Clinical trial NCT02605863
Conditions: Bladder Cancer
Keywords: Enzalutamide Non-Muscle Invasive Bladder Cancer Androgen Deprivation Therapy
Sponsor: University of Rochester
Start date: 2016-01-01; Completion date: 2018-02-01
Enrollment: 1 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine the effect of androgen deprivation therapy through administration of enzalutamide on preventing bladder cancer recurrences in patients with non-muscle invasive bladder cancer (NMIBC).

Detailed description:
* A blood draw and an electrocardiogram (EKG). The blood draw will check levels of testosterone, dihydro-testosterone, estradiol, and Vitamin D. Pre-study blood-work will also include a complete blood count (CBC), basic metabolic panel (BMP/CHEM8) and liver function test (LFT) if any of these labs were not drawn within 1 month prior to the transurethral resection of bladder tumor (TURBT).
* Bladder tumor sample that is stored in the Department of Pathology will have additional tests run on it to confirm study eligibility and to test for certain cell markers.
* After 1 month following the original TURBT, subjects will begin therapy with enzalutamide. The study drug will be administered orally at a dose of 160mg daily for 12 months.
* Subjects will be monitored for adverse reactions or side effects from enzalutamide at scheduled office visits.
* If the bladder tumor is classified as being "intermediate risk", regularly scheduled office visits will occur at 2 months post-operatively (i.e., 1 month after starting enzalutamide), and then again at post-operative months 3, 6, 9 and 12, as is part of the usual standard of care.
* If the bladder tumor is classified as being "high risk" and the subject receives BCG therapy, then the office visits will occur on a slightly different schedule to conform to the standard of care for this type of disease. Subjects in this group typically start their intravesical BCG instillations 4-6 weeks post-operatively. Therefore, the subjects will be seen approximately 1 month following the initial TURBT, and will begin therapy with enzalutamide at that time, as described above. Subjects will be on study drug at least 7 days prior to the initiation of BCG therapy, which will occur once a week for 6 weeks. Similar to the subjects in the intermediate risk group, the subjects receiving BCG will also be seen 1 month after initiation of enzalutamide therapy to ensure there are no adverse reactions to the study drug. Following this visit, they will be seen again at the time of the post-BCG cystoscopy, which occurs 1 month after your 6th instillation. Subjects will be seen again at the 3, 6, 9 and 12-month post-BCG cystoscopy office visits, as part of routine care.
* Repeat blood work (CBC, BMP and LFTs) will be checked 1 month after starting enzalutamide (approximately 2 months post-operatively). For subjects with intermediate risk bladder cancer, these labs will be checked again at 3, 6, 9 and 12 months post-operatively (as per the regularly scheduled office visits). For the high risk patients receiving BCG therapy, these labs will be checked again at the 1, 3, 6 and 9-month post-BCG office visits (per the regularly scheduled office visits for these patients).
* An EKG will be obtained at baseline (before starting the study drug), but will also be re-checked at approximately 6 months (half-way through therapy with enzalutamide) to ensure there are no signs of worsening cardiac disease while on the study drug.
* A cystoscopy will be done every 3 months as part of the standard of care for bladder cancer follow-up. Lesions suspicious for tumor recurrence will be biopsied as per usual standard of care. If a recurrence is documented, subjects will discontinue use of enzalutamide.
* For subjects scheduled to undergo therapy with BCG, additional tests will be run on the urine samples that subjects will already be providing in the Urology office as part of the standard of care.

Arms: arm 1: Enzalutamide 160mg by mouth daily for 12 months arm 2: Enzalutamide 160mg by mouth daily for 12 months
Interventions: intervention 1: Enzalutamide
Intervention descriptions: intervention 1: 160 mg by mouth daily for 12 months

Protocol documents:
Prot_SAP_000.pdf: 
  
Enzalutamide for Bladder Cancer Chemoprevention 
 
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NCT # 02605863 
Principal Investigator: 
Edward Messing, MD, FACS 
 
 
Sub-Investigators: 
Anees Fazili, MD 
Erdal Erturk, MD 
Jeanne O’Brien, MD 
Guan Wu, MD 
 
Full Contact Information: 
Edward M. Messing, MD, FACS 
Chair, Dept. of Urology 
University of Rochester School of Medicine and Dentistry 
601 Elmwood Avenue, Box 656 
Rochester, NY 14642 
Admin phone:  (585) 275-3345 
Clinical phone:  (585) 275-0998 
Fax:  (585) 273-1068 
edward_messing@urmc.rochester.edu 
 
 
 
Study Title: 
The Effect of Androgen Deprivation Therapy with Enzalutamide on Bladder Cancer 
Chemoprevention 
 
Trial Category: 
Phase 2 
 
 
Type of Support Requested: 
Drug and Funding 


  
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Study Overview: 
Previous studies conducted by our group have demonstrated that androgen-mediated signals and 
the androgen receptor (AR) promote bladder carcinogenesis. Based on the results from our animal 
experiments, we are proposing a single arm, open label Phase 2 study to evaluate the effect of androgen 
deprivation therapy (ADT) through administration of Enzalutamide on preventing bladder cancer (BC) 
recurrence in patients with non-muscle invasive bladder cancer (NMIBC). 
 
Scientific Rationale for Study: 
Bladder cancer, primarily urothelial carcinoma, is the fifth most commonly diagnosed non- 
cutaneous malignancy in the United States, with more than 70,000 new cases diagnosed per year. 
Over 70% of these cases are non-muscle invasive BCs (NMIBC)1. Although recurrence rates depend 
on a variety of factors—including tumor grade, stage, size, multiplicity, and associated genetic 
mutations—the data from multiple trials has consistently shown that in aggregate, approximately 
45% of patients with NMIBC will have a recurrence of their disease within 2 years of their initial 
transurethral resection of bladder tumor (TURBT), and approximately 35% will have a recurrence 
within the first year alone2-7. More than 14,000 Americans ultimately die from BC each year, and 
there has been little reduction in BC mortality over the past 20 years. Interestingly, BC is the fourth 
most common cancer among men in the United States, but only the tenth most common cancer 
among women. Epidemiological studies have shown that males have approximately three times the 
risk of developing bladder cancer as females. The etiology of this sex difference in the incidence of 
bladder cancer remains unknown, and it cannot be explained entirely by different rates of carcinogen 
exposure8. 
Several recent studies have suggested the involvement of androgens in bladder 
carcinogenesis. Using AR knockout (ARKO) mice, preliminary studies from our own institution 
found that the AR might play a critical role in the development of chemical carcinogen-induced 
bladder cancer. In addition, we discovered that at least two bladder cancer cell lines express a 
functional AR, and that androgens promoted tumor cell growth in these cell lines while anti- 
androgens antagonized this effect9,10. Multiple studies from various institutions have ultimately 
demonstrated AR expression in approximately half of all human bladder cancer tissues examined, 
with preliminary results indicating the AR as a potential therapeutic target11-18. 
There is further evidence that anti-androgens may increase the anti-tumor effects of BCG therapy 
for NMIBC. Instillations of BCG have been shown in numerous phase 3 randomized studies to be the 
most effective means to prevent recurrences of high risk NMIBC. It is also the only therapy (when 
combined with TURBT) that has been repeatedly shown to prevent progression of high risk NMIBC to 


  
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muscle invasion19. It is believed that BCG must bind to urothelial tumor cells, usually through α5β1 
integrin, and that binding and subsequent internalization induces cytokine release, including that of 
interleukins (IL-6 and IL-8) and tumor necrosis factor alpha (TNFα)20. If there is depletion of cells of the 
innate immune system, BCG loses its effect in animal models, indicating that its key activity is via this 
immunologically mediated mechanism. AR activity, however, has been shown to inhibit expression of 
α5β1 integrin in human BC cells in vitro, thereby preventing this cascade of events from occurring. AR 
signaling has also been shown to directly inhibit the expression of IL-6 by human BC cells exposed in 
vitro to BCG—an effect that could be blocked by anti-androgens. Moreover, activation of the AR in cells 
of the innate immune system has been shown to inhibit these cells’ activity directly as well11. 
Taken together, these observations form the basis of our hypothesis that androgens and the 
AR play a key role in bladder carcinogenesis, and may be an important mediator of the response to 
BCG. Through this Phase 2 study we therefore hope to demonstrate that anti-androgens can be used 
to retard bladder carcinogenesis, and may even be an effective adjunct to BCG therapy. By 
administering Enzalutamide (MDV 3100) and using historical control data, we hope to achieve a 
15% reduction in the overall risk of recurrence of NMIBC within the first year following TURBT. 


  
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Figure 1:  Study Design Flowchart: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Includes Testosterone, Dihydrotestosterone, Estrogen, & Vitamin D levels 
** Includes testing TURBT specimens for AR+/- status 
 
 
Target: 50 subjects total (25 intermediate-risk and 25 high-risk + BCG) 
Maximum AR(-) subjects in either cohort = 8 subjects (1/3 of each cohort) 
(+) Recurrence for bladder CA at any time-point 
(-) Recurrence 
Patient undergoes TURBT for bladder tumor 
Patient presents to office for post-operative visit to discuss pathology & treatment plan 
Office visits @ approximately 1, 2, 3, 6, 9 & 12 months post-operatively 
Office cystoscopy @ approximately 3, 6, 9 & 12 months post-operatively 
CBC, CHEM8, LFTs @ approximately 2, 3, 6, 9 & 12 months post-operatively 
EKG @ approximately 6 months after starting study drug 
If receiving BCG, will check pre-instillation urine for IL-6 @ instillations 1, 3 & 6 
Stop Enzalutamide, document time of recurrence 
& pathologic diagnosis of recurrent tumor 
Continue Enzalutamide until completes 12mo. of therapy 
Yes 
Consent patient for study. Subject will return to clinic 
after obtaining baseline bloodwork*, EKG & confirming 
they meet all other inclusion/exclusion criteria**. Will 
then start Enzalutamide 160mg po qd x 12months. 
No 
Intermediate Risk (25 pts) 
High Risk (25 pts) 
No BCG treatment, or 
will receive chemotherapy 
or other  alternative therapy 
Patient scheduled for BCG 
Low risk 
Excluded 
Meets initial inclusion/exclusion criteria 
Excluded 
Excluded 


  
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Study Design/Description: 
The proposed study is a single arm, open label, Phase 2 study to evaluate the effect of androgen 
deprivation therapy (ADT) via Enzalutamide on preventing bladder cancer (BC) recurrence in patients 
with non-muscle invasive bladder cancer (NMIBC). Subjects will be enrolled in the study at the time of 
their return to the office to discuss the results of their TURBT, which usually occurs 7-10 days post- 
operatively. Subjects will ultimately be categorized based on their risk of bladder cancer recurrence per 
the European Association of Urology guidelines, and only subjects with intermediate or high risk disease 
will be enrolled.  These patients have a 24-38% and 55-67% risk of recurrence at 1 year, respectively21. 
The standard of care for patients with high risk disease is to offer treatment with a course of 
intravesical BCG, which is known to reduce the risk of recurrence at 1 year by approximately one half, 
thereby giving subjects in this cohort a 27-32% expected recurrence rate at 1 year22. Patients with high 
risk disease who do not undergo treatment with BCG will ultimately be excluded. Hence, we expect both 
our intermediate risk group and our high risk+BCG group to have an approximately 30% risk of 
recurrence at 1 year. 
There will be a pre-screening process to identify potential subjects via the Urology Clinic 
schedules and eRecord. Once a potential subject is identified and the urologist is notified, the study team 
member will approach the potential subject to introduce the study. The exam room door will be closed to 
ensure privacy. The subject may take the consent form home to discuss with family and friends.  The 
study team member may telephone the potential subject to check interest in participation and answer any 
questions they may have.  If a subject is interested, a screening visit will be scheduled. 
After subjects consent to be enrolled in the study, baseline blood-work and an EKG will be 
obtained.  This blood draw will check levels of testosterone, dihydro-testosterone, estradiol, and Vitamin 
D. Pre-study blood-work will also include a complete blood count (CBC), basic metabolic panel 
(BMP/CHEM8) and liver function test (LFT) if any of these labs were not drawn within 1 month prior to 
the subject’s TURBT. Surgical Pathology will also perform immuno-histochemical staining for the AR in 
the TURBT specimen, since the maximum AR(-) subjects allowable in either the intermediate risk cohort 
or high risk+BCG cohort will be 8 subjects in each cohort (1/3 of each cohort). AR(+) status will be 
assessed according to the German Scoring System, which takes into account both the percentage and 
intensity of positively staining cells on immuno-histochemical assay, with a cut-off of score of ≥ 2 being 
used to define AR(+) tumor specimens.  Once eligibility criteria is confirmed, the subject will return to 
the office for dispense of the study drug. 


  
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After eligibility for the study has been confirmed by the aforementioned testing, subjects will 
return to the office approximately 1 month following their original TURBT to begin therapy with 
Enzalutamide.  The study drug will be administered orally at a dose of 160 mg daily for 12 months. 
Dosing Instructions will be given to all subjects (attached). Study drug compliance will be monitored at 
intervals throughout the study. Subjects will be monitored for adverse reactions or side effects from 
Enzalutamide at scheduled office visits and 2 weeks after study drug discontinuance. In order to track 
adverse events in the study, an Adverse Event form (attached) will be distributed to the subject with 
verbal instructions for completion and reviewed at scheduled visits.  Subjects will also be given a card 
with pertinent study information and contact numbers to give to their healthcare providers or in case of an 
emergency while in the study (attached). Subjects with partners of child-bearing potential will be 
contacted and reminded about maintaining birth control until 3 months after study drug discontinuance. 
 
 
For subjects in the intermediate risk cohort, these visits will occur at 2 months post- 
operatively (1 month after initiation of Enzalutamide), and then again at post-operative 
months 3, 6, 9 and 12, as is part of the usual standard of care for these patients (Figure 
2A). 
 
For subjects in the high risk+BCG cohort, office visits will occur on a slightly different 
schedule to conform to the standard of care for these patients (Figure 2B).  Subjects in 
this cohort typically start their intravesical BCG instillations 4-6 weeks post-operatively. 
Therefore, subjects in this cohort will still be seen approximately 1 month following 
their initial TURBT, and they will begin therapy with Enzalutamide at that time as 
described above.  These subjects will need to be on the study drug for at least 7 days 
prior to initiation of their BCG therapy to ensure adequate blockade of the androgen 
receptor prior to BCG therapy, which will occur once a week for 6 weeks. Similar to the 
subjects in the intermediate risk cohort, the subjects receiving BCG will also be seen 1 
month after initiation of Enzalutamide therapy to ensure there are no adverse reactions to 
the study drug.  Adverse events will be reviewed during the 6 weekly instillations of 
BCG at Visits 1, 3, 4, and 6. Following this visit, they will be seen again at the time of 
their initial post-BCG cystoscopy, which occurs 1 month after their 6th instillation. They 
will then be seen again at their 3, 6, 9 and 12-month post-BCG cystoscopy office visits. 


  
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Subjects will be withdrawn from the study for the following reasons: 
1) Weekly BCG treatments delayed more than twice (i.e., adverse events, gross hematuria, 
urinary tract infections or any other reason BCG treatments cannot be completed at the 
scheduled office visit) 
2) Unable to complete all 6 BCG treatments 
3) Development of any serious side effects or significant complications associated with this 
therapy. This will include development of painful gynecomastia, heart attack, stroke, 
DVT/PE, elevation of hepatic enzymes, alkaline phosphatase or bilirubin to greater than 
twice the upper limit of normal, or development of renal insufficiency with eGFR < 30. 
CBC, CHEM8 and LFTs will be checked 1 month after initiation of Enzalutamide 
(approximately 2 months post-operatively). For subjects with intermediate risk bladder 
cancer, these labs will be checked again at 3, 6, 9 and 12 month post-operatively (as per the 
regularly scheduled office visits, Figure 2A). For the high risk+BCG cohort, these labs will 
be checked again at the 1, 3, 6 and 9-month post-BCG office visits (per the regularly 
scheduled office visits for these patients, Figure 2B). EKGs will be obtained at baseline as 
mentioned above, but will also be re-checked at approximately 6 months (half-way through 
therapy with Enzalutamide) to ensure there are no signs of worsening cardiac disease while 
on the study drug. 
Subjects will undergo quarterly cystoscopies as part of the standard of care for bladder cancer 
follow-up (as detailed in Figure 2A & 2B). Lesions suspicious for tumor recurrence will be biopsied as 
per usual standard of care. If a recurrence is documented, the subject will be notified at the TURBT post- 
op visit to discontinue use of Enzalutamide and will be withdrawn from the study at this time. The final 
pathologic diagnosis of the recurrent tumor will also be noted in order to assess for any potential tumor 
progression.  Subjects who are terminated early from the study (i.e., bladder tumor recurrence, or any 
other early termination) will receive a telephone call from the study staff 2 weeks after the last dose of 
study drug to check for any new or ongoing adverse events. 
The tissue obtained from the initial TURBT will be sent to Surgical Pathology for diagnosis, 
staging and grading as is part of the usual standard of care. In addition, slides will be created from this 
tissue by Surgical Pathology and will undergo histologic analysis to stain for the AR, Estrogen Receptor 
alpha and beta (ER-a, ER-b), as well as the Vitamin-D Receptor (VDR). TURBT specimens will also be 
analyzed for the presence of the following cell cycle markers with known prognostic value in NMIBC: 
FGFR3, p53, pRb and p2116,17. TURBT specimens will also be analyzed for the following downstream 
markers of AR signaling that have been implicated in bladder cancer tumorigenesis: EGFR, ERBB2 and 
CD24.  For those subjects undergoing a 6 week induction course of BCG instillations, we will also check 


  
Enzalutamide for Bladder Cancer Chemoprevention 
 
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their pre-instillation urine samples for IL-6 levels at weeks 1, 3 and 6, since previous data has suggested 
that anti-androgens can augment the induction of IL-6 by BCG, and thereby might increase its therapeutic 
efficacy11. Subjects undergoing BCG therapy will also have their TURBT specimens analyzed for alpha- 
5-beta-1-integrin and the IL6-receptor (CD126). 


  
Enzalutamide for Bladder Cancer Chemoprevention 
 
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~POD#270 
Regularly 
scheduled 9 month 
post-op visit (with 
cystoscopy) 
~POD#390 
Research  Visit 4, 
after completing 12 
months of study 
drug treatment 
~POD#180 
Regularly 
scheduled 6 month 
post-op visit (with 
cystoscopy) 
~POD#360 
Regularly 
scheduled 12 month 
post-op visit (with 
cystoscopy) 
~POD#480* 
Research Telephone 
call to check birth 
control adherence after 
enzalutamide 
discontinuance (if 
applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
~POD#90 
Regularly 
scheduled 3 month 
post-op visit (with 
cystoscopy) 
~POD#404* 
Research Telephone 
call to check AE’s 
NOTE: 2 weeks after 
enzalutamide 
discontinuance 
Figure 2A: 
Expected Clinical Follow-up for Study Subjects 
with Intermediate Risk Bladder Cancer 
(NOT Receiving BCG Therapy) 
Day of TURBT, 
Post-Operative 
Day#0 (POD#0) 
Post-op visit 
~POD#10. 
Consent patient 
for study or may 
combine with 
Research Visit 1 
~POD#20 – Research Visit 1 
- Subject EKG & bloodwork 
obtained, & TURBT tissue 
checked for AR status to 
confirm study eligibility 
~POD#30 
Research Visit 
2, start study 
drug 
~POD#60 
Research Visit 3, 
1month check-up 
after starting study 
drug 


  
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Note: All patients will receive a total of 12 months of Enzalutamide therapy unless they terminate the study drug prematurely. 
*The 2-week and 3-month telephone call will take place when the subject discontinues Enzalutamide use (i.e., completes study or 
early withdrawal) 
 
Number of subjects: We anticipate enrolling 50 subjects with confirmed NMIBC. 25 subjects will 
be patients classified as having “intermediate-risk” bladder cancer, and 25 subjects will be patients 
classified as having “high-risk” bladder cancer, as per the EAU guidelines for non-muscle invasive 
bladder cancer21. As mentioned above, only subjects with high-risk bladder cancer who undergo 
therapy with BCG will be eligible for study enrollment. 
 
Gender of subjects: Only male subjects will be enrolled in this study. Although women and their 
bladder tumors both express androgen receptors, we will limit this study to men primarily because of 
the low overall number of subjects we expect to enroll, and because the side effects of Enzalutamide 
at the dose to be used are not as well known in women as they are in men. 
Figure 2B: 
Expected Clinical Follow-up for Study 
Subjects with High Risk Bladder Cancer 
(Receiving BCG Therapy) 
Day of 
TURBT, Post- 
Op Day#0 
Post-op visit 
~POD#10. 
Consent patient 
for study or may 
combine with 
Research Visit 1 
~POD#20 – Research Visit 
1 - Subject EKG & 
bloodwork obtained, & 
TURBT tissue checked for 
AR status to confirm study 
eligibility 
~POD#30 
Research Visit 
2, start study 
drug 
~POD#37 
Office visit, subject 
starts BCG therapy, 
1x/week x 6 weeks 
POD#37-72 
6 weekly visits for 
BCG therapy 
 
~POD#60—1 month 
check-up after 
starting study drug 
~POD#372 
Regularly scheduled 
10 month visit 
following completion 
of BCG (office visit 
with cystoscopy) 
~POD#386 
Research Visit 
after completing 
12 months of 
study drug 
treatment 
~POD#400* 
Research Telephone call 
to check AE’s 
NOTE: 2 weeks after 
enzalutamide 
discontinuance 
~POD#476* 
Research Telephone call to 
check birth control 
adherence after enzalutamide 
discontinuance 
(if applicable) 
~POD#102 
Regularly scheduled 1 
month visit following 
completion of BCG 
therapy (office visit 
with cystoscopy) 
~POD#192 
Regularly scheduled 4 
month visit following 
completion of BCG 
(office visit with 
cystoscopy) 
~POD#282 
Regularly scheduled 7 
month visit following 
completion of BCG 
(office visit with 
cystoscopy) 


  
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Age of subjects: All subjects will be adults 18 years of age and older. Given the epidemiology of 
bladder cancer, the vast majority of our subjects will be greater than 60 years old. 
 
Racial and Ethnic Origin: The intended racial and ethnic distribution of the study population would be 
approximately 90% Caucasian with the remaining 10% being African American, Hispanic, or Asian. 
This represents the demographics typical of this patient population in this geographic area. Further, it has 
been found that BC is roughly twice as common in Caucasians as in African Americans and Hispanics. 
 
Objectives: 
1) The primary endpoint of the study will be to evaluate the 1-year rate of recurrence in NMIBC 
subjects treated with ADT via Enzalutamide, for comparison with historical rates of BC 
recurrence without ADT. 
2) A secondary endpoint will be to estimate the rate of tumor progression in NMIBC subjects 
treated with Enzalutamide, for comparison with historical rates of progression without ADT. 
3) Another secondary endpoint will be to assess for cancer-specific and patient-specific factors (such 
as tumor grade and stage, AR status, FGFR3 mutation status, and baseline hormonal status) that 
may affect any response to Enzalutamide in terms of bladder tumor recurrence and/or 
progression. 
 
Duration of Enrollment: 
We estimate that 18-24 months of patient accrual will be necessary to meet the goal accrual of 50 
subjects. Subjects will ultimately be followed for approximately 13 months after study entry, and they 
will be assessed as described above for any tumor recurrences during that 1 year time period while on the 
study drug. 


  
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Inclusion Criteria: 
1) Males, age 18 or greater 
 
2) Subjects with histologically confirmed NMIBC who have undergone their TURBT. 
 
3) Per the European Association of Urology (EAU) guidelines, only subjects with “Intermediate” or 
“High risk” bladder cancer will be enrolled21: 
 
For patients with “high risk” bladder cancer, only those who undergo BCG therapy following their 
TURBT will be eligible for enrollment. 
 
4) Subjects who receive BCG instillations post-operatively will be eligible for enrollment. 
 
5) Subjects whose tumors are AR(+) as well as AR(-) will be included, but we will restrict inclusion of 
AR(-) subjects so that they represent no more than 1/3 of the total study population, or any single 
cohort (ie. the intermediate or high-risk groups). 
6) Subjects with partners of child-bearing potential must agree to 2 acceptable forms of birth control and 
be continued for at least 3 months after study drug is discontinued. 
 
Exclusion Criteria: 
1) Subjects with “low risk” bladder cancer, as defined by the EAU guidelines21, will be ineligible for 
enrollment. 
2) Subjects with “high risk” bladder cancer who do not undergo BCG therapy following their TURBT 
will be ineligible for enrollment. 
3) Subjects who have “failed” BCG therapy in the past (had a recurrence of bladder cancer despite prior 
use of BCG) will be ineligible for enrollment. 
4) Subjects who receive an immediate post-TURBT single instillation of intravesical chemotherapy will 
be ineligible for enrollment. 
5) Subjects who receive a post-operative induction course of intravesical chemotherapy (ie. more than 
just a single immediate post-operative dose of intravesical chemotherapy) will be ineligible for 
enrollment. 
6) Subjects who undergo blue-light/fluorescence cystoscopy will be ineligible for enrollment. 


  
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7) Subjects with a history of heart attack within the previous 12 months or who have unstable 
cardiovascular status will be ineligible for enrollment. 
8) Subjects who have uncontrolled hypertension (for our purposes, defined as those having a systolic 
blood pressure > 160 documented on 2 occasions despite appropriate medical therapy) will similarly 
be ineligible. 
9) Subjects with a history of venous thrombo-embolism (DVT/PE) within the past 3 years. 
10) Subjects with a history of seizure disorders, or those with a history of stroke or transient ischemic 
attacks (TIA) within the previous 12 months will be ineligible. 
11) Subjects with a history of liver disease whose hepatic enzymes, alkaline phosphatase or bilirubin are 
greater than twice the upper limit of normal will be ineligible. 
12) Subjects with kidney disease with an estimated glomerular filtration rate (eGFR) < 30 will be 
ineligible. 
13) Subjects with neutropenia (< 3,000/μL) will be ineligible. 
14) Subjects with clinical hypogonadism, those on androgen replacement therapy, or those with prostate 
cancer or other diseases treated with various forms of hormonal therapy (not including 5-alpha 
reductase inhibitors) will also be ineligible for study enrollment. 
15) Subjects who have undergone treatment for any malignancy other than bladder cancer within the past 
2 years except for non-melatomatas skin cancers and basal and squamous cell carcinomas of the skin. 
16) Subjects who have undergone treatment for bladder cancer in the past 1 year. 
17) Subjects with prior histories of prostate cancer treated by definitive local therapy > 5 years ago will 
only be eligible if they have had no clinical or biochemical evidence of recurrent prostate cancer. 
18) Subjects taking an investigational drug within 3 weeks of enrollment into this study. 
 
 
 
Data Analysis and Monitoring: 
A password-protected file will be generated using the RedCap software program to store and maintain the 
data generated during this study in accordance with the scope of the project. The following variables will 
be recorded for each subject: 
 
1) Age, race and ethnic origin 
2) Total testosterone level, dihydro-testosterone levels, and estradiol levels 
3) 25-Hydroxyvitamin D2 and D3 levels 
4) Complete blood counts, liver function tests and basic metabolic panel results will be recorded from 
scheduled office visits as outlined above. 


  
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5) Tumor grade and stage, as well as AR, ER-a, ER-b and VDR staining intensity of the tumor 
specimens. AR, ER-a/b and VDR staining intensity will be assessed using the German Scoring 
System, which combines the percentage of positive staining cells with overall staining intensity. 
6) Use of other adjunctive therapies for bladder cancer, such as BCG. 
 
 
Subjects will undergo quarterly cystoscopies as part of their BC follow-up protocol. They will require 
histologic confirmation from bladder biopsies to document BC recurrence, and they will not continue on 
the study drug once recurrence is documented. In this fashion, we will calculate the BC recurrence rate of 
our study population at 13 months following their TURBT, and compare this to the expected rate of 
recurrence from historical control data. Subset analyses will also be performed to determine if patients 
with high risk bladder cancer who undergo BCG and/or patients with AR(+) tumors have significantly 
decreased rates of BC recurrence on Enzalutamide as compared to intermediate risk patients or AR(-) 
patients. 
 
 
 
Power Analysis and Statistical Data Analysis: 
(1) Power analysis. The historical data shows that without administration of Enzalutamide, the risk 
of recurrence of NMIBC in the first year following TURBT for our selected patient population 
(ie. intermediate risk BC as well as high risk BC+BCG) is approximately 30%. We project that 
with Enzalutamide, we will be able to achieve a 15% overall risk reduction in BC recurrence (our 
primary objective). In the power analysis we calculated the required sample sizes with a wide 
range of projected risk. Our calculation shows that a sample size of 49 subjects achieves 81% 
power to detect an absolute risk difference of 15% using a one-sided binomial test (with 
significance level 0.05). It should be noted that we have not performed separate statistical 
analyses and power calculations for our secondary objectives (as outlined above), as these will 
remain exploratory at this time and will be used to help guide potential future areas of study. 
 
(2) Statistical data analysis. For continuous variables, the means and standard deviations will be 
calculated. For categorical variables, the frequencies will be calculated. Multiple logistic 
regression analysis (with model section) will be used to study the effects of some covariates (such 
as tumor stage and grade) on the risk of recurrence of NMIBC within the first year following 
TURBT. 


  
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Patient Safety & Adverse Event Reporting 
 
 
Study Investigators will conduct continuous review of data and patient safety. The Investigator will 
submit semi-annualprogress reports of these data to the Wilmot Cancer Center’s Data Safety Monitoring 
Committee (DSMC) for review. The review will include for each treatment arm: the number of subjects 
enrolled, withdrawals, significant toxicities as described in the protocol, serious adverse events both 
expected and unexpected, and responses observed. The Principal Investigator (PI) maintains a database 
of all adverse events with toxicity grade and information regarding treatment required complications or 
sequelae. The Investigator will submit a copy of the adverse events (AE) spreadsheet along with the 
Progress Report to the DSMC for review. 
 
 
Any serious adverse event that is serious, related AND unexpected must be reported within 10 
calendar days to both the DSMC and the Research Subjects Review Board (see RSRB 
guidelines). 
 
 
Serious adverse events that are related AND expected or unrelated AND unexpected will be 
reported to the DSMC for review at the quarterly meeting. Serious AE reports are expected to 
include sufficient detail so that the DSMC can determine the severity, toxicity grade, 
expectedness, treatment required, and a follow up report documenting resolution or if there are 
sequelae. Unless otherwise specified in the protocol, serious adverse events that require detailed 
reports (but not necessarily expedited) are expected, related, non-hematologic toxicities of grades 
3, 4 or 5. 
 
The DSMC provides oversight of study progress and safety by review of accrual and events at regularly 
scheduled meetings. The frequency of review is determined by the size, risk and complexity of the trial 
and is assigned by the Wilmot Cancer Center’s Protocol Review Committee at the time of their initial 
review and approval. The DSMC will monitor all adverse event rates utilizing a cumulative spreadsheet 
listing of all events submitted along with progress reports by the PI. All serious adverse events that have 
occurred in the prior 3 months will be reviewed at the regular quarterly meeting of the DSMC in order to 
confirm toxicity grade, expectedness, relatedness, sequelae, follow up required, and risk to current or 
future subjects. Events that are serious, unexpected and related will require expedited review within 10 
calendar days to the Safety Coordinator. The DSMC Chair will determine whether further action is 
required, and when patient safety is of concern, an interim meeting may be called. 


  
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Reporting of only SAEs will be sent to Astellas for their own internal review. Per Astellas protocols, 
within 24 hours of awareness of a serious adverse event, whether or not related to the study drug, the 
Investigator will complete and submit a Medwatch 3500A Form to FDA, containing all required 
information (reference 21 CFR 312.32). The Investigator will submit a copy of this MedWatch 3500A 
form to Astellas by either e-mail or fax, within the same timeframe (Appendix 3). 
 
The effect of Enzalutamide in pregnant and lactating women is not known, and the exposure of a fetus or 
nursing infant is considered a potential risk. Enzalutamide can cause fetal harm when administered to a 
pregnant woman based on its mechanism of action. Subjects receiving Enzalutamide are advised to use 2 
acceptable methods of birth control (one of which must include a condom as a barrier method of 
contraception) starting at the time of screening for an Enzalutamide study and continuing throughout the 
course of treatment and for at least three months after Enzalutamide is discontinued (See Appendix 3 for 
full protocol related to handling of exposure of Enzalutamide to a fetus or lactating woman). 
 
The safety of Enzalutamide at the dosage and frequency used in this study has already been demonstrated 
in the initial Phase 1 and Phase 2 studies conducted for its original use with castration-resistant prostate 
cancer. Per these studies, the most common grade 3-4 AE was dose-dependent fatigue (11% patients), 
which generally resolved after dose reduction23. Please also refer to Appendix 2 which includes the 
package insert for Enzalutamide. 
 
Furthermore, per discussions with the University of Rochester’s Department of Regulatory Support and 
per Section V, Part A.1 of the FDA's Guidance for Industry Document for IND Exemptions for Studies of 
Lawfully Marketed Drug or Biologic Products for the Treatment of Cancer (Appendix 4), our proposed 
clinical study should be exempt from the filing of an IND application. We will be utilizing the same dose 
and schedule for Enzalutamide as those already approved for the treatment of prostate cancer. We expect 
no difference in AE’s from those already described in the original studies for the use of Enzalutamide for 
the treatment of prostate cancer and already outlined in the drug package insert23, Appendix 2. Lastly, the use 
of Enzalutamide in this study will be in addition to the current standard of care, and therefore, no proven 
effective therapies will be withheld from the study population. 


  
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References: 
 
 
1 Messing, E. M.. Urothelial tumors of the urinary tract. In: Campbell-Walsh Urology, 9th ed. Edited by A. J. Wein, 
L. R. Kavoussi, A. C. Novick, A. W. Partin & C. A. Peters. Philadelphia: W. B. Saunders, Co., pp. 2407–2446, 
2007. 
 
2 Donat SM. Evaluation and follow-up strategies for superficial bladder cancer. Urol Clin North Am. 30(4): 765, 
2003. 
 
3 Oosterlinck, W., Kurth, K. H., Schroder, F., et al. A prospective European Organization for Research and 
Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single 
intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J Urol, 149: 
749, 1993 
 
4 Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy 
decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of 
randomized clinical trials. J Urol 171: 2186, 2004. 
 
5 Solsona E, Iborra I, Ricós JV, et al. Effectiveness of a single immediate mitomycin C instillation in patients with 
low risk superficial bladder cancer: short and long-term followup. J Urol. 161(4): 1120, 1999. 
 
6 Burger M, Grossman HB, Droller M, et al. Photodynamic Diagnosis of Non-muscle-invasive Bladder Cancer with 
Hexaminolevulinate Cystoscopy: A Meta-analysis of Detection and Recurrence Based on Raw Data. Eur Urol 
(2013). 
 
7 Geavlete B, Multescu R, Georgescu D, et al. Treatment changes and long-term recurrence rates after 
hexaminolevulinate (HAL) fluorescence cystoscopy: does it really make a difference in patients with non-muscle- 
invasive bladder cancer (NMIBC)? BJU Int. 109(4): 549, 2012. 
 
8 Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 60(5):277, 2010. 
 
9 Izumi, K., Zheng, Y., Hsu, J., et. al. Androgen receptor signals regulate UDP-glucuronosyltransferases in the 
urinary bladder: a potential mechanism of androgen-induced bladder carcinogenesis. Mol Carcinog. 52(2): 94, 2013. 
10 Izumi, K., Li, Y., Ishiguro, H., et. al. Expression of UDP-glucuronosyltransferase 1A in bladder cancer: 
Association with prognosis and regulation by estrogen. Mol Carcinog, 2012 Nov 9. doi: 10.1002/mc.21978. 
 
11 Li, Y., Izumi, K., Miyamoto H. The role of the androgen receptor in the development and progression of bladder 
cancer. Jpn J Clin Oncol, 42(7): 569, 2012. 
 
12 Gakis, G., Stenzl, A., Renninger, M. Evolution of the concept of androgen-sensitive bladder cancer. Scand J Urol. 
2013 Jan 21. [Epub ahead of print] 
 
13 Shiota, M., Ario, T., Akira, Y., et. al. Androgen Receptor Signaling Regulates Cell Growth and Vulnerability to 
Doxorubicin in Bladder Cancer. J Urol. 188: 276, 2012. 
 
14 Miyamoto, H., Yao, J., Chaux, A., et al. Expression of Androgen and Oestrogen Receptors and Its Prognostic 
Significance in Urothelial Neoplasm of the Urinary Bladder. BJUI, 109: 1716, 2012. 
 
15 Marcinkiewicz, K., Scotland, K. B., Boorjian, S. A. The androgen receptor and stem cell pathways in prostate and 
bladder cancers. Intl J Oncol, 40: 5, 2012. 


  
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16 Bolenz, C., Lotan, Y. Translational research in bladder cancer: from molecular pathogenesis to useful tissue 
biomarkers. Cancer Biol Ther. 2010 Sep 1;10(5):407-15. 
 
17 Kamat, A. M., Hegarty, P. K., Gee, J. R., et. al. ICUD-EAU International Consultation on Bladder Cancer 2012: 
screening, diagnosis, and molecular markers. Eur Urol. 2013 Jan;63(1):4-15. 
 
18 Overdevest, J. B., Knubel, K. H., Duex, J. E., et. al. CD24 expression is important in male urothelial 
tumorigenesis and metastasis in mice and is androgen regulated. Proc Natl Acad Sci U S A. 2012 Dec 18; 109(51): 
E3588-96. 
 
19 Jones, J. S., Campbell, S. C. Non-Muscle Invasive Bladder Cancer (Ta, T1, CIS). In: Campbell-Walsh Urology, 
9th ed. Edited by A. J. Wein, L. R. Kavoussi, A. C. Novick, A. W. Partin & C. A. Peters. Philadelphia: W. B. 
Saunders, Co., pp. 2447-2467, 2007. 
 
20 Zhang, G. J., Crist, S. A., McKerrow, A. K., et al. Autocrine IL-6 production by human transitional carcinoma 
cells upregulates expression of the alpha5beta1 firbonectin receptor.  J Urol, 163(5): 1553, 2000. 
 
21 Babjuk, M., Oosterlinck, W., Sylvester, R., et al. Guidelines on non-muscle-invasive bladder cancer (TaT1 and 
CIS). European Association of Urology, 2012. 
 
22 Han RF, Pan JG. Can intravesical bacillus Calmette-Guérin reduce recurrence in patients with superficial bladder 
cancer? A meta-analysis of randomized trials. Urology. 2006 Jun;67(6):1216-23. 
 
23 Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a 
phase 1-2 study. Lancet. 2010 Apr 24;375(9724):1437-46. 
 
 
 


  
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APPENDIX 1: 
 
 
European Association of Urology Risk Stratification for Non-Muscle Invasive 
Bladder Cancer and Projected Risk of Recurrence at 1 Year: 
 
 
 


  
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APPENDIX 2: 
 
Drug Packet Insert for Enzalutamide (Xtandi®) 


  
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APPENDIX 3: 
Astellas Protocol for Adverse Event Reporting 
 
 
1.1 
Definition of Adverse Events (AEs) 
 
An adverse event (AE) is defined as any untoward medical occurrence in a subject administered a study 
drug and which does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a study drug, whether or not related to the study drug. 
 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, physical 
exam) should be defined as an AE only if the abnormality meets one of the following criteria: 
 
Induces clinical signs or symptoms. 
 
Requires active intervention. 
 
Requires interruption or discontinuation of study medication. 
 
The abnormality or investigational value is clinically significant in the opinion of the investigator. 
 
All adverse events, whether or not related to the study drug, must be fully and completely documented. 
 
 
1.2 
Definition of Serious Adverse Events (SAEs) 
 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in any of the 
following outcomes: 
 
 
Results in death, 
 
Is life threatening (an AE is considered “life-threatening” if, in the view of either the investigator 
or sponsor, its occurrence places the subject at immediate risk of death. It does not include an AE 
that, had it occurred in a more severe form, might have caused death.), 
 
Results in persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions, 
 
Results in congenital anomaly, or birth defect, 
 
Requires inpatient hospitalization or leads to prolongation of hospitalization (hospitalization for 
treatment/observation/examination caused by AE is to be considered as serious), 
 
Other medically important events. 
 
1.2.1 
Serious Adverse Event Reporting 
 
Within 24 hours of awareness of a serious adverse event, whether or not related to the study drug, the 
Investigator will complete and submit a Medwatch 3500A Form to FDA, containing all required 
information (reference 21 CFR 312.32). 


  
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The Investigator will submit a copy of this MedWatch 3500A form to Astellas by either e-mail or fax, 
within the same timeframe. 
 
If submission of this SAE to FDA or Astellas or is not possible within 24 hours, the Investigator’s local 
drug safety contact (IRB, etc.) should be informed by phone. 
 
The SAE documentation, including the Medwatch 3500A Form and available source records should be 
emailed or faxed to: 
 
Astellas Pharma Global Development – United States 
Email: Safety-us@us.astellas.com 
Fax number: (847) 317-1241 
 
The following minimum information is required: 
 
Study number/IIT regulatory identifier 
 
Subject number, sex and age 
 
The date of report 
 
A description of the SAE (event, seriousness of the event) 
 
Causal relationship to the study drug 
 
Follow-up information for the event should be sent within promptly (within 7 days) as necessary. 
 
 
1.2.2 
Procedure in Case of Pregnancy 
 
The effect of enzalutamide in pregnant and lactating women is not known, and the exposure of a fetus or 
nursing infant is considered a potential risk. Enzalutamide can cause fetal harm when administered to a 
pregnant woman based on its mechanism of action. Subjects receiving enzalutamide are advised to use 2 
acceptable methods of birth control (one of which must include a condom as a barrier method of 
contraception) starting at the time of screening for an enzalutamide study and continuing throughout the 
course of treatment and for at least three months after enzalutamide is discontinued. 
 
If during the conduct of the clinical trial, a male subject impregnates his partner, the subject should report 
the pregnancy to the Investigator. The Investigator should report the pregnancy to the Sponsor as an SAE 
within 24 hours of awareness of the event.  The expected date of delivery or expected date of the end of 
the pregnancy, last menstruation, estimated fertility date, pregnancy result and neonatal data etc., should 
be included in this information. 
 
The Investigator should report the outcome of the pregnancy (independent of outcome, eg. full term 
delivery, pre-term delivery, spontaneous abortion, induced abortion, stillbirth, death of newborn, 
congenital anomaly [including anomaly in a miscarried fetus, etc] in accordance with the same reporting 
procedure as for SAEs. The date of outcome of the pregnancy, gestational age, date of birth and neonatal 
data etc., should be included in this information. 


  
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APPENDIX 4: 
 
FDA's Guidance for Industry for IND Exemptions for Studies of Lawfully 
Marketed Drug or Biologic Products for the Treatment of Cancer