Clinical trial NCT02849990
Conditions: Stage III Prostate Adenocarcinoma AJCC v7 Stage III Prostate Cancer AJCC v7 Stage IV Prostate Adenocarcinoma AJCC v7 Stage IV Prostate Cancer AJCC v7
Sponsor: University of Washington
Start date: 2017-03-09; Completion date: 2020-12-10
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well apalutamide, abiraterone acetate, prednisone, degarelix, and indomethacin work in treating patients with prostate cancer that has spread from where it started to nearby tissue or lymph nodes before surgery. Androgen can cause the growth of tumor cells. Hormone therapy using apalutamide, abiraterone acetate, prednisone, degarelix, and indomethacin may fight prostate cancer by lowering the amount of androgen the body makes and/or blocking the use of androgen by the tumor cells.

Detailed description:
PRIMARY OBJECTIVES:

I. The rate of the pathologic complete response (pCR) (i.e. no evidence of residual tumor) as assessed on prostatectomy specimens following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin.

SECONDARY OBJECTIVES:

I. To determine the negative margin rate as assessed on prostatectomy specimens following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin.

II. To determine the rate of near pCR (i.e. =\< 5 mm of residual tumor) as assessed on prostatectomy specimens following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin.

III. To determine the rate of pathologic T3 disease as assessed on prostatectomy specimens following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin.

IV. To determine the rate of nodal metastases as assessed on surgical lymph node specimens following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin.

V. To determine the apoptotic index (i.e. percentage of tumor cells undergoing apoptosis) as determined by cleaved caspase-3 immunohistochemistry following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin.

VI. To determine the proportion of men who receive adjuvant radiation therapy within 1-year of prostatectomy.

VII. To determine the biochemical (i.e. prostate-specific antigen \[PSA\]) progression free survival estimate two years after the last patient has accrued (i.e. confirmed PSA post-radical prostatectomy \>= 0.2 ng/mL).

VIII. To determine the overall survival estimate two years after the last patient has accrued.

IX. Safety as assessed by the incidence and severity of adverse events and serious adverse events graded according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

X. Exploratory biomarker assessment.

OUTLINE:

Patients receive apalutamide and abiraterone acetate orally (PO) daily, prednisone PO twice per day (BID) and indomethacin PO three times per day (TID). Patients also receive degarelix subcutaneously (SC) on day 1 and every 4 weeks for 3 doses. Treatment continues for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo prostatectomy on day 85.

After completion of study treatment, patients are followed up at 28, 113, 450 and 815 days.

Arms: arm 1: Patients receive androgen receptor antagonist ARN-509 and abiraterone acetate PO daily, prednisone PO BID and indomethacin PO TID. Patients also receive degarelix SC on day 1 and every 4 weeks for 3 doses. Treatment continues for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo prostatectomy on day 85.
Interventions: intervention 1: Abiraterone Acetate intervention 2: Apalutamide intervention 3: Degarelix intervention 4: Indomethacin intervention 5: Laboratory Biomarker Analysis intervention 6: Prednisone
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given SC intervention 4: Given PO intervention 5: Correlative study intervention 6: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
1 
 
 
 
A Phase II neoadjuvant study of Apalutamide, abiraterone acetate, 
prednisone, degarelix and indomethacin in men with localized prostate cancer 
pre-prostatectomy 
 
University of Washington / Seattle Cancer Care Alliance 
Cancer Consortium Protocol Number: 9628 
IND Number: 129692 
ClinicalTrials.gov: NCT02849990 
Protocol Version Number: 4.0 
 
March 23, 2018 
 
 
 
 
 
Sponsor-Investigator / Principal Investigator: 
Site: 
 
Michael T. Schweizer, MD 
University of Washington / Seattle Cancer Care Alliance 
Email: schweize@uw.edu 
 
 
Biostatistician: 
 
Roman Gulati 
Fred Hutchinson Cancer Research Center 
Email: rgulati@fhcrc.org  
 
University of Washington / Seattle 
Cancer Care Alliance 
 
Medication Support Provided by: 
 
Janssen Scientific Affairs, LLC 
 
 
 
 
 
 
 
 
 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
2 
 
Title: A Phase II neoadjuvant study of Apalutamide, abiraterone acetate, prednisone, degarelix 
and indomethacin in men with localized prostate cancer pre-prostatectomy 
Objectives: To assess the pathologic effects of 3-months (12 weeks) of neoadjuvant 
apalutamide, abiraterone acetate, degarelix and indomethacin in men with localized prostate 
cancer pre-prostatectomy. 
Study Design: Open label, single-site, Phase II study designed to determine the pathologic 
effects that 3-months (12 weeks) of neoadjuvant therapy has on men with localized prostate 
cancer. 
Primary Center: University of Washington/Seattle Cancer Care Alliance  
Participating Institutions: 1 site in the United States. 
Medication Support: Janssen Scientific Affairs, LLC 
Timeline: This study is planned to complete enrollment in one year, with 2-years of additional 
follow up following accrual of the last subject. 
Concept Rationale: For the majority of patients, prostate cancer is highly curable when caught 
at an early stage, with 10-year biochemical (i.e., PSA) progression free survival (PFS) and 
prostate cancer specific overall survival (OS) rates following radical prostatectomy (RP) reported 
at 68% and 97%, respectively.1 Historically, those with higher risk localized disease have not 
had as favorable of outcomes, however. For instance, those with clinical stage T3 disease (i.e., 
tumor that extends beyond the prostatic capsule) the 10-year biochemical PFS rate has been 
reported to be 44% and the prostate cancer specific OS rate 85%.2 Likewise, >50% of men 
classified as high risk per the D’Amico classification (PSA >20 ng/ml and/or biopsy Gleason 
score >7) have been reported to have a biochemical recurrence at 5-years post-RP.3,4 Given these 
relatively poor outcomes following RP in high risk patients, peri-operative (i.e., neoadjuvant or 
adjuvant) systemic therapy remains an attractive option to attenuate these high rates of relapse. 
Neoadjuvant systemic therapy has been established as a standard in bladder, breast, as 
well as others cancers; however, pre-surgical neoadjuvant approaches have yet to be proven 
beneficial in prostate cancer.5-8 To date, there have been several randomized trials testing 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
3 
 
neoadjuvant hormonal therapies (HT) (i.e., LHRH agonists and antiandrogens), as well as a 
number of single-arm trials testing chemo-hormonal and novel prostate cancer agents in the pre-
surgical space.6,7 While most of the data thus far has shown that neoadjuvant treatment can lead 
to favorable pathologic outcomes (e.g. lower rates of capsular penetration and positive margins), 
none have shown that these approaches have any impact on long-term outcomes such as 
biochemical PFS or OS rates.9-13 Of note, while favorable pathologic outcomes post-neoadjuvant 
therapy have been described, rates of negative pathologic complete response (pCR) in these 
studies have only been documented in approximately 5% of patients.10,14-17 Given this historic 
lack of clinical efficacy, it seems likely that pre-surgical neoadjuvant therapies may only 
translate into improved clinical outcomes if a pCR rate substantially higher than 5% is achieved. 
Over the past decade a number of new therapies have been proven effective in the 
treatment of castration-resistant prostate (CRPC) – a more advanced, HT-resistant and ultimately 
lethal form of prostate cancer.18 Theoretically, these agents may provide an opportunity to 
develop more effective neoadjuvant treatment strategies. One such agent, abiraterone acetate, is a 
potent CYP-17 inhibitor capable of suppressing testosterone from the castrate (i.e., <20 ng/dL) to 
undetectable range when combined with a GnRH agonist.19,20 A recent report by Taplin and 
colleagues found that 24 weeks of neoadjuvant GnRH agonist plus abiraterone acetate led to a 
pCR rate of 10%, with an additional 14% of patients achieving a near pCR (defined as ≤5 mm 
residual tumor).17 Our group has also reported on our efforts to more completely target AR-
signaling in men pre-prostatectomy.21 In the “Total Androgen Pathway Suppression (TAPS) 
Study”, reported by Mostaghel, the GnRH agonist goserelin was combined with the following: 1) 
dutasteride (N=12), 2) bicalutamide and dutasteride (N=10) or 3) bicalutamide, dutasteride, and 
ketoconazole (N=13) for 3-months pre-prostatectomy. There were two (8.7%) pCR and nine 
(30.4%) near pCR (defined as ≤2 mm residual tumor) between cohort 2 (gosereline, bicalutamide 
and dutasteride) and cohort 3 (gosereline, bicalutamide, dutasteride, and ketoconazole). 
It is notable that the rates of pCR achieved on both the Taplin and Mostaghel studies 
were comparable to those reported in older neoadjuvant HT trials, leaving the possibility that if a 
pre-surgical neoadjuvant HT strategy is going to ultimately prove beneficial, maximal inhibition 
of AR-signaling may be necessary. Fortunately, our toolbox of AR-directed drugs effective in 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
4 
 
the CRPC setting continues to expand. In addition to abiraterone acetate, enzalutamide, a potent 
AR-antagonist, was also approved on the basis of Phase III data that it leads to improvements in 
OS.22,23 Recently, a newer AR-antagonist with several theoretical advantages over enzalutamide, 
apalutamide, has also entered Phase III clinical testing [clinicaltrials.gov: NCT01946204]. 
Another explanation for the lack of demonstrable long-term efficacy with neoadjuvant 
HTs is that these agents may not target more resistant cancer clones and/or emergent resistance 
pathways. A plausible mechanism by which resistance may develop in this context is via 
intratumoral steroidogenesis. Indeed, a number of steroidogenic enzymes have been shown to be 
upregulated in heavily pre-treated prostate cancer patients in comparison to primary 
prostatectomy samples.24 Specifically, AKR1C3, which is capable of converting DHEA-S 
metabolites into the potent AR-ligands testosterone and dihydrotestosterone, is frequently found 
to be upregulated in clinical specimens and to correlate with stage of disease.24-26 In addition, cell 
culture and xenografts models of CRPC have implicated AKR1C3 in the emergence of resistance 
to both enzalutamide and abiraterone acetate.27,28 Importantly, in both the Mostaghel and Taplin 
trials, a significant residual amount of DHEA-S remained in circulation (~20 μg/dL) following 
combination GnRH agonist and CYP17 inhibitor therapy.17,21 In theory, this persistent serum 
DHEA-S may serve as a depot for intratumoral conversion to testosterone and DHT, with the 
final steps of conversion catalyzed by AKR1C3.26  
Taken in total, dual targeting of AKR1C3 and AR-signaling is likely to result in a more 
profound anti-tumor effect than previously reported in the literature. Indomethacin, a non-
steroidal anti-inflammatory, has been shown to have the off target effect of inhibiting AKR1C3, 
and to inhibit prostate cancer cells in pre-clinical models.29,30 In addition, synergy between 
indomethacin and either abiraterone acetate or enzalutamide has been reported in otherwise 
resistant prostate cancer cell lines.27,28 Indomethacin has been FDA approved for decades, and 
has a long safety track record. Therefore, we propose a pre-surgical neoadjuvant trial testing 12-
weeks of indomethacin combined with a regimen designed to completely ablate AR-signaling: 
abiraterone acetate, apalutamideand degarelix. The hypothesis of this study is that 12-weeks of 
combination indomethacin, degarelix, apalutamide and abiraterone acetate will result in a 
robust anti-tumor effect manifested as a high pathologic complete response rate. 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
5 
 
Treatment Plan: This is an open label, multi-site, Phase II neoadjuvant study in men with 
localized prostate cancer planning to undergo prostatectomy. This study will assess the pCR rate 
after 3-months (12 weeks) of neoadjuvant treatment with apalutamide, abiraterone acetate, 
degarelix and indomethacin as assessed on prostatectomy specimens.  
All subjects must have localized, high or very-high risk (per NCCN criteria) prostate 
cancer and be willing to undergo prostatectomy as primary treatment. Subjects will be treated 
with neoadjuvant therapy for a total of 3-months (12 weeks) prior to prostatectomy. Therapy will 
consist of apalutamide, abiraterone acetate, degarelix and indomethacin. Abiraterone acetate, 
degarelix and indomethacin will be dosed at their respective FDA approved dose. These dosages 
are as follows: abiraterone acetate 1000 mg by mouth daily, indomethacin 50 mg by mouth three 
times daily (TID) and degarelix 240 mg subcutaneous (SC) injection on day 1 followed by two 
additional 80 mg SC injections every 4 weeks. All men will also be treated with prednisone 5 mg 
by mouth twice daily while on abiraterone acetate in order to blunt its associated 
mineralocorticoid side effects.* Apalutamide was recently approved by the FDA for use in men 
with non-metastatic castration resistant prostate cancer on the basis of Phase III data showing 
that it significantly prolonged the time to development of metastatic disease. Apalutamide is still 
under development as an investigational product for other types of prostate cancer. Apalutamide 
will be administered at the FDA approved dose for treating non-metastatic CRPC, 240 mg daily 
by mouth. The GnRH antagonist degarelix was chosen over other forms of HT (i.e., GnRH 
agonists) given that the neoadjuvant treatment period is relatively short at 12-weeks, and 
degarelix has been shown to result in more rapid castration and PSA suppression compared to 
the GnRH agonist leuprolide.31 Following 12-weeks of neoadjuvant treatment, patients will 
undergo prostatectomy. Lymph node dissection will be required for all patients with a ≥2% 
estimated risk of nodal metastases per the Partin Nomogram.32 Patients should have clinical 
follow-up visits following prostatectomy per the standard practice of their treating urologist. 
 
* Note: Because steroids can lead to hyperglycemia, subjects with a history of diabetes will be 
required to monitor their daily fasting blood glucose using a home glucometer. Fasting blood 
glucose values will be reviewed at scheduled follow up appointments. Patients will also be 
instructed to contact their provider if their fasting glucose is >150 mg/dL. Based on the daily 
fasting blood glucose levels, anti-hyperglycemic medications will be adjusted by the treating 
oncologist and/or the patient’s primary care doctor or endocrinologist.  


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
6 
 
However, at a minimum, patients should be evaluated in clinic 28 days following their 
prostatectomy. Of note, the combination of apalutamide, abiraterone acetate and GnRH analogue 
therapy has been shown to have an acceptable safety profile when administered at these doses 
[see Investigator’s Brochure]. 
Study scheme: 
 
 
*Three doses of subcutaneous (SC) degarelix will be administered. Degarelix is administered every 4-weeks, with a 
240 mg loading dose given for the first SC injection followed by 80 mg SC injections thereafter.  
This study will be open to patients age ≥ 18 years who have a histologic diagnosis of prostatic 
adenocarcinoma and are planning to undergo prostatectomy as primary treatment of their prostate cancer. 
All patients must have high to very high-risk prostate cancer as defined per the NCCN criteria (i.e. high-
risk = Gleason score 8-10 or T3a or PSA > 20 ng/mL; very high-risk = T3b-T4).  
The primary endpoint will be the pathologic complete response (pCR) rate (i.e., no 
evidence of tumor) as assessed on prostatectomy specimens following 3-months (12 weeks) of 
neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin. Secondary pathologic 
endpoints to be assessed from prostatectomy specimens following 3-months (12 weeks) of 
neoadjuvant therapy include: the negative margin rate, negative nodal metastases rate, near pCR 
(i.e., ≤5 mm of residual tumor) rate, the rate of pathologic T3 disease and apoptotic index (i.e. 
percentage of tumor cells undergoing apoptosis) as determined by cleaved caspase-3 
immunohistochemistry. Other secondary endpoints will include: the proportion of men who 
receive adjuvant radiation therapy within 1-year of prostatectomy, the biochemical (i.e., PSA) 
progression free survival estimate two years after the last patient has accrued, the overall survival 
estimate two years after the last patient has accrued and safety (as assessed by CTCAE version 
4.0). 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
7 
 
In addition, excess tissue from prostatectomy specimens and plasma samples will be 
stored at -80°C. These biologic specimens will be used for additional correlative work. When 
possible, we also conduct exploratory biomarker studies on pre-treatment/archival biopsy 
specimens. Examples of studies to be conducted may include, but are not limited to: PTEN 
immunohistochemistry (IHC), assessment for alteration in MYC/chromosome 8q24 via FISH, 
RNAseq analysis, serum drug/androgen levels and intraprostatic drug/androgen levels.  
Study Population: Men with high (Gleason score 8-10 or T3a or PSA > 20 ng/mL) or very-high 
risk (T3b-T4) prostate cancer per the NCCN criteria who are willing to undergo radical 
prostatectomy as primary treatment for their prostate cancer. 
Number of Patients: For this study we plan on enrolling 20 evaluable patients. Up to 22 patients 
will be enrolled if necessary in order to account for a potential 10% dropout rate. 
Inclusion Criteria: 
1. Willing and able to provide written informed consent. 
2. Age ≥ 18 years 
3. Eastern cooperative group (ECOG) performance status ≤2 
4. Documented histologically confirmed adenocarcinoma of the prostate 
5. Willing to undergo prostatectomy as primary treatment for localized prostate cancer 
6. High risk prostate cancer (per NCCN criteria): Gleason score 8-10 or T3a or PSA > 20 
ng/mL  
or 
Very-high risk prostate cancer (per NCCN criteria): T3b-T4  
7. Serum testosterone ≥150 ng/dL 
8. Able to swallow the study drugs whole 
9. Willing to take abiraterone acetate on an empty stomach (no food should be consumed at 
least two hours before and for one hour after dosing). 
10. Agrees to use a condom (even men with vasectomies) and another effective method of birth 
control if he is having sex with a woman of childbearing potential or agrees to use a condom 
if he is having sex with a woman who is pregnant while on study drug and for 3 months 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
8 
 
following the last dose of study drug. Must also agree not to donate sperm during the study 
and for 3 months after receiving the last dose of study drug. 
11. Medications known to lower the seizure threshold (see list under prohibited meds) must be 
discontinued or substituted at least 4 weeks prior to study entry. 
 
Exclusion Criteria: 
 
1. Prior local therapy to treat prostate cancer (e.g. radical prostatectomy, radiation therapy, 
brachytherapy) 
2. Prior use of apalutamide, abiraterone acetate or degarelix 
3. Prior or ongoing systemic therapy for prostate cancer including, but not limited to: 
a. Hormonal therapy (e.g., leuprolide, goserelin, triptorelin, degarelix) 
b. CYP-17 inhibitors (e.g., ketoconazole) 
c. Antiandrogens (e.g., bicalutamide, nilutamide) 
d. Second generation antiandrogens (e.g., enzalutamide, apalutamide) 
e. Immunotherapy (e.g., sipuleucel-T, ipilimumab) 
f. Chemotherapy (e.g., docetaxel, cabazitaxel) 
4. Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition 
(including laboratory abnormalities) that could interfere with patient safety or provision of 
informed consent to participate in this study 
5. Any psychological, familial, sociological, or geographical condition that could potentially 
interfere with compliance with the study protocol and follow-up schedule. 
6. Abnormal bone marrow function (absolute neutrophil count [ANC]<1500/mm3, platelet 
count <100,000/mm3, hemoglobin <9 g/dL) 
7. Abnormal liver function (total bilirubin >1.5 x upper limit of normal [ULN]; AST or ALT ≥ 
2.5 x ULN) 
Note: In subjects with Gilbert’s syndrome, if total bilirubin is >1.5 × ULN, measure direct 
and indirect bilirubin and if direct bilirubin is ≤1.5 × ULN, subject may be eligible 
8. Abnormal kidney function (GFR <45 mL/min) 
9. Serum albumin <3 g/dL 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
9 
 
10. Serum potassium <3.5 mmol/L 
11. Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1year to 
randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign 
CNS or meningeal disease which may require treatment with surgery or radiation therapy) 
12. Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial 
or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident 
including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 
months prior to randomization  
13. History of stroke within the last 5-years 
14. History of gastrointestinal (GI) bleed requiring transfusion 
15. History of peptic ulcer disease requiring treatment within the last 5-years 
16. History of asthma that is NSAID-induced or with asthma that is classified as ‘mild-persistent’ 
or worse (based on symptoms occurring more than 2 days per week) 
17. Uncontrolled hypertension 
18. Gastrointestinal disorder affecting absorption 
19. Active infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis) 
20. Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg 
prednisone/prednisolone once daily  
21. Any condition that in the opinion of the investigator, would preclude participation in this 
study 
22. Child Pugh Class B & C 
23. Pre-existing viral hepatitis 
Primary Endpoints: 
The rate of pCR (i.e., no evidence of residual tumor) as assessed on prostatectomy specimens 
following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and 
indomethacin. 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
10 
 
Secondary Endpoints: 
1. The negative margin rate as assessed on prostatectomy specimens following 3-months 
(12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin. 
2. The rate of near pCR (i.e. ≤5 mm of residual tumor) as assessed on prostatectomy 
specimens following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone 
acetate, degarelix and indomethacin. 
3. The rate of pathologic T3 disease as assessed on prostatectomy specimens following 3-
months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and 
indomethacin. 
4. The rate of nodal metastases as assessed on surgical lymph node specimens following 3-
months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and 
indomethacin. 
5. Apoptotic index (i.e., percentage of tumor cells undergoing apoptosis) as determined by 
cleaved caspase-3 immunohistochemistry following 3-months (12 weeks) of neoadjuvant 
apalutamide, abiraterone acetate, degarelix and indomethacin. 
6. The proportion of men who receive adjuvant radiation therapy within 1-year of 
prostatectomy. 
7. The biochemical (i.e., PSA) progression free survival estimate two years after the last 
patient has accrued (i.e., confirmed PSA post-radical prostatectomy ≥0.2 ng/mL). 
8. The overall survival estimate two years after the last patient has accrued. 
9. Safety as assessed by the incidence and severity of adverse events and serious adverse 
events graded according to the National Cancer Institute – Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 
10. Exploratory biomarker Assessment. Examples of these may include, but are not limited 
to: assessment for genomic PTEN loss via fluorescence in situ hybridization (FISH), 
PTEN immunohistochemistry (IHC), assessment for alteration in MYC/chromosome 
8q24 via FISH, RNAseq analysis, serum drug/androgen levels and intraprostatic 
drug/androgen levels. 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
11 
 
Statistical Considerations: This is an open-label, multi-site Phase II trial testing 3-months (12-
weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin. The 
primary endpoint will be the pCR rate as assessed from prostatectomy specimens. Prior 
neoadjuvant hormonal therapy trials have documented pCR rates on the order of 5%, while still 
failing to show improvements in biochemical PFS or OS.10,11,14 Therefore, we would consider a 
pCR rate of ≤5% to be insufficient evidence of activity to warrant further study in this patient 
population. The minimum level of activity we would require to consider further study with the 
proposed regimen would be a pCR rate of ≥25%. Therefore, based on an exact binomial test, if 
we observe ≥3 pCR out of a total sample size of 20, we would have 91% power at a one-sided 
alpha of 7.5% to detect a difference between H0 = 5% and a H1 = 25.33 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
12 
 
SYNOPSIS………………………………………………………………………………..2 
                Study scheme…….  .............................................................................................6 
1. INTRODUCTION   ....................................................................................................14 
1.1 
Overview and Rational ....................................................................................14 
1.2 
Androgen/Androgen Receptor Directed Therapies .........................................16 
1.3 
Indomethacin and AKR1C3 Inhibition ...........................................................25 
1.4 
Exploratory Biomarkers ..................................................................................26 
2. STUDY OBJECTIVES ..............................................................................................28 
2.1 
Primary Objective ............................................................................................28 
2.2 
Secondary Objectives ......................................................................................28 
3. PATIENT POPULATION AND SELECTION  .....................................................29 
 
3.1   
Inclusion Criteria .............................................................................................30 
 
3.2  
Exclusion Criteria ............................................................................................30 
 
3.3  
Inclusion of Minorities and Women ................................................................32 
4.  TREATMENT PLAN ................................................................................................32 
4.1  
Study Design  ...................................................................................................33 
4.2  
Dose Adjustment, Delays and Treatment Discontinuation  .............................35 
4.3  
Removal of Patients from Study  .....................................................................36 
5. Treatment Assessment and Evaluation ....................................................................38 
5.1  
Screening Studies  ............................................................................................38 
5.2  
Neoadjuvant Treatment ....................................................................................38 
 
5.3  
Surgery……………………………………………………………….……. ...38 
 
5.4  
Follow-up…. ....................................................................................................39 
6.   STUDY CALENDAR ................................................................................................40 
7.  STUDY ASSESSMENTS ..........................................................................................41 
7.1  
Pathologic Assessment  ....................................................................................41 
7.2  
Exploratory Biomarkers  ..................................................................................41 
7.3  
Safety…….. .....................................................................................................44 
8.  PHARMACEUTICAL INFORMATION ................................................................45 
8.1  
Abiraterone acetate ..........................................................................................45 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
13 
 
8.2  
Apalutamide…. ................................................................................................51 
8.3  
Degarelix …. ....................................................................................................58 
8.4  
Indomethacin …. ..............................................................................................63 
9. DATA MONITORING AND REPORTING REQUIREMENTS ...........................76 
 
9.1  Management of Safety Data ...................................................................................77 
 
9.2  Definitions ..............................................................................................................78 
 
9.3  Pregnancy ...............................................................................................................84 
 
 
9.4  Adverse Event Monitoring and Reporting .............................................................84 
 
9.5 Company Reporting Procedures ............................................................................86 
 
9.6  Evaluating Adverse Events ....................................................................................88 
 
9.7  IRB Reporting ........................................................................................................91 
 
9.8  Protocol Amendments ............................................................................................92 
 
9.9  Informed Consent ...................................................................................................92 
10. STATISTICAL METHODS  ....................................................................................94 
 
10.1 
Data Analysis ...................................................................................................94 
11. REFERENCES ...........................................................................................................96 
APPENDICES ................................................................................................................103 
 
 
 
 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
14 
 
1. Introduction 
1.1. Overview and Rationale 
For the majority of patients, prostate cancer is highly curable when caught at an early stage, 
with 10-year biochemical (i.e., PSA) progression free survival (PFS) and prostate cancer 
specific overall survival (OS) rates following radical prostatectomy (RP) reported at 68% and 
97%, respectively.1 Historically, those with higher risk localized disease have not had as 
favorable of outcomes, however. For instance, those with clinical stage T3 disease (i.e. tumor 
that extends beyond the prostatic capsule) the 10-year biochemical PFS rate has been 
reported to be 44% and the prostate cancer specific OS rate 85%.2 Likewise, >50% of men 
classified as high risk per the D’Amico classification (PSA >20 ng/ml and/or biopsy Gleason 
score >7) have been reported to have a biochemical recurrence at 5-years post-RP.3,4 Given 
these relatively poor outcomes following RP in high risk patients, peri-operative (i.e., 
neoadjuvant or adjuvant) systemic therapy remains an attractive option to attenuate these 
high rates of relapse. 
Neoadjuvant systemic therapy has been established as a standard in bladder, breast, as 
well as others cancers; however, pre-surgical neoadjuvant approaches have yet to be proven 
beneficial in prostate cancer.5-8 To date, there have been several randomized trials testing 
neoadjuvant hormonal therapies (HT) (i.e., LHRH agonists and antiandrogens), as well as a 
number of single-arm trials testing chemo-hormonal and novel prostate cancer agents in the 
pre-surgical space.6,7 While most of the data thus far has shown that neoadjuvant treatment 
can lead to favorable pathologic outcomes (e.g., lower rates of capsular penetration and 
positive margins), none have shown that these approaches have any impact on long-term 
outcomes such as biochemical PFS or OS rates.9-13 Of note, while favorable pathologic 
outcomes post-neoadjuvant therapy have been described, rates of negative pathologic 
complete response (pCR) in these studies have only been documented in approximately 5% 
of patients.10,14-17 Given this historic lack of clinical efficacy, it seems likely that pre-surgical 
neoadjuvant therapies may only translate into improved clinical outcomes if a pCR rate 
substantially higher than 5% is achieved. 
Over the past decade a number of new therapies have been proven effective in the 
treatment of castration-resistant prostate (CRPC) – a more advanced, HT-resistant and 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
15 
 
ultimately lethal form of prostate cancer.18 Theoretically, these agents may provide an 
opportunity to develop more effective neoadjuvant treatment strategies. One such agent, 
abiraterone acetate, is a potent CYP-17 inhibitor capable of suppressing testosterone from the 
castrate (i.e. <20 ng/dL) to undetectable range when combined with a GnRH agonist.19,20 A 
recent report by Taplin and colleagues found that 24 weeks of neoadjuvant GnRH agonist 
plus abiraterone acetate led to a pCR rate of 10%, with an additional 14% of patients 
achieving a near pCR (defined as ≤5 mm residual tumor).17 Our group has also reported on 
our efforts to more completely target AR-signaling in men pre-prostatectomy.21 In the “Total 
Androgen Pathway Suppression (TAPS) Study,” reported by Mostaghel, the GnRH agonist 
goserelin was combined with the following: 1) dutasteride (N=12), 2) bicalutamide and 
dutasteride (N=10) or 3) bicalutamide, dutasteride, and ketoconazole (N=13) for 3-months 
pre-prostatectomy. There were two (8.7%) pCR and nine (30.4%) near pCR (defined as ≤2 
mm residual tumor) between cohort 2 (gosereline, bicalutamide and dutasteride) and cohort 3 
(gosereline, bicalutamide, dutasteride, and ketoconazole). 
It is notable that the rates of pCR achieved on both the Taplin and Mostaghel studies 
were comparable to those reported in older neoadjuvant HT trials, leaving the possibility that 
if a pre-surgical neoadjuvant HT strategy is going to ultimately prove beneficial, maximal 
inhibition of AR-signaling may be necessary. Fortunately, our toolbox of AR-directed drugs 
effective in the CRPC setting continues to expand. In addition to abiraterone acetate, 
enzalutamide, a potent AR-antagonist, was also approved on the basis of Phase III data that it 
leads to improvements in OS.22,23 Recently, a newer AR-antagonist with several theoretical 
advantages over enzalutamide, apalutamide, has also entered Phase III clinical testing 
[clinicaltrials.gov: NCT01946204]. 
Another explanation for the lack of demonstrable long-term efficacy with neoadjuvant 
HTs is that these agents may not target more resistant cancer clones and/or emergent 
resistance pathways. A plausible mechanism by which resistance may develop in this context 
is via intratumoral steroidogenesis. Indeed, a number of steroidogenic enzymes have been 
shown to be upregulated in heavily pre-treated prostate cancer patients in comparison to 
primary prostatectomy samples.24 Specifically, AKR1C3, which is capable of converting 
DHEA-S metabolites into the potent AR-ligands testosterone and dihydrotestosterone, is 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
16 
 
frequently found to be upregulated in clinical specimens and to correlate with stage of 
disease.24-26 In addition, cell culture and xenografts models of CRPC have implicated 
AKR1C3 in the emergence of resistance to both enzalutamide and abiraterone acetate.27,28 
Importantly, in both the Mostaghel and Taplin trials, a significant residual amount of DHEA-
S remained in circulation (~20 μg/dL) following combination GnRH agonist and CYP17 
inhibitor therapy.17,21 In theory, this persistent serum DHEA-S may serve as a depot for 
intratumoral conversion to testosterone and DHT, with the final steps of conversion catalyzed 
by AKR1C3.26  
Taken in total, dual targeting of AKR1C3 and AR-signaling is likely to result in a more 
profound anti-tumor effect than previously reported in the literature. Indomethacin, a non-
steroidal anti-inflammatory, has been shown to have the off target effect of inhibiting 
AKR1C3, and to inhibit prostate cancer cells in pre-clinical models.29,30 In addition, synergy 
between indomethacin and either abiraterone or enzalutamide has been reported in otherwise 
resistant prostate cancer cell lines.27,28 Indomethacin has been FDA approved for decades, 
and has a long safety track record. Therefore, we propose a pre-surgical neoadjuvant trial 
testing 12-weeks of indomethacin combined with a regimen designed to completely ablate 
AR-signaling: abiraterone acetate, apalutamide and degarelix. The hypothesis of this study is 
that 12-weeks of combination indomethacin, degarelix, apalutamide and abiraterone acetate 
will result in a robust anti-tumor effect manifested as a high pathologic complete response 
rate. 
1.2. Androgen/Androgen Receptor Directed Therapies 
The initial management of advanced prostate cancer, as well as higher risk localized prostate 
cancer being treated with radiation therapy, typically involves targeting the 
androgen/androgen receptor (AR) signaling axis through lowering serum testosterone levels 
to the castrate range (i.e. testosterone <20-50 ng/dL).18,34 This is accomplished either through 
surgical castration or now more commonly medical castration with a GnRH 
agonist/antagonist [i.e., hormonal therapy (HT)]. Hormonal therapy is initially highly 
effective in those with metastatic prostate cancer, leading to objective responses in >85% of 
individuals.35 Unfortunately, after a variable period of symptom relief, androgen ablation 
invariably ceases to suppress prostate cancer growth and patients eventually succumb to their 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
17 
 
disease. This disease state defined by progression in spite of androgen ablation has been 
termed castrate resistant prostate cancer (CRPC) (Figure 1).36  
 
Figure 1: Prostate cancer clinical states model (adapted from Scher et al, 2000). 
Recently it has come to light that CRPC is still largely dependent on androgen/AR 
axis signaling. This realization has led to the development of multiple newer AR directed 
therapies. Mechanistically these agents primarily work either through ligand depletion (e.g., 
abiraterone acetate) or through interference with AR trafficking and signaling (e.g., 
enzalutamide, apalutamide).18 The current standard treatment of CRPC entails the 
continuation of hormonal therapy with the sequential administration of a number of 
secondary androgen-directed agents (e.g., abiraterone acetate, enzalutamide), 
immunotherapeutics (e.g., sipuleucel-t), radiopharmaceuticals (e.g., radium-223) and/or 
chemotherapeutics (e.g., docetaxel, cabazitaxel) (Figure 1).18-20,22,23,37-39 
1.2.1. Abiraterone Acetate 
Developed through rational design based on a parent pregnenolone structure, abiraterone 
acetate functions through inhibition of cytochrome P450-17 (CYP-17), a key family of 
enzymes involved in gonadal, adrenal and intratumoral androgen synthesis.40-43 When 
given in conjunction with a GnRH analogue, it has the ability to rapidly drive castrate 
level testosterone (i.e. <20-50 ng/dL) to undetectable.44,45 Unlike ketoconazole, another 
CYP-17 inhibitor used in the CRPC setting, abiraterone acetate is highly specific for the 
CYP-17 family of enzymes, making it generally better tolerated than ketoconazole.42,46,47 
It can lead to mineralocorticoid excess, however, through a compensatory elevation in 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
18 
 
adrenocorticotropic hormone (ACTH) that occurs in response to depressed cortisol levels. 
When prednisone is co-administered with abiraterone acetate, mineralocorticoid 
associated side effects (e.g., fluid retention, hypokalemia and hypertension) are mostly 
prevented, although these are observed more frequently in those receiving abiraterone 
acetate compared to placebo.19,20,48 Abiraterone acetate is currently FDA approved for the 
treatment of CRPC in patients who are either pre- or post-docetaxel. In addition, 
abiraterone acetate was more recently FDA approved for the treatment of metastatic high-
risk castration-sensitive prostate cancer on the basis of Phase III data demonstrating a 
robust overall survival advantage in this population.49 
1.2.1.1. 
Abiraterone Acetate Clinical Trial Experience 
Two dose escalation Phase I studies were completed utilizing abiraterone acetate.44,50 
Neither study documented dose-limiting toxicities, however, side effects of note 
included: hypertension (12-29%), hypokalemia (24-48%) and peripheral edema (5-
24%). This side effect profile was felt most likely to be a result of mineralocorticoid 
excess secondary to a compensatory elevation in ACTH occurring in the context of 
partially blocking adrenal steroid synthesis. These side effects were managed with 
eplerenone, beta-blockers, diuretics and/or corticosteroids. Furthermore, these studies 
provided preliminary evidence for abiraterone acetate’s efficacy in men with 
chemotherapy naïve CRPC. 
A subsequent Phase II study evaluated abiraterone acetate in men with CRPC 
post-docetaxel treatment.51 This study incorporated prednisone 5 mg twice daily into 
the treatment regimen in an effort to mitigate the aforementioned mineralocorticoid 
associated side effects. At a dose of 1000 mg daily, abiraterone acetate was found to 
produce PSA declines of at least 50% in 22/58 (36%) men. Partial responses by 
Response Evaluation Criteria in Solid Tumors (RECIST) criteria were seen in 4/22 
(18%) patients with evaluable tumors. Importantly, no significant hypertension or 
hypokalemia was noted – likely due to the co-administration of prednisone. 


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
19 
 
Proof of principle that further androgen suppression is effective in controlling 
CRPC was provided for in the landmark Phase III COU-AA-301 trial. In that study it 
was demonstrated that abiraterone acetate, when given to men with CRPC previously 
treated with docetaxel, resulted in a significant reduction in the risk of death 
compared to placebo (HR 0.65, 95% CI, 0.54-0.77; P<0.001).19 Subsequently the 
COU-AA-302 trial demonstrated similar efficacy in men with CRPC pre-docetaxel 
(HR 0.79, 95% CI, 0.66-0.96; P < .0151).20 These two trials demonstrated a higher 
incidence of mineralocorticoid associated side effects in spite of the co-administration 
of prednisone. Hypokalemia, peripheral edema and hypertension occurred at 
approximate rates of 17%, 28-31% and 10-22% in the abiraterone acetate cohorts 
respectively. Other adverse events observed were generally low grade. Of note there 
did appear to be higher rates of fatigue, arthralgias, aminotransferase abnormalities 
and non-fatal cardiac events with abiraterone acetate. Overall, abiraterone acetate was 
felt to be generally well tolerated, however. A summary of the adverse events 
observed in these two Phase III trials are listed in Table 1. Ultimately, on the basis of 
the COU-AA-301 and COU-AA-302 trials abiraterone acetate was approved in the 
post- and pre-docetaxel setting respectively.  
 
More recently, the Phase III LATITUDE study testing abiraterone acetate in 
men with metastatic castration-sensitive prostate cancer was completed.49 This study 
showed a robust overall survival advantage in men with at least two of the three 
following high-risk factors: a Gleason score of 8 or more, at least three bone lesions, 
and the presence of measurable visceral metastasis. The median overall survival was 
significantly longer in the abiraterone acetate group than in the placebo group (not 
reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 
0.51 to 0.76; P<0.001). Adverse events on the LATITUDE study were consistent with 
those observed in COU-AA-301 and COU-AA-302 (Table 2).  
 


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Neoadjuvant therapy in high-risk Prostate Cancer 
Protocol Version: 4.0; March 23, 2018 
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COU-AA-301 
COU-AA-302 
Adverse Event 
Abiraterone acetate + 
Prednisone (n=791) 
Placebo + Prednisone 
(n=394) 
Abiraterone acetate + 
Prednisone (n=542) 
Placebo + Prednisone 
(n=540) 
  
All Grades (%) 
Grade 3-4 
(%) 
All Grades 
(%) 
Grade 3-4 
(%) 
All Grades 
(%) 
Grade 3-4 
(%) 
All Grades 
(%) 
Grade 3-4 
(%) 
Anemia 
23 
7.5 
26 
7.4 
- 
- 
- 
- 
Thrombocytopenia 
4 
1.4 
3 
0.5 
- 
- 
- 
- 
Neutropenia 
1 
0.1 
0.3 
0.3 
- 
- 
- 
- 
Febrile neutropenia 
0 
0 
0 
0 
- 
- 
- 
- 
Diarrhea 
18 
0.6 
53 
1.3 
22  
18   
Fatigue 
44 
8.3 
169 
9.9 
39  
34   
Asthenia 
13 
2.3 
52 
2 
- 
- 
- 
- 
Back pain 
30 
5.9 
129 
9.6 
32  
32   
Nausea 
30 
1.6 
124 
2.5 
- 
- 
- 
- 
Vomiting 
21 
1.8 
97 
2.8 
- 
- 
- 
- 
Hematuria 
8 
1.4 
31 
2.3 
- 
- 
- 
- 
Abdominal pain 
12 
2 
44 
1.5 
- 
- 
- 
- 
Pain in arm or leg 
17 
2.4 
79 
5 
17  
16   
Dyspnea 
13 
1.3 
46 
2.3 
- 
- 
- 
- 
Constipation 
26 
1 
120 
1 
23  
19   
Pyrexia 
9 
0.4 
35 
1.3 
- 
- 
- 
- 
Arthralgia 
27 
4.2 
89 
4.1 
28  
24   
Urinary tract infection 
12 
2.1 
28 
0.5 
- 
- 
- 
- 
Pain 
2 
0.6 
19 
1.8 
- 
- 
- 
- 
Bone pain 
25 
5.6 
110 
7.4 
20  
19   
Fluid retention or edema 
31 
2.3 
88 
1 
28 
0.7 
24 
2 
Hypokalemia 
17 
3.8 
33 
0.8 
17 
2 
13 
2 
Cardiac disorder* 
13 
4.1 
42 
2.3 
19 
6 
16 
3 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
Protocol Version: 4.0; March 23, 2018 
21 
 
Liver-function test 
abnormalities or 
Hepatotoxicity 
10 
3.4 
32 
3 
4.2 
8 
9.8 
3 
Hypertension 
10 
1.3 
31 
0.3 
- 
- 
- 
- 
Hot flush 
- 
- 
- 
- 
22  
18   
Muscle spasm 
- 
- 
- 
- 
14  
20   
Cough 
- 
- 
- 
- 
17   
14   
Table 1: Adverse events observed on the COU-AA-301 [de Bono et al, 2011] and COU-AA-302 [Ryan et al, 2013] trials. 
*Cardiac disorders included: ischemic heart disease, myocardial infarction, supraventricular tacharrhythmias, ventricular tachyarrhythmias, 
cardiac failure and possible arrhythmia-related tests, signs and symptoms 


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
22 
 
 
Table 2: Adverse events observed on the LATITUDE trial [Fizazi, et al. 2017].  
Abiraterone acetate plus the GnRH agonist leuprolide have also been tested in 
the neoadjuvant setting. Taplin and colleagues recently reported on the results of a 
randomized Phase II study.17 In that trial men were randomized between 24 weeks of 
neoadjuvant GnRH agonist plus 12 weeks of abiraterone acetate (N=28) and 24 
weeks of both neoadjuvant GnRH plue abiraterone acetate (N=30). That trial 
demonstrated a negative margin rate of 90% and pCR rate of 10% in the cohort 
receiving 24 weeks of both leuprolide and abiraterone acetate, with an additional 14% 
of patients achieving a near pCR (defined as ≤5 mm residual tumor). The cohort 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
23 
 
receiving 24 weeks of GnRH agonist and 12 weeks of abiraterone acetate achieved a 
negative margin rate of 81%, a pCR rate of 4% and a near pCR rate of 0%. 
Differences in pathologic outcomes between cohorts were not statistically significant; 
although, the trial was not powered to detect these differences.  
 
1.2.2. Apalutamide 
Apalutamide works through competitive AR inhibition and unlike the older anti-
androgens (e.g., bicalutamide, nilutamide), is a pure AR antagonist. It additionally has the 
ability to prevent AR nuclear translocation and DNA binding to nuclear response 
elements.52 It is generally felt to function similarly to enzalutamide, another AR targeted 
therapy approved for men with mCRPC pre- and post-docetaxel. In docetaxel pre-treated 
patients enzalutamide was shown to result in a 37% reduced risk of death compared to 
placebo (HR 0.63, 95% CI, 0.53-0.75; P<0.001), and in docetaxel naïve patients it led to 
a 29% reduction in the risk of death compared to placebo (HR 0.71, 95% CI, 0.60 to 0.84; 
P<0.001).53,54 Preclinical work comparing apalutamide to enzalutamide, however, 
demonstrated that apalutamide may have several theoretical advantages over 
enzalutamide.55 Namely, in mouse models apalutamide was able to achieve a maximal 
therapeutic effect at 30 mg/kg/day compared to 100 mg/kg/day of enzalutamide (Figure 
2). apalutamide is also able to achieve equivalent intra-tumoral concentrations at a lower 
plasma steady state concentration compared to enzalutamide. Finally, while high-dose 
apalutamide (i.e., 3-fold higher than the Phase II dose of 240 mg/day based on dose per 
m2 body surface area and standard species conversion factors) has resulted in tremors and 
seizures in dogs, apalutamide is less effective than enzalutamide at crossing the blood-
brain barrier. This may result in decreased CNS toxicities in those treated with 
apalutamide compared to enzalutamide. For instance, while enzalutamide has been 
implicated in causing seizures in a minority of patients, possibly through off target 
inhibition of GABA-A, no seizure have occurred in subjects treated on the Phase I/II 
studies of apalutamide (see apalutamide Investigator’s Brochure).53,56  


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
24 
 
 
Figure 2: Apalutamide comparative efficacy to enzalutamide (MDV-3100) in mouse 
xenograft models. Apalutamide is able to achieve maximal therapeutic effect at 30 
mg/kg/day compared to 100 mg/kg/day of enzalutamide. 
 
1.2.2.1. Apalutamide Clinical Trial Experience 
The first in human Phase I/II study of apalutamide is currently ongoing 
[Clinicaltrials.gov, NCT01171898]. This study is evaluating men with mCRPC. 
Results from the Phase I portion of this study (N=30) demonstrated that 
apalutamide is generally safe and well tolerated. At the maximum tested dose of 
300 mg daily by mouth only 1/4 subjects experienced a grade 3 adverse event 
(AE) (abdominal pain). The other three individuals receiving a dose of 300 mg 
daily did not experience dose-limiting toxicities (DLT) (see Apalutamide 
Investigator’s Brochure). Common grade 1-2 AEs observed in the Phase I study 
included: fatigue (47%), nausea (30%), abdominal pain (20%), arthralgias (13%), 
diarrhea (17%), dyspnea (13%) and peripheral sensory neuropathy (13%). Five 
patients experienced serious adverse events and one patient discontinued the study 
due to an adverse event (atrial fibrillation) deemed unrelated to study treatment. 
PSA declines ≥50% were observed in 12 (55%) patients. 18F-16β-fluoro-5α-
dihydrotestosterone (FDHT) PET evaluation demonstrated AR blockade at four 
weeks across multiple doses. Given promising activity observed across all doses 
in conjunction with no appreciable difference in FDHT-PET uptake at 240 mg 
compared to 300 mg of apalutamide, a dose of 240 mg has been selected for 
Phase II testing.52,53 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
25 
 
The Phase II portion of this study is ongoing and will evaluate three 
expansion cohorts with a total enrollment of 97 patients (see Apalutamide 
Investigator’s Brochure).53 The primary endpoint of the Phase II study is PSA 
response at 12 weeks according to Prostate Cancer Working Group 2 (PCWG2) 
Criteria.57 All cohorts will consist of men who are chemotherapy naïve and have 
CRPC. Specific cohorts are: 1) non-metastatic CRPC, 2) mCRPC pre-abiraterone 
acetate and 3) mCRPC post-abiraterone acetate. Preliminary results for the non-
metastatic CRPC cohort, mCRPC pre-abiraterone acetate cohort and the mCRPC 
post-abiraterone acetate cohort demonstrated ≥50% PSA declines at 12-weeks in 
89%, 88% and 22% of subjects, respectively (see Apalutamide Investigator’s 
Brochure).58  As of 31 March 2017, the most common drug-related treatment-
related adverse events (TEAEs) across Cohorts 1, 2, and 3 respectively were 
fatigue, diarrhea, and nausea. Most AEs across the cohorts were Grade 1 or 2. 
Grade 3 AEs in >1 subject included hypertension and hyponatremia, malignant 
melanoma, and fatigue in Cohort 1; anemia in Cohort 2; and back pain in Cohort 
3. Grade 4 TEAEs included abdominal adhesions, duodenal ulcer, anemia, and 
glioblastoma multiforme in Cohort 1; dehydration, asthenia, and confusional state 
in Cohort 2; no Grade 4 TEAEs were reported in Cohort 3. The most common 
TEAE leading to discontinuation was fatigue. Serious adverse events were 
reported in 32 (33%) subjects. No SAEs in Phase 2 were assessed as drug-related. 
No new deaths or seizures were reported for this Phase 2 portion of the study. 
Hypothyroidism or increased blood thyroid stimulating hormone (TSH) was 
reported as an TEAE in in all 3 cohorts. Most TEAEs of rash or pruritus were 
Grade 1 or 2 in severity, were treated topically, and none were reported as serious. 
Over the Phase 2 duration of the study, the TEAE of fracture was reported in 
Cohorts 1 and 2, and none of the events were considered related to study drug or 
led to discontinuation of study drug. Falls were only reported in Cohort 1, none of 
the TEAEs of fall were reported as serious, and none led to discontinuation of 
study drug. Refer to the apalutamide Investigator’s Brochure for additional details 
on AEs. 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
26 
 
Apalutamide was recently approved by the FDA for use in men with non-
metastatic CRPC on the basis of Phase III data showing that it significantly 
prolonged the time to development of metastatic disease59. In the pivotal Phase III 
study, patients with a PSA doubling time ≤10 months were randomized 2:1 
between apalutamide or placebo. Men in the apalutamide group had a median 
metastasis-free survival of 40.5 months vs. 16.2 months in the placebo group (HR 
= 0.28; 95% CI 0.23 to 0.35; P<0.001).59 The following adverse events were 
considered to be related to apalutamide and occurred at a higher rate in the 
apalutamide group than in the placebo group: fatigue (30.4% vs. 21.1%), rash 
(23.8% vs. 5.5%), falls (15.6% vs. 9.0%), fracture (11.7% vs. 6.5%), 
hypothyroidism (8.1% vs. 2.0%), and seizure (0.2% vs. 0%). Several additional 
studies evaluating apalutamide are ongoing, including a Phase I trial evaluating it 
in combination with abiraterone acetate in a mCRPC population 
[clinicaltrials.gov, NCT01792687]. 
 
1.3. Indomethacin and AKR1C3 Inhibition 
Indomethacin is a non-steroidal anti-inflammatory that has been approved for the treatment 
of mild to moderate acute pain in adults for several decades. Pre-clinical work has shown that 
it has the off target effect of inhibiting AKR1C3, a steroidogenic enzyme responsible for 
converting androgenic substrates downstream of DHEA-S into the potent androgens 
testosterone and dihydrotestosterone (DHT) (Figure 3).26,30 Our group has shown that 
following neoadjuvant treatment with a CYP-17 inhibitor (i.e., abiraterone acetate or 
ketoconazole) plus GnRH analogue, persistent DHEA-S (~20 μg/dL) is present in circulation. 
It has been hypothesized that this persistent DHEA-S may serve as an intratumoral depot for 
conversion to testosterone and DHT via AKR1C3 – potentially driving resistance.17,21,26 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
27 
 
 
Figure 3: following CYP-17 inhibition with abiraterone acetate (AA) or ketoconazole 
(Keto), DHEA-S serum concentrations remain high (~20 μg/dL) and may serve as a 
precursor for intracrine production of testosterone and DHT. Resistance to CYP-17 inhibition 
may proceed via intratumoral AKR1C3 over expression coupled with the DHEA-S depot.26 
In support of its viability as a drug target, AKR1C3 is also frequently found to be 
upregulated in clinical specimens and to correlate with stage of disease.24-26 In addition, cell 
culture and xenografts models of CRPC have implicated AKR1C3 in the emergence of 
resistance to both enzalutamide and abiraterone acetate.27,28 Importantly, indomethacin has 
been shown to inhibit enzalutamide resistant cell lines (in vitro and in vivo) and to result in 
synergistic cell death when used in combination with enzalutamide.27 Given that chronic 
COX inhibition has been associated with deleterious side effects, indomethacin analogues 
that specifically inhibit AKR1C3 are under development.30 However, it is anticipated that a 
short course of indomethacin, as outlined in this protocol, should be well tolerated and offer a 
cost effective means to inhibit steroidogenesis within the tumor microenvironment.  
 
1.4. Exploratory Biomarkers 
We plan to incorporate a number of exploratory biomarkers into this study design. In the 
event that this trial fails to meet its primary endpoint, these correlatives will provide valuable 
insights into potential mechanisms of resistance to combinatorial AR-signaling suppression. 
Given our rapidly evolving understanding of prostate cancer pathobiology, genetics and 
epigenetics, it is impossible to prospectively define all the relevant biomarkers for the patient 
population enrolled on this study. So as to not miss an opportunity to assess a yet to be 
described biomarker; we will plan to store prostatectomy specimens and plasma samples at  


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
28 
 
-80°C for future biomarker work. When possible, we also conduct exploratory biomarker 
studies on pre-treatment/archival biopsy specimens. Key biomarkers and exploratory 
analyses we plan to conduct are described below. 
1.4.2. PTEN 
PTEN is a tumor suppressor gene implicated in the tumorigenesis and progression of 
prostate cancer.60-63 It plays an important role in the modulation of phosphatidylinositol-
3-kinase (PI3K) signaling, most likely though preventing the activation of the protein 
kinase Akt.64 Loss or inactivation of PTEN can in turn lead to the upregulation of 
PI3K/AKT signaling as well as downstream mTOR signaling.65 Genomic PTEN loss as 
determined through Fluorescence in situ hybridization (FISH) as well as lost PTEN 
expression as determined by immunohistochemistry (IHC) have been associated with 
adverse pathological markers as well as increased risk of recurrence following 
prostatectomy.66-70 
1.4.3. MYC 
MYC is an onco-protein that functions as a transcription factor, regulating cell 
proliferation, metabolism, protein synthesis, mitochondrial function and stem cell 
renewal.71  Like PTEN, its expression has been associated with prostate cancer initiation 
and progression.71-73  Indeed, MYC has been shown to be able to transform benign 
prostate cancer cells in a single step and its overexpression has been documented at the 
earliest stages of transformation in prostatic intraepithelial neoplasia samples.72,74 The 
region on chromosome 8q24 that encompasses the MYC locus is often altered (e.g. 
amplified, deleted) in more advanced disease.71,75-77 Interestingly, while alterations in 
chromosome 8q24 have been documented in more advanced cases of prostate cancer, 
MYC protein expression seems to be higher in Gleason 3 disease compared to Gleason 4-
5 disease.71 
1.4.4. ERG 
Gene fusions between the androgen receptor regulated TMPRSS2 gene and members of 
the ETS family of nuclear transcription factors (primarily ERG) are frequently 


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recognized in prostate cancer specimens.78 Furthermore, these gene fusions may 
synergize with PTEN loss, leading to more aggressive prostate cancer behavior.66,79 
1.4.5. KI-67 
KI-67 (Ki67) is a nuclear protein complex that is present during all active phases of the 
cell cycle, but absent during the G0 phase, making it a marker of cellular proliferation.80 
In men with localized prostate cancer, Ki67 has been found to independently associate 
with the risk of developing progressive disease following both radiation therapy and 
radical prostatectomy.66,81  
1.4.6. RNAseq 
In order to explore signaling pathways that may be implicated in the emergences of 
resistance to AR-directed therapy, we will perform RNAseq on tumor samples. Micro 
and macrodissection methods (as described in the lab manual) will be used to obtain 
samples that are enriched for cancer cells.  
1.4.7. Intraprostatic and Serum Drug/Androgen Levels 
Heterogeneity in intraprostatic drug and androgen levels has been documented in prostate 
surgical specimens in men treated with neoadjuvant AR-directed therapies.17,21 
Furthermore, prior studies have correlated intraprostatic abiraterone acetate levels with 
intraprostatic androgen levels and complete response rates following neoadjuvant 
therapy.17 
2. Study Objective: 
2.1. Primary Objective: 
The rate of pCR (i.e. no evidence of residual tumor) as assessed on prostatectomy specimens 
following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix 
and indomethacin. 
2.2. Secondary Objectives: 
 


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1. To determine the negative margin rate as assessed on prostatectomy specimens following 
3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and 
indomethacin. 
2. To determine the rate of near pCR (i.e., ≤5 mm of residual tumor) as assessed on 
prostatectomy specimens following 3-months (12 weeks) of neoadjuvant apalutamide, 
abiraterone acetate, degarelix and indomethacin. 
3. To determine the rate of pathologic T3 disease as assessed on prostatectomy specimens 
following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, 
degarelix and indomethacin. 
4. To determine the rate of nodal metastases as assessed on surgical lymph node specimens 
following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, 
degarelix and indomethacin. 
5. To determine the apoptotic index (i.e. percentage of tumor cells undergoing apoptosis) as 
determined by cleaved caspase-3 immunohistochemistry following 3-months (12 weeks) 
of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin. 
6. To determine the proportion of men who receive adjuvant radiation therapy within 1-year 
of prostatectomy. 
7. To determine the biochemical (i.e., PSA) progression free survival estimate two years 
after the last patient has accrued (i.e., confirmed PSA post-radical prostatectomy ≥0.2 
ng/mL). 
8. To determine the overall survival estimate two years after the last patient has accrued. 
9. Safety as assessed by the incidence and severity of adverse events and serious adverse 
events graded according to the National Cancer Institute – Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 
10. Exploratory biomarker Assessment. Examples of these may include, but are not limited 
to: PTEN immunohistochemistry (IHC), assessment for alteration in MYC/chromosome 
8q24 via FISH, RNAseq analysis, serum drug/androgen levels and intraprostatic 
drug/androgen levels. 
 
3. Patient Population 


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For this study we plan on enrolling 20 evaluable patients. Up to 22 patients will be enrolled if 
necessary in order to account for a potential 10% dropout rate. 
3.1. Inclusion Criteria: 
1. Willing and able to provide written informed consent. 
2. Age ≥ 18 years 
3. Eastern cooperative group (ECOG) performance status ≤2 
4. Documented histologically confirmed adenocarcinoma of the prostate 
5. Willing to undergo prostatectomy as primary treatment for localized prostate 
cancer 
6. High risk prostate cancer (per NCCN criteria): Gleason score 8-10 or T3a or PSA 
> 20 ng/mL  
or 
Very-high risk prostate cancer (per NCCN criteria): T3b-T4  
7. Serum testosterone ≥150 ng/dL 
8. Able to swallow the study drugs whole 
9. Willing to take abiraterone acetate on an empty stomach (no food should be 
consumed at least two hours before and for one hour after dosing). 
10. Agrees to use a condom (even men with vasectomies) and another effective 
method of birth control if he is having sex with a woman of childbearing potential 
or agrees to use a condom if he is having sex with a woman who is pregnant while 
on study drug and for 3 months following the last dose of study drug. Must also 
agree not to donate sperm during the study and for 3 months after receiving the last 
dose of study drug. 
11. Medications known to lower the seizure threshold (see list under prohibited meds) 
must be discontinued or substituted at least 4 weeks prior to study entry. 
 
3.2. Exclusion Criteria: 
 


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1. Prior local therapy to treat prostate cancer (e.g., radical prostatectomy, 
radiation therapy, brachytherapy) 
2. Prior use of apalutamide, abiraterone acetate or degarelix 
3. Prior or ongoing systemic therapy for prostate cancer including, but not 
limited to: 
a. Hormonal therapy (e.g., leuprolide, goserelin, triptorelin, 
degarelix) 
b. CYP-17 inhibitors (e.g., ketoconazole) 
c. Antiandrogens (e.g., bicalutamide, nilutamide) 
d. Second generation antiandrogens (e.g., enzalutamide, apalutamide) 
e. Immunotherapy (e.g., sipuleucel-T, ipilimumab) 
f. Chemotherapy (e.g., docetaxel, cabazitaxel) 
4. Evidence of serious and/or unstable pre-existing medical, psychiatric or other 
condition (including laboratory abnormalities) that could interfere with 
patient safety or provision of informed consent to participate in this study 
5. Any psychological, familial, sociological, or geographical condition that 
could potentially interfere with compliance with the study protocol and 
follow-up schedule. 
6. Abnormal bone marrow function [absolute neutrophil count 
(ANC)<1500/mm3, platelet count <100,000/mm3, hemoglobin <9 g/dL] 
7. Abnormal liver function (total bilirubin >1.5 x upper limit of normal [ULN]; 
AST or ALT ≥ 2.5 x ULN) 
Note: In subjects with Gilbert’s syndrome, if total bilirubin is >1.5 × ULN, 
measure direct and indirect bilirubin and if direct bilirubin is ≤1.5 × ULN, 
subject may be eligible 
8. Abnormal kidney function (GFR <45 mL/min) 
9. Serum albumin <3 g/dL 
10. Serum potassium <3.5 mmol/L 
11. Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke 
within 1 year to randomization, brain arteriovenous malformation, 


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Schwannoma, meningioma, or other benign CNS or meningeal disease which 
may require treatment with surgery or radiation therapy) 
12. Severe or unstable angina, myocardial infarction, symptomatic congestive 
heart failure, arterial or venous thromboembolic events (eg, pulmonary 
embolism, cerebrovascular accident including transient ischemic attacks), or 
clinically significant ventricular arrhythmias within 6 months prior to 
randomization  
13. History of stroke within the last 5-years 
14. History of gastrointestinal (GI) bleed requiring transfusion 
15. History of peptic ulcer disease requiring treatment within the last 5-years 
16. History of asthma that is NSAID-induced or with asthma that is classified as 
‘mild-persistent’ or worse (based on symptoms occurring more than 2 days per 
week) 
17. Uncontrolled hypertension 
18. Gastrointestinal disorder affecting absorption 
19. Active infection (eg, human immunodeficiency virus [HIV] or viral hepatitis) 
20. Any chronic medical condition requiring a higher dose of corticosteroid than 
10 mg prednisone/prednisolone once daily  
21. Any condition that in the opinion of the investigator, would preclude 
participation in this study 
22. Child Pugh Class B & C 
23. Pre-existing viral hepatitis 
 
3.3. Inclusion of Women and Minorities 
This study is focused on prostate cancer; therefore the treatment cohort is only applicable to 
men. Men from all ethnic and race groups are eligible for this study. 
4. Treatment Plan 


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4.1. Study Design 
This is an open label, multi-site, Phase II neoadjuvant study in men with localized prostate 
cancer planning to undergo prostatectomy. This study will assess the pCR rate after 3-months 
(12 weeks) of neoadjuvant treatment with apalutamide, abiraterone acetate, degarelix and 
indomethacin as assessed on prostatectomy specimens.  
All subjects must have localized, high or very-high risk (per NCCN criteria) prostate 
cancer and be willing to undergo prostatectomy as primary treatment. Subjects will be treated 
with neoadjuvant therapy for a total of 3-months (12 weeks) prior to prostatectomy. Therapy 
will consist of apalutamide, abiraterone acetate, degarelix and indomethacin (Figure 4). 
Abiraterone acetate, degarelix and indomethacin will be dosed at its respective FDA 
approved dose. These dosages are as follows: abiraterone acetate 1000 mg (four 250mg 
tablets) by mouth daily, indomethacin 50 mg by mouth three times daily (TID) and degarelix 
240 mg subcutaneous (SC) injection on day 1 followed by two additional 80 mg SC 
injections every 4 weeks. All men will also be treated with prednisone 5 mg by mouth twice 
daily while on abiraterone acetate in order to blunt its associated mineralocorticoid side 
effects.† Apalutamide was recently approved by the FDA for use in men with non-metastatic 
castration resistant prostate cancer on the basis of Phase III data showing that it significantly 
prolonged the time to development of metastatic disease. Apalutamide is still under 
development as an investigational product for other types of prostate cancer. Apalutamide 
will be administered at the FDA approved dose for treating non-metastatic CRPC, 240 mg 
daily by mouth. The GnRH antagonist degarelix was chosen over other forms of HT (i.e., 
GnRH agonists) given that the neoadjuvant treatment period is relatively short at 12-weeks, 
and degarelix has been shown to result in more rapid castration and PSA suppression 
compared to the GnRH agonist leuprolide.31 Following 12-weeks of neoadjuvant treatment, 
patients will undergo prostatectomy. Lymph node dissection will be required for all patients 
 
† Note: Because steroids can lead to hyperglycemia, subjects with a history of diabetes will be 
required to monitor their daily fasting blood glucose using a home glucometer. Fasting blood 
glucose values will be reviewed at scheduled follow up appointments. Patients will also be 
instructed to contact their provider if their fasting glucose is >150 mg/dL. Based on the daily 
fasting blood glucose levels, anti-hyperglycemic medications will be adjusted by the treating 
oncologist and/or the patient’s primary care doctor or endocrinologist. 


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with a ≥2% estimated risk of nodal metastases per the Partin Nomogram.32 Patients should 
have clinical follow-up visits following prostatectomy per the standard practice of their 
treating urologist. However, at a minimum, patients should be evaluated in clinic 28 days 
following their prostatectomy. Of note, the combination of apalutamide, abiraterone acetate 
and GnRH analogue therapy has been shown to have an acceptable safety profile when 
administered at these doses [see Investigator’s Brochure]. 
Figure 4: Study scheme. 
*Three doses of subcutaneous (SC) degarelix will be administered. Degarelix is administered every 4-weeks, 
with a 240 mg loading dose given for the first SC injection followed by 80 mg SC injections thereafter.  
This study will be open to patients age ≥ 18 years who have a histologic diagnosis of 
prostatic adenocarcinoma and are planning to undergo prostatectomy as primary treatment of 
their prostate cancer. All patients must have high to very high-risk prostate cancer as defined 
per the NCCN criteria (i.e., high-risk = Gleason score 8-10 or T3a or PSA > 20 ng/mL; very 
high-risk = T3b-T4).  
The primary endpoint will be the pathologic complete response (pCR) rate (i.e., no 
evidence of tumor) as assessed on prostatectomy specimens following 3-months (12 weeks) 
of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin. Secondary 
pathologic endpoints to be assessed from prostatectomy specimens following 3-months (12 
weeks) of neoadjuvant therapy include: the negative margin rate, negative nodal metastases 
rate, near pCR (i.e., ≤5 mm of residual tumor) rate, the rate of pathologic T3 disease and 
apoptotic index (i.e. percentage of tumor cells undergoing apoptosis) as determined by 
cleaved caspase-3 immunohistochemistry. Other secondary endpoints will include: the 
proportion of men who receive adjuvant radiation therapy within 1-year of prostatectomy, the 
biochemical (i.e., PSA) progression free survival estimate two years after the last patient has 


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Protocol Version: 4.0; March 23, 2018 
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accrued, the overall survival estimate two years after the last patient has accrued and safety 
(as assessed by CTCAE version 4.0). 
In addition, excess tissue from prostatectomy specimens and plasma samples will be 
stored at -80°C. These biologic specimens will be used for additional correlative work. When 
possible, we also conduct exploratory biomarker studies on pre-treatment/archival biopsy 
specimens. Examples of studies to be conducted may include, but are not limited to: PTEN 
immunohistochemistry (IHC), assessment for alteration in MYC/chromosome 8q24 via 
FISH, RNAseq analysis, serum drug/androgen levels and intraprostatic drug/androgen levels.  
4.2. Dose Adjustment, Delays and Treatment Discontinuation 
4.2.1. Adverse Events Attributed to a Study Drug 
For the purpose of determining how to dose adjust a study drug, an AE will be considered 
attributed to a given study drug if it is felt that the AE was probably or definitely related 
to that study drug (see Section 9.6: Evaluating Adverse Events). Please refer to Section 8: 
Pharmaceutical Information for guidelines on how to dose adjust/delay treatment with 
each study drug. Note that for AEs that are attributed to a study drug, treatment should be 
permanently discontinued for recurrent Grade 3 toxicity, Grade 3 toxicity lasting longer 
than 5 days, or any Grade toxicity that has not resolved to Grade 1 or less within 2 
weeks.   
 
4.2.2. Adverse Events Not Attributed to a Study Drug 
If a Grade 1 or 2 AE occurs that is not attributed to one of the study drugs, that patient 
may continue on treatment without dose adjustment/delays. If a Grade ≥3 AE occurs that 
is not attributed to a study drug, all drugs should be held until that AE returns to Grade 2 
or lower (prednisone may be continued). If a Grade ≥3 AE persists for more than two 
weeks, that patient should be removed from the study. The algorithm for managing 
toxicities that are not attributed to a study drug is provided below: 
Toxicity 
Action Required 
Grade 1 or 2 
No change 


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Protocol Version: 4.0; March 23, 2018 
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≥Grade 3 
Hold all drugs except prednisone until 
return to Grade 1 or 2, resume at full dose* 
*Note: Treatment will be permanently discontinued for Grade 3 toxicity lasting longer 
than 2 weeks. Prednisone should be tapered if study drugs are permanently discontinued. 
 
 
 
4.3. Removal of Patients from Study 
A patient may be removed from the study for a variety of reasons, including: 
1. 
Worsening symptoms that can be attributed to prostate cancer 
2. 
Unacceptable adverse event(s)  
• Patients develop urinary outlet obstruction requiring urinary catheterization 
and/or surgical intervention 
• Patients who develop grade 3 or higher liver function abnormalities: 
o Bilirubin ≥ 3 times institutional upper limit of normal (ULN) 
o AST (SGOT) or ALT (SGPT) ≥ 5 times ULN 
• Patients with AST/ALT elevation >3 times ULN with bilirubin elevation >2 
times ULN 
• Patients develop decreased renal function with serum creatinine  ≥ 2.5 times 
baseline level 
• Patients develop hypersensitivity or anaphylactoid reactions to abiraterone 
acetate, apalutamide, indomethacin or degarelix. 
3. 
Intercurrent illness that prevents further participation 
4. 
Experiencing a treatment delay of longer than 2 weeks; however, if the patient is 
receiving clinical benefit, treatment may be delayed for longer than 2 weeks and 
then resumed at the discretion of the Investigator. 
5. 
Patient refuses further treatment through the study and/or withdraws consent to 
participate 


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6. 
Patient is noncompliant with respect to taking drugs, keeping appointments, or 
having tests required for the evaluation of drug safety and efficacy  
7. 
General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in this study in the judgment of the investigator. 
Under no circumstance will care of a withdrawn patient be adversely affected by a decision to 
withdraw or be withdrawn from the study.


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5.0  Treatment Assessment and Evaluation 
All required treatment and end of study procedures and assessments must be done within 7 days 
(+/-) of the specified study visit date unless otherwise noted. Screening study procedures and 
assessments must be done 30 days prior to enrollment. The results of tests and/or procedures 
conducted as per standard of care purposes may be used for research purposes if conducted 
within the protocol-defined window. Long-term follow-up procedures and assessments should 
occur within 30 days (+/-) from the specified study visit date. 
5.1.Screening (performed within 30 days of enrollment) 
1. Comprehensive medical history and physical exam, including height and weight, 
medications, ECOG performance status assessment, blood pressure and heart rate. 
2. CBC (Complete blood count) with differential and platelet count. 
3. CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, Serum 
Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, Alkaline 
Phosphatase, CO2). 
4. Serum testosterone. 
5. TSH (thyroid stimulating hormone). 
Note: Free T3 and T4 should be checked if TSH is abnormal. 
6. Electrocardiogram (EKG). 
5.2.Neoadjuvant Treatment (Days 1 to 57) 
1. Comprehensive medical history and physical exam, including weight, medications, 
ECOG performance status assessment, blood pressure and heart rate (Days 1, 29 and 
57). 
2. Serum PSA (Days 1, 29 and 57). 
3. CBC (Days 1, 29 and 57). 
4. CMP (Days 1, 15, 29, 43, 57 and 71). 
5. TSH (Days 1, 29 and 57). 
Note: Free T3 and T4 should be checked if TSH is abnormal. 
6. Androgen panel (Day 1). 
5.3.Exploratory biomarker collection: blood samples and pre-treatment prostate biopsy 
specimens. (Day 1) Surgery (Day 85) 


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Protocol Version: 4.0; March 23, 2018 
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1. Nursing assessment. 
2. Prostatectomy specimen pathologic assessment. 
3. CBC. 
4. CMP. 
5. Serum PSA. 
6. Androgen panel. 
7. Exploratory biomarker collection: blood samples and post-treatment prostatectomy 
specimens.. 
5.4.Follow Up 
1. Comprehensive medical history and physical exam, including weight, medications, 
ECOG performance status assessment, blood pressure and heart rate (Day 113). 
2. Serum PSA (Days 113, 450 and 815). 
3. Telephone, mail or email follow up (Days 450 and 815) (see Appendix C). 
 


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6. Study Calendar 
 


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7. Study Assessments 
7.1. Pathologic Assessment 
Prostatectomy specimens will be submitted in their entirety. Pathologic CR is defined as 
no evidence of cancer on fully submitted prostatectomy specimens using standard 
surgical pathology assessments (i.e. H&E assessment will be used for the purpose of 
defining pathologic CR per protocol). For complete details on handling of prostatectomy 
specimens, please refer to the lab manual.  
7.2. Exploratory Biomarkers 
This study will incorporate a number of additional exploratory biomarkers. Given our 
rapidly evolving understanding of prostate cancer pathobiology, genetics and 
epigenetics, it is impossible to prospectively define all the relevant biomarkers for the 
patient population enrolled on this study. So as to not miss an opportunity to assess the 
utility of yet to be described biomarkers in the context of combinatorial AR-pathway 
suppression; we will plan to store prostatectomy specimens and plasma samples at -80°C 
for future analyses. These samples will be stored for up to 5 years.  
Prostate tissue will be obtained post-treatment with apalutamide, abiraterone 
acetate, indomethacin and degarelix, and other biospecimens (e.g., plasma) will be 
obtained pre- and post-treatment. When possible, we will also obtain pre-
treatment/archival prostate biopsy specimens for these exploratory studies. All biopsy 
material will be Formalin-Fixed Paraffin Embedded (FFPE) and IHC and FISH assays 
will be performed on these FFPE samples in Lawrence True’s laboratory at University of 
Washington. RNAseq will be performed in Peter Nelson’s laboratory at Fred Hutchinson 
Cancer Research Center and will be performed on tumor samples that have been 
processed as described in the lab manual. Liquid chromatography/mass spectrometry 
(LC/MS) assessment of intraprostatic drug and androgen levels will be determined in Dr. 
Mostaghel’s laboratory at the Fred Hutchinson Cancer Research Center. Admittedly, 
given that we may not be able to obtain adequate tumor tissue to assess all of these 
biomarkers, we will prioritize assessing them in the order that they are described below. 
Samples will not be labeled with identifiable patient information, and instead will have a 


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coded study ID unique to each enrolled subject. The study PI (Dr. Michael T. Schweizer) 
and his designees will have access to these samples. Samples will be stored in the GU 
Cancer Research Lab at the University of Washington Medical Center or in Peter 
Nelson’s lab at the Fred Hutchinson Cancer Research Center. 
PTEN: PTEN protein expression will be determined via IHC using a rabbit monoclonal 
anti-PTEN antibody (clone D4.3, #9188, Cell Signaling Technologies). PTEN IHC and 
FISH assays will be conducted similar to the methods previously described by Lotan and 
colleagues.68 
MYC: Alterations in chromosome 8q24, the region that encompasses the MYC locus, 
will be assessed via FISH. FISH hybridization will be done with the multicolor probes 
(ProVysion, Vysis, Inc., Downers Grove, IL) to detect and quantify chromosome 8 
centromere probe [chromosome enumeration probe 8 (CEP8)] and with two locus-
specific probes, the lipoprotein lipase (LPL; 8p21.3) and the c-MYC8q24 probe. 
MYC/chromosome 8q24 FISH assays will be conducted similar to the methods 
previously described by Jenkins and colleagues.76 
ERG: Given that ERG protein expression has been shown to be an excellent surrogate 
of TMPRSS2-ERG fusion status, we will plan to assess ERG expression using IHC.82-84 
ERG IHC will be done using an anti-ERG mouse monoclonal antibody (clone 9FY; 
Biocare, Concord, CA). ERG IHC assays will be conducted similar to the methods 
described by Chaux and colleagues.82 
KI-67: Ki67 will be assessed via IHC using an anti-Ki67 mouse monoclonal (clone 
7B11; Zymed Laboratories, South San Francisco, Calif). The mouse PowerVision+ kit 
(Leica Microsystems, Buffalo Grove, Ill) will be used for these assays. Ki67 IHC assays 
will be conducted using standard lab practices and in accordance with the mouse 
PowerVisionþ kit instructions. 
RNAseq: After RNA extraction, total RNA (~200 ng) will be quality controlled using 
the Agilent bioanalyzer, to ensure that specimens have RIN scores > 7.0. Strand-specific 
sequencing libraries will be prepared using the TruSeq Stranded Total RNA library kit 
(Illumina). If 200 ng of total RNA are not available, then we will use a high-sensitivity, 
strand-agnostic workflow, using the Ovation RNA-seq System v2.0 kit (NuGen) 


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Protocol Version: 4.0; March 23, 2018 
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according to manufacturer’s protocols with some modifications, which we have 
validated with Total RNA input amounts as low as 500 picograms to have high 
correlation (R2 > 0.85) with the high input workflow in terms of gene-level expression 
measures. Barcoded libraries will be quality-controlled using the Kappa PCR kit and 
pooled in equimolar ratios for subsequent cluster generation and sequencing on an 
Illumina HiSeq 2000 or 2500 instrument to yield ~50,000,000 paired end 100x100 bp 
tags for each sample.  Paired-end reads will then be mapped to the human genome (build 
hg19, NCBIv.38) and isoform specific gene expression measures will be derived using 
the RSEM package, which uses an expectation maximization algorithm to derive the 
abundance of each gene isoform after taking into account the read mapping uncertainty 
with a statistical model.85 This analysis will yield information on the relative abundance, 
with 95% Confidence Interval, of all known gene isoforms annotated in RefSeq, 
Ensembl, and UCSC gene annotations. Differential expression between groups will be 
determined using the RSEM output with the EBseq pipeline.86 The unaligned reads after 
RSEM analysis may contain information on splice junctions of novel transcriptional 
isoforms and fusion genes. Using these unaligned reads, the relative abundance of novel 
splice junctions in each sample, independent of existing known exon annotation, will be 
estimated using the SpliceMap package.87 To identify fusion transcripts, we will use 
TopHat-Fusion with all reads as well as specifically those reads that were not aligned by 
RSEM.88 Since it can be used independent of gene annotation, TopHat-Fusion can also 
provide redundant information to SpliceMap on novel splice variant junctions. 
Completely novel RNA species will be identified as peaks of expressed sequence tags 
(ESTs) using Bowtie to align sub-segments of each read, followed by peak calling using 
MACS, SICER, and GCLS, and DEseq analysis of detected peaks to identify differential 
expression of novel transcript peaks between samples when present in at least one 
sample.89-92 Aligned RNA-seq data will be output as .bam files and coverage tracks (wig 
and tdf format) and visualized using IGV and the UCSC Genome browser.93-95 This suite 
of analytical approaches will therefore allow us to identify and visualize known genes 
and isoforms, novel splice junctions, and fusion genes present in expressed transcripts. 


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PI: Michael T. Schweizer, MD 
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Protocol Version: 4.0; March 23, 2018 
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Intraprostatic and Serum Drug/Androgen Levels: Abiraterone acetate and 
apalutamide drug levels will be determined in serum, and benign fresh frozen prostate 
specimens using LC/MS. An Agilent 1290 UPLC, AB Sciex 550 LC/MS system will be 
used along with a Phenomemex Kinetex column to do the quantification according to 
standard lab procedure developed in Dr. Mostaghel’s laboratory. Similarly, intraprostatic 
androgens (i.e., DHT and testosterone) will be quantified with LC/MS according to 
standard lab methods developed in the Mostaghel laboratory. 
 
7.3. Safety 
Safety will be evaluated based on the incidence, severity, duration, causality, seriousness, 
and type of adverse events (AEs), and changes in the patient’s physical examination, vital 
signs, and clinical laboratory results.  Investigators will use the NCI CTCAE version 4.0 
(published 14 June 2010) to assess the severity of AEs and toxicities (see Appendix A). 
For safety considerations specific to the study drugs, see section 8 of the protocol.  
 
 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
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8. Pharmaceutical Information 
8.1. Drug Name: Abiraterone acetate [Adapted from FDA prescribing information, refer to 
this document for more detail.] 
 
• Chemical Name: (3β) 17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate 
• Molecular Formula: C26H33NO2  
Molecular Weight:  391.55 g/mol 
• Description: Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline 
powder. The 250 mg tablets are oval-shaped tablets debossed with AA250 on one side. 
Its molecular formula is C26H33NO2 and it has a molecular weight of 391.55. Abiraterone 
acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log 
P) and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19. Inactive 
ingredients in the tablets are colloidal silicon dioxide, croscarmellose sodium, lactose 
monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium 
lauryl sulfate. 
8.1.1. Clinical Pharmacology 
Abiraterone acetate is administered in 250 mg tablets, with the FDA approved dose being 
1000 mg (4 tablets) by mouth daily. Following administration abiraterone acetate is 
hydrolyzed in vivo to abiraterone, a 17 α-hydroxylase/C17,20-lyase (CYP17) inhibitor. 
Following ingestion the time to maximum plasma concentration of abiraterone acetate is 
2 hours. At a dose of 1000 mg daily abiraterone acetate achieves a steady-state Cmax of 
226 +/- 178 ng/mL (mean +/- SD) and an area under the curve (AUC) of 1173 +/- 690 
ng.hr/mL (mean +/- SD). Systemic exposure of abiraterone acetate is increased when 
administered with food, with an approximate 7- and 5-fold increase in the Cmax and AUC 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
47 
 
respectively when given with a low-fat meal. When given with a fatty meal, the Cmax and 
AUC increased 17- and 10-fold respectively. Given this variation, no food should be 
consumed at least 2 hours before and one hour after taking abiraterone acetate. 
Abiraterone acetate sulphate and N-oxide abiraterone acetate sulphate are the two 
main circulating inactive metabolites. CYP3A4 is involved in the formation of N-oxide 
abiraterone acetate sulphate and SULT2A1 is involved in the formation of N-oxide 
abiraterone acetate sulphate and Abiraterone acetate sulphate. Abiraterone acetate is 
highly bound (>99%) to human plasma proteins, albumin and alpha-1 acid glycoprotein. 
The apparent steady-state volume of distribution is (mean +/- SD) 19669 +/- 13358 L. 
The mean (+/- SD) terminal half-life of abiraterone acetate in plasma is 12 +/- 5 hours. It 
is predominately excreted in feces (88%), with the major compounds present in feces 
being unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of 
administered dose respectively).  
8.1.2. Safety/Precautions 
• Mineralocorticoid excess: Use abiraterone acetate with caution in patients with a 
history of cardiovascular disease. The safety of abiraterone acetate in patients with 
LVEF < 50% or NYHA Class III or IV heart failure in Study 1 or LVEF < 50 % or 
NYHA Class II to IV heart failure in Study 2 was not established. Control 
hypertension and correct hypokalemia before treatment. Monitor blood pressure, 
serum potassium and symptoms of fluid retention at least monthly. 
• Adrenocortical insufficiency: Monitor for symptoms and signs of adrenocortical 
insufficiency. Increased dosage of corticosteroids may be indicated before, during 
and after stressful situations. 
•  Hepatotoxicity: Increases in liver enzymes have led to drug interruption, dose 
modification and/or discontinuation. Monitor liver function and modify, interrupt, or 
discontinue abiraterone acetate dosing as recommended. 


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• Food effect: abiraterone acetate must be taken on an empty stomach. Exposure (area 
under the curve) of abiraterone acetate increases up to 10 fold when abiraterone 
acetate is taken with meals. 
• Unforeseeable risks to embryo or fetus: Patients should be informed that 
abiraterone acetate may harm a developing fetus; thus, women who are pregnant or 
women who may be pregnant should not handle abiraterone acetate without 
protection, e.g., gloves. Patients should also be informed that it is not known whether 
abiraterone acetate or its metabolites are present in semen and they should use a 
condom if having sex with a pregnant woman. The patient should use a condom and 
another effective method of birth control if he is having sex with a woman of child-
bearing potential. These measures are required during and for one week after 
treatment with abiraterone acetate. 
 
8.1.3. Information for Patients 
• Patients should be informed that abiraterone acetate and prednisone are used 
together and that they should not interrupt or stop either of these medications 
without consulting their physician.  
• Patients should be informed that abiraterone acetate must not be taken with food and 
that no food should be consumed for at least two hours before the dose of 
abiraterone acetate is taken and for at least one hour after the dose of abiraterone 
acetate is taken. Patients should be informed that taking abiraterone acetate with 
food causes increased exposure and this may result in adverse reactions.  
• Patients should be apprised of the common side effects associated with abiraterone 
acetate, including peripheral edema, hypokalemia, hypertension, elevated liver 
function tests, and urinary tract infection. Patients should be instructed to report any 
perceived adverse events (including the aforementioned). 
8.1.4. Laboratory tests 


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Protocol Version: 4.0; March 23, 2018 
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• Liver function tests (e.g. AST/ALT, bilirubin) should be monitored periodically 
while on abiraterone acetate. 
• Electrolytes (e.g., sodium, potassium) should be monitored periodically while on 
abiraterone acetate. 
 
8.1.5. Drug Interactions 
Abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. As 
such, drugs metabolized by this route can exhibit increased plasma concentrations when 
co-administered with abiraterone acetate. Drugs with narrow therapeutic indices (e.g., 
thioridazine) that are metabolized via CYP2D6 should be avoided. 
Based on in vitro data, abiraterone acetate is a CYP3A4 substrate. Strong 
CYP3A4 inhibitors or inducers on pharmacokinetics of abiraterone acetate have not been 
evaluated in vivo; however, caution should be taken when strong CYP3A4 
inhibitors/inducers are being co-administered.  
In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of 
pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given 
together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be 
monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow 
therapeutic index (e.g., paclitaxel) if used concomitantly with abiraterone acetate. 
8.1.6. Adverse Reactions 
The most common adverse reactions (≥ 10%) are fatigue, joint swelling or discomfort, 
edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract 
infection and contusion. The most common laboratory abnormalities (> 20%) are anemia, 
elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, 
hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. 
Additional adverse events observed in the Phase III trials can be found in Table 1. 
 
8.1.7. Dose Modifications for LFT Abnormalities Attributed to Abiraterone 
Acetate When Given in Combination with Apalutamide 


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Dose modifications are provided as guidance and should not replace the investigator’s 
own clinical judgment. 
Toxicity 
Dose of abiraterone acetate 
Dose of   apalutamide 
Dose of prednisone 
Grade 1 
No change 
No change 
No change 
Grade 2 
Hold until return to Grade 1 or 
baseline, resume after 
discussion and agreement with 
medical monitor* 
No change 
No change 
≥Grade 3 
Discontinue 
 
 
Discontinue 
 
Taper off 
*Note: Treatment will be permanently discontinued for Grade 3 toxicity lasting longer than 5 
days, or any grade toxicity that has not resolved to Grade 1 or less within 2 weeks  
8.1.8. Dose Modifications for Hypokalemia Attributed to Abiraterone Acetate 
When Given in Combination with Apalutamide 
Dose modifications are provided as guidance and should not replace the investigator’s 
own clinical judgment. 
Toxicity 
Dose of abiraterone acetate 
Dose of  Apalutamide 
Dose of prednisone 
Grade 1 or 2 
Initiate oral potassium 
supplementation, titrate to 
≥3.5 to ≤5.0 mmol/L, 
maintenance at ≥4.0 mmol/L 
recommended* 
No change 
No change 
≥Grade 3 
Hold and initiate IV potassium and 
cardiac monitoring, resume only 
after discussion and approval by 
the medical monitor* 
No change 
 
No change 
Recurrence ≥Grade 3, 
or Grade 4 
Discontinue 
 
Discontinue 
Taper off 


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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*Note: Treatment will be permanently discontinued for Grade 3 toxicity lasting longer than 5 
days, or any grade toxicity that has not resolved to Grade 1 or less within 2 weeks. Subjects will 
be allowed to resume/continue treatment if serum potassium level is maintained ≥3.5 to ≤5.0 
mmol/L with oral potassium supplementation. 
8.1.9. Dose Modifications for Hypertension and Edema/Fluid Retention Attributed 
to Abiraterone Acetate When Given in Combination with Apalutamide 
Dose modifications are provided as guidance and should not replace the investigator’s 
own clinical judgment. 
Toxicity 
Dose of abiraterone acetate 
Dose of  Apalutamide 
Dose of prednisone 
Grade 1  
No change 
No change 
No change 
Grade 2 
Hold until return to Grade 1 or 
baseline, resume at full dose* 
No change 
No change 
 
≥Grade 3 
Hold until Grade 1 or baseline, 
resume at full dose* 
 
No change 
 
No change 
Recurrence 
≥Grade 3, or 
Grade 4 
Discontinue 
Discontinue 
Taper off 
*Note: Treatment will be permanently discontinued for Grade 3 toxicity lasting longer than 5 
days, or any grade toxicity that has not resolved to Grade 1 or less within 2 weeks. 
8.1.10. Administration, Supply and Storage 
Abiraterone acetate is marketed but not approved for the indication under study.  
8.1.10.1. Administration 
Abiraterone acetate is available in tablets and should only be taken orally. The current 
FDA approved dose of 1000 mg daily, or four 250 mg tablets by mouth daily, will be 
administered. A 28-day supply will be provided at the beginning of each month of the 
trial. Abiraterone acetate must be taken with prednisone 5 mg by mouth twice daily to 
prevent symptoms of mineralocorticoid excess and must be taken on an empty 
stomach (i.e. no food 2 hours prior and 1 hour after ingestion). 


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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8.1.10.2. Supply 
Abiraterone acetate is available in 250 mg tablets.  
 
 
8.1.10.3. Storage 
Store at 20oC to 25oC (68oF to 77oF); excursions permitted in the range from 15oC to 
30oC (59oF to 86°F) 
 
8.2. Apalutamide[Adapted from the ApalutamideInvestigator’s Brochure; refer to this 
document for more detail] 
 
 
 
• Chemical Name: 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-
diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide 
• Molecular Formula: C21H15F4N5O2S 
Molecular Weight:  477.43 g/mol 
• Description:  Apalutamide is an immediate release oral tablet containing 60-mg 
of drug substance, with a non-functional green film coat. Each 60-mg tablet 
contains the following inactive ingredients: hydroxypropyl methylcellulose 
acetate succinate (HPMC-AS), colloidal anhydrous silica, croscarmellose sodium, 
microcrystalline cellulose, silicified microcrystalline cellulose, and magnesium 
stearate. Commercially available Opadry® coating powder is used for the film 
coating, which is comprised of polyvinyl alcohol (partially hydrolyzed), titanium 
dioxide, polyethylene glycol, talc, and colorants iron oxide yellow and iron oxide 
black (E172). 
8.2.1. Clinical Pharmacology 
Please refer to the investigator’s brochure for complete details (section 5).  


CC Protocol Number: 9628 
 
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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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Note: no studies to assess special populations have been conducted with 
apalutamideat this time. Please refer to the apalutamide investigator’s brochure 
section 4.3.3: Absorption, Distribution, Metabolism, and Elimination in Humans. 
8.2.2. Safety/Precautions 
• Seizures: At very high doses, dogs treated with apalutamide had tremors and 
generalized seizures. Seizures in dogs were observed at a dose of 25 mg/kg/day 
with an average plasma concentrations of 30.2 μg/mL (ranging from 26 to 34 
μg/mL) at the time of seizure. Given the known susceptibility of Beagle dogs to 
seizures, and the 2-fold lower plasma-free fraction of apalutamide in humans 
compared with dogs, the critical dose and plasma concentration of concern may 
be higher in patients. 
Subjects will be closely monitored for seizures in clinical studies of 
apalutamide. In the event of a treatment-related seizure, apalutamide treatment 
will be permanently discontinued. Any unexplained loss of consciousness should 
raise the suspicion of a seizure episode. Witnessed or suspected seizures should 
be evaluated with appropriate diagnostic studies, including radiologic imaging of 
the brain, and treated according to standard medical practice. 
As an added precaution, during treatment with apalutamide, the following 
medications are prohibited in clinical studies with apalutamide: 
• Aminophylline/theophylline  
• Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, 
ziprasidone)  
• Buproprion  
• Lithium  
• Meperidine and pethidine  
• Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, 
thioridazine)  
• Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, 
doxepin, imipramine, maprotiline, mirtazapine) 
 


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• Pharmacologic effects of androgen ablation: Administration of apalutamide to 
men already in a castrate state may exacerbate symptoms associated with 
castration. These include infertility, impotence, prostate, testicular and muscle 
atrophy; loss of bone density, hot flashes, gynecomastia, decreased appetite, and 
fatigue. As of 30 November 2013, in Study ARN-509-001, fatigue (>50% of 
subjects) is the most frequently reported treatment-emergent AE. Hot flushes 
were reported as an AE in 5 (17%) subjects in the Phase 1 and 11 (11%) subjects 
in Phase 2. Decreased appetite was reported as an AE in 2(7%) subjects in Phase 
1 and 17 (18%) subjects in Phase 2. In Phase 2, fatigue and decreased appetite led 
to discontinuation of treatment for 3 (3%) subjects and 1 (1%) subject, 
respectively.  
 
Alterations in lipid profiles including increases in blood cholesterol are 
also a pharmacologic effect of androgen ablation and have been observed in 
animal toxicology studies with apalutamide. Fasting lipid profiles can be 
monitored. As of 30 November 2013, 1 subject in Phase 1 and 7 (7%) subjects in 
Phase 2 have reported AEs of hypercholesterolemia. 
 
• Pregnancy and Lactation: To avoid risk of drug exposure through the ejaculate 
(even men with vasectomies), patients must use a condom during sexual activity 
while on study drug and for 3 months following the last dose of study drug. 
Donation of sperm is not allowed during the study and for 3 months following the 
last dose of study drug. 
There are no data on the use of apalutamide in pregnancy. Maternal use of 
an anti-androgen is expected to produce changes in hormone levels that may 
affect fetal development. It is not known if apalutamide or its metabolites are 
present in semen. 
If the patient is engaged in sexual activity with a woman of childbearing 
potential, a condom is required along with another effective contraceptive method 
consistent with local regulations regarding the use of birth control methods for 
patients participating in clinical studies and their partners. 


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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Two highly effective forms of contraception are required during the study 
and for 3 months after the last dose of study drug. 
 
8.2.3. Information for Patients 
• Patients should be apprised of the common side effects associated with 
apalutamide, including fatigue, diarrhea, nausea, vomiting, skin rash, 
changes in thyroid function, taste alterations, constipation, decreased 
appetite, hot flashes, dizziness and abdominal pain. Patients should be 
instructed to report any perceived adverse events (including the 
aforementioned). For additional side effects please see section 8.2.6. 
8.2.4. Prohibited Concomitant Medications 
As a class effect, AR antagonists have been associated with seizures due to an off-
target mechanism of action (gamma amino butyric acid chloride channel [GABAA] 
inhibition). Drugs known to lower the seizure threshold or cause seizures are 
prohibited and a representative list is included below:  
• 
Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, 
ziprasidone) 
• 
Bupropion 
• 
Lithium 
• 
Meperidine and pethidine 
• 
Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, 
thioridazine) 
• 
Tricyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, 
imipramine, maprotiline, mirtazapine 
Please see Appendix B for a more comprehensive list (with brand names). 
 


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8.2.5. Restricted Concomitant Medications 
Apalutamide is metabolized primarily by human CYP3A4, thus co-administration 
with strong inhibitors or inducers of CYP3A4 should be avoided as much as 
possible. Apalutamide may also induce CYP3A4; therefore, caution should be 
taken when administered in conjunction with CYP3A4 substrates that have a 
narrow therapeutic index. Examples of the strong CYP3A4 inhibitors and 
inducers include the following:  
• Strong CYP3A4 inhibitors: itraconazole, clarithromycin, erythromycin, 
diltiazem, verapamil, delavirdine, atazanavir, indinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit 
juice (or grapefruits); co-administration with any of these agents may 
increase apalutamide plasma concentrations 
• Strong CYP inducers: phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentin, phenobarbital, efavirenz, tipranivir, St. John's wort; co-
administration with any of these agents may decrease apalutamideplasma 
concentrations 
The potential for drug-drug interaction between apalutamide and warfarin (eg, 
Coumadin) is unknown at present. If a subject is taking warfarin, re-assess PT 
(prothrombin time)/international normalized ratio (INR) as clinically indicated 
and adjust the dose of warfarin accordingly. 
8.2.6. Adverse Reactions 


CC Protocol Number: 9628 
 
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Protocol Version: 4.0; March 23, 2018 
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Likely (>10%) 
Less Likely (1– 10%) 
Rare but serious (<1%) 
Fatigue 
Itching 
Seizure  
 
Joint Pain (Arthralgia)  
Changes in thyroid function 
(Hypothyroidism) 
Weight Loss  
 
Skin rash  
Increase in cholesterol 
Fall  
Increase in triglycerides 
Fracture  
 
 
8.2.7. Dose Modification for Toxicity Attributed to Apalutamide 
Dose modifications are provided as guidance and should not replace the 
investigator’s own clinical judgment. 
  
Toxicity 
Dose of abiraterone acetate 
Dose of apalutamide 
Dose of 
prednisone 
Grade 1 
No change 
No change 
No change 
Grade 2 
No change 
Hold until return to Grade 1 or 
baseline, resume at full dose* 
No change 
≥Grade 3 or higher 
No change 
Hold until Grade 1 or baseline, resume 
at full dose* 
No change 
Recurrence ≥Grade 3, 
or Grade 4 
Discontinue 
Discontinue 
Discontinue 
First occurrence of 
seizure  
Discontinue 
Discontinue 
Discontinue 
*Note: Treatment will be permanently discontinued for Grade 3 toxicity lasting longer than 5 
days, or any grade toxicity that has not resolved to Grade 1 or less within 2 weeks. 
Rash 
Dose modifications for rash are allowed only for apalutamide and are summarized in below 
table. 
If the skin rash has any component of desquamation, mucosal involvement or pustules, stop 
dosing with apalutamide, refer to dermatologist for evaluation, and a skin biopsy is 
recommended (in addition to the interventions listed in below Table). If the skin rash is Grade 3 


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Protocol Version: 4.0; March 23, 2018 
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or higher, asking the subject to consent to documentation by a photograph and further evaluation 
by a dermatologist should also be considered. 
 
 
Severity 
Intervention 
Grade 1 
• 
Continue apalutamide at current dose 
• 
Initiate dermatological treatmenta 
o Topical steroid cream AND 
o Oral Antihistamines 
• 
Monitor for change in severitya 
Grade 2 (or symptomatic 
Grade 1)b 
• 
Hold apalutamide for up to 28 days 
• 
Initiate dermatological treatmenta 
o Topical steroid cream AND 
o Oral Antihistamines 
• 
Monitor for change in severitya 
o If rash or related symptoms improve, reinitiate 
apalutamide when rash is Grade≤1. Consider dose 
reduction at a 1 dose level reductionc. 
Grade ≥3d 
• 
Hold apalutamide for up to 28 days 
• 
Initiate dermatological treatmenta 
o Topical steroid cream AND 
o Oral Antihistamines AND 
o Consider short course of oral steroids 
• 
Reassess after 2 weeks (by site staff), and if the rash is the same 
or has worsened, initiate oral steroids (if not already done) and 
refer the subject to a dermatologist 
o Reinitiate apalutamide at a 1 dose level reductione when 
rash is Grade≤1. 
o If the dose reduction will lead to a dose less than 120mg, 
the study drug must be stopped (discontinued) 
• 
If after 28 days, rash has not resolved to Grade≤1, contact Janssen 
to discuss further management and possible discontinuation of 
study drug.  
 
Note: Rash may be graded differently according to the type of rash and associated symptoms. For 
example, maculo-papular rash is graded by body surface area covered and not severity of the rash. Please 
consult NCI-CTCAE Version 4.03 for specific grading criteria for other types of rash. 
a Obtain bacterial/viral cultures if infection is suspected 
b Subject presents with other rash related symptoms such as pruritus, stinging, or burning 
c 1 dose level reduction = 60mg (1 apalutamide tablet) 
d If there is blistering or mucosal involvement, stop apalutamide dosing immediately and contact 
Janssen 
e If a subject previously started oral corticosteroids, continue for at least 1 week after resumption 
of reduced dose of apalutamide. If the proposed total oral steroid use will exceed 28 days, contact 
Janssen. 


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Protocol Version: 4.0; March 23, 2018 
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8.2.8. Administration, Supply and Storage 
Apalutamide was recently approved by the FDA for use in men with non-
metastatic castration resistant prostate cancer on the basis of Phase III data 
showing that it significantly prolonged the time to development of metastatic 
disease. Apalutamide is still under development as an investigational product for 
other types of prostate cancer. A supply of apalutamide will be supplied by 
Janssen Scientific Affairs, LLC for the purposes of this study. Apalutamide 
tablets are packaged in 120-count, 160 cc high-density polyethylene (HDPE) 
bottles with child-resistant closure (CRC) and include desiccant and should at all 
times be kept in the original packaging. 
 
8.2.8.1. 
Administration 
Apalutamide will come in 60 mg Tablets. The current recommended 
Phase III dose (see Investigator’s Brochure) is 240 mg, or four 60 mg 
tablets by mouth daily, will be administered. A 28-day supply will be 
provided at the beginning of each month of the trial.  
 
8.2.8.2. 
Supply 
Apalutamide-Tablets, 60 mg are packaged in 120-count, 160 cc high 
density polyethylene (HDPE) bottles with child-resistant closures (CRC) 
and tamper-proof heat induction seals. 
8.2.8.3. 
Storage 
Store at 15°C to 30°C (59°F to 86°F) at all times. Store in the original 
container in order to protect from light. 
8.3. Drug Name: Degarelix [Adapted from FDA prescribing information, refer to this 
document for more detail] 


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Protocol Version: 4.0; March 23, 2018 
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• Chemical Name: D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-
Dphenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-2,6-dioxo-
4pyrimidinyl]carbonyl]amino]-L phenylalanyl-4-[(aminocarbonyl)amino]-D-
phenylalanyl-L leucyl-N6–(1methylethyl)-L-lysyl-L-prolyl  
• Molecular Formula: C82H103N18O16Cl 
• Molecular Weight:  1632.3 Da  
• Description: Degarelix (as the acetate) is formulated as a sterile lyophilized powder for 
injection. Degarelix is a synthetic linear decapeptide amide containing seven unnatural 
amino acids, five of which are D-amino acids. The acetate salt of degarelix is a white to 
off-white amorphous powder of low density as obtained after lyophilization. Firmagon 
(the trade name of degarelix) delivers degarelix acetate, equivalent to 120 mg of 
degarelix for the starting dose, and 80 mg of degarelix for the maintenance dose. The 80 
mg vial contains 200 mg mannitol and the 120 mg vial contains 150 mg mannitol. 
 
 
8.3.1. Clinical Pharmacology 
Degarelix forms a depot upon subcutaneous administration, from which it is released to 
the circulation. Following administration of degarelix 240 mg at a product concentration 
of 40 mg/mL, the mean Cmax was 26.2 ng/mL (coefficient of variation, CV 83%) and the 
mean AUC was 1054 ng∙day/mL (CV 35%). Typically Cmax occurred within 2 days 
after subcutaneous administration. In prostate cancer patients at a product concentration 
of 40 mg/mL, the pharmacokinetics of degarelix were linear over a dose range of 120 to 


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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240 mg. The pharmacokinetic behavior of the drug is strongly influenced by its 
concentration in the injection solution. 
The distribution volume of degarelix after intravenous (> 1 L/kg) or subcutaneous 
administration (> 1000 L ) indicates that degarelix is distributed throughout total body 
water. In vitro plasma protein binding of degarelix is estimated to be approximately 90%. 
Degarelix is subject to peptide hydrolysis during the passage of the hepato-biliary 
system and is mainly excreted as peptide fragments in the feces. No quantitatively 
significant metabolites were detected in plasma samples after subcutaneous 
administration. In vitro studies have shown that degarelix is not a substrate, inducer or 
inhibitor of the CYP450 or p-glycoprotein transporter systems. 
Following subcutaneous administration of 240 mg degarelix at a concentration of 
40 mg/mL to prostate cancer patients, it is eliminated in a biphasic fashion, with a median 
terminal half-life of approximately 53 days. The long half-life after subcutaneous 
administration is a consequence of a very slow release of degarelix from the depot 
formed at the injection site(s). Approximately 20-30% of a given dose of degarelix was 
renally excreted, suggesting that approximately 70-80% is excreted via the hepato-biliary 
system in humans. Following subcutaneous administration of degarelix to prostate cancer 
patients the clearance is approximately 9 L/hr. 
 
8.3.2. Safety/Precautions 
• Hypersensitivity reactions: Hypersensitivity reactions, including anaphylaxis, 
urticaria and angioedema, have been reported post-marketing with degarelix. In case 
of a serious hypersensitivity reaction, discontinue degarelix immediately if the 
injection has not been completed, and manage as clinically indicated. Patients with a 
known history of serious hypersensitivity reactions to degarelix should not be re-
challenged with degarelix. 
• Effect on QT/QTc interval: Long-term androgen deprivation therapy prolongs the 
QT interval. Physicians should consider whether the benefits of androgen deprivation 
therapy outweigh the potential risks in patients with congenital long QT syndrome, 
electrolyte abnormalities, or congestive heart failure and in patients taking Class IA 


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
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(e.g. quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic 
medications.  
In the randomized, active-controlled trial comparing degarelix to leuprolide, 
periodic electrocardiograms were performed. Seven patients, three (<1%) in the 
pooled degarelix group and four (2%) patients in the leuprolide 7.5 mg group, had a 
QTcF ≥ 500 msec. From baseline to end of study the median change for degarelix 
was 12.3 msec and for leuprolide was 16.7 msec.  
• Laboratory testing: Therapy with degarelix results in suppression of the pituitary 
gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal 
functions conducted during and after degarelix may be affected. The therapeutic 
effect of degarelix should be monitored by measuring serum concentrations of 
prostate-specific antigen (PSA) periodically. If PSA increases, serum concentrations 
of testosterone should be measured.   
8.3.3. Information for Patients 
• Patients should be informed of the possible side effects of androgen deprivation 
therapy, including hot flashes, flushing of the skin, increased weight, decreased sex 
drive, and difficulties with erectile function. Possible side effects related to therapy 
with degarelix include redness, swelling, and itching at the injection site; these are 
usually mild, self-limiting, and decrease within three days.  
8.3.4. Drug Interactions 
No drug-drug interaction studies have been conducted with degarelix. Degarelix is not a 
substrate for the human CYP450 system. Degarelix is not an inducer or inhibitor of the 
CYP450 system in vitro. Therefore, clinically significant CYP450 pharmacokinetic drug-
drug interactions are unlikely.  
8.3.5. Adverse Reactions 
A total of 1325 patients with prostate cancer received degarelix either as a 
monthly treatment (60-160 mg) or as a single dose (up to 320 mg). A total of 1032 
patients (78%) were treated for at least 6 months and 853 patients (64%) were treated for 
one year or more. The most commonly observed adverse reactions during degarelix 


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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therapy included injection site reactions (e.g., pain, erythema, swelling or induration), hot 
flashes, increased weight, fatigue, and increases in serum levels of transaminases and 
gamma-glutamyltransferase (GGT). The majority of the adverse reactions were Grade 1 
or 2, with Grade 3/4 adverse reaction incidences of 1% or less. 
Degarelix was studied in an active-controlled trial (N = 610) in which patients 
with prostate cancer were randomized to receive degarelix (subcutaneous) or leuprolide 
(intramuscular) monthly for 12 months. Adverse reactions reported in 5% of patients or 
more are shown in Table 2. 
 
 
Degarelix 240/160 mg 
(subcutaneous) N = 202  
Degarelix 240/80 mg 
(subcutaneous) N = 207 
Degarelix 7.5 mg 
(intramuscular) N = 
201 
Percentage of subjects 
with adverse events  
83%  
79%  
78%  
Body as a whole 
 
 
 
Injection site adverse 
events  
44%  
35%  
<1%  
Weight increase  
11%  
9%  
12%  
Fatigue  
6%  
3%  
6%  
Chills  
4%  
5%  
0%  
Cardiovascular system 
 
 
 
Hot flash  
26%  
26%  
21%  
Hypertension  
7%  
6%  
4%  
Musculoskeletal system  
 
 
 
Back pain  
6%  
6%  
8%  
Arthralgia  
4%  
5%  
9%  
Urogenital system 
 
 
 
Urinary tract infection  
2%  
5%  
9%  
Digestive system 
 
 
 
Increases in 
Transaminases and GGT  
10%  
10%  
5%  
Constipation  
3%  
5%  
5%  
Table 2: Adverse reactions reported in ≥5% of patients treated with degarelix in a randomized 
controlled trial. 
8.3.6. Dose Modifications for Toxicities Attributed to Degarelix 
No dose modifications are allowed for degarelix. If a Grade 2 or higher AE 
persists at the time a subsequent dose of degarelix is due, the drug should be 
discontinued.  


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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8.3.7. Administration, Supply and Storage 
Degarelix is marketed but not approved for the indication under study. 
8.3.7.1. 
Administration 
Degarelix is administered as a subcutaneous injection in the abdominal region. As 
with other drugs administered by subcutaneous injection, the injection site should 
vary periodically. Injections should be given in areas of the abdomen that will not be 
exposed to pressure, e.g., not close to waistband or belt nor close to the ribs. 
Degarelix is available as: 
• 
NDC 55566-8401-2, Starting dose – One carton contains: Two vials each with 120 
mg powder for injection Two prefilled syringes containing 3 mL of sterile water for 
injection, USP Two vial adapters Two administration needles  
• 
NDC 55566-8301-2, Maintenance dose – One carton contains: One vial with 80 mg 
powder for injection One prefilled syringe containing 4.2 mL of sterile water for 
injection, USP One vial adapter One administration needle  
 
8.3.7.2. 
Supply 
Degarelix is supplied as a powder to be reconstituted with Sterile Water for Injection, 
USP (WFI). The instruction for reconstitution needs to be carefully followed. 
Administration of other concentrations is not recommended. Refer to the FDA 
package insert for details regarding how to properly reconstitute degarelix.  
8.3.7.3. 
Storage 
Store degarelix at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).  
 
8.4. Drug Name: Indomethacin [Adapted from FDA prescribing information, refer to this 
document for more detail] 


CC Protocol Number: 9628 
 
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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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• Chemical Name: 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid 
• Molecular Formula: C19H16ClNO4 
• Molecular Weight:  357.79 Da  
• Description: Indomethacin is commonly available as capsules for oral administration 
that contain either 25 mg or 50 mg of indomethacin. Indocin®, the brand of indomethacin 
manufacture by Merck, is formulated with the following inactive ingredients: colloidal 
silicon dioxide, FD&C Blue 1, FD&C Red 3, gelatin, lactose, lecithin, magnesium 
stearate, and titanium dioxide.  
8.4.1. Clinical Pharmacology 
Following single oral doses of indomethacin 25 mg or 50 mg, indomethacin is readily 
absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively at 
about 2 hours. Orally administered indomethacin is virtually 100% bioavailable, with 
90% of the dose absorbed within 4 hours.  
Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. 
Indomethacin undergoes appreciable enterohepatic circulation. The mean half-life of 
indomethacin is estimated to be about 4.5 hours. With a typical therapeutic regimen of 25 
or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 
times those following the first dose.  
Indomethacin exists in the plasma as the parent drug and its desmethyl, 
desbenzoyl, and desmethyl-desbenzoyl metabolites, all in the unconjugated form. About 
60 percent of an oral dosage is recovered in urine as drug and metabolites (26 percent as 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
66 
 
indomethacin and its glucuronide), and 33 percent is recovered in feces (1.5 percent as 
indomethacin). About 99% of indomethacin is bound to protein in plasma over the 
expected range of therapeutic plasma concentrations. Indomethacin has been found to 
cross the blood-brain barrier and the placenta. 
8.4.2. Safety/Precautions 
8.4.2.1. 
Warnings 
• Cardiovascular Thrombotic Events: Clinical trials of several COX-2 selective 
and nonselective NSAIDs of up to three years duration have shown an increased 
risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and 
stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, 
may have a similar risk. Patients with known CV disease or risk factors for CV 
disease may be at greater risk. To minimize the potential risk for an adverse CV 
event in patients treated with an NSAID, the lowest effective dose should be used 
for the shortest duration possible. Physicians and patients should remain alert for 
the development of such events, even in the absence of previous CV symptoms. 
Patients should be informed about the signs and/or symptoms of serious CV 
events and the steps to take if they occur. 
There is no consistent evidence that concurrent use of aspirin mitigates the 
increased risk of serious CV thrombotic events associated with NSAID use. The 
concurrent use of aspirin and an NSAID does increase the risk of serious GI 
events (see GI warnings). 
Two large, controlled, clinical trials of a COX-2 selective NSAID for the 
treatment of pain in the first 10- 14 days following CABG surgery found an 
increased incidence of myocardial infarction and stroke.  
• Hypertension: NSAIDs, including indomethacin, can lead to onset of new 
hypertension or worsening of pre-existing hypertension, either of which may 
contribute to the increased incidence of CV events. Patients taking thiazides or 
loop diuretics may have impaired response to these therapies when taking 
NSAIDs. NSAIDs, including indomethacin, should be used with caution in 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
67 
 
patients with hypertension. Blood pressure (BP) should be monitored closely 
during the initiation of NSAID treatment and throughout the course of therapy. 
• Congestive Heart Failure and Edema: Fluid retention and edema have been 
observed in some patients taking NSAIDs. Indomethacin should be used with 
caution in patients with fluid retention or heart failure. 
In a study of patients with severe heart failure and hyponatremia, 
indomethacin was associated with significant deterioration of circulatory 
hemodynamics, presumably due to inhibition of prostaglandin dependent 
compensatory mechanisms. 
• Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation: 
NSAIDs, including indomethacin, can cause serious gastrointestinal (GI) adverse 
events including inflammation, bleeding, ulceration, and perforation of the 
esophagus, stomach, small intestine, or large intestine, which can be fatal. These 
serious adverse events can occur at any time, with or without warning symptoms, 
in patients treated with NSAIDs. Only one in five patients, who develop a serious 
upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross 
bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients 
treated for 3-6 months, and in about 2-4% of patients treated for one year. These 
trends continue with longer duration of use, increasing the likelihood of 
developing a serious GI event at some time during the course of therapy. 
However, even short-term therapy is not without risk. 
Rarely, in patients taking indomethacin, intestinal ulceration has been 
associated with stenosis and obstruction. Gastrointestinal bleeding without 
obvious ulcer formation and perforation of pre-existing sigmoid lesions 
(diverticulum, carcinoma, etc.) have occurred. Increased abdominal pain in 
ulcerative colitis patients or the development of ulcerative colitis and regional 
ileitis have been reported to occur rarely. 
NSAIDs should be prescribed with extreme caution in those with prior 
history of ulcer disease or gastrointestinal bleeding. Patients with a prior history 
of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
68 
 
greater than 10-fold increased risk for developing a GI bleed compared to patients 
with neither of these risk factors. Other factors that increase the risk for GI 
bleeding in patients treated with NSAIDs include concomitant use of oral 
corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, 
use of alcohol, older age, and poor general health status. Most spontaneous 
reports of fatal GI events are in elderly or debilitated patients and therefore, 
special care should be taken in treating this population. 
To minimize the potential risk for an adverse GI event in patients treated 
with an NSAID, the lowest effective dose should be used for the shortest possible 
duration. Patients and physicians should remain alert for signs and symptoms of 
GI ulceration and bleeding during NSAID therapy and promptly initiate additional 
evaluation and treatment if a serious GI adverse event is suspected. This should 
include discontinuation of the NSAID until a serious GI adverse event is ruled 
out. For high risk patients, alternate therapies that do not involve NSAIDs should 
be considered. 
• Renal Effects: Long-term administration of NSAIDs has resulted in renal 
papillary necrosis and other renal injury. Renal toxicity has also been seen in 
patients in whom renal prostaglandins have a compensatory role in the 
maintenance of renal perfusion. In these patients, administration of a nonsteroidal 
anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin 
formation and, secondarily, in renal blood flow, which may precipitate over renal 
decompensation. Patients at greatest risk of this reaction are those with impaired 
renal function, heart failure, liver dysfunction, those taking diuretics and ACE 
inhibitors, patients with volume depletion, and the elderly. Discontinuation of 
NSAID therapy is usually followed by recovery to the pretreatment state. 
Increases in serum potassium concentration, including hyperkalemia, have 
been reported with use of indomethacin, even in some patients without renal 
impairment. In patients with normal renal function, these effects have been 
attributed to a hyporeninemic-hypoaldosteronism state. 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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• Anaphylactic/Anaphylactoid Reactions: As with other NSAIDs, 
anaphylactic/anaphylactoid reactions may occur in patients without known prior 
exposure to indomethacin. Indomethacin should not be given to patients with the 
aspirin triad. This symptom complex typically occurs in asthmatic patients who 
experience rhinitis with or without nasal polyps, or who exhibit severe, potentially 
fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should 
be sought in cases where an anaphylactic/anaphylactoid reaction occurs. 
• Skin Reactions: NSAIDs, including indomethacin, can cause serious skin 
adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), 
and toxic epidermal necrolysis (TEN), which can be fatal. These serious events 
may occur without warning. Patients should be informed about the signs and 
symptoms of serious skin manifestations and use of the drug should be 
discontinued at the first appearance of skin rash or any other sign of 
hypersensitivity. 
• Ocular Effects: Corneal deposits and retinal disturbances, including those of the 
macula, have been observed in some patients who had received prolonged therapy 
with indomethacin. The prescribing physician should be alert to the possible 
association between the changes noted and indomethacin. It is advisable to 
discontinue therapy if such changes are observed. Blurred vision may be a 
significant symptom and warrants a thorough ophthalmological examination. 
Since these changes may be asymptomatic, ophthalmologic examination at 
periodic intervals is desirable in patients where therapy is prolonged. 
• Central Nervous System Effects: Indomethacin may aggravate depression or 
other psychiatric disturbances, epilepsy, and parkinsonism, and should be used 
with considerable caution in patients with these conditions. If severe CNS adverse 
reactions develop, indomethacin should be discontinued. 
Indomethacin may cause drowsiness; therefore, patients should be cautioned 
about engaging in activities requiring mental alertness and motor coordination, 
such as driving a car. Indomethacin may also cause headache. Headache which 
persists despite dosage reduction requires cessation of therapy with indomethacin. 


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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8.4.2.2. 
Precautions 
• Hepatic Effects: Borderline elevations of one or more liver tests may occur in up 
to 15% of patients taking NSAIDs including indomethacin. These laboratory 
abnormalities may progress, may remain unchanged, or may be transient with 
continuing therapy. Notable elevations of ALT or AST (approximately three or 
more times the upper limit of normal) have been reported in approximately 1% of 
patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic 
reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and 
hepatic failure, some of them with fatal outcomes have been reported. 
A patient with symptoms and/or signs suggesting liver dysfunction, or in 
whom an abnormal liver test has occurred, should be evaluated for evidence of the 
development of a more severe hepatic reaction while on therapy with 
indomethacin. If clinical signs and symptoms consistent with liver disease 
develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), 
indomethacin should be discontinued. 
• Hematological Effects: Anemia is sometimes seen in patients receiving NSAIDs, 
including indomethacin. This may be due to fluid retention, occult or gross GI 
blood loss, or an incompletely described effect upon erythropoiesis. Patients on 
long-term treatment with NSAIDs, including indomethacin, should have their 
hemoglobin or hematocrit checked if they exhibit any signs or symptoms of 
anemia. 
NSAIDs inhibit platelet aggregation and have been shown to prolong 
bleeding time in some patients. Unlike aspirin, their effect on platelet function is 
quantitatively less, of shorter duration, and reversible. Patients receiving 
indomethacin who may be adversely affected by alterations in platelet function, 
such as those with coagulation disorders or patients receiving anticoagulants, 
should be carefully monitored.  
• Preexisting Asthma: Patients with asthma may have aspirin-sensitive asthma. 
The use of aspirin in patients with aspirin- sensitive asthma has been associated 
with severe bronchospasm which can be fatal. Since cross reactivity, including 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs 
has been reported in such aspirin-sensitive patients, indomethacin should not be 
administered to patients with this form of aspirin sensitivity and should be used 
with caution in patients with preexisting asthma. 
8.4.3. Information for Patients 
Patients should be informed of the following information before initiating therapy with 
indomethacin: 
• Indomethacin, like other NSAIDs, may cause serious CV side effects, such as MI or 
stroke, which may result in hospitalization and even death. Although serious CV 
events can occur without warning symptoms, patients should be alert for the signs and 
symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should 
ask for medical advice when observing any indicative sign or symptoms. Patients 
should be apprised of the importance of this follow-up.  
• Indomethacin, like other NSAIDs, can cause GI discomfort and, rarely, serious GI 
side effects, such as ulcers and bleeding, which may result in hospitalization and even 
death. Although serious GI tract ulcerations and bleeding can occur without warning 
symptoms, patients should be alert for the signs and symptoms of ulcerations and 
bleeding, and should ask for medical advice when observing any indicative sign or 
symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients 
should be apprised of the importance of this follow-up. 
• Indomethacin, like other NSAIDs, can cause serious skin side effects such as 
exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even 
death. Although serious skin reactions may occur without warning, patients should be 
alert for the signs and symptoms of skin rash and blisters, fever, or other signs of 
hypersensitivity such as itching, and should ask for medical advice when observing 
any indicative signs or symptoms. Patients should be advised to stop the drug 
immediately if they develop any type of rash and contact their physicians as soon as 
possible.  
• Patients should promptly report signs or symptoms of unexplained weight gain or 
edema to their physicians.  


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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• Patients should be informed of the warning signs and symptoms of hepatotoxicity 
(e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, 
and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy 
and seek immediate medical therapy.  
• Patients should be informed of the signs of an anaphylactic/anaphylactoid reaction 
(e.g., difficulty breathing, swelling of the face or throat). If these occur, patients 
should be instructed to seek immediate emergency help.  
8.4.4. Drug Interactions 
• ACE-Inhibitors and Angiotensin II Antagonists: Reports suggest that NSAIDs 
may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II 
antagonists. Indomethacin can reduce the antihypertensive effects of captopril and 
losartan. These interactions should be given consideration in patients taking NSAIDs 
concomitantly with ACE- inhibitors or angiotensin II antagonists. In some patients 
with compromised renal function, the co- administration of an NSAID and an ACE-
inhibitor or an angiotensin II antagonist may result in further deterioration of renal 
function, including possible acute renal failure, which is usually reversible. 
• Aspirin: When indomethacin is administered with aspirin, its protein binding is 
reduced, although the clearance of free indomethacin is not altered. The clinical 
significance of this interaction is not known. 
The use of indomethacin in conjunction with aspirin or other salicylates is not 
recommended. Controlled clinical studies have shown that the combined use of 
indomethacin and aspirin does not produce any greater therapeutic effect than the use 
of indomethacin alone. In a clinical study of the combined use of indomethacin and 
aspirin, the incidence of gastrointestinal side effects was significantly increased with 
combined therapy. 
In a study in normal volunteers, it was found that chronic concurrent 
administration of 3.6 g of aspirin per day decreases indomethacin blood levels 
approximately 20%. 
• Beta-adrenoceptor blocking agents: Blunting of the antihypertensive effect of beta-
adrenoceptor blocking agents by non-steroidal anti- inflammatory drugs including 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
73 
 
indomethacin has been reported. Therefore, when using these blocking agents to treat 
hypertension, patients should be observed carefully in order to confirm that the 
desired therapeutic effect has been obtained. 
• Cyclosporine: Administration of non-steroidal anti-inflammatory drugs 
concomitantly with cyclosporine has been associated with an increase in 
cyclosporine-induced toxicity, possibly due to decreased synthesis of renal 
prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, 
and renal function should be carefully monitored. 
• Diflunisal: In normal volunteers receiving indomethacin, the administration of 
diflunisal decreased the renal clearance and significantly increased the plasma levels 
of indomethacin. In some patients, combined use of indomethacin and diflunisal has 
been associated with fatal gastrointestinal hemorrhage. Therefore, diflunisal and 
indomethacin should not be used concomitantly. 
• Digoxin: Indomethacin given concomitantly with digoxin has been reported to 
increase the serum concentration and prolong the half-life of digoxin. Therefore, 
when indomethacin and digoxin are used concomitantly, serum digoxin levels should 
be closely monitored. 
• Diuretics: In some patients, the administration of indomethacin can reduce the 
diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and 
thiazide diuretics. This response has been attributed to inhibition of renal 
prostaglandin synthesis. 
Indomethacin reduces basal plasma renin activity (PRA), as well as those 
elevations of PRA induced by furosemide administration, or salt or volume depletion. 
These facts should be considered when evaluating plasma renin activity in 
hypertensive patients. 
It has been reported that the addition of triamterene to a maintenance schedule 
of indomethacin resulted in reversible acute renal failure in two of four healthy 
volunteers. Indomethacin and triamterene should not be administered together. 
Indomethacin and potassium-sparing diuretics each may be associated with 
increased serum potassium levels. The potential effects of indomethacin and 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
74 
 
potassium-sparing diuretics on potassium kinetics and renal function should be 
considered when these agents are administered concurrently. 
Most of the above effects concerning diuretics have been attributed, at least in 
part, to mechanisms involving inhibition of prostaglandin synthesis by indomethacin. 
During concomitant therapy with NSAIDs, the patient should be observed 
closely for signs of renal failure, as well as to assure diuretic efficacy.  
• Lithium: Indomethacin 50 mg t.i.d. produced a clinically relevant elevation of 
plasma lithium and reduction in renal lithium clearance in psychiatric patients and 
normal subjects with steady state plasma lithium concentrations. This effect has been 
attributed to inhibition of prostaglandin synthesis. As a consequence, when NSAIDs 
and lithium are given concomitantly, the patient should be carefully observed for 
signs of lithium toxicity. (Read circulars for lithium preparations before use of such 
concomitant therapy.) In addition, the frequency of monitoring serum lithium 
concentration should be increased at the outset of such combination drug treatment. 
• Methotrexate: NSAIDs have been reported to competitively inhibit methotrexate 
accumulation in rabbit kidney slices. This may indicate that they could enhance the 
toxicity of methotrexate. Caution should be used when NSAIDs are administered 
concomitantly with methotrexate. 
• NSAIDs: The concomitant use of indomethacin with other NSAIDs is not 
recommended due to the increased possibility of gastrointestinal toxicity, with little or 
no increase in efficacy. 
• Oral anticoagulants: Clinical studies have shown that indomethacin does not 
influence the hypoprothrombinemia produced by anticoagulants. However, when any 
additional drug, including indomethacin, is added to the treatment of patients on 
anticoagulant therapy, the patients should be observed for alterations of the 
prothrombin time. In post-marketing experience, bleeding has been reported in 
patients on concomitant treatment with anticoagulants and indomethacin. Caution 
should be exercised when indomethacin and anticoagulants are administered 
concomitantly. The effects of warfarin and NSAIDs on GI bleeding are synergistic, 
such that users of both drugs together have a risk of serious GI bleeding higher than 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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users of either drug alone.  
• Probenecid: When indomethacin is given to patients receiving probenecid, the 
plasma levels of indomethacin are likely to be increased. Therefore, a lower total 
daily dosage of indomethacin may produce a satisfactory therapeutic effect. When 
increases in the dose of indomethacin are made, they should be made carefully and in 
small increments. 
Drug/Laboratory Test Interactions: False-negative results in the dexamethasone 
suppression test (DST) in patients being treated with indomethacin have been 
reported. Thus, results of the DST should be interpreted with caution in these patients. 
8.4.5. Adverse Reactions 
Headaches (12% to 16%) and vomiting (≤12%) are the most frequently reported adverse 
reactions on indomethacin. Less frequent adverse reactions, include: presyncope (≤3%), 
syncope (≤2%), dizziness (3% to 9%), depression (<3%), drowsiness (<3%), fatigue 
(<3%), malaise (<3%), vertigo (<3%), pruritus (1% to 4%), hyperhidrosis (2%), skin rash 
(1% to 2%), hot flash (2%), epigastric pain (3% to 9%), heartburn (3% to 9%), nausea 
(3% to 9%), dyspepsia (2% to 9%), constipation (≤6%), diarrhea (≤3%), abdominal pain 
(<3%), decreased appetite (≥2%), rectal irritation (suppository), tenesmus (suppository), 
tinnitus (<3%) and swelling (3%). For additional information on adverse reactions 
associated with indomethacin, please refer to the FDA prescribing information. 
 
8.4.6. Dose Modifications for Toxicities Attributed to Indomethacin 
Dose modifications are provided as guidance and should not replace the 
investigator’s own clinical judgment. 
 
Toxicity 
Dose of Indomethacin 
Grade 1 
No change 
Grade 2 
Hold until return to Grade 1 or baseline, 
resume after discussion and agreement 
with medical monitor* 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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≥Grade 3 or higher 
Hold until Grade 1 or baseline, resume at 25 
mg three times daily*,** 
Recurrence 
≥Grade 3 
Discontinue 
*Note: Treatment will be permanently discontinued for Grade 3 toxicity lasting 
longer than 5 days, or any grade toxicity that has not resolved to Grade 1 or less 
within 2 weeks. 
**Note: if a dose reduction is required, the patient will be provided with a supply of 
indomethacin 25 mg capsules.   
 
8.4.7. Administration, Supply and Storage 
Indomethacin is marketed, but not approved for the indication under study. 
8.4.7.1. 
Administration 
Indomethacin (Indocin®) will come in 50 mg capsules. The dose being tested in this 
study is 50 mg, or one capsule, by mouth three times daily. A 28-day supply will be 
provided at the beginning of each month of the trial. 
8.4.7.2. 
Supply 
Indomethacin (Indocin®) 50 mg capsules (opaque blue and white capsules, coded 
INDOCIN and MSD 50) will be packaged in 100 cc high-density polyethylene 
(HDPE) bottles with child-resistant closures (CRC). A 28-day supply will be 
provided at the beginning of each month of the trial. 
8.4.7.3. 
Storage 
Store at room temperature, between 59 and 86 °F (15 and 30 °C). Store away from 
heat, moisture, and light. 
 
 


CC Protocol Number: 9628 
 
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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
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9. Data Monitoring and Adverse Event Reporting Requirements 
Institutional support of trial monitoring will be in accordance with the FHCRC/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan.  Under the 
provisions of this plan, FHCRC Clinical Research Support coordinates data and compliance 
monitoring conducted by consultants, contract research organizations, or FHCRC employees 
unaffiliated with the conduct of the study.  Independent monitoring visits occur at specified 
intervals determined by the assessed risk level of the study and the findings of previous visits 
per the institutional DSMP.  
 
In addition, protocols are reviewed at least annually and as needed by the Consortium Data 
and Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) 
and the FHCRC/University of Washington Cancer Consortium Institutional Review Board 
(IRB).  The review committees evaluate accrual, adverse events, stopping rules, and 
adherence to the applicable data and safety monitoring plan for studies actively enrolling or 
treating patients.  The IRB reviews the study progress and safety information to assess 
continued acceptability of the risk-benefit ratio for human subjects.  Approval of committees 
as applicable is necessary to continue the study. 
 
The trial will comply with the standard guidelines set forth by these regulatory committees 
and other institutional, state and federal guidelines. 
 
Additionally, scheduled meetings will take place weekly and will include the protocol 
Principal Investigator (Michael Schweizer, MD), research nurse, data manager, and, when 
appropriate, the collaborators, sub-investigators, and biostatistician involved with the conduct 
of the protocol. 
 
During these meetings the investigators will discuss matters related to: safety of protocol 
participants, validity and integrity of the data, enrollment rate relative to expectation, 
characteristics of participants, retention of participants, adherence to protocol (potential or 
real protocol violations), data completeness, and progress of data for secondary objectives. If 


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≥3 out of the first 10 subjects enrolled are removed from the study due to a safety issue, the 
trial will terminate prematurely. Depending on the number of patients removed from the 
study due to safety issues, study accrual may have to be put on hold until the 10th subject has 
completed the treatment period (i.e., through Day 85). For example, if 2 subjects were 
removed for safety reasons prior to accruing the 10th subject, accrual would not continue until 
the 10th subject completes the treatment period. Safety issues will be continually monitored 
and safety oversight will be provided through the weekly meetings between the PI and 
relevant staff.  
 
9.1. Management of Safety Data 
As the Sponsor-Investigator / Principal Investigator of the Study, Dr. Michael T. 
Schweizer shall be solely responsible for complying with required timelines, any safety-
reporting obligation to competent Health Authorities, IRB/ECs and any participating (co 
or sub) investigators, as defined in applicable laws and regulations.   
This Study has been designated as an interventional study.  As such, all adverse events 
regardless of causality and special situations excluding those from subjects not exposed 
to apalutamide, abiraterone, degarelix and/or indomethacin (hereafter referred to as 
Study Drugs) and product quality complaints with or without an adverse event as 
described in this clinical protocol, and pregnancies of partners, will be reported from the 
time a subject has signed and dated an Informed Consent Form (ICF) until completion of 
the subject’s last study-related procedure (which may include contact for follow-up 
safety).  Serious adverse events will be reported for 30 days after the last dose of study 
drug. Note, adverse event collection is not expected to occur at the time of long-term 
telephone follow up (i.e., Days 450 and 815).  
The following list of adverse events are expected and clearly related to prostatectomy 
and associated procedures. These will not be collected or reported at the Day 113 visit. 
• 
Post-operative pain 
• 
Constipation 


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• 
Hematuria 
• 
Nausea 
• 
Vomiting 
• 
Bleeding 
• 
Anemia 
• 
Bladder leak 
For the purposes of this study, the Janssen medicinal products are: 
Abiraterone Acetate 
Apalutamide   
9.2. Definitions 
Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An adverse 
event does not necessarily have a causal relationship with the treatment. An adverse 
event can therefore be any unfavorable and unintended sign (including an abnormal 
finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational or non- investigational) product, whether or not related to that medicinal 
(investigational or non-investigational) product. (Definition per International Conference 
on Harmonisation [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities. 
Adverse Events of Special Interest  
Adverse events of special interest are events that Janssen Scientific Affairs is actively 
monitoring as a result of a previously identified signal (even if non-serious).  
For Abiraterone acetate, the adverse events of special interest are: 


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• Mineralocorticoid excess (Hypertension, Hypokalemia, Fluid retention) 
• Hepatotoxicity 
• Cardiac disorders 
• Osteoporosis including osteoporosis-related fractures 
• Increased exposure with food 
• Rhabdomyolysis/myopathy 
• Acute liver failure/hepatitis which might be fatal 
• Drug-drug interaction (CYP2D6) 
• Allergic alveolitis  
For apalutamide, the adverse events of special interest are: 
• Seizure/convulsions 
• Fractures 
• Fall 
• Hypothyroidism 
• Rashes 
Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory 
reporting requirements. 
• an identifiable subject (but not disclosing personal information such as the 
subject’s name, initials or address) 
• an identifiable reporter (investigational site) 


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• The name of the investigational product (i.e. apalutamide, abiraterone, 
degarelix and/or indomethacin) 
• an adverse event, outcome, or certain special situations 
The minimum information required is: 
• date of therapy (start and end date, if available) 
• batch or lot number, if available 
• Suspected Janssen medicinal product (doses, indication) 
• subject details (subject ID and country) 
• gender 
• age at AE onset 
• reporter ID 
• adverse event detail (AE verbatim in English), onset date, relatedness, causality, 
action taken, outcome, (if available) 
• Janssen protocol ID 
Adverse Drug Reaction (ADR) 
A noxious and unintended response to any dose of the drug (or biological) product for 
which there is a reasonable possibility that the product cause the response.  ‘‘Reasonable 
possibility’’ means there is evidence to suggest a causal relationship between the drug 
and the adverse event. Suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug. 
 
Product Quality Complaint (PQC) 


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A product quality compliant is defined as any suspicion of a product defect related to a 
potential quality issue during manufacturing, packaging, release testing, stability 
monitoring, dose preparation, storage or distribution of the product, or delivery system.  
Not all PQCs involve a subject.  Lot and batch numbers are of high significance and 
need to be collected whenever available. 
Examples of PQC include but not limited to: 
• Functional Problem: e.g., altered delivery rate in a controlled release product 
• Physical Defect:  e.g. abnormal odor, broken or crushed tablets 
• Potential Dosing Device Malfunction: e.g.,  autoinjector button not working, 
needle detaching from syringe 
• Suspected Contamination 
• Suspected Counterfeit 
Serious Adverse Event (SAE) 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any 
dose: 
• Results in death 
• Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an event 
that hypothetically might have caused death if it were more severe.) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 


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• Is a suspected transmission of any infectious agent via a medicinal product 
• Is medically important* 
*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that 
may not be immediately life threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should usually be considered serious. 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS 
ADVERSE EVENT. 
Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 
Any event requiring hospitalization or prolongation of hospitalization that occurs during 
the study must be reported as a serious adverse event, except hospitalizations for the 
following: 
• Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care facility) 
• Surgery or procedure planned before entry into the study. [Note: Hospitalizations 
that were planned before the start of data collection and where the underlying 
condition for which the hospitalization was planned has not worsened will not be 
considered serious adverse events. Any adverse event that results in a 
prolongation of the originally planned hospitalization is to be reported as a new 
serious adverse event.] 
 
Life-Threatening Conditions 


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The cause of death of a subject in a study within 30-days of the last dose of one or more 
of the Study Drugs, whether or not the event is expected or associated with the study 
drug, is considered a serious adverse event. 
Disease progression should not be recorded as an adverse event or serious adverse event 
term; instead, signs and symptoms of clinical sequelae resulting from disease 
progression/lack of efficacy will be reported if they fulfill the serious adverse event 
definition. 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An adverse event is considered unlisted if the nature or severity is not consistent with 
the applicable product reference safety information. For a medicinal product(s) with a 
marketing authorization, the expectedness of an adverse event will be determined by 
whether or not it is listed in the applicable product information.  
For apalutamide, the expectedness of an adverse event will be determined by whether or 
not it is listed in the Investigator's Brochure.   
For degarelix, abiraterone acetate and indomethacin, the expectedness of an adverse 
event will be determined by whether or not it is listed in the FDA prescribing 
information.   
Special Reporting Situations  
Safety events of interest for apalutamide and/or abiraterone acetate that require 
expediting reporting and/or safety evaluation include, but are not limited to: 
• Drug exposure during pregnancy (maternal and paternal) 
• 
Overdose of apalutamide or abiraterone acetate product  
• 
Exposure to a apalutamide or abiraterone acetate from breastfeeding  
• 
Suspected abuse/misuse of apalutamide or abiraterone acetate 
• 
Inadvertent or accidental exposure to apalutamide or abiraterone acetate 
• For abiraterone acetate only, failure of expected pharmacological action (i.e., 
lack of effect)  


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• 
Medication error involving apalutamide or abiraterone acetate (with or 
without patient exposure to apalutamide or abiraterone acetate, e.g., 
name confusion) 
• 
Suspected transmission of any infectious agent via administration of 
apalutamide or abiraterone acetate 
• For abiraterone acetate only, unexpected therapeutic or clinical benefit from 
use of a Janssen medicinal product 
 
These safety events may not meet the definition of an adverse event; however, from 
Janssen Scientific Affairs perspective, they are treated in the same manner as adverse 
events. Special situations should be recorded on the Adverse Event page of the CRF. 
 
Any special situation that meets the criteria of a serious adverse event should be 
recorded on a Serious Adverse Event Report Form and be reported to Janssen Scientific 
Affairs within 24 hours of becoming aware of the event. 
 
9.3. Pregnancy 
Because apalutamide and abiraterone acetate may have an effect on sperm, pregnancies in 
partners of male subjects exposed to apalutamide or abiraterone acetate will be reported by 
the Principal Investigator within 24 hours of their knowledge of the event using the 
Serious Adverse Event Form to Janssen Scientific Affairs.  Depending on local legislation 
this may require prior consent of the partner. 
Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
9.4. Adverse Event Monitoring and Reporting 
The PI, Sub-Investigators, and/or the research nurse will monitor each patient closely for 
the development of adverse events and toxicities and record all such events. Patients will 
be evaluated for toxicity if they have received one dose of any of the Study Drugs. The 


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timely reporting of adverse events (including toxic deaths) is required by the Food and 
Drug Administration (FDA). 
In general, the sponsor must immediately report (i.e. within 24 hours) to Janssen 
Scientific Affairs, LLC any serious adverse event and Special Reporting Situations, 
whether or not considered drug related. Study endpoints that are serious adverse events 
(e.g., all-cause mortality) must be reported in accordance with the protocol unless there 
is evidence suggesting a causal relationship between the drug and the event (e.g., death 
as a result of anaphylactic reaction or fatal hepatic necrosis). In that case, the 
investigator must immediately report the event to Janssen Scientific Affairs, LLC. The 
sponsor must record non-serious adverse events and report them to Janssen Scientific 
Affairs, LLC according to the timetable for reporting as specified either in the protocol 
or to fulfill regulatory reporting requirements. 
For each subject, AEs SAEs, and Special Reporting Situations should be recorded after 
informed consent is obtained until the subject has completed participation in the study as 
follows: 
A Serious Adverse event or Special Reporting Situations must be reported if it occurs 
during a subject’s participation in the Study (whether receiving Study Product or not) 
and within 30 days of receiving the last dose of Study Product. 
Any serious adverse event or Special Reporting Situations that is ongoing when a subject 
completes his/her participation in the Study must be followed until any of the following 
occurs: 
• the event resolves or stabilizes; 
• the event returns to baseline condition or value (if a baseline value is available); 
• the event can be attributed to agents(s) other than the Study Product, or to 
factors unrelated to Study conduct. 


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9.5. Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
Janssen Medicinal Products to Janssen Scientific Affairs, LLC 
All adverse events and special situations, whether serious or non-serious, related or not 
related, following exposure to apalutamide or abiraterone acetate are to be documented 
by the investigator and recorded in the CRF and in the subject’s source records. 
Investigators must record in the CRF their opinion concerning the relationship of the 
adverse event to apalutamide or abiraterone.  
All (serious and non-serious) adverse events reported for apalutamide or abiraterone 
acetate should be followed-up in accordance with clinical practice. 
9.5.1. Serious Adverse Events (SAE) and Special Reporting Situations 
All serious adverse events that have not resolved by the end of the study, or that 
have not resolved upon discontinuation of the subject's participation in the study, 
must be followed until any of the following occurs: 
• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value/status is available 
• The event can be attributed to agents other than the study drug or to 
factors unrelated to study conduct 
• It becomes unlikely that any additional information can be obtained 
(subject or health care practitioner refusal to provide additional 
information, lost to follow-up after demonstration of due diligence with 
follow-up efforts) 
The Principal Investigator will transmit all SAEs and special situations (see 
Section 9.2) following exposure to the Study Drugs in a form provided by the 
Janssen Scientific Affairs, LLC within 24-hours of becoming aware of the 
event(s). 


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All follow-up information for serious adverse events that are not resolved at the 
end of the study or by the time of patient withdrawal must be reported directly by 
the Principal Investigator, within 24 hours becoming aware, to Janssen 
Scientific Affairs, LLC using their Serious Adverse Event Report  
All available clinical information relevant to the evaluation of a related SAE, 
serious ADR or special situation is required. 
• The Principal Investigator is responsible for ensuring that these cases are 
complete and if not are promptly followed-up. A safety report is not 
considered complete until all clinical details needed to interpret the case 
are received. Reporting of follow-up information should follow the same 
timeline as initial reports. 
• Copies of any and all relevant correspondences with regulatory authorities 
and ethics committees regarding any and all serious adverse events, 
irrespective of association with the Study Drugs, are to be provided to the 
Janssen Scientific Affairs, LLC within 24 hours of such report or 
correspondence being sent to applicable health authorities. 
9.5.2. Product Quality Complaints Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, 
accurate, and complete reporting and analysis of PQC information from studies 
are crucial for the protection of patients, investigators, and Janssen Scientific 
Affairs, LLC, and are mandated by regulatory agencies worldwide. Janssen 
Scientific Affairs, LLC has established procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of PQC information. Lot 
and/or Batch #s shall be collected or any reports failure of expected 
pharmacological action (i.e., lack of effect). The product should be quarantined 
immediately and if possible, take a picture. 
All initial PQCs involving apalutamide must be reported to Janssen Scientific 
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aware of the event. The Janssen contact will provide additional information/form 
to be completed. 
 
If the defect for the Lot and/or Batch of apalutamide under study is combined 
with either a serious adverse event or non-serious adverse event, the Principal 
Investigator must report the PQC to Janssen Scientific Affairs, LLC according to 
the serious adverse event reporting timelines.  A sample of the suspected product 
should be maintained for further investigation if requested by Janssen Scientific 
Affairs, LLC. 
 
For SAEs, special reporting situations and PQCs following exposure to a non-
Janssen medicinal product under study, the principal investigator should notify 
the appropriate regulatory/competent authority or the manufacturer of that 
medicinal product (in the absence of appropriate local legislation) as soon as 
possible. 
 
9.5.3. Non-Serious AEs 
All non-serious adverse events should be reported to Janssen Scientific Affairs, 
LLC according to the timeframe outlined in the Research Funding Agreement 
section entitled Reporting of Data. 
9.6. Evaluating Adverse Events 
The grade and severity of the event will be determined using the DCT/NCI Common 
Terminology Criteria, CTCAE v.4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP home page (http://ctep.cancer.gov). All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. Study staff must 
use one of the CTCAE criteria to define the event. Adverse events not included in the 
CTCAE v.4.0 should be reported and graded under the “Other” adverse event within the 
appropriate category and grade 1 to 5 according to the general grade definitions, mild, 
moderate, severe, life-threatening, fatal or disabling, as provided in the CTCAE. 


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The event will be determined to be expected or unexpected 
The determination of whether an AE is expected is based on agent-specific adverse 
event information provided in Section 7and 8 Pharmaceutical Information. Unexpected 
AEs are those not listed in the agent-specific adverse event information provided in 
Section 7and 8 Pharmaceutical Information.  
The event will be evaluated for relationship to the medical treatment or procedure. The 
Investigator should document his/her opinion of the relationship of the event to study 
medication as follows: 
• Unrelated- The adverse event is clearly not related to the investigational 
agent(s). 
• Unlikely- The adverse event is doubtfully related to the investigational 
agent(s). 
• Possible-The adverse event may be related to the investigational agent(s). 
• Probable-The adverse event is most likely related to the investigational 
agent(s). 
• Definite- The adverse event is clearly related to the investigational agent(s). 
Based on this information, a decision will be made whether an adverse event should be 
reported as an expedited report (Serious Adverse Event, section 3.0) in addition to the 
routinely reported clinical data. All expedited adverse event reports that meet reporting 
criteria per institutional requirements should be submitted to the Institutional Review 
Board (IRB) and to the FDA. Additionally, all SAEs should be submitted to Janssen 
Scientific Affairs, LLC within 24 hours of becoming aware of event and via secure e-
mail. 
9.6.1. Documenting Adverse Events 


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Each individual sign or symptom must be documented separately. Worksheets 
must be signed and dated by person conducting evaluation to be used as source 
documentation. The attribution of all adverse events must be verified by an 
investigator. Evaluation of laboratory toxicities may be documented directly on a 
printed laboratory report or CRF provided it is signed by the investigator. 
However, if an action was conducted due to this abnormality (e.g. RBC 
transfusion due to low Hgb) this would be recorded on the AE form also. 
Recording should be done in a concise manner using standard, acceptable medical 
terms. 
The adverse event recorded should not be a procedure or a clinical measurement 
(i.e. a laboratory value or vital sign) but should reflect the reason for the 
procedure or the diagnosis based on the abnormal measurement. 
Preexisting conditions that worsen in severity or frequency during the Study 
should also be recorded (a preexisting condition that does not worsen is not an 
adverse event). 
Further, a procedure or surgery is not an adverse event; rather, the event leading 
to the procedure or surgery is considered an adverse event. Any event requiring 
in-patient hospitalization that occurs during the course of a subject’s participation 
in a trial must be reported as an SAE. Hospitalizations that do not meet the criteria 
for SAE reporting are: 
A. Reasons described in the Protocol, e.g. drug administration, Protocol-
required testing 
B. Surgery or procedure planned prior to entry into the Study. 
If, in the Sponsor Investigator’s judgment, a clinical significant worsening from 
baseline is observed in any laboratory or other test parameter (e.g. 
electrocardiogram (ECG), angiogram), physical exam finding, or vital sign, a 
corresponding clinical adverse event should be recorded. 


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If a specific medical diagnosis has been made, that diagnosis or syndrome should 
be recorded as the adverse event, whenever possible.  However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an adverse event, using appropriate 
medical terminology (e/g/ thrombocytopenia, peripheral edema, QT 
prolongation). 
9.6.2. Maintenance of Safety Information 
All safety data should be maintained in a clinical database in a retrievable format. 
The Principal Investigator shall provide all adverse events, both serious and non-
serious, in report format. However, in certain circumstances more frequent 
provision of safety data may be necessary, e.g. to fulfill a regulatory request, and 
as such the data shall be made available within a reasonable timeframe at Janssen 
Scientific Affairs’ request. 
9.6.3. Reconciliation of SAEs 
At a minimum, on a quarterly basis and at the end of the Study, Janssen Scientific 
Affairs will provide to the Principal Investigator a listing of all SAEs reported to 
the Janssen Scientific Affairs.  The Principal Investigator will review this listing 
and provide any discrepancies to Janssen Scientific Affairs. 
 
Upon request, the Principal Investigator shall provide Janssen Scientific Affairs 
with a summary list of all SAEs, and AEs of Special Interest and Special 
Reporting Situation reports to date, for reconciliation purposes. 
 
9.7. IRB Reporting 
The Principal Investigator is responsible to report serious adverse events and protocol 
problems (e.g. protocol deviations, non-adherence) to the FHCRC/University of 
Washington Cancer Consortium Institutional Review Board (IRB). Adverse events 
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risk of greater harm from the research than previously known will be reported to the IRB 
per institutional policy. 
In addition, all safety data must be submitted to Janssen Scientific Affairs, LLC. The 
following methods are acceptable for transmission of safety information to Janssen 
Scientific Affairs, LLC.: 
• Electronically via Janssen SECURE Email service  (preferred) 
• For business purposes, if SECURE Email is non-functional: 
o Facsimile (fax), receipt of which is evidences in a successful fax 
transmission report 
o Telephone (if fax is non-functional) 
Contact information for Janssen Scientific Affairs, LLC. is below: 
SAE email: IIS-BIO-VIRO-GCO@its.jnj.com  
SAE fax: 1-866-651-0219 
 
 
Follow-up reports must be submitted in a timely fashion as additional information 
becomes available.  The initial SAE report should be updated with the pertinent follow 
up information. 
9.8. Protocol Amendments 
Any changes to the protocol will be made in the form of an amendment and must be 
approved by the IRB before implementation. Changes to the protocol or informed 
consent will be reviewed and approved by Janssen Scientific Affairs, LLC prior to 
submitting to the IRB for approval. 
9.9. Informed consent 
Written informed consent will be obtained by a study investigator or study research 
nurse working on this study. An explanation of the nature of study, its purpose, 


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procedures involved, expected duration, potential risks and benefits will be provided to 
each participant by the investigator or the research nurse. Each participant will be 
informed that participation in the study is voluntary and that he may withdraw from the 
study at any time, and that withdrawal of consent will not affect his subsequent medical 
treatment. Participants will be allowed time needed to make an informed decision. 
Participants will be encouraged to ask questions about the study and the consent before 
signing the consent form. Original signed consent forms will be filed in each patient’s 
research chart, while each patient will receive a copy of the consent document. No 
patient will enter the study before his informed consent has been obtained. 
 
 
 
 


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10. Statistical Methods 
This is an open-label, multi-site Phase II trial testing 3-months (12-weeks) of neoadjuvant 
apalutamide, abiraterone acetate, degarelix and indomethacin. The primary endpoint will be the 
pCR rate as assessed from prostatectomy specimens. Prior neoadjuvant hormonal therapy trials 
have documented pCR rates on the order of 5%, while still failing to show improvements in 
biochemical PFS or OS.10,11,14 Therefore, we would consider a pCR rate of ≤5% to be insufficient 
evidence of activity to warrant further study in this patient population. The minimum level of 
activity we would require to consider further study with the proposed regimen would be a pCR 
rate of ≥25%. Therefore, based on an exact binomial test, if we observe ≥3 pCR out of a total 
sample size of 20, we would have 91% power at a one-sided alpha of 7.5% to detect a difference 
between H0 = 5% and a H1 = 25.33 
 
10.1. Data Analysis 
The primary objective of this trial is to determine the pCR rate as determined from 
prostatectomy specimens following neoadjuvant treatment with 3-months (12-weeks) of 
apalutamide, abiraterone acetate, indomethacin and degarelix in men with high to very-high 
risk prostate cancer (per NCCN guideline). We will use a 1-sample chi-square test to 
compare the proportion with a pCR to the null hypothesis value of 5%. The 95% confidence 
interval (CI) of the primary endpoint estimate will be computed. 
Secondary pathologic endpoints to be assessed from prostatectomy specimens 
following 3-months (12 weeks) of neoadjuvant therapy include: the negative margin rate, 
negative nodal metastases rate, near pCR (i.e. ≤5 mm of residual tumor) rate, the rate of 
pathologic T3 disease and apoptotic index (i.e. percentage of tumor cells undergoing 
apoptosis) as determined by cleaved caspase-3 immunohistochemistry. Other secondary 
endpoints will include: the proportion of men who receive adjuvant radiation therapy within 
1-year of prostatectomy, the biochemical (i.e. PSA) progression free survival estimate two 
years after the last patient has accrued, the overall survival estimate two years after the last 
patient has accrued and safety (as assessed by CTCAE version 4.0). In addition, 
prostatectomy specimens and plasma samples will be stored at -80°C. These biologic 
specimens will be used for additional correlative work. Examples of studies to be conducted 


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
96 
 
may include, but are not limited to: assessment for genomic PTEN loss via fluorescence in 
situ hybridization (FISH), PTEN immunohistochemistry (IHC), assessment for alteration in 
MYC/chromosome 8q24 via FISH, RNAseq analysis, intraprostatic drug/androgen levels and 
serum drug/androgen levels.  
The proportions of men who achieve pCR and near pCR, exhibit pathologic T3 
disease, have no evidence for nodal metastases, and the proportion who receive adjuvant 
radiation therapy within the first year post-prostatectomy, and the proportions with specific 
adverse event grades will be computed along with their 95% CI. In addition, the PSA PFS 
and overall survival at 2 years after the last enrollment will be estimated using Kaplan-Meier 
methods and 95% CI will be estimated using Greenwood’s formula.96 PSA progression (i.e. 
biochemical failure) will be defined per the American Urological Association (AUA) 
guidelines (i.e. confirmed PSA post-radical prostatectomy ≥0.2 ng/mL). 
We will characterize toxicity as percentage by type and grade. Changes in exploratory 
biomarkers pre- and post-treatment will be assessed using paired t-test or signed-rank test for 
continuous variables, or McNemar chi-square tests for categorical variables. In addition, 
baseline exploratory biomarker levels/values, as well as changes in these levels/values pre-
/post-treatment will be correlated with the primary endpoint and secondary endpoints using 
chi-square tests and logistic regression, or (for PFS and OS) using proportional hazards 
models, Kaplan-Meier methods and log-rank tests. 
 


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11. References 
1. 
Roehl KA, Han M, Ramos CG, Antenor JA, Catalona WJ. Cancer progression and 
survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive 
patients: long-term results. The Journal of urology 2004;172:910-4. 
2. 
Carver BS, Bianco FJ, Jr., Scardino PT, Eastham JA. Long-term outcome following 
radical prostatectomy in men with clinical stage T3 prostate cancer. The Journal of urology 
2006;176:564-8. 
3. 
D'Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical 
prostatectomy, external beam radiation therapy, or interstitial radiation therapy for 
clinically localized prostate cancer. JAMA : the journal of the American Medical Association 
1998;280:969-74. 
4. 
Kane CJ, Presti JC, Jr., Amling CL, Aronson WJ, Terris MK, Freedland SJ. Changing 
nature of high risk patients undergoing radical prostatectomy. The Journal of urology 
2007;177:113-7. 
5. 
Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus 
cystectomy compared with cystectomy alone for locally advanced bladder cancer. The New 
England journal of medicine 2003;349:859-66. 
6. 
Lou DY, Fong L. Neoadjuvant therapy for localized prostate cancer: Examining 
mechanism of action and efficacy within the tumor. Urologic oncology 2014. 
7. 
McKay RR, Choueiri TK, Taplin ME. Rationale for and review of neoadjuvant therapy 
prior to radical prostatectomy for patients with high-risk prostate cancer. Drugs 
2013;73:1417-30. 
8. 
von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic 
complete response on prognosis after neoadjuvant chemotherapy in various intrinsic 
breast cancer subtypes. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 2012;30:1796-804. 
9. 
Aus G, Abrahamsson PA, Ahlgren G, et al. Hormonal treatment before radical 
prostatectomy: a 3-year followup. The Journal of urology 1998;159:2013-6; discussion 6-7. 
10. 
Klotz LH, Goldenberg SL, Jewett MA, et al. Long-term followup of a randomized trial 
of 0 versus 3 months of neoadjuvant androgen ablation before radical prostatectomy. The 
Journal of urology 2003;170:791-4. 
11. 
Schulman CC, Debruyne FM, Forster G, Selvaggi FP, Zlotta AR, Witjes WP. 4-Year 
follow-up results of a European prospective randomized study on neoadjuvant hormonal 
therapy prior to radical prostatectomy in T2-3N0M0 prostate cancer. European Study 
Group on Neoadjuvant Treatment of Prostate Cancer. European urology 2000;38:706-13. 
12. 
Soloway MS, Pareek K, Sharifi R, et al. Neoadjuvant androgen ablation before radical 
prostatectomy in cT2bNxMo prostate cancer: 5-year results. The Journal of urology 
2002;167:112-6. 
13. 
Yee DS, Lowrance WT, Eastham JA, Maschino AC, Cronin AM, Rabbani F. Long-term 
follow-up of 3-month neoadjuvant hormone therapy before radical prostatectomy in a 
randomized trial. BJU international 2010;105:185-90. 


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14. 
Gleave ME, Goldenberg SL, Chin JL, et al. Randomized comparative study of 3 versus 
8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and 
pathological effects. The Journal of urology 2001;166:500-6; discussion 6-7. 
15. 
Labrie F, Cusan L, Gomez JL, et al. Neoadjuvant hormonal therapy: the Canadian 
experience. Urology 1997;49:56-64. 
16. 
van der Kwast TH, Tetu B, Candas B, Gomez JL, Cusan L, Labrie F. Prolonged 
neoadjuvant combined androgen blockade leads to a further reduction of prostatic tumor 
volume: three versus six months of endocrine therapy. Urology 1999;53:523-9. 
17. 
Taplin ME, Montgomery B, Logothetis CJ, et al. Intense androgen-deprivation 
therapy with abiraterone acetate plus leuprolide acetate in patients with localized high-risk 
prostate cancer: results of a randomized phase II neoadjuvant study. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2014;32:3705-15. 
18. 
Schweizer MT, Antonarakis ES. Abiraterone and other novel androgen-directed 
strategies for the treatment of prostate cancer: a new era of hormonal therapies is born. 
Therapeutic advances in urology 2012;4:167-78. 
19. 
de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in 
metastatic prostate cancer. The New England journal of medicine 2011;364:1995-2005. 
20. 
Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer 
without previous chemotherapy. The New England journal of medicine 2013;368:138-48. 
21. 
Mostaghel EA, Nelson PS, Lange P, et al. Targeted androgen pathway suppression in 
localized prostate cancer: a pilot study. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2014;32:229-37. 
22. 
Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in Metastatic Prostate 
Cancer before Chemotherapy. The New England journal of medicine 2014. 
23. 
Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate 
cancer after chemotherapy. The New England journal of medicine 2012;367:1187-97. 
24. 
Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral 
androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor 
growth. Cancer research 2008;68:4447-54. 
25. 
Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting 
adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer 
research 2006;66:2815-25. 
26. 
Tamae D, Mostaghel E, Montgomery B, et al. The DHEA-sulfate depot following 
P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and 
advanced castration resistant prostate cancer. Chemico-biological interactions 2014. 
27. 
Liu C, Lou W, Zhu Y, et al. Intracrine androgens and AKR1C3 activation confer 
resistance to enzalutamide in prostate cancer. Cancer research 2015. 
28. 
Cai C, Chen S, Ng P, et al. Intratumoral de novo steroid synthesis activates androgen 
receptor in castration-resistant prostate cancer and is upregulated by treatment with 
CYP17A1 inhibitors. Cancer research 2011;71:6503-13. 
29. 
Desmond JC, Mountford JC, Drayson MT, et al. The aldo-keto reductase AKR1C3 is a 
novel suppressor of cell differentiation that provides a plausible target for the non-
cyclooxygenase-dependent antineoplastic actions of nonsteroidal anti-inflammatory drugs. 
Cancer research 2003;63:505-12. 


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
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30. 
Liedtke AJ, Adeniji AO, Chen M, et al. Development of potent and selective 
indomethacin analogues for the inhibition of AKR1C3 (Type 5 17beta-hydroxysteroid 
dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer. Journal of 
medicinal chemistry 2013;56:2429-46. 
31. 
Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-
month, comparative, randomized, open-label, parallel-group phase III study in patients 
with prostate cancer. BJU international 2008;102:1531-8. 
32. 
Eifler JB, Feng Z, Lin BM, et al. An updated prostate cancer staging nomogram 
(Partin tables) based on cases from 2006 to 2011. BJU international 2013;111:22-9. 
33. 
Khan I, Sarker SJ, Hackshaw A. Smaller sample sizes for phase II trials based on exact 
tests with actual error rates by trading-off their nominal levels of significance and power. 
British journal of cancer 2012;107:1801-9. 
34. 
Roach M, 3rd, Thomas K. Overview of randomized controlled treatment trials for 
clinically localized prostate cancer: implications for active surveillance and the United 
States preventative task force report on screening? J Natl Cancer Inst Monogr 
2012;2012:221-9. 
35. 
Leuprolide versus diethylstilbestrol for metastatic prostate cancer. The Leuprolide 
Study Group. The New England journal of medicine 1984;311:1281-6. 
36. 
Scher HI, Heller G. Clinical states in prostate cancer: toward a dynamic model of 
disease progression. Urology 2000;55:323-7. 
37. 
de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or 
mitoxantrone for metastatic castration-resistant prostate cancer progressing after 
docetaxel treatment: a randomised open-label trial. Lancet 2010;376:1147-54. 
38. 
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-
resistant prostate cancer. The New England journal of medicine 2010;363:411-22. 
39. 
Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in 
metastatic prostate cancer. The New England journal of medicine 2013;369:213-23. 
40. 
Haidar S, Ehmer PB, Barassin S, Batzl-Hartmann C, Hartmann RW. Effects of novel 
17alpha-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis 
in vitro and in vivo. J Steroid Biochem Mol Biol 2003;84:555-62. 
41. 
Ryan CJ, Tindall DJ. Androgen receptor rediscovered: the new biology and targeting 
the androgen receptor therapeutically. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2011;29:3651-8. 
42. 
Vasaitis TS, Bruno RD, Njar VC. CYP17 inhibitors for prostate cancer therapy. J 
Steroid Biochem Mol Biol 2011;125:23-31. 
43. 
Ye L, Su ZJ, Ge RS. Inhibitors of testosterone biosynthetic and metabolic activation 
enzymes. Molecules 2011;16:9983-10001. 
44. 
Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, 
abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains 
hormone driven. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 2008;26:4563-71. 
45. 
O'Donnell A, Judson I, Dowsett M, et al. Hormonal impact of the 17alpha-
hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with 
prostate cancer. British journal of cancer 2004;90:2317-25. 


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Neoadjuvant therapy in high-risk Prostate Cancer 
 
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46. 
Bryce A, Ryan CJ. Development and clinical utility of abiraterone acetate as an 
androgen synthesis inhibitor. Clin Pharmacol Ther 2012;91:101-8. 
47. 
Small EJ, Halabi S, Dawson NA, et al. Antiandrogen withdrawal alone or in 
combination with ketoconazole in androgen-independent prostate cancer patients: a phase 
III trial (CALGB 9583). Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 2004;22:1025-33. 
48. 
Attard G, Reid AH, Auchus RJ, et al. Clinical and biochemical consequences of 
CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in 
castrate men with advanced prostate cancer. J Clin Endocrinol Metab 2012;97:507-16. 
49. 
Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-
Sensitive Prostate Cancer. The New England journal of medicine 2017;377:352-60. 
50. 
Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor 
abiraterone acetate demonstrating clinical activity in patients with castration-resistant 
prostate cancer who received prior ketoconazole therapy. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 2010;28:1481-8. 
51. 
Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone 
acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant 
prostate cancer. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 2010;28:1496-501. 
52. 
Rathkopf D, Scher HI. Androgen receptor antagonists in castration-resistant 
prostate cancer. Cancer J 2013;19:43-9. 
53. 
Rathkopf DE, Danila DC, Morris MJ, et al. Phase I/II safety and pharmacokinetic (PK) 
study of ARN-509 in patients with metastatic castration-resistant prostate cancer 
(mCRPC): Phase I results of a Prostate Cancer Clinical Trials Consortium study.  
Genitourinary Cancers Symposium; 2012; San Francisco, CA. 
54. 
Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate 
cancer before chemotherapy. The New England journal of medicine 2014;371:424-33. 
55. 
Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate 
cancer treatment. Cancer research 2012;72:1494-503. 
56. 
Foster WR, Car BD, Shi H, et al. Drug safety is a barrier to the discovery and 
development of new androgen receptor antagonists. Prostate 2011;71:480-8. 
57. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for 
patients with progressive prostate cancer and castrate levels of testosterone: 
recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2008;26:1148-59. 
58. 
Smith MR, Antonarakis ES, Ryan CJ, et al. ARN-509 in men with high-risk 
nonmetastatic castration-resistant prostate cancer (CRPC).  Genitourinary Cancers 
Symposium; 2013; Orlando, FL. 
59. 
Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free 
Survival in Prostate Cancer. The New England journal of medicine 2018. 
60. 
Carracedo A, Alimonti A, Pandolfi PP. PTEN level in tumor suppression: how much is 
too little? Cancer research 2011;71:629-33. 
61. 
Haffner MC, Mosbruger T, Esopi DM, et al. Tracking the clonal origin of lethal 
prostate cancer. The Journal of clinical investigation 2013;123:4918-22. 


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62. 
Halvorsen OJ, Haukaas SA, Akslen LA. Combined loss of PTEN and p27 expression is 
associated with tumor cell proliferation by Ki-67 and increased risk of recurrent disease in 
localized prostate cancer. Clinical cancer research : an official journal of the American 
Association for Cancer Research 2003;9:1474-9. 
63. 
Han B, Mehra R, Lonigro RJ, et al. Fluorescence in situ hybridization study shows 
association of PTEN deletion with ERG rearrangement during prostate cancer progression. 
Modern pathology : an official journal of the United States and Canadian Academy of 
Pathology, Inc 2009;22:1083-93. 
64. 
Besson A, Robbins SM, Yong VW. PTEN/MMAC1/TEP1 in signal transduction and 
tumorigenesis. European journal of biochemistry / FEBS 1999;263:605-11. 
65. 
Goberdhan DC, Wilson C. PTEN: tumour suppressor, multifunctional growth 
regulator and more. Human molecular genetics 2003;12 Spec No 2:R239-48. 
66. 
Antonarakis ES, Keizman D, Zhang Z, et al. An immunohistochemical signature 
comprising PTEN, MYC, and Ki67 predicts progression in prostate cancer patients receiving 
adjuvant docetaxel after prostatectomy. Cancer 2012;118:6063-71. 
67. 
Chaux A, Peskoe SB, Gonzalez-Roibon N, et al. Loss of PTEN expression is associated 
with increased risk of recurrence after prostatectomy for clinically localized prostate 
cancer. Modern pathology : an official journal of the United States and Canadian Academy 
of Pathology, Inc 2012;25:1543-9. 
68. 
Lotan TL, Gurel B, Sutcliffe S, et al. PTEN protein loss by immunostaining: analytic 
validation and prognostic indicator for a high risk surgical cohort of prostate cancer 
patients. Clinical cancer research : an official journal of the American Association for Cancer 
Research 2011;17:6563-73. 
69. 
McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, Sellers WR. Loss of PTEN 
expression in paraffin-embedded primary prostate cancer correlates with high Gleason 
score and advanced stage. Cancer research 1999;59:4291-6. 
70. 
Yoshimoto M, Cunha IW, Coudry RA, et al. FISH analysis of 107 prostate cancers 
shows that PTEN genomic deletion is associated with poor clinical outcome. British journal 
of cancer 2007;97:678-85. 
71. 
Gurel B, Iwata T, Koh CM, et al. Nuclear MYC protein overexpression is an early 
alteration in human prostate carcinogenesis. Modern pathology : an official journal of the 
United States and Canadian Academy of Pathology, Inc 2008;21:1156-67. 
72. 
Koh CM, Bieberich CJ, Dang CV, Nelson WG, Yegnasubramanian S, De Marzo AM. MYC 
and Prostate Cancer. Genes & cancer 2010;1:617-28. 
73. 
Koh CM, Gurel B, Sutcliffe S, et al. Alterations in nucleolar structure and gene 
expression programs in prostatic neoplasia are driven by the MYC oncogene. The American 
journal of pathology 2011;178:1824-34. 
74. 
Gil J, Kerai P, Lleonart M, et al. Immortalization of primary human prostate epithelial 
cells by c-Myc. Cancer research 2005;65:2179-85. 
75. 
Bethel CR, Faith D, Li X, et al. Decreased NKX3.1 protein expression in focal prostatic 
atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason 
score and chromosome 8p deletion. Cancer research 2006;66:10683-90. 
76. 
Jenkins RB, Qian J, Lieber MM, Bostwick DG. Detection of c-myc oncogene 
amplification and chromosomal anomalies in metastatic prostatic carcinoma by 
fluorescence in situ hybridization. Cancer research 1997;57:524-31. 


CC Protocol Number: 9628 
 
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102 
 
77. 
Sato K, Qian J, Slezak JM, et al. Clinical significance of alterations of chromosome 8 in 
high-grade, advanced, nonmetastatic prostate carcinoma. Journal of the National Cancer 
Institute 1999;91:1574-80. 
78. 
Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS 
transcription factor genes in prostate cancer. Science (New York, NY) 2005;310:644-8. 
79. 
Leinonen KA, Saramaki OR, Furusato B, et al. Loss of PTEN is associated with 
aggressive behavior in ERG-positive prostate cancer. Cancer epidemiology, biomarkers & 
prevention : a publication of the American Association for Cancer Research, cosponsored 
by the American Society of Preventive Oncology 2013;22:2333-44. 
80. 
Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a 
cell proliferation-associated human nuclear antigen defined by the monoclonal antibody 
Ki-67. Journal of immunology (Baltimore, Md : 1950) 1984;133:1710-5. 
81. 
Verhoven B, Yan Y, Ritter M, et al. Ki-67 is an independent predictor of metastasis 
and cause-specific mortality for prostate cancer patients treated on Radiation Therapy 
Oncology Group (RTOG) 94-08. International journal of radiation oncology, biology, physics 
2013;86:317-23. 
82. 
Chaux A, Albadine R, Toubaji A, et al. Immunohistochemistry for ERG expression as a 
surrogate for TMPRSS2-ERG fusion detection in prostatic adenocarcinomas. The American 
journal of surgical pathology 2011;35:1014-20. 
83. 
Furusato B, Tan SH, Young D, et al. ERG oncoprotein expression in prostate cancer: 
clonal progression of ERG-positive tumor cells and potential for ERG-based stratification. 
Prostate cancer and prostatic diseases 2010;13:228-37. 
84. 
van Leenders GJ, Boormans JL, Vissers CJ, et al. Antibody EPR3864 is specific for ERG 
genomic fusions in prostate cancer: implications for pathological practice. Modern 
pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 
2011;24:1128-38. 
85. 
Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or 
without a reference genome. BMC bioinformatics 2011;12:323. 
86. 
Leng N, Dawson JA, Thomson JA, et al. EBSeq: an empirical Bayes hierarchical model 
for inference in RNA-seq experiments. Bioinformatics (Oxford, England) 2013;29:1035-43. 
87. 
Au KF, Jiang H, Lin L, Xing Y, Wong WH. Detection of splice junctions from paired-
end RNA-seq data by SpliceMap. Nucleic acids research 2010;38:4570-8. 
88. 
Kim D, Salzberg SL. TopHat-Fusion: an algorithm for discovery of novel fusion 
transcripts. Genome biology 2011;12:R72. 
89. 
Anders S, Huber W. Differential expression analysis for sequence count data. 
Genome biology 2010;11:R106. 
90. 
Garmire LX, Garmire DG, Huang W, Yao J, Glass CK, Subramaniam S. A global 
clustering algorithm to identify long intergenic non-coding RNA--with applications in 
mouse macrophages. PloS one 2011;6:e24051. 
91. 
Zang C, Schones DE, Zeng C, Cui K, Zhao K, Peng W. A clustering approach for 
identification of enriched domains from histone modification ChIP-Seq data. Bioinformatics 
(Oxford, England) 2009;25:1952-8. 
92. 
Zhang Y, Liu T, Meyer CA, et al. Model-based analysis of ChIP-Seq (MACS). Genome 
biology 2008;9:R137. 


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93. 
Karolchik D, Hinrichs AS, Kent WJ. The UCSC Genome Browser. Current protocols in 
bioinformatics / editoral board, Andreas D Baxevanis  [et al] 2012;Chapter 1:Unit1 4. 
94. 
Kent WJ, Sugnet CW, Furey TS, et al. The human genome browser at UCSC. Genome 
research 2002;12:996-1006. 
95. 
Robinson JT, Thorvaldsdottir H, Winckler W, et al. Integrative genomics viewer. 
Nature biotechnology 2011;29:24-6. 
96. 
Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York, 
NY: John Wiley and Sons; 1980. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A 
NCI COMMON TOXICITY CRITERIA, VERSION 4.0 
 
Version 4.0 of the NCI CTC, dated 14 June 2010, may be viewed and/or downloaded by 
accessing the following website:  
Http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 


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Appendix B 
Prohibited Concomitant Medications 
Generic Name 
Brand Name* 
aminophylline 
Aminocont; Aminomal; Diaphyllin; Filotempo; Neophyllin; Norphyl; 
Phyllocontin; Syntophyllin; Tefamin; Truphylline; Xing You Shan;  
aminophylline in 
combination 
Asmeton; Cha Xin Na Min; Emergent-Ez; Fufang Dan An Pian; Ke Zhi 
 
amitriptyline 
Amirol; Amitrip; Amixide; Deprelio; Diapatol; Elatrol; cElatrolet; 
Elavil; Endep; Enovil; Emitrip; Klotriptyl; Laroxyl; Levate; Limbitrol; 
Limbitryl; Mutabase; Mutabon; Nobritol; Novo-Triptyn; Pertriptyl; 
Redomex; Saroten; Sarotex; Sedans; Syneudon; Teperin; Triptizol; 
Triptyl; Tryptizol 
amitriptyline in 
combination 
PMS-Levazine 
 
bupropion 
 
Aplenzin; Buproban; Contrave; Elontril; Forfivo; Fortivo XL; Le Fu 
Ting; Prexaton; Quomem; Voxra; Wellbutrin; Wellbutrin XL; 
Wellbutrin SR; Yue Ting; Zyban 
chlorpromazine 
Aminazin; Chlorazin; Hibernal; Klorproman; Largactil; Megaphen; 
Ormazine; Plegomazin; Solidon; Taroctyl;Thorazine; Vegetamin; 
Wintermin; Zuledin 
Note: in Ireland  also called “Clonazine” – very easy to confuse with 
clozapine. 
clozapine 
Azaleptin; Clopine; Closastene; Clozaril; CloZAPine; Denzapine; 
Elcrit; Fazacio ODT; Klozapol; Lanolept; Leponex; Lozapine; Nemea; 
Ozapim; Synthon, Versacloz; Zaponex 
desipramine  
Deprexan; Norpramin; Nortimil; Pertofrane 
doxepin 
Adapin; Anten; Aponal; Deptran; Gilex; Li Ke Ning; Quitaxon; Silenor; 
Sinepin; Sinequan; Zonalon 
imipramine 
Impril; Melipramin; Mipralin; Norfranil,; Novo-Pramine; Persamine; 
Pertofram; Pryleugan; Talendep; Tofranil; Tolerade 
lithium 
Arthriselect; Camcolit; Carbolith; Carbolithium; Eskolith; Hypnorex; 
Li-Liquid; Licarbium; Limas; Liskonum; Litarex; Lithane; Lithicarb; 
Lithioderm; Lithionit; Lithobid; Liticarb; Litiomal; Lito; Maniprex; 
Neurolepsin; Plenur; Priadel; Quilonorm; Quilonum; Saniquiet; 
Sedalit; Teralithe 
lithium in 
combination 
Boripharm No 23; Emser Salz; Girheulit HOM; Helidonium-Plus; 
Heweurat N; rheuma-loges; Rhus Toxicodendron Compose; Rhus-
Plus; Ricinus Compose 
maprotiline 
Cronmolin; Deprilept; Ludiomil; Mapromil; Melodil; Neuomil; 
Psymion 
meperidine/pethidine Alodan ; Atropine and Demerol; Centralgine ; Demerol ; Dolantin ; 
Dolantina,; Dolantine ; Dolargan,; Dolcontral,; Dolestine ; Dolosal ; 
Dolsin; Fada; Hospira; Liba; Mepergan ; Meprozine,; Mialgin,; 
Opystan; Pethidine ; Petigan Miro ; Psyquil compositum 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
106 
 
meperidine/pethidine  
in combination 
Pamergan P100 
 
mesoridazine 
Serentil, Mesorin 
mirtazapine 
 
Arintapin; Avanza; Axit; Combar; Esprital; Mi Er Ning; Miro; Mirta 
TAD; Mirtabene; Mirtachem; Mirtadepi; Mirtagamma; Mirtalan; 
MirtaLich; Mirtamylan; Mirtaron; Mirtaz; Mirtazelon; Mirtazon; 
Mirtazonal; Mirtel; Mirtin; Mirtor; Mirzaten; Norset; Noxibel; 
Paidisheng; Psidep; Remergil; Remergon; Remeron; Remirta; Rexer; 
Yarocen; Zispin 
olanzapine 
Anzorin, Arenbil; Arkolamyl; Atyzyo; Bloonis; Clingozan; Egolanza; 
Lansyn; Lanzek; Lazapix; Nolian; Nykob; Olafid; Olanzaran; Olanzep; 
Olanzin; Olanzine; Olapin; Olasyn; Olazax; Olpinat; Olzapin; Olzin; Ou 
Lan Ning; Ozilormar; Parnassan; Ranofren; Sanza; Stygapon; Synza; 
Ximin; Zalasta; Zamil; Zappa; Zapris; Zerpi; Zolafren; Zolaxa; 
Zonapir; Zopridoxin; Zylap; Zypadhera; Zypine; Zyprexa; Zyprexa 
Relprew; Zydis 
olanzapine in 
combination 
Symbyax 
 
risperidone 
Aleptan; Apo-Risperid; Arketin; Calmapride; Diaforin; Doresol; 
Hunperdal; Jing Ping; Ke Tong; Leptinorm; Lergitec; Orizon; Ozidal; 
Perdox; Ranperidon; Resdone; Ridal; Ridonex; Rileptid; Ripedon; 
Risepro; Rispa; Rispaksole; Rispefar; Rispemylan; Rispen; Rispera; 
Risperanne; Risperdal; Risperdalconsta; Risperdaloro; 
Risperigamma; Risperon; Rispolept; Rispolux; Rispond; Rispons; 
Risset; Rixadone; Rorendo; Ryspolit; Si Li Shu; Sizodon; Speridan; 
Suo Le; Torendo; Zhuo Fei; Zhuo Fu; Ziperid; Zoridal 
theophylline 
Aerolate; Afonilum; Aminomal; An Fei Lin; Apnecut; Apo-Theo; Asmalix; 
Asmalon; Bi Chuan; Bronchoparat; Bronchoretard; Cylmin; Diffumal; 
Elixifilin; Elixophyllin; Etipramid; Euphyllin; Euphyllina; Euphylline; 
Euphylong; Frivent; Gan Fei Lin; Nuelin; Protheo; Pulmophylline; 
Quelesu; ratio-Theo-Bronc; Respicur; Retafyllin; Shi Er Ping; Slo-Bid; 
Slo-Phyllin; Telbans; Teotard; Terdan; Teromol; Theo-24; Theo-Dur; 
Theo; Theochron; Theodur; Theofol; Theolair; Theoplus; 
Theospirex; Theostat ;  Theotard; Theotrim; Theovent; Tromphyllin; 
Unicon; Unicontin; Unifyl; Uniphyl; Uniphyllin Continus; Uniphyllin; 
UniXan; Xanthium; Xi Fu Li; Yan Er 
theophylline in 
combination 
Antong; Baladex; Bi Chuan; Binfolipase; Broncho-Euphyllin; 
Broncomar; Do-Do ChestEze; Elixophyllin-GG; Elixophyllin-KI; 
Insanovin; Marax ; Neoasma; Theofol Comp; Theophedrinum-N; Xu 
Hong; Yi Xi Qing 
thioridazine 
Detril; Elperil; Melleril; Ridazin; Ridazine; Thiodazine; Thioril; 
Sonapa 
ziprasidone 
Geodon; Li Fu Jun An; Pramaxima; Si Bei Ge; Ypsila; Zeldox; Zipwell; 
Zypsila; Zypsilan 
 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
107 
 
** Note:  this document is intended as an aid in identifying prohibited meds, but due to the 
global scope of the Apalutamide studies may not be all inclusive.  
Appendix C 
Follow-up Letter Template 
Dear Mr. [insert subject name], 
 
I am writing to follow up with you regarding the clinical trial you participated in around the time of 
your prostate surgery. In this trial you received apalutamide, abiraterone acetate, prednisone 
and indomethacin, which were pills taken every day for 3 months. You also received monthly 
injection of degarelix during this time period. 
As part of this study, we are seeking to determine if you have received any additional treatment 
for your prostate cancer and if your cancer has relapsed. We kindly ask that you answer the 
following questions to the best of your ability and respond either by phone, postal mail or email 
(contact information is below). 
 
Questions: 
 
1. What was your most recent PSA? On what date was this test done? 
 
2. Have you had any imaging tests to determine if your prostate cancer has spread anywhere? 
These could include CT scans, bone scans, or other similar tests.  
 
If yes, please indicate the type of scan(s), date the scan was performed and if the scan 
revealed signs of cancer. 
 
3. Since your prostate surgery, have you received any additional treatment for prostate 
cancer? These could include radiation therapy or hormone therapies (also known as 
androgen deprivation therapy).  
 
If yes, please indicate the type of treatment(s) and on what date each treatment was started 
and stopped. 
 
Sincerely, 
[Insert study coordinator’s name, address, email and phone number] 


CC Protocol Number: 9628 
 
PI: Michael T. Schweizer, MD 
Neoadjuvant therapy in high-risk Prostate Cancer 
 
Protocol Version: 4.0; March 23, 2018 
108