
PROMIS was developed as part of the NIH Roadmap Initiative, focused on developing a publicly available 
resource of standardized, accurate, and efficient PRO measures of symptoms, distress, and functioning. Two 
content domains of fatigue, experience and impact, were identified by a panel of experts. An item pool of 58 
fatigue experience and 54 fatigue impact items were developed. The psychometric properties of these items were 
evaluated in a sample of 450 individuals from the general US population using classical test theory indices, 
monotonicity, and scalability. The expert panel selected the 10 best items in each domain. These 20 items were 
presented to a panel of clinical experts. Only one item was dropped because of redundancy. A fatigue short-form 
measure of 7 items was created using items selected for consistency in the response scale, broad coverage across 
the fatigue continuum (i.e., high to low), and good precision of measurement (discrimination function).  

  
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Pittsburgh Sleep Quality Index (PSQI)  
Sleep quality will be measured by the PSQI, a self-rated questionnaire which measures sleep quality and 
disturbances. The Pittsburgh Sleep Quality Index was developed to discriminate between good and poor sleepers. 
The PSQI has good internal consistency (Cronbach’s alpha=0.83), stability (test-retest reliability=.85, P<.001) and 
discriminant validity. It has been used in patients with cancer and demonstrated sleep problems as expected  
  
9.3 Serum Hormone Levels  
Serum hormone levels include DHEA sulfate, estrone, free testosterone, total testosterone, estradiol (estrogen),  
androstenedione. These should be done while fasting.                                                                                                             
See Study Calendar (Section 9) for the measurement time points.  
  
9.4 Anthropomorphic Measures  
Anthropomorphic measurements include Triceps skin fold, mid-upper arm circumference (biceps), shoulder blade 
and waist.  (Section 8). Skin measurements will be done using Slim Guide Skinfold Caliper. Skin Measure will be 
taken at four different areas as below. A standard caliper will be supplied to all sites.   
  
Measurement of body fat percentage is done using skinfold caliper by adding the measurements at four different 
locations (Triceps, Biceps, Shoulder blade and Waist).    
  
Back of Upper Arm (right):   
The back of upper arm (Triceps) is located halfway between the shoulder and elbow joints. The skinfold is taken  
in a vertical direction on the center of the back of the arm.
  
  
Front of Upper Arm (right)  
The Front of upper arm (Biceps) is located halfway between the shoulder and elbow joints. The skinfold is taken 
in a vertical direction on the center of the front of the arm.   
  
  
 
 
 
 

  
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Upper Back (right):  
Located just below the shoulder blade (Subscapular). The skinfold is taken at a 45° angle.  
  
Waist (right):   
Waist (Suprailiac) is located just above the iliac crest, the protrusion of the hip bone, a little towards the front from 
the side of the waist. The skinfold is taken horizontal.  
  
Skinfold Testing Technique  
  
Use your thumb and index finger of your left hand to pinch an area of skin wide enough to get a good fold.  
  
  
 
Pull out the fold of skin and underlying layer of fat with your left hand away from the body. You do not have to 
worry about getting any muscle as the muscle is firm and will not come into a fold with the skin and fat.  
  

  
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While holding the skinfold with the left hand, place the jaws of the calipers about 1/4" from the fingers of the left 
hand. Release the trigger of the caliper so the entire force of the jaws are on the skinfold. Without releasing the 
skinfold with the left hand, let the force of the caliper creep a bit for a few seconds to settle to the correct reading. 
Write down the measurement and proceed to the next location.  
  
  
Measurement of lean muscle mass is done by multiplying the weight (in lbs.) by the body fat percentage.  See 
Appendix G.  
  
The breast enlargement assessment will be done with calipers. The maximum diameter of the larger breast (if there 
is asymmetry) at Baseline (Day One Cycle 1), Cycle 4/day 1, End of Cycle 6 and assess it according to these 
parameters: grade 1 (<=2cm), grade 2 (>2-<=4cm), grade 3 (>4-6cm), and grade 4 (>6cm).  
  
Technique for measuring male breast tissue:   
Proper technique is needed to examine the male breast. The thumb and index finger are used to grasp and gently 
pinch the periareolar area of the breast and to palpate glandular breast tissue, which is rubbery in consistency and 
firmer than the surrounding adipose tissue. With this technique, gynecomastia can usually be distinguished from 
excessive breast adipose tissue, called pseudo gynecomastia, which is often associated with generalized obesity. 
Gynecomastia is usually bilateral and relatively symmetric, but occasionally it is asymmetric and more prominent 
on one side. If present, asymmetric gynecomastia may suggest breast carcinoma, which is usually rock-hard and 
irregular and may be associated with skin dimpling (peau d’orange), nipple retraction or discharge, and axillary 
lymphadenopathy. The diameter of palpable breast tissue is used as an objective measure of gynecomastia. 
Gynecomastia of recent onset is usually tender on palpation, and men usually complain of nipple irritation 
associated with rubbing against clothing. The proper method of examining the male breast is to use the thumb and 
index finger to grasp the periareolar area of the breast and to gently pinch the thumb and index finger together on 
either side of the breast toward the nipple. Glandular breast tissue feels like a rubbery disc of tissue that extends 
concentrically from under the nipple and subareolar area and is firmer than the surrounding adipose tissue. The 
size of gynecomastia is estimated by measurement of the diameter of palpable breast tissue.10  
  

  
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9.5   Correlative Endpoint  
Prostate biopsy samples from patients obtained during fiducial placement will be formalin fixed and paraffin 
embedded analogous to routine prostate biopsies. Freshly cut sections will be stained for AR using commercially 
available antibodies. Patient samples that have tumor will be analyzed for AR overall expression. High powered 
tumor sections demonstrate that at least 50% of the tumor cells express AR.  These will be graded for nuclear 
expression as none, rare, less than expression in the cytoplasm or greater or equal to cytoplasmic expression.     
  
Please page the study coordinator, Cesar Vazquez at 617-632-9289 and Bonnie Wong at 617-632-9279 or page 
through the BIDMC operator at 617-632-PAGE.  
10. ADVERSE EVENT REPORTING REQUIREMENTS  
10.1 Definitions 10.1.1 Adverse 
Event (AE)  
  
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or any procedure 
specified in the protocol, even if the event is not considered to be related to the study.   
  
Abnormal laboratory values or diagnostic test results constitute adverse events only if they induce 
clinical signs or symptoms or require treatment or further diagnostic tests.  10.1.2 Serious adverse event 
(SAE)  
  
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that:   
• 
Results in death  

  
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• 
Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form.  
• 
Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier than planned).  
• 
Results in persistent or significant disability/incapacity. Disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions.  
• 
Is a congenital anomaly or birth defect; or  
• 
Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.  
  
Events not considered to be serious adverse events are hospitalizations for:  
• 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures  
• 
elective or pre-planned treatment for a pre-existing condition that did not worsen  
• 
emergency outpatient treatment for an event not fulfilling the serious criteria outlined above 
and not resulting in inpatient admission  
• 
respite care  
  
10.1.3 Expectedness  
  
Adverse events can be 'Expected' or 'Unexpected.'   
10.1.3.1 Expected adverse event  
  
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk.    
  
Refer to Section 6.1 for a partial listing of expected adverse events associated with the 
study agent(s). 10.1.3.2 Unexpected adverse event  
  
  
For the purposes of this study, an adverse event is considered unexpected when it varies in 
nature, intensity or frequency from information provided in the current adverse event list, 

  
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the Investigator’s Brochure, the package insert or when it is not included in the informed 
consent document as a potential risk.    
10.1.4 Attribution  
  
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows:  
  
• Definite – The AE is clearly related to the study treatment.  
• Probable – The AE is likely related to the study treatment.  
• Possible – The AE may be related to the study treatment.   
• Unlikely - The AE is doubtfully related to the study treatment.  
• Unrelated - The AE is clearly NOT related to the study treatment.  
  
  
  
10.2 Procedures for AE and SAE Recording and Reporting  
  
Participating investigators will assess the occurrence of AEs and SAEs at all participant evaluation time 
points during the study.   
  
All AEs and SAEs whether reported by the participant, discovered during questioning, directly observed, 
or detected by physical examination, laboratory test or other means, will be recorded in the participant’s 
medical record and on the appropriate study-specific case report forms.   
  
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should 
have access to a copy of the CTCAE version 4.0.  
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at:  
  
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
10.3 Reporting Requirements  
  
For multi-site trials where a DF/HCC investigator is serving as the principal investigator, each 
participating investigator is required to abide by the reporting requirements set by the DF/HCC. The 
study must be conducted in compliance with FDA regulations, local safety reporting requirements, and 
reporting requirements of the principal investigator.   
  
Each investigative site will be responsible to report SAEs that occur at that institution to their respective 
IRB. It is the responsibility of each participating investigator to report serious adverse events to the study 
sponsor and/or others as described below.   

  
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10.4 Reporting to the Study Sponsor 10.4.1 
Serious Adverse Event Reporting  
  
All serious adverse events that occur after the initial dose of study treatment, during treatment, or 
within 30 days of the last dose of treatment must be reported to the DF/HCC Overall Principal 
Investigator on the local institutional SAE form. This includes events meeting the criteria outlined 
in Section 10.1.2, as well as the following:  
  
• 
Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are unexpected and 
possibly, probably or definitely related/associated with the intervention.  
  
• 
All Grade 4 (life-threatening or disabling) Events – Unless expected AND specifically 
listed in the protocol as not requiring reporting.  
  
• 
All Grade 5 (fatal) Events – When the participant is enrolled and actively participating in 
the trial OR when the event occurs within 30 days of the last study intervention.   
  
Note: If the participant is in long term follow up, report the death at the time of continuing 
review.   
  
Participating investigators must report each serious adverse event to the DF/HCC Overall Principal 
Investigator as well as the Astellas Safety Department within 24 hours of learning of the 
occurrence. In the event that the participating investigator does not become aware of the serious 
adverse event immediately (e.g., participant sought treatment elsewhere), the participating 
investigator is to report the event within 24 hours after learning of it and document the time of his 
or her first awareness of the adverse event. Report serious adverse events by telephone, email or 
facsimile both to:  
  
DF/HCC Overall Principal Investigator and Medical Monitor:  
  
  
Glenn Bubley, MD 
 
            gbubley@bidmc.harvard.edu    
  
  
Phone 617-735-2062    
   
  
 
   
 
 
Fax 617-735-2060  
  
  
  
  
  
Astellas Safety Department:  
  
  
Astellas Pharma Global Development – United States  
  
  
Email: Safety-us@us.astellas.com 
   
  
Fax number: (847) 317-1241  
  
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the event 
has resolved or continues, if and how the event was treated, and whether the participant will 
continue or discontinue study participation.  

  
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10.4.2 Non-Serious Adverse Event Reporting   
  
Non-serious adverse events will be reported to the DF/HCC Overall Principal Investigator on the 
toxicity Case Report Forms.    
10.5 Reporting to the Institutional Review Board (IRB)  
  
Investigative sites within DF/HCC will report all serious adverse events directly to the DFCI Office for 
Human Research Studies (OHRS).  
  
Other investigative sites should report serious adverse events to their respective IRB according to the 
local IRB’s policies and procedures in reporting adverse events. A copy of the submitted institutional 
SAE form should be forwarded to:  
  
 
   
Office for Human Research Studies  
         Dana Farber Cancer Institute  
 
    
20 Overland St., 2nd Floor (physical location)  
        450 Brookline Ave, OS229 (mailing 
location)  
Boston, MA - 02215          
Phone 617-632-3029          
Fax 617-632-2686  
The DF/HCC Principal Investigator will submit SAE reports from outside institutions to the DFCI Office 
for Human Research Studies according to DFCI IRB policies and procedures in reporting adverse events.   
10.6 Reporting to the Food and Drug Administration (FDA)  
  
              Use on Med watch form 3500A   
10.7 Reporting to Hospital Risk Management  
  
Participating investigators will report to their local Risk Management office any subject safety reports or 
sentinel events that require reporting according to institutional policy.  
10.8 Monitoring of Adverse Events and Period of Observation  
  
All adverse events, both serious and non-serious, and deaths that are encountered from initiation of study 
intervention, throughout the study, and within 30 days of the last study intervention should be followed 
to their resolution, or until the participating investigator assesses them as stable, or the participating 
investigator determines the event to be irreversible, or the participant is lost to follow-up. The presence 

  
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and resolution of AEs and SAEs (with dates) should be documented on the appropriate case report form 
and recorded in the participant’s medical record to facilitate source data verification.   
  
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or monitoring visit 
to obtain additional case details deemed necessary to appropriately evaluate the SAE report (e.g., 
hospital discharge summary, consultant report, or autopsy report).   
  
Participants should be instructed to report any serious post-study event(s) that might reasonably be 
related to participation in this study. Participating investigators should notify the DF/HCC Overall 
Principal Investigator of greater or equal to grade 3 events and the IRB of any unanticipated death or 
adverse event occurring after a participant has discontinued or terminated study participation that may 
reasonably be related to the study.    
  
  
11. DATA AND SAFETY MONITORING  
11.1 Data Reporting  
11.1.1 Method   
The QACT will collect, manage, and monitor data for this study.   
11.1.2 Data Submission   
The schedule for completion and submission of case report forms (paper or electronic) to the QACT 
is as follows:  
  
Form  
Submission Timeline  
Eligibility Checklist  
Complete prior to registration with QACT  
On Study Form  
Within 14 days of registration  
Baseline Assessment Form  
Within 14 days of registration  
Treatment Form  
Within 10 days of the last day of the cycle  
Adverse Event Report Form  
Within 10 days of the last day of the cycle  
Response Assessment Form  
Within 10 days of the completion of the cycle 
required for response evaluation  
Off Treatment/Off Study Form 
Within 14 days of completing treatment or 
being taken off study for any reason  

  
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Follow up/Survival Form  
Within 14 days of the protocol defined follow 
up visit date or call  
  
11.2 Safety Meetings  
  
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this trial. The committee is composed of clinical specialists with experience in 
oncology and who have no direct relationship with the study. Information that raises any questions about 
participant safety will be addressed with the Principal Investigator and study team.  
  
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual data.  
Information to be provided to the committee may include:  up-to-date participant accrual; current dose 
level information; DLT information; all grade 2 or higher unexpected adverse events that have been 
reported; summary of all deaths occurring within 30 days; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be provided 
upon request.   
11.3 Ongoing Monitoring of Protocol Compliance   
  
At the Discretion of the Overall Investigator, the Participating Institutions will be required to submit 
participant source documents to the DF/HCC Lead Institution for remote monitoring by the Clinical Trial 
Specialist and or Lead site coordinator.  
  
At the Discretion of the Overall Investigator, the Participating Institution may require at least one on-site 
monitoring visit conducted by the Overall Investigator and or Clinical Trial Specialist and or Lead site 
Coordinator. The DF/HCC Lead Institution will implement monitoring activities ongoing to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data quality, and 
participant safety. Additional monitoring practices may include but are not limited to: source verification, 
review and analysis of the following: eligibility requirements of all participants , informed consent 
procedures, adverse events and all associated documentation, study drug administration / treatment, 
regulatory records and site trial master files, protocol deviations, pharmacy records, response 
assessments, and data management.  
  
Monitoring can occur during any time during a site’s participation up unto and including study 
completion.  
  
All data submitted to the DF/HCC QACT will be monitored for timeliness of submission, completeness, 
and adherence to protocol requirements. The Lead Institution or designee and if applicable QACT Data 
Analysts assigned to the Protocol will perform the ongoing protocol data compliance monitoring with 
the support of the Participating Institution’s Principal Investigator and research team. The DF/HCC 
Lead Institution will maintain regular and ongoing communication to Participating Institutions about 
study related information.  
  

  
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12. REGULATORY CONSIDERATIONS  
12.1 Protocol Review and Amendments  
This protocol, the proposed informed consent and all forms of participant information related to the study 
(e.g., advertisements used to recruit participants) and any other necessary documents must be submitted, 
reviewed and approved by a properly constituted IRB governing each study location.   
Any changes made to the protocol must be submitted as amendments and must be approved by the  
IRB prior to implementation. Any changes in study conduct must be reported to the IRB. The DF/HCC 
Overall Principal Investigator (or Protocol Chair) will disseminate protocol amendment information to 
all participating investigators.   
All decisions of the IRB concerning the conduct of the study must be made in writing.  
12.2 Informed Consent  
  
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. The 
formal consent of a participant, using the IRB approved consent form, must be obtained before the 
participant is involved in any study-related procedure. The consent form must be signed and dated by the 
participant or the participant’s legally authorized representative, and by the person obtaining the consent. 
The participant must be given a copy of the signed and dated consent document. The original signed 
copy of the consent document must be retained in the medical record or research file.   
12.3 Ethics and Good Clinical Practice (GCP)  
This study is to be conducted according to the following considerations, which represent good and sound 
research practice:  
• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf   
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and ethical principles that 
have their origin in the Declaration of Helsinki  
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html  
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html   
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html   
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html   

  
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o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html   
• 
State laws  
• 
DF/HCC research policies and procedures        http://www.dfhcc.harvard.edu/clinical-
researchsupport/clinical-research-unit-cru/policies-and-procedures/   
It is understood that deviations from the protocol should be avoided, except when necessary to eliminate 
an immediate hazard to a research participant. In such case, the deviation must be reported to the IRB 
according to the local reporting policy.   
12.4 Study Documentation  
  
The investigator must prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the study for each research participant. This information enables 
the study to be fully documented and the study data to be subsequently verified.  
  
Original source documents supporting entries in the case report forms include but are not limited to 
hospital records, clinical charts, laboratory and pharmacy records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays.   
12.5 Records Retention  
  
All study-related documents must be retained for the maximum period required by applicable federal regulations 
and guidelines or institutional policies.   
  
13. STATISTICAL CONSIDERATIONS   
13.1 Sample Size/Accrual Rate  
  
The primary objective is to estimate the proportion of patients having intermediate risk CaP treated with external 
beam radiation therapy (EBRT) and enzalutamide whose PSA level at the end of six cycles of enzalutamide and 
EBRT is ≤0.2 ng/ml. In a single stage design, seventy-one patients will be enrolled. Assuming 10% ineligibility, 
the target evaluable sample size is 64 patients. The null hypothesis is 60% of patients achieving PSA nadir ≤0.2 
ng/ml. The historical rate will serve as the alternative in this design. Based on research by D’Amico et al, the 
proportion of patients achieving PSA level <0.20 ng/ml at the end of EBRT and 6 months of leuprolide acetate 
neo-adjuvant/adjuvant treatment is 75%. With a sample size of 64 evaluable patients, if the number achieving PSA 
level <0.2 ng/ml is 44 or more, then the hypothesis that the percentage achieving PSA level <0.2 ng/ml is ≤60% is 
rejected with a target error rate of α=0.10 (actual error 0.095), whereas if the number is 43 or less, then the 
hypothesis that the percentage achieving PSA level <0.2 ng/ml is ≥75% is rejected with a target error rate of 
β=0.10 (actual β=0.099). We also will report exact binomial 90% confidence intervals on the observed proportion.  
Patients that discontinue early or are missing the end of treatment (cycle 6) PSA will be considered failures. 
Sensitivity analysis on the primary endpoint that includes counting a patient as a success if there is record of PSA 
level <0.20 ng/ml ever on treatment will be performed. We expect to accrue 2-3 patients per month at the three 
DF/HCC hospitals, BWH and DFCI and therefore accrual duration is expected to be 24-36 months.   

  
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13.2 Analysis of Secondary Endpoints  
13.2.1 Health related quality of life   
The primary HRQoL aim is to assess the change from baseline to the end of cycle 6 in the vitality or hormonal 
function score as well as the sexuality score on the EPIC-26 questionnaire. It is anticipated approximately 75% of 
patients will have both scores for each domain. A one-sample t-test will be used to assess the overall change in 
score. To be considered a clinically meaningful difference will be defined as half historical standard deviation for 
the specific domain. Given 48 evaluable patients, there is 80% power to detect a 0.41 change in the hormonal 
domain score of the EPIC-26 assuming 2-sided 5% alpha. Results in this study will be evaluated in the context of 
past research by Sanda et al showing patients that received radiotherapy with non-hormonal therapy had a score on 
the vitality or hormonal function domain of approximately 80 and a score on the sexuality domain of 26.    
  
Descriptive statistics at each time point and changes over time will be provided for each of the EPIC-26 domains 
as well as for the PROMIS-Fatigue and PSQ1. Mixed models will be used to explore the impact of time on quality 
of life adjusting for prognostic baseline factors.  
  
13.2.2 Safety and Tolerability: We will monitor toxicities experienced by all treated patients. Frequency and 
severity of worst grade 3 or higher treatment-related AEs by type will be reported along with the incidence of 
overall grade 3 or higher treatment-related AEs. With 71 treated patients, the maximum width of a 90% CI for a 
given toxicity is 21%. The probability of observing one rare severe toxicity (true rate=5%) is 97%. Tolerability 
endpoints include the number of dose reductions and treatment interruptions as well as the number of patients that 
discontinue treatment due to AEs. The safety summary will include clinical laboratory, ECG and vital signs data.   
  
13.2.3 Hormone Levels: Descriptive statistics at each time point and changes over time will be provided for all 
hormone measures. Paired t-tests and two-sample t-tests (or non-parametric equivalents) will be used to assess 
significance of change over 6 cycles of treatment in hormone levels for the overall cohort and by status on primary 
clinical endpoint (yes or no achieving PSA level <0.20 ng/ml at the end of 6 cycles of treatment with enzalutamide 
and EBRT).   
   
13.2.4. Anthropomorphic Measurements: Descriptive statistics at each time point and change over 6 cycles will be 
provided for all anthropomorphic measures.   
13.3 Analysis of Correlative Endpoint   
We anticipate that at approximately 75% of patients will consent to have prostate samples removed at the time of 
the fiducial placement. We expect to detect tumor from samples from at least half of these patients. Therefore we 
expect that we will have conservatively ~24 patients that have samples that are evaluable. Nuclear expression 
grade will be tabulated. This unique resource will serve as a pilot to help in the understanding of the mechanism of 
enzalutamide action when the pattern of AR expression is compared to pre-treatment biopsy samples and samples 
from other patient tumors.      
  
            
14. REFERENCES   
  
1) 
D'Amico AV, Chen MH, de Castro M, Loffredo M, Lamb DS, Steigler A, Kantoff PW, Denham 
JW .Surrogate endpoints for prostate cancer-specific mortality after radiotherapy and androgen 

  
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suppression therapy in men with localised or locally advanced prostate cancer: an analysis of two 
randomised trials .Lancet Oncol. 2012 189-195.   
2) 
Tran C, Ouk S, Clegg NJ et al. Development of a second-generation antiandrogen for treatment of 
advanced prostate cancer. Science 2009; 324(5928):787-790.  
  
3) 
Scher HI, Beer TM, Higano CS et al. Antitumour activity of enzalutamide in castration resistant 
prostate cancer: a phase 1-2 study. Lancet 2010; 375(9724):1437-1446.  
  
4.) Scher HI, Fizazi K, Saad F et al Increased survival with enzalutamide in prostate cancer after chemotherapy 
New Eng J Med . 2012; 367: 1187-1197  
  
5) 
Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, Bruner DW, Leibenhaut MH, Husain SM, 
Rotman M, Souhami L, Sandler HM, Shipley WU Radiotherapy and short-term androgen deprivation for localized 
prostate cancer.N Engl J Med. 2011 365:107-18.  
  
6) 
O'Connell MD, Roberts SA, Srinivas-Shankar U, Tajar A, Connolly MJ, Adams JE, Oldham JA, Wu FC. 
Do the effects of testosterone on muscle strength, physical function, body composition, and quality of life persist 
six months after treatment in intermediate-frail and frail elderly men? J Clin Endocrinol Metab. 2011:96:454-8.   
  
7) 
Kintzel PE, Chase SL, Schultz LM, O'Rourke TJ. Increased risk of metabolic syndrome, diabetes mellitus, 
and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer. Pharmacotherapy. 
2008 28:1511-22.  
  
8) 
Taylor LG, Canfield SE, Du XL. Review of major adverse effects of androgen-deprivation therapy in men 
with prostate cancer. Cancer. 2009 Jun 115:2388-99.  
  
9) 
Tseng YD, Chen MH, Beard CJ, Martin NE, Orio PF, Loffredo M, Renshaw AA, Choueiri TK, Hu JC, 
Kantoff PW, D'Amico AV, Nguyen PL.  Post treatment prostate specific antigen nadir predicts prostate cancer 
specific and all cause mortality. J Urol. 2012 187:2068-73.   
  
10) 
Matsumoto AM. The testis. In: Felig P, Frohman LA, eds. Endocrinology and Metabolism, 4th ed. New 
York, NY: McGraw-Hill; 2001:635-705.) 
 
 
 
 
 
 
 
 

  
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15. APPENDICES   
  
Appendix A: PROMIS Sleep Survey  
  
Appendix B: Pittsburg Sleep Quality Index  
  
Appendix C: EPIC-26  
  
Appendix D: Eastern Cooperative Oncology Group Performance Status  
  
Appendix E: Research Labs   
  
Appendix F: Drugs to be used with caution or avoided   
  
Appendix G: Charts to calculate body fat %  
  
Appendix H: Pill Diary 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  
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Appendix A:  
  
Investigator Format © 2008-2012 PROMIS Health Organization and PROMIS Cooperative Group Page 1 of 1   
  
 
 
  
 

  
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https://www.sleep.pitt.edu/wp-content/uploads/Study_Instruments_Measures/PSQI-Instrument.pdf 
 
 

  
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          Version 13.0 Protocol Version Date: 1/09/2015 
 
 
  
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                                                        Version 13.0 Protocol Version Date: 1/09/2015 
 
 
  
© 1989, University of Pittsburgh. All rights reserved. Developed by Buysse,D.J., Reynolds,C.F., 
Monk,T.H., Berman,S.R., and Kupfer,D.J. of the University of Pittsburgh using National Institute of 
Mental Health Funding. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ: Psychiatry Research, 
28:193-213, 1989. 

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https://www.sleep.pitt.edu/instruments/ 
 
  

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22 
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21  
  

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23 
  
  

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24 
  
  
 
 

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25 
 
 
Appendix C   
 
EPIC -26   
The 
Expanded 
Prostate 
Cancer 
Index 
Composite 
 
 
 
 

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30 
Appendix D:   
 
 
 
https://ecog-acrin.org/resources/ecog-performance-status/ 
 
 
 
ECOG PERFORMANCE STATUS*  
Grade  ECOG  
0  
Fully active, able to carry on all pre-disease performance without restriction  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work  
2  
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours  
3  
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours  
4  
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair  
5  
Dead  
 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-655. PMID: 7165009

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 Appendix E: Research Labs  
Bone Metabolism Markers (should be drawn in AM and fasting)  
1. Collagen Type I C‐telopeptide   
 Serum; 1 ml; red top without serum separator; CPT4 code: 82523  
2. Bone Specific alkaline phosphatase   
  Serum, 1 ml serum separator tube;  
3. Procollagen Type I Intact N terminal propeptide  Serum, 1 ml CPT 
code 83519     
  
Hormone Metabolism Markers (should be drawn in AM and fasting)  
1. DHEA‐S (also called DHEA‐sulfate or dehydroepiandrosterone 
sulfate Serum; .25 ml; serum separator tube; CPT4 code  80158  
2. Androstenedione   
Serum; 1 ml; red top tube without serum separator; CPT4 code 82157  
3. Testosterone  
Serum; 0.5 ml; serum separator tube  
4. Free testosterone  
Serum; 0.5ml. serum separator tube  
5. Estrone (precursor or estradiol which is also called estrogen)  
   Serum; 2 ml. serum separator tube; CPT4 code 82679  
6. Estradiol (estrogen)  
Serum; 2 ml. serum separator tube; CPT4 code 84231   
  
These tubes are to be drawn through their normal process for ordering blood work and should 
be sent to the clinical laboratory. 
 
  
 
 

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Appendix F:  
  
Drugs to avoid because of interaction with CYP2C8 or CYP3A4 metabolic pathways  
Gemfibrizil, carbamazepine, phenobarbital, pentobarbital, phenytoin, rifabutin, rifampin, 
rifapentine, nafcillin,modafinial, etavirenz, efavirenz, bosentan, cyclosporin, ergotamine, 
quininide, sirolimus tacrolimus, alfentanil, pimozide, St. John’s Wort, ketoconazole, sertraline, 
digitoxin, haloperidol, ketamine, doxocycline, isoniazid, etravirine, dihydroergotamine and 
fentanyl.  
  
Drugs to be used with caution  
Warfarin (will likely require a change in warfarin dosing), omeprazole, midazolam, 
ciprofloxacin.     
  
  
  
  
  
  
  
  
 
  
  
  
  
  

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Appendix G  
Charts to calculate body fat %  
Chart (Men)  
 
% Fat for Sum of Measurements at All 4 Locations  
Sum in mm  
Age 16‐29  Age 30‐49  Age 50+  
20  
8.1  
12.1  
12.5  
22  
 
 
    9.2                  13.2               13.9 
24                                          10.2                 14.2               15.1  
26  
11.2  
15.2  
16.3  
28  
12.1  
16.1  
17.4  
30  
12.9  
16.9  
18.5  
35  
14.7  
18.7  
20.8  
40  
16.3  
20.3  
22.8  
45  
                                 17.7               21.8  
       24.7 
50  
                                 19.0               23.0  
       26.3 
55  
                                 20.2               24.2  
        27.8  
60  
21.2  
25.3  
29.1  
65  
22.2  
26.3  
30.4  
70  
23.2  
27.2  
31.5  
75  
24.0  
28.0  
32.6  
80  
24.8  
28.8  
33.7  
85  
25.6  
29.6  
34.6  
90  
26.3  
30.3  
35.5  
95  
 
 
   27.0               31.0  
       36.5 
100  
                                 27.6               31.7  
       37.3  
110  
28.8  
32.9  
38.8  
120  
                                 29.9               34.0  
       40.2 
130  
                                 31.0                35.0  
       41.5 
140  
                                 31.9                36.0  
       42.8  
150  
32.8  
36.8  
43.9  
160  
33.6  
37.7  
45.0  
170  
34.4  
38.5  
46.0  
180  
35.2  
39.2  
47.0  
190  
                                 35.9               39.9  
       47.9 
200  
                                 36.5               40.6  
       48.8  
  
.  
 
 

 
 
 Appendix H: Pill Diary  
Study Participant_________ 
Self-Administration 
Study Drug Diary 
Dana-Farber/Harvard Cancer Center 
 
   
   
 
  
  
Participant Identifier: ____________________  
Protocol # : Enzalutamide with  
External Beam Radiation for Intermediate 
Risk Prostate Cancer:  
A Phase II study  
Your MD ____________________ Phone _____________ 
Your RN _____________________ Phone ______________  
STUDY DRUG INSTRUCTIONS:  
Study Drug: Enzalutamide  
How Much:  Your dose is160 mg   
How Often: You will take 4 (40mg) capsules per day  
When: You should take your capsules at the same time each day.  
 
  
  
  
  
  
 
  
  
  
  
SPECIAL INSTRUCTIONS: Do not make up missed or vomited doses if It has 
been longer than 12 hours since you were supposed to take your dose.  Do 
not chew or crush capsules. Take with or without food. Bring in your Used pill 
bottles at each visit.   
  
 
Study Participant Initials ________  
Date _________  
 

 
 
   
   
FOR STUDY TEAM USE ONLY 
   
   
  
Staff Initials:     
   
   
   
   
   
   
Date Dispensed:  
   
Date Returned:    
# pills/caps/tabs dispensed:  
   
   
   
   
# pills/caps/tabs 
returned:  
   
   
# pills/caps/tabs that should have been taken:  
   
   
   
 
   
   
Discrepancy Notes:  
   
   
   
   
   
   
   
DOSING LOG  
SYMPTOMS/SIDE EFFECTS  
Cycle: ___  
For each dose take:   
                         Please record any side effects experienced during this cycle. 
Include the date the particular symptom started and when it ended. 
Please evaluate the severity of the symptom according to  
Please indicate the date, time, amount taken and any comments.   
the following scale:  
Mild: Awareness of sign or symptom; easily tolerated and did   
 Not affect ability to perform normal daily activities. Symptom did not 
require medication or therapeutic intervention. Moderate: Significant 
discomfort which interfered with ability to perform normal daily 
activities. Symptom was easily resolved   with at home medication or 
simple therapeutic intervention. Severe: Marked discomfort with an 
inability to carry out normal daily activities. Symptom required new 
medication and/or therapeutic intervention in order to resolve 
 
Date  
Amount Taken  
Comments  
Time/ Dose  
  
Ex:  
6/1/2009  
8 AM 4 capsules  
took with breakfast  
Day 1  
   
   
   
Day 2  
   
   
   
Day 3  
   
   
   
Day 4  
   
   
   

 
 
Day 5  
   
   
   
Day 6  
   
   
   
Day 7  
   
   
   
Day 8  
   
   
   
Day 9  
   
   
   
Day 10  
   
   
   
Day 11  
   
   
   
Day 12  
   
   
   
Day 13  
   
   
   
Day 14  
   
   
   
Day 15  
   
   
   
Day 16  
   
   
   
Day 17  
   
   
   
Day 18  
   
   
   
Day 19  
   
   
   
Day 20  
   
   
   
Day 21  
   
   
   
Day 22  
   
   
   
Day 23  
   
   
   
Day 24  
   
   
   
Day 25  
   
   
   
Day 26  
   
   
   

 
 
  
 
 Please Note: The severity should reflect the most severe level experienced during the time period.   
   
   
   
   
   
  
 
Day 27  
   
   
   
Day 28  
   
   
   
   
Symptom  
   
Start Date  
End Date