Clinical trial NCT02494713
Conditions: Prostate Cancer
Keywords: Advanced Prostate Cancer Neoadjuvant Hormone therapy ADT Androgen Deprivation Therapy Chemotherapy Radical Prostatectomy
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2015-10-01; Completion date: 2017-09-14
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a study for men who have locally-advanced prostate cancer and are eligible to undergo prostatectomy. Standard treatment is prostatectomy alone, but there is a chance that cancer may spread to other organs in the future, even after the prostate is removed. If this were to occur, standard treatment would be androgen deprivation therapy (ADT; hormone therapy that blocks testosterone) plus chemotherapy. Clinical trials suggest that neoadjuvant treatment (treatment given before primary therapy) may prevent a recurrence. The purpose of this research study is to assess the safety and benefit of ADT plus chemotherapy given before prostate removal.

Detailed description:
This is an open-label, single-arm study of neoadjuvant ADT and chemotherapy in subjects with non-metastatic, locally-advanced prostate cancer who are eligible for radical prostatectomy.

Patients will be treated with 4 monthly injections of degarelix along with two 8-week cycles of chemotherapy. Each cycle of chemotherapy will consist of 6 weeks of chemotherapy and 2 weeks of rest. In the absence of toxicity or disease progression, patients will receive 2 cycles of treatment prior to radical prostatectomy.

The primary endpoint will be complete or near-complete pathologic response.

Safety will be assessed on any patient receiving at least one dose of study drug by the reporting of adverse events, vital signs and by the assessment of findings on physical exam and routine safety laboratory determinations. The severity of adverse events and certain abnormal laboratory findings will be assessed according to the NCI CTCAE V4.03.

Laboratory-based studies will evaluate the following:

* Complete metabolic profile

  o BUN, creatinine, alkaline phosphatase, ALT/AST, total bilirubin, LDH, calcium, albumin, glucose, magnesium, uric acid, phosphorous
* Electrolytes

  o Sodium, potassium, chloride, CO2 content
* Hematology

  * CBC with differential, platelet count
  * PT, INR, PTT
* Testosterone
* Biomarkers

  * PSA
  * CTCs

Arms: arm 1: Patients will be treated with 4 monthly injections of degarelix along with two 8-week cycles of chemotherapy (doxorubicin and ketoconazole, weeks 1, 3, 5 and docetaxel and estramustine, weeks 2, 4, 6). Each cycle of chemotherapy will consist of 6 weeks of chemotherapy and 2 weeks of rest. In the absence of toxicity or disease progression, patients will receive 2 cycles of treatment prior to radical prostatectomy.
Interventions: intervention 1: Degarelix intervention 2: Doxorubicin intervention 3: Ketoconazole intervention 4: Docetaxel intervention 5: Estramustine
Intervention descriptions: intervention 1: Subcutaneous injection, once/month for 4 months intervention 2: 20 mg/m2 as a 24-hour intravenous infusion on day 1 each week, weeks 1, 3, and 5 intervention 3: 400 mg orally 3 times daily for 7 days, in weeks 1, 3, and 5 intervention 4: 35 mg/m2 intravenously on day 1 of each week, weeks 2, 4, and 6 intervention 5: 280 mg orally 3 times daily for 7 days, in weeks 2, 4, and 6

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-14-0424 
IRB APPROVAL DATE: 01/21/2016 
 
 
 
 
 
 
 
 
 
 
 
Neoadjuvant Androgen Deprivation Therapy and Chemotherapy followed by Radical 
Prostatectomy in Patients with Prostate Cancer 
 
NCT02494713 
 
Version Date: 01/21/2016 
 
 


IRB NUMBER: HSC-MS-14-0424 
IRB APPROVAL DATE: 01/21/2016 
 
 
 
 
 
 
 
 
 
 
Neoadjuvant Androgen Deprivation Therapy and Chemotherapy followed by 
Radical Prostatectomy in Patients with Prostate Cancer 
 
 
 
Protocol No:  GU-14-101 
 
 
 
Principal Investigator: 
Robert Amato, DO 
Professor, Department of Internal Medicine, Division of Oncology 
 
Imaging 
Varaha Tammisetti, MD 
Assistant Professor 
Department of Diagnostic & Interventional Imaging 
 
Pathology Gustavo 
Ayala, MD Professor 
and Chair 
Department of Pathology and Laboratory Medicine 
 
Urology Steven 
Canfield, MD Associate 
Professor Department 
of Surgery 
 
Pharmacy 
Nwabugwu S. Ochuwa, PharmD, BCOP 
Clinical Specialist in Oncology 
UT Memorial Hermann Cancer Center 
 
 
 
Version 1: 
January 20, 2015 
Version 2: 
October 1, 2015 
Version 3: 
November 17, 2015 
Version 4: 
January 13, 2016 
 
 
 
 
The study is to be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP) and other applicable regulatory requirements. 
 
 
 
 
 
Signature:  
 
Date:  
 
Robert Amato, DO 


IRB NUMBER: HSC-MS-14-0424 
IRB APPROVAL DATE: 01/21/2016 
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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ........................................................................................................... 4 
 
1.0 
INTRODUCTION ............................................................................................................ 8 
1.1  Prostate Cancer ............................................................................................................. 8 
1.2  Rationale ........................................................................................................................ 9 
 
2.0 
STUDY OBJECTIVES...................................................................................................10 
2.1  Primary Objective ..........................................................................................................10 
2.2  Secondary Objective .....................................................................................................10 
2.3  Tertiary Objective ..........................................................................................................10 
 
3.0 
INVESTIGATIONAL PLAN ...........................................................................................10 
3.1  Study Design .................................................................................................................10 
3.2  Duration of Study...........................................................................................................11 
 
4.0 
PATIENT POPULATION AND SELECTION .................................................................11 
4.1  Inclusion Criteria............................................................................................................11 
4.2  Exclusion Criteria ..........................................................................................................12 
4.3  Removal of Patient from Study ......................................................................................13 
4.4  Patient Replacement .....................................................................................................13 
 
5.0 
TREATMENT ................................................................................................................13 
5.1  Description of ADT ........................................................................................................13 
5.2  Description of Chemotherapy ........................................................................................13 
5.3  Concomitant Medications and Therapies .......................................................................14 
 
6.0 
STUDY ASSESSMENTS ..............................................................................................14 
6.1  Screening Assessments (-7 to -1)..................................................................................14 
6.2  For each cycle: Days 1, 8, 15, 22, 29, 36 (±1) of Chemotherapy Administration ............15 
6.3  Days 1, 29, 57, 85 (±1) of Androgen-Deprivation Therapy Administration......................15 
6.4  End of 2 ADT Treatments and First Cycle of Chemotherapy Visit ..................................15 
6.5  Completion of ADT and Chemotherapy Visit..................................................................15 
6.6  Pathologic Assessment Associated with Radical Prostatectomy (Day 133 ± 7 days) .....16 
6.7  Long-Term Follow-Up ....................................................................................................16 
 
7.0 
TOXICITY CRITERIA ALTERATION OF THERAPY.....................................................16 
7.1  Hematologic Toxicity .....................................................................................................16 
7.2  Specific Non-Hematologic Toxicities..............................................................................17 
7.3  Other Non-Hematologic Toxicities .................................................................................18 
 
8.0 
METHODOLOGY AND STATISTICAL CONSIDERATIONS ........................................19 
8.1  Study Populations .........................................................................................................19 
8.2  Primary Objective ..........................................................................................................19 
8.3  Secondary Objectives....................................................................................................19 
8.4  Tertiary Objectives.........................................................................................................20 
 
9.0 
SAFETY MONITORING ................................................................................................20 
9.1  Adverse Events .............................................................................................................20 
9.2  Serious Adverse Events (SAE) ......................................................................................21 
9.3  Adverse Event Reporting...............................................................................................21 
9.4  Relatedness to Study Drug............................................................................................22 
9.5  Maximum Intensity.........................................................................................................22 
9.6  Data and Safety Review ................................................................................................23 


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10.0 
STUDY MANAGEMENT ...............................................................................................23 
10.1 Ethical Considerations ...................................................................................................23 
10.2 Informed Consent ..........................................................................................................23 
10.3 Institutional Review Board (IRB) Approval and Consent ................................................23 
10.4 Confidentiality................................................................................................................24 
10.5 Subject Data Protection .................................................................................................24 
10.6 Record Retention ..........................................................................................................24 
10.7 Obligations of Investigators ...........................................................................................24 
 
11.0 
REFERENCES ..............................................................................................................26 
Appendix 1:  NCI Common Terminology Criteria for Adverse Eveents, Version 4.03 ............28 
Appendix 2:  Assessment of Performance Status..................................................................29 
Appendix 3:  Schedule of Assessment ..................................................................................30 


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PROTOCOL SYNOPSIS 
 
TITLE 
Neoadjuvant Androgen Deprivation Therapy and Chemotherapy 
followed by Radical Prostatectomy in Patients with Prostate Cancer 
PROTOCOL NUMBER 
GU-14-101 
PHASE OF 
DEVELOPMENT 
Phase 2 
STUDY OBJECTIVES 
Primary Objective 
To assess rates of complete pathologic response or near-complete 
pathologic response of androgen deprivation therapy (ADT) plus 
chemotherapy prior to radical prostatectomy in prostate patients 
presenting with localized high-risk prostate cancer. 
Secondary Objectives 
 
To assess the efficacy of therapy prior to prostatectomy based on: 
o Prostate-specific antigen (PSA) response 
o Circulating tumor cell (CTC) response 
o Volume and profusion of the prostate utilizing multiparametric 
prostate magnetic resonance imaging (mpMRI) 
 
To assess the safety of preoperative administration of ADT and 
chemotherapy 
 
To assess the surgical morbidity following therapy with ADT and 
chemotherapy 
Tertiary Objective 
To assess the effect of ADT and chemotherapy administered in the 
neoadjuvant setting on the natural disease history of patients with 
locally advanced prostate cancer who undergo radical prostatectomy 
STUDY DESIGN 
This is an open-label, single-arm of neoadjuvant ADT and 
chemotherapy in subjects with non-metastatic, locally-advanced 
prostate cancer who are eligible for radical prostatectomy. 
Patients will be treated with 4 monthly injections of degarelix along 
with two 8-week cycles of chemotherapy. Each cycle of 
chemotherapy will consist of 6 weeks of chemotherapy and 2 weeks 
of rest. In the absence of toxicity or disease progression, patients will 
receive 2 cycles of treatment prior to radical prostatectomy. 
The primary endpoint will be complete or near-complete pathologic 
response. 
Safety will be assessed on any patient receiving at least one dose of 
study drug by the reporting of adverse events, vital signs and by the 
assessment of findings on physical exam and routine safety 
laboratory determinations. The severity of adverse events and certain 
abnormal laboratory findings will be assessed according to the NCI 
CTCAE V4.03. 
Laboratory-based studies will evaluate the following: 
 
Complete metabolic profile 
o BUN, creatinine, alkaline phosphatase, ALT/AST, total 


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bilirubin, LDH, calcium, albumin, glucose, magnesium, uric 
acid, phosphorous 
 
Electrolytes 
o Sodium, potassium, chloride, CO2 content 
 
Hematology 
o CBC with differential, platelet count 
o PT, INR, PTT 
 
Testosterone 
 
Biomarkers 
o PSA 
o CTCs 
NUMBER OF 
PATIENTS 
Up to 24 evaluable patients 
INCLUSION 
CRITERIA 
 
Pathologic proof of prostatic adenocarcinoma without evidence of 
regional and/or distant metastasis, clinical stage T1c or T2a with 
high grade disease (Gleason 8-10) on initial biopsy, clinical stage 
T2b-T2c with Gleason grade 7 (4+3), or clinical stage T3. No 
neuroendocrine differentiation or small cell features. 
 
Recent (<6 weeks prior to study entry) negative bone scan and 
CT of the chest and abdomen. 
 
Appropriate surgical candidate for radical prostatectomy and a 
performance status of <2 (ECOG scale). 
 
Adequate bone marrow function as defined as an absolute 
peripheral granulocyte count >1500 and platelet count >100,000. 
 
Adequate hepatic function per the following criteria: 
o Albumin ≥2.8 g/dL 
o AST and ALT ≤5 x ULN 
o Total bilirubin <2 mg/dL 
 
Adequate renal function per the following criteria: 
o Serum creatinine ≤1.5 x ULN 
 
Normal coagulation profile (INR ≤ 1.5, aPTT ≤ 1.5 x ULN for the 
lab) and no history of substantial non-iatrogenic bleeding 
diatheses. Use of anticoagulants is limited to local use only (for 
control of central line patency). 
 
Age ≥ 18 years 
 
Written informed consent to participate in this study. 
EXCLUSON 
CRITERIA 
 
Prostatic adenocarcinoma with neuroendocrine differentiation or 
small cell features 
 
Surgical resection or major surgery within 4 weeks or stereotactic 
biopsy within 1 week of first ADT and chemotherapy treatment 
 
Previous or current hormonal treatment, chemotherapy, radiation 
therapy, immunotherapy, or investigational study drug. 
 
Unable to tolerate multiparametric MRI or is contraindicated. 
 
Patients not appropriate surgical candidates for radical 
prostatectomy based on the evaluation of coexistent medical 
diseases and competing causes of death. 
 
Patients with uncontrolled cardiac, hepatic, renal, or 
neurologic/psychiatric disorder. 
 
Severe gastrointestinal bleeding within 12 weeks of treatment with 


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ADT and chemotherapy 
 
Patients who are HIV positive or have chronic hepatitis B or C 
infections. 
 
Congestive heart failure New York Heart Association (NYHA) 
class 3 or 4, or history of congestive heart failure New York Heart 
Association (NYHA) class 3 or 4, unless a 2D echocardiogram or 
multi-gated acquisition scan (MUGA) performed within 3 months 
of enrollment demonstrates a left ventricular ejection fraction 
>45%. 
 
Sensory neuropathy grade >1. 
 
History of another malignancy within the previous 5 years other 
than curatively treated non-melanoma skin cancer. 
 
Use of herbal products that may decrease PSA levels (e.g., saw 
palmetto) or systemic corticosteroids greater than the equivalent 
of 10 mg of prednisone per day within 4 weeks of enrollment. 
 
Any other condition, including concurrent medical condition, social 
circumstance or drug dependency, which in the opinion of the 
investigator could compromise patient safety and/or compliance 
with study requirements 
DURATION OF 
TREATMENT AND 
STUDY 
PARTICIPATION 
Patients may remain on study for two 8-week cycles or until any of the 
following: 
 
Progressive disease 
 
Initiation of treatment with an alternative therapy 
 
Patient withdraws consent to continue in the trial 
 
Patient develops an adverse event or intercurrent condition that 
precludes further participation or requires a prohibited treatment 
 
The  investigator  withdraws  the  subject  in  the  subject’s  best 
interest 
 
The subject is lost to follow-up 
STUDY DRUG 
ADMINISTRATION 
Treatment will be ADT plus chemotherapy. 
 
ADT 
Patients will be treated with degarelix monthly for 4 months. 
 
Chemotherapy 
Patients will receive two 8-week cycles of chemotherapy (6 weeks 
of chemotherapy followed by 2 weeks of rest). In weeks 1, 3, and 
5, patients will receive doxorubicin (20 mg/m2 as a 24-hour 
intravenous infusion on day 1 of each applicable week) and 
ketoconazole (400 mg orally 3 times daily for 7 days); in weeks 2, 
4, and 6, patients will receive docetaxel (35 mg/m2 intravenously 
on day 1 of each applicable week) and estramustine (280 mg 
orally 3 times daily for 7 days). 
Patients will be pretreated with dexamethasone 4 mg p.o. b.i.d. 24 
hours pre- docetaxel, day of docetaxel administration, and 24 
hours post-docetaxel. Ondansetron 8 mg p.o. and 
diphenhydramine 25 mg i.v. 30 minutes prior to docetaxel 
infusion. 


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Maintenance hydrocortisone (20 mg morning and 10 mg 
afternoon) will be administered daily throughout chemotherapy to 
counteract potential ketoconazole-induced adrenal complications. 
To increase absorption, 250 mg of vitamin C is coadministered 
with ketoconazole. 
 
Androgen Deprivation Therapy 
Patients will be treated with degarelix for 4 months starting week 
1. 
Agent 
Dose and Schedule 
Chemotherapy 
8-week cycle of chemotherapy 
Doxorubicin (ADRIA) 
20 mg/m2 CIV over 24 h on days 
1, 15, 29 
Ketoconazole (KETO) 
400 mg p.o. t.i.d. on days 1-7, 
15-21, 29-35 
Docetaxel (TAXOT) 
35 mg/m2 IVPB on days 8, 22, 
36 
Estramustine (EMCYT) 
280 mg p.o. t.i.d on days 8-14, 
22-28, 36-42 
Hydrocortisone 
20 mg p.o. a.m. & 10 mg p.o. 
p.m. EVERY DAY 
No cytotoxic therapy 
Days 43-56 (hydrocortisone 
continues) 
Week 
ADRIA 
TAXOT 
ADRIA 
TAXOT 
ADRIA 
TAXOT 
i.v. 
KETO 
EMCYT 
KETO 
EMCYT 
KETO 
EMCYT 
(weekly) 
ADT 
 ADT 
ADT 
  ADT 
  5↓ 
 6↓ 
p.o. (3 
1↓ 
2↓ 
3↓ 
4↓ 
times 
daily) 
Weeks 7-8: rest 
CRITERIA TO 
EVALUATE PRIMARY 
ENDPOINT 
Pathology 
CRITERIA TO 
EVALUATE SAFETY 
Safety will  be  assessed  by  the  reporting  of  adverse  events,  vital 
signs, assessment of findings on physical exam and routine safety 
laboratory determinations, and changes in dosing regimen. The 
severity of adverse events and abnormal laboratory findings will be 
assessed according to the NCI CTCAE V4.03. 


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1.0      INTRODUCTION 
 
1.1      Prostate Cancer 
More than one-third of patients with non-metastatic prostate cancer who undergo radical 
prostatectomy eventually relapse with distant disease.1-3 Certain predictors have been identified 
to help delineate those patients with locally advanced prostate cancer who have a high risk of 
regional or distant metastases following radical prostatectomy. These predictors are: serum 
PSA ≥10 ng/mL, Gleason scores of 7(4+3) or ≥8, and clinical stage T3 or T4.4  Extracapsular 
extension,  seminal  vesicle  involvement,  neurovascular  bundle  involvement,  lymph  node 
positivity, and positive surgical margins also are associated with radical prostatectomy failure.5-8 
 
Locally advanced and metastatic prostate cancer is treated with systemic therapy, the standard 
of which is chemotherapy and ADT. We have established the regimen to be used in this study in 
two previously published studies. In one retrospective analysis,9 we examined the records of 31 
men presenting with locally advanced or metastatic castration-resistant prostate cancer. These 
patients were treated with two 8-week cycles of chemotherapy consisting of doxorubicin, 
ketoconazole, docetaxel, and estramustine along with ADT during and after chemotherapy. At 1 
year of follow-up, PSA levels among these patients had decreased by 99%, and their median 
time to progression was >34 months. 
 
Based on the intriguing data from that retrospective study, we conducted a phase 2, prospective 
trial of the same regimen in a similar patient population.10  We found similarly encouraging 
results in that group of 45 patients. Median progression-free survival was 23.4 months, medial 
overall survival was 53.7 months, and nearly 50% of patients had an objective response rate. 
These two  studies  formed the  basis for our current  standard-of-care systemic therapy for 
patients with locally advanced or metastatic castration-resistant prostate cancer. 
 
Neoadjuvant systemic therapy has been shown to improve disease-specific survival and reduce 
recurrences in several cancers, including breast,11 bladder,12 and colon.13 It is generally thought 
that  neoadjuvant  systemic  therapy  decreases  local  tumor  burden  and  eradicates 
micrometastatic disease,  leading  to improved outcome for  patients.  In  those with  prostate 
cancer who undergo local therapy (radical prostatectomy) alone, recurrence rates of 30%-50% 
have been documented; failure of radical prostatectomy is believed to be the result of residual 
disease at the primary site and occult metastatic disease. 
 
Previous neoadjuvant hormonal therapy using 5-alpha reductase inhibitors or GnRH analogs 
has been successfully used to reduce PSA and tumor volumes in patients with prostate cancer; 
however, this approach has not been shown to improve disease-free or overall survival.14-16 
 
Based on the observed benefits of docetaxel chemotherapy in patients with metastatic prostate 
cancer, several studies have examined the role of taxane-based chemotherapy in the 
neoadjuvant setting for high-risk prostate cancers. Phase II studies using docetaxel as a single 
agent have demonstrated biochemical and histologic effects of reducing PSA and down-staging 
tumor  volume.17,18   There  has been some success with chemo-hormonal therapy,  in  which 
taxane-based chemotherapy is used in combination with androgen deprivation therapy with 
GnRH  agonists,  but  complete  pathologic  response  has  been  rare.19   Other  studies  have 
evaluated docetaxel in combination with other agents with anti-androgen activity, including 
estramustine and  ketoconazole.  These regimens also have  demonstrated biochemical and 
some pathologic response, but no complete responses (pCRs) were observed.20,21 


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Abiraterone has been shown to lower serum testosterone and DHT to <1 ng/dL and has 
improved survival in patients with advanced prostate cancer.22 A Phase II study was conducted 
to  evaluate  abiraterone  plus  leuprolide  acetate  administered  in  the  neoadjuvant  setting  in 
patients with localized high-risk prostate cancer. In this study, the effect of leuprolide alone on 
intra-prostatic testosterone/DHT was compared with leuprolide plus abiraterone. Secondary 
endpoints were PSA, pathological complete response, near pathological complete response (≤ 
0.2 cm3 of residual tumor), and safety. Fifty-eight men were treated; 27 received leuprolide and 
29 received leuprolide plus abiraterone. Twenty-five percent (14/56) of patients had a complete 
response or near complete response. Grade 3 adverse events included elevated AST/ALT 
(5/58,  9%)  and  hypokalemia  (3/58,  5%).  Neoadjuvant  androgen  deprivation  therapy  in 
combination with abiraterone was well-tolerated. Declines in PSA were high and achieved 
earlier  when  abiraterone  was  given  alongside  leuprolide  vs.  leuprolide  alone.  Complete 
response rate were higher for 24 weeks of abiraterone (34%) vs. 12 weeks of abiraterone 
(15%). 
The 
authors 
concluded 
that 
aggressive 
androgen 
deprivation 
therapy 
as 
neoadjuvant/adjuvant therapy for patients with localized high-risk prostate cancer needed to be 
further evaluated. 
 
Further studies have continued to bolster the support for the combination of ADT and 
chemotherapy in the neoadjuvant setting for high-risk, locally advanced prostate cancer. A small 
study in Japan23 found that all patients were eligible for radical prostatectomy after their 
neoadjuvant treatment, 77.8% of whom remained disease-free after 18 months of follow-up. A 
larger, NIH-funded, multicenter trial in the United States24  enrolled almost 800 men presenting 
with metastatic prostate cancer and administered neoadjuvant docetaxel with ADT. The three- 
year survival rate in men receiving the neoadjuvant chemotherapy was 69.0%, compared with 
52.5% in men who received ADT alone. These encouraging results underscore the need to 
determine optimal regimens for administering neoadjuvant chemotherapy for the treatment of 
high-risk, locally advanced prostate cancer. 
 
 
 
 
1.2      Rationale 
Thirty to fifty percent of patients with localized high-risk prostate cancer who undergo radical 
prostatectomy eventually relapse with distant disease. Clinical trials suggest that neoadjuvant 
treatment in this patient population is promising, but additional approaches are warranted. 
 
We previously conducted a retrospective analysis of combined neoadjuvant ADT and 
chemotherapy. Records for 20 patients were assessed for pathological parameters comparing 
the diagnostic biopsy to the surgical specimen for changes in Gleason grade, proliferation and 
apoptosis to evaluate for complete pathological response and near complete pathological 
response (≤ 0.2 cm3 of residual tumor). We also assessed the efficacy of therapy prior to 
prostatectomy based on PSA response and the volume and profusion of the prostate utilizing 
multiparametric prostate magnetic resonance imaging (mpMRI). The retrospective review 
indicated that the combination of ADT and chemotherapy in the neoadjuvant setting 
demonstrated pathologic benefit and PSA regression in all patients with minimal reversible 
treatment-related adverse events. 
 
Here we will conduct a prospective clinical trial of neoadjuvant ADT and chemotherapy in 
patients with localized high-risk prostate cancer prior to radical prostatectomy. 


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2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
 
 
To assess rates of complete pathologic response or near-complete pathologic 
response of androgen deprivation therapy (ADT) plus chemotherapy prior to radical 
prostatectomy in prostate patients presenting with localized high-risk prostate cancer. 
 
2.2 
Secondary Objective 
 
 
To assess the efficacy of therapy prior to prostatectomy based on: 
o Prostate-specific antigen (PSA) response 
o Circulating tumor cell (CTC) response 
o Volume and profusion of the prostate utilizing multiparametric prostate 
magnetic resonance imaging (mpMRI) 
 
To assess the safety of preoperative administration of ADT and chemotherapy 
 
To assess the surgical morbidity following therapy with ADT and chemotherapy 
 
2.3 
Tertiary Objective 
 
 
To assess the effect of ADT and chemotherapy administered in the neoadjuvant 
setting  on  the  natural  disease  history  of  patients  with  locally  advanced  prostate 
cancer who undergo radical prostatectomy 
 
 
 
 
3.0 
INVESTIGATIONAL PLAN 
 
3.1 
Study Design 
This study is a single-arm, prospective clinical trial of neoadjuvant ADT and chemotherapy in 
patients   with   locally-advanced,   high-risk   prostate   cancer   who   are   eligible   for   radical 
prostatectomy. 
 
Patients will undergo a screening period. Those who are deemed eligible will be entered into the 
study. A total of 24 patients will be enrolled in this study and, in the absence of prohibitive 
toxicity, will receive 4 monthly treatments with ADT and 2 cycles chemotherapy prior to 
prostatectomy. 
 
Patients will be treated with 4 monthly injections of degarelix along with two 8-week cycles of 
chemotherapy. Each cycle of chemotherapy will consist of 6 weeks of chemotherapy and 2 
weeks of rest. 
 
Patients will receive two 8-week cycles of chemotherapy (6 weeks of chemotherapy followed by 
2 weeks of rest). In weeks 1, 3, and 5, patients will receive doxorubicin (20 mg/m2 as a 24-hour 
intravenous infusion on day 1 of each applicable week) and ketoconazole (400 mg orally 3 times 
daily for 7 days); in weeks 2, 4, and 6, patients will receive docetaxel (35 mg/m2 intravenously on 
day 1 of each applicable week) and estramustine (280 mg orally 3 times daily for 7 days). 
 
Patients will be pretreated with dexamethasone 4 mg p.o. b.i.d. 24 hours pre- docetaxel, day of 
docetaxel administration, and 24 hours post-docetaxel. Ondansetron 8 mg p.o. and 
diphenhydramine 25 mg i.v. 30 minutes prior to docetaxel infusion. 
 
Maintenance hydrocortisone (20 mg morning and 10 mg afternoon) will be administered daily 
throughout chemotherapy to counteract potential ketoconazole-induced adrenal complications. 


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Since all of the drugs in this trial are standard of care, there may be instances when subjects will 
receive their treatment at other infusion centers as well as their standard blood draws due to 
insurance network provider determinations, cost, etc. Dr. Amato will work closely with referring 
physicians and infusion centers. The lab results and clinic/infusion notes will be obtained and 
reviewed by Dr. Amato. All subjects will still come to the cancer center for restaging study visits. 
 
The primary objective of the study is to evaluate the biologic activity of ADT and chemotherapy 
administered  in  the  neoadjuvant  setting  prior to  radical  prostatectomy.  Tissue  collected for 
disease diagnosis, Gleason score, proliferation and apoptotic index will be measured. After 4 
months of ADT and 2 cycles of chemotherapy, the patient will undergo radical prostatectomy and 
these same parameters will be assessed on the surgical specimen. It is anticipated that ADT and 
chemotherapy will bring about pathologic or near pathology complete responses. 
 
The safety of ADT and chemotherapy in this patient population will be assessed based on the 
incidence, severity, duration, causality, seriousness and type of adverse events (AEs) and 
changes in the patient’s physical examinations, vital signs, and clinical laboratory results. The 
severity of adverse events and abnormal laboratory findings will be assessed according to the 
NCI CTCAE V4.03. 
 
The effect of ADT and chemotherapy on PSA and CTC levels will be assessed at 8-week 
intervals after beginning treatment for the first 4 months. 
 
The volume and perfusion of the prostate will be assessed by multiparametric prostate magnetic 
resonance imaging (mpMRI) before beginning treatment with ADT and chemotherapy. The effect 
of ADT and chemotherapy on volume and perfusion will be assessed after 2 cycles of 
chemotherapy. 
 
 
3.2      Duration of Study 
It is anticipated that all patients will be enrolled within 12 months of study initiation. With 4 
months of ADT treatment, 2 cycles of chemotherapy, and surgery performed at Week 18-20, it is 
anticipated that active participation in the study will conclude within 18 months of study initiation. 
Long-term indirect follow-up to assess patient outcome by chart review will continue for up to 10 
years. 
 
 
 
4.0      PATIENT POPULATION AND SELECTION 
 
Patients who meet all eligibility criteria, are able and willing to participate in the study, and who 
provide written informed consent to participate will be enrolled. 
 
4.1      Inclusion Criteria 
 
Patients must meet all of the inclusion criteria to participate in this study: 
 
4.1.1 Pathologic confirmation of prostatic adenocarcinoma without evidence of regional 
and/or distant metastasis 
 
4.1.2 Negative bone scan and CT of chest and abdomen within 6 weeks of first 
treatment 
 
4.1.3 Candidate for radical prostatectomy (i.e., disease confined to the prostate) and 
ECOG performance status <2 (Appendix 2) 


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4.1.4 Adequate bone marrow function, defined as absolute peripheral granulocyte count 
>1500 and platelet count >100,000 cells/mm3 
 
4.1.5 Clinical stage T1c or T2a with high-grade disease (Gleason 8-10) on initial biopsy, 
clinical stage T2b-T2c with Gleason grade 7 (4+3), or clinical stage T3 
 
4.1.6 Most recent liver function tests performed within 7 days prior to the first infusion of 
treatment indicate adequate hepatic function per the following criteria: 
 
 
Albumin ≥ 2.8 g/dL 
 
AST and ALT ≤ 5 x ULN for the lab 
 
Total bilirubin < 2 mg/dL 
 
4.1.7 Most recent renal function tests performed within 7 days prior to the first dose of 
study therapy indicate adequate renal function per the following criteria: 
 
 
Serum creatinine ≤ 1.5 x ULN for the lab 
 
4.1.8 Use of anticoagulants is limited to local use only (for control of central line 
patency). Most recent coagulation studies performed within 2 weeks prior to the 
first dose of study therapy indicate an acceptable coagulation profile per the 
following criteria and no history of substantial non-iatrogenic bleeding diatheses: 
 
 
INR ≤ 1.5 
 
aPTT ≤ 1.5 x ULN for the lab 
 
4.1.9 Age ≥ 18 years 
 
4.1.10 Written, informed consent to participate in this study. 
 
4.2 
Exclusion Criteria 
Subjects  meeting  any  of  the  exclusion  criteria  at  baseline  will  be  excluded  from  study 
participation: 
 
4.2.1 Prostatic adenocarcinoma with neuroendocrine differentiation or small cell 
features 
 
4.2.2 Surgical resection or major surgery within 4 weeks or stereotactic biopsy within 1 
week of first ADT and chemotherapy treatment 
 
4.2.3 Previous  or  current  hormonal  treatment,  chemotherapy,  radiation  therapy, 
immunotherapy, or investigational drug for the patient’s prostatic adenocarcinoma 
 
4.2.4 Unable to tolerate multiparametric MRI or is contraindicated 
 
4.2.5 Patients not appropriate surgical candidates for radical prostatectomy based on 
the evaluation of coexisting medical diseases and competing causes of death 
 
4.2.6 Severe or uncontrolled medical disease, including uncontrolled cardiac, hepatic, 
renal, or neurologic/psychiatric disorder 
 
4.2.7 Severe  gastrointestinal  bleeding  within  12  weeks  of  treatment  with  ADT  and 
chemotherapy 
 
4.2.8 Positive for HIV or chronic hepatitis B or hepatitis C infection 
 
4.2.9   Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or 
history of congestive heart failure NYHA class 3 or 4, unless a 2D echocardiogram 
or multi-gated acquisition scan performed within 3 months of enrollment 
demonstrates a left ventricular ejection fraction >45%. 


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4.2.10 Another primary malignancy that has not been in remission for at least 2 years. 
Non-melanoma skin cancer or intraepithelial carcinoma of the cervix is allowed. 
 
4.2.11 Use of herbal products that may decrease PSA levels (e.g., saw palmetto) or 
systemic corticosteroids greater than the equivalent of 10 mg of prednisone per 
day within 4 weeks of screening laboratory studies. 
 
4.2.12 Any other condition, including concurrent medical condition, social circumstance 
or drug dependency, which in the opinion of the investigator could compromise 
patient safety and/or compliance with study requirements 
 
 
4.3   Removal of Patient from Study 
A patient may be removed from the study for a variety of reasons, including: 
 
       Progressive disease 
       Patient becomes ineligible for radical prostatectomy 
       Initiation of nonstudy treatment for prostate carcinoma 
       Patient withdraws consent to continue in the trial 
 
Patient  develops  an  adverse  event  or  intercurrent  condition  that  precludes  further 
participation or requires a prohibited treatment 
       The investigator withdraws the subject in the subject’s best interest 
 
The subject is lost to follow-up (defined as inability to contact the subject on at least 2 
separate occasions over a period of 4 weeks) 
 
Administrative reasons (the patient is unable to return to the site, moves away from the 
investigational site, other social reasons) 
 
Patients  who  withdraw  in  the  absence  of  progressive  disease  will  be  followed  for  disease 
progression, recurrence after prostatectomy, and survival. 
 
4.4   Patient Replacement 
 
 
If a patient completes at least 1 cycle of chemotherapy with 2 doses of ADT and has to undergo 
prostatectomy operation early (rather than at weeks 18-20 after 2 cycles of chemotherapy), that 
patient will be considered evaluable for the primary objective. Otherwise, the patient will be 
replaced in the study. 
 
 
 
5.0      TREATMENT 
 
5.1      Description of ADT 
 
 
Patients will be treated with degarelix every 28 days for 4 months. 
 
5.2      Description of Chemotherapy 
 
 
Patients will receive two 8-week cycles of chemotherapy (6 weeks of chemotherapy 
followed by 2 weeks of rest). In weeks 1, 3, and 5, patients will receive doxorubicin (20 
mg/m2 as a 24-hour intravenous infusion on day 1 of each applicable week) and 
ketoconazole (400 mg orally 3 times daily for 7 days); in weeks 2, 4, and 6, patients will 


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receive docetaxel (35 mg/m2 intravenously on day 1 of each applicable week) and 
estramustine (280 mg orally 3 times daily for 7 days). 
 
Patients will be pretreated with dexamethasone 4 mg p.o. b.i.d. 24 hours pre- docetaxel, 
day of docetaxel administration, and 24 hours post-docetaxel. Ondansetron 8 mg p.o. 
and diphenhydramine 25 mg i.v. 30 minutes prior to docetaxel infusion. 
 
Maintenance hydrocortisone (20 mg morning and 10 mg afternoon) will be administered 
daily throughout chemotherapy to counteract potential ketoconazole-induced adrenal 
complications. To increase absorption, 250 mg of vitamin C is coadministered with 
ketoconazole. 
 
5.3      Concomitant Medications and Therapies 
 
5.3.1 Permitted Medications 
All intercurrent medical conditions and adverse events should be treated in accordance 
with community standards of medical care. Any changes in documented, permitted 
concomitant medications being taken at the beginning of the clinical trial or permitted 
concomitant medications added during the time the patient is participating in this study 
must be recorded. 
 
5.3.2 Prohibited Medications 
 
Any other anti-cancer therapy, including radiotherapy and other investigational agents, 
are prohibited during the study. 
 
5.3.3 End of Treatment 
 
Patients may remain on study for two 8-week cycles or until any of the following: 
 
Progressive disease 
 
Initiation of treatment with an alternative therapy 
 
Patient withdraws consent to continue in the trial 
 
Patient develops an adverse event or intercurrent condition that precludes further 
participation or requires a prohibited treatment 
 
The investigator withdraws the subject in the subject’s best interest 
 
The subject is lost to follow-up 
 
 
 
6.0      STUDY ASSESSMENTS 
 
All study assessments, including safety and response assessments, are described in Appendix 3 
and summarized by type of study visit in the following pages. All visit dates and procedures are 
relative to Day 1, defined as the first day of treatment infusion, of each cycle. 
 
6.1      Screening Assessments (-7 to -1) 
    Collection of written informed consent 
    Medical history 
    Concomitant medications assessment 
    Physical examination, vital signs, height, weight 
    Performance status assessment 
    Testosterone 


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 
Hematology 
 
Serum chemistry 
 
Coagulation panel 
 
Urinalysis 
 
ECG, echocardiogram 
 
Disease assessment (DRE, bone scan, CT of chest and abdomen, mpMRI of the pelvis) 
 
Collection of tissue for laboratory studies 
 
Collection of blood for PSA and CTCs 
 
Adverse Events assessment 
 
6.2 
For each cycle: Days 1, 8, 15, 22, 29, 36 (±1) of Chemotherapy Administration 
 
Interim physical examination 
 
Vital signs, weight 
 
Hematology and serum chemistry, if not performed in previous 72 hours 
 
Concomitant medications assessment 
 
Adverse events assessment 
 
Administration of treatment, including pre-medications, post-infusion observation period 
 
6.3 
Days 1, 29, 57, 85 (±1) of Androgen-Deprivation Therapy Administration 
 
Interim physical examination 
 
Vital signs, weight 
 
Hematology and serum chemistry, if not performed in previous 7 days 
 
Testosterone 
 
Concomitant medications assessment 
 
Adverse events assessment 
 
6.4 
End of 2 ADT Treatments and First Cycle of Chemotherapy Visit 
 
Interim physical examination 
 
Vital signs 
 
Performance Status assessment 
 
Hematology and serum chemistry 
 
Testosterone 
 
Urinalysis and coagulation panel 
 
Disease assessment (mpMRI) 
 
Concomitant medications assessment 
 
Adverse events assessment 
 
Collection of blood for PSA, CTCs 
 
6.5 
Completion of ADT and Chemotherapy Visit 
 
Physical examination 
 
Vital signs 
 
Performance Status assessment 
 
Hematology and serum chemistry 
 
Testosterone 
 
Urinalysis and coagulation panel 
 
Disease assessment (mpMRI) 


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    Concomitant medications assessment 
    Adverse events assessment 
    Collection of blood for PSA, CTCs 
 
6.6      Pathologic Assessment Associated with Radical Prostatectomy (Day 133 ± 7 days) 
    Collection of blood for PSA, CTCs 
    Collection of prostatectomy tissue for pathologic assessment 
 
6.7      Long-Term Follow-Up 
PSA and CTCs will be assessed every 3 months for the first 2 years after the completion of the 
therapy program. PSA will be assessed every 6 months for the following 3 years and annually 
thereafter. Other follow-up measurements include mpMRI and bone scans at yearly intervals 
beginning when PSA elevation (>0.3 ng/mL) is detected or earlier if clinically indicated, 
documentation of recurrence and survival. When applicable, follow-up may be assessed by 
medical record review, telephone call or review of the Social Security Index. 
 
7.0      TOXICITY CRITERIA ALTERATION OF THERAPY 
 
 
Ketoconazole/ estramustine dose level 
Dose Level 
Tablet/capsule 
0 
2 tablets t.i.d 
1 tablet t.i.d 
-1 
If >1 dose level reduction is required, patient will be removed from the study. 
 
Doxorubicin dose level 
Dose Level 
Dose (mg/m2) 
0 
20 
-1 
15 
If >1 dose level reduction is required, patient will be removed from the study. 
 
Docetaxel dose level 
Dose Level 
Dose (mg/m2) 
0 
35 
-1 
30 
-2 
25 
If >2 dose level reductions are required, patient will be removed from the study. 
 
Previous studies on the use of this regimen, including our retrospective analysis,9 have indicated 
no combinatorial effects of the regimen and only minimal, reversible adverse events during 
treatment. However, patients will be questioned about unexpected adverse events during clinic 
visits. 
 
 
7.1      Hematologic Toxicity 
Patients must have an absolute granulocyte (neutrophil) count (ANC) >1,000 and platelet count 
>75,000 in order to receive doxorubicin or docetaxel. If these counts are not obtained, treatment 
should be withheld for 1 week and counts rechecked. Filgrastim can be administered as needed 
to increase ANC counts. When counts have recovered, treatment should resume with the drug 
that was due when therapy was suspended (i.e., docetaxel and doxorubicin will continue to 


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alternate). Weeks 7 and 8 will be “rest” weeks no matter how many doses of chemotherapy were 
actually delivered in weeks 1-6. 
 
If >1 week is required for cell counts recover, treatment will be resumed with doxorubicin at 15 
mg/m2  and docetaxel at 30 mg/m2  (i.e., 25% reduction). This 25% dose reduction should also 
apply if a patient has a second or third treatment delay. If therapy is delayed >3 times or >3 
weeks are required for cell count recovery, chemotherapy will be discontinued and the patient 
will proceed directly to androgen deprivation. 
 
 
 
7.2      Specific Non-Hematologic Toxicities 
 
Patients unable to tolerate ketoconazole due to GI upset should be offered sucralfate, 1 g 
p.o. q.i.d., observing the convention of taking it 1 hour before or 2 hours after a dose of 
ketoconazole. If that is not helpful, ketoconazole should be reduced by 50% to 200 mg 
p.o.  t.i.d.  If  patients  still  cannot  tolerate  ketoconazole,  it  will  be  discontinued.  Such 
patients may continue with the rest of the regimen at the discretion of the treating 
physician. 
 
 
Patients with transaminases >4 × ULN should discontinue ketoconazole/estramustine 
until the transaminases are <2 × ULN. Ketoconazole may be restarted at 200 mg p.o. 
t.i.d. at the discretion of the treating physician, with weekly liver enzyme monitoring. 
 
 
Patients  developing  a  deep  venous  thrombosis  or  pulmonary  embolism  will  have 
estramustine discontinued. They may continue on the remainder of the regimen at the 
discretion of the treating physician. 
 
 
Patients   who   have   myocardial   infarction   or   stroke   will   have   all   chemotherapy 
discontinued and proceed to androgen deprivation. 
 
 
After starting an antiandrogen, patients experiencing an increase in hepatic enzymes to 
>4 × ULN will have the agent withdrawn for a month. If the patients had been on 
flutamide, it is suggested that bicalutamide or nilutamide be substituted. Patients unable 
to tolerate an alternative anti-androgen will be maintained on testicular suppression only. 
 
 
Other hepatotoxicities: 
 
 
If a grade 1 increase in AST, ALT, or bilirubin occurs (e.g., increase in AST or ALT 
from ULN to 2.5× ULN or increase in total bilirubin from ULN to 1.5× ULN), the 
frequency of liver function test monitoring should be increased if the Investigator 
judges that the laboratory abnormalities are potentially related to study medication. 
No study treatment dose reduction is required. 
 
 
If a grade 2 increase in AST, ALT, or bilirubin occurs (e.g., AST or ALT to >2.5-5× 
ULN or total bilirubin to 1.5-3× ULN), the frequency of liver function test monitoring 
should be increased to at least once per week if the Investigator judges that the 
laboratory  abnormalities  are  potentially  related  to  study  medication.  No  study 
treatment dose reduction is required. 
 
 
If a grade 3 increase in AST, ALT, or bilirubin occurs (e.g., AST or ALT to >5× ULN or 
total bilirubin to >3× ULN), hold study medication and all other concomitant 
medications that are potentially hepatotoxic. Frequent laboratory evaluations (at least 
once per week) should be conducted until liver function results return to baseline 
value or grade 1. Liver enzymes should be measured immediately, regardless of 
when the next study visit or monitoring interval is scheduled. 


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o If study treatment resumption is considered for subjects who have experienced 
grade 3 increases in AST, ALT, or bilirubin, and the Medical Monitor agrees, 
resume study treatment with the first dose level reduction when grade 3 
toxicities resolve to grade 1 or baseline. 
 
o If  grade  ≥3  increases  in  AST,  ALT,  or  bilirubin  recur  after  the  first  dose 
reduction, hold study medication and all other concomitant medications that are 
potentially hepatotoxic. Frequent laboratory evaluations should be conducted 
(at least once per week) until liver function results return to baseline value or 
grade 1. Liver enzymes should be measured immediately, regardless of when 
the next study visit or monitoring interval is scheduled. 
 
o If study treatment resumption is considered for patients who have experienced 
grade 3 increases in AST, ALT, or bilirubin with the first dose reduction and the 
Medical Monitor agrees, resume study treatment with the second dose level 
reduction (see table) when AST, ALT, or bilirubin returns to baseline value or 
grade 1. 
 
 
If grade 4 increases in AST, ALT, or bilirubin occur (e.g., AST or ALT to >20× ULN or 
total bilirubin to >10× ULN), patients must discontinue study treatment immediately 
and will not be re-challenged.  They should be followed until resolution of abnormal 
liver function tests. 
 
 
Doxorubicin is extensively metabolized in the liver and eliminated primarily in bile. Up 
to 40% of an administered dose is eliminated through the bile duct. Very small 
amounts of drug are eliminated through the urinary system. Doxorubicin is well 
tolerated. Common side effects include alopecia (92%), nausea (>10%) and vomiting 
(34%-37%), myelosuppression, cardiomyopathy, and secondary malignancies. It is 
unclear which mechanisms play the biggest role in the cytotoxicity. However, it is 
clear that free radical formation, as a result of reactions with metal catalysts (e.g. iron, 
copper) and hydrogen peroxide is responsible for the cumulative cardiac toxicity seen 
with doxorubicin. Although commonly seen at total doses in excess of 500 mg/m2, it 
is  clear  that  some  patients  have  clinically  significant  cardiac  dysfunction  at 
substantially lower doses. 
 
 
Docetaxel-associated neuropathy is usually mild and predominantly sensory. In most 
cases  symptoms  resolve  after  treatment  discontinuation,  but  the  toxicity  can  be 
severe and dose limiting, with symptoms that persist (and may even worsen) long 
after the last dose has been administered. Symptoms of neuropathy include 
paresthesia (skin sensation such as burning, prickling, itching, or tingling, with no 
apparent  physical  cause),  weakness,  feeling  of  heaviness  in  hands  and  feet, 
numbness and loss of ankle and knee jerk. These symptoms often result in 
clumsiness, loss of dexterity and unsteadiness of gait, and can be both painful and 
disabling. Peripheral neuropathy is most commonly prevented by dose reduction. 
Whether the incidence of neuropathy is reduced by corticosteroid use remains 
unproven. There is also some anecdotal evidence that vitamin B6 may help to guard 
against neuropathy, and published preliminary evidence that glutathione may be 
protective. These measures require further study. There are no evidence-based 
management strategies for docetaxel-induced neuropathy 
 
 
 
7.3 
Other Non-Hematologic Toxicities 


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NCI standard toxicity criteria are included as Appendix A. Any grade 3 or 4 toxicity should be 
reported promptly to the Principal Investigator, and therapy should be held. Since such events 
are  anticipated  to  be  distinctly  uncommon,  dosage  adjustment  will  be  determined  on  an 
individual basis. 
 
 
 
8.0      METHODOLOGY AND STATISTICAL CONSIDERATIONS 
 
8.1      Study Populations 
The Safety population will consist of all subjects who have received at least one cycle of ADT 
and chemotherapy. 
 
The Evaluable population will consist of all subjects who received at least two cycles of ADT and 
chemotherapy and underwent radical prostatectomy. 
 
Safety analyses will be performed in the Safety population. Other objectives will be assessed in 
the Evaluable population. 
 
 
8.2      Primary Objective 
 
To assess rates of complete pathologic response or near-complete pathologic 
response of androgen deprivation therapy (ADT) plus chemotherapy prior to radical 
prostatectomy in prostate patients presenting with localized high-risk prostate cancer. 
 
8.2.1   Power and Sample Size for Primary Objective 
 
This is a single-arm study with pathologic complete response (CR) and near-complete 
response (PR) as the primary efficacy end point. Using the one-step Fleming design, 
while considering a response rate <25% not sufficient to warrant further research, 24 
patients were needed to assure with 90% power and a type I error of 0.05 that if the 
response rate is ≥40% this regimen can be recommended for further investigation. 
Therefore, a CR and PR among ≥10 of the 24 patients would indicate that this regimen 
merits further study.  Patients with CR will be compared with those with PR and examined 
for differences in patient, tumor, and laboratory factors. Fisher’s exact test or chi-square 
test will be used to compare categorical variables, and Student's t test or the Wilcoxon 
two-sample test will be used to compare continuous variables. Significance is set at 
P≤0.05. 
 
8.3      Secondary Objectives 
 
To characterize the clinical activity of neoadjuvant ADT and chemotherapy by 
evaluation of: 
o PSA response 
o CTC response 
o Volume and profusion of the prostate utilizing mpMRI 
 
To investigate the safety profile of ADT and chemotherapy in patients with localized, 
high-risk prostate cancer prior to radical prostatectomy 
 
To assess surgical morbidity after preoperative administration of ADT and 
chemotherapy 
 
8.3.1   Analysis of Secondary Objectives 


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With exception of the safety investigations, secondary endpoint analyses will be performed 
for all patients having received at least 2 cycles of chemotherapy. These studies are 
essentially exploratory in nature and are not designed to meet statistical significance.  
Data from these studies will be summarized using descriptive statistics.  As necessary, 
more definitive statistical methods can be applied to evaluate apparent trends. Subgroup 
analyses will be performed as appropriate. 
 
 
8.3.2 Safety Assessments 
 
Adverse events, including outcome, severity and relationship to the study treatment, will 
be listed. Incidence rates of adverse events and the proportion of subjects prematurely 
withdrawn from the study due to adverse events will be shown.  Treatment-emergent 
adverse events and concomitant medications will be summarized over the entire study 
period. Treatment-emergent adverse events also will also be summarized by severity 
and by relatedness to study medication.  Serious adverse events (SAE) will be 
summarized.  Reasons for withdrawal from the study will be summarized. 
 
8.4      Tertiary Objectives 
 
 
To assess the effect of ADT and chemotherapy administered in the neoadjuvant 
setting  on  the  natural  disease  history  of  patients  with  locally  advanced  prostate 
cancer who undergo radical prostatectomy. 
 
8.4.1 Analysis of Tertiary Objectives 
After prostatectomy, patients will undergo routine standard of care per the Investigator’s 
recommendation.  Long-term follow-up will consist of chart abstractions and will attempt 
to collect PSA levels at 9 months, 12 months, every 6 months for 5 years and annually 
thereafter;  CTCs at 9 months and 12 months;  mpMRI and bone scans at yearly intervals 
beginning when PSA elevation (>0.3 ng/mL) is detected or earlier if clinically indicated; 
documentation of recurrence;  documentation of survival. 
 
 
9.0      SAFETY MONITORING 
9.1      Adverse Events 
The Investigator is responsible for monitoring the safety of patients who have entered the study. 
An adverse event (AE) is any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of the investigational 
product, whether or not related to the investigational product. 
 
Adverse events will be graded according to the NCI Common Terminology Criteria for Adverse 
Events version 4.03. All AEs, including observed or volunteered problems, complaints or 
symptoms, must be recorded. Investigators must document all AEs occurring during the clinical 
trial, commencing with the first administration of ADT and chemotherapy. Patients will be 
instructed to report to the Investigator any AE that they experience. Laboratory data will be 
collected in this study and analyzed using objective toxicity criteria. Abnormal laboratory values 
that are determined to be SAEs will be captured. Laboratory value changes from baseline 
generally will not be recorded as AEs unless they become an SAE and/or DLT. Disease 
progression is considered an efficacy outcome parameter and not an AE. 
 
Each adverse event should be evaluated to determine: 


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    duration (start and end dates) 
    severity (grade) 
    seriousness 
    relationship to study agent 
    action taken (i.e., none, study agent modification, medical intervention) 
    outcome (i.e., resolved without sequelae, resolved with sequelae, ongoing) 
 
All patients experiencing a documented adverse event at least possibly related to the study drug 
will be monitored until: 
 
the adverse event resolves or the symptoms or signs that constitute the adverse event return 
to baseline or stabilize; 
    there is a satisfactory explanation other than the study drug for the changes observed; 
    the patient begins alternative treatment; or 
    death. 
 
 
 
9.2      Serious Adverse Events (SAE) 
A Serious Adverse Event (SAE) is defined in regulatory terminology as any untoward medical 
occurrence that: 
    Results in death 
 
 
Is life-threatening (The patient 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 in-patient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 
 
    Results in persistent or significant disability or incapacity 
 
    Is a congenital anomaly/birth defect 
 
    Is an important medical event 
 
 
Any event that does not meet the above criteria, but that in the judgment of the investigator 
jeopardizes the patient, may be considered for reporting as a serious adverse event. The event 
may  require  medical  or  surgical  intervention  to  prevent  one  of  the  outcomes  listed  in  the 
definition of “Serious Adverse Event”. Examples include: allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
 
 
 
9.3      Adverse Event Reporting 
Adverse events that are serious, unexpected, and at least possibly related to study participation 
will be reported to the Institutional Review Board and the DSMB according to their respective 
requirements. 
 
9.3.1   Expedited Reporting 
The Principal Investigator must be notified within 24 hours of learning of any serious 
adverse events, regardless of attribution, occurring during the study or within 30 days of 
the last administration of the study drug. 


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Serious Adverse Events (SAE) that are determined by the PI to be unexpected + related 
will be submitted to the DSMB within 7 calendar days of the determination by telephone 
or fax; written report no later than 15 calendar days of the determination.  Deaths should 
be reported to the IRB within 24 hours of investigator knowledge.  Any unexpected, 
serious, related adverse experiences should be reported to the IRB within 7 calendar 
days of investigator knowledge. 
 
The IRB will be notified within 7 calendar days of “any unanticipated problems involving risk 
to subjects or others” (UPR). Examples include: 
 
Any adverse event which in the opinion of the PI is both unexpected and related and 
places patients or others at risk of harm 
 
Protocol deviation that harmed patients or placed patients in increased risk of harm 
 
Unanticipated adverse device effect 
 
A breach of confidentiality 
 
Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic 
used in a research protocol 
 
Information that indicates a change to the risks or potential benefits of the research 
 
 
9.4 
Relatedness to Study Drug 
The Investigator must attempt to determine if an adverse event or serious adverse event is 
related to the use of the study drug. This relationship should be described as follows: 
 
Unlikely     The event is clearly due to causes distinct from the use of the study drug, such as a 
documented pre-existing condition, the effect of a concomitant medication, a new 
condition   which,   based   on   the   pathophysiology   of   the   condition   and   the 
pharmacology of the study drug, would be unlikely to be related to use of the study 
drug. 
Possible    The event follows a reasonable temporal sequence from administration of the study 
drug and the event follows a known response pattern to the study drug BUT the 
event could have been produced by an intercurrent medical condition which, based 
on the pathophysiology of the condition and the pharmacology of the study drug, 
would be unlikely to be related to the use of the study drug OR the event could be 
the effect of a concomitant medication. 
Probable   The event follows a reasonable temporal sequence from administration of the study 
drug and the event follows a known response pattern to the study drug AND the 
event cannot have been reasonably explained by an intercurrent medical condition 
OR the event cannot be the effect of a concomitant medication. 
Definite     The event follows a reasonable temporal sequence from administration of the study 
drug, the event follows a known response pattern to the study drug and based on the 
known pharmacology of the study drug, the event is clearly related to the effect of the 
study drug. 
Unknown  Based on the evidence available, causality cannot be ascribed. 
 
 
 
9.5 
Maximum Intensity 
The Investigator will evaluate all AEs and SAEs with regard to maximum intensity and 
relationship to study drug. Maximum intensity should be assigned using one of the severity 
grades as outlined in the NCI CTCAE v4.03. If the adverse event is not specifically listed in 
CTCAE v4.03, the following grades will be used: 


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    Grade 1: mild 
    Grade 2: moderate 
    Grade 3: severe 
    Grade 4: life-threatening or disabling 
    Grade 5: death 
 
 
9.6      Data and Safety Review 
 
 
Subjects enrolled to the trial will be monitored for adverse events by the Investigator and clinical 
co-investigators. Safety data will be reviewed after every 5 patients have completed their first 
cycle by the investigators and the medical monitor. Adverse events will be graded according to 
the NCI Common Terminology Criteria for Adverse Events version 4.03. Toxicity assessments 
are required prior to study treatment, at the beginning of each treatment cycle, following 
termination of study treatment, and may be performed at any additional time at the discretion of 
the treating physician. 
 
To ensure that the protocol and Good Clinical Practices (GCP) are being followed and that study 
data are accurate, complete and reliable, the trial will be monitored by a Data Safety Monitoring 
Board (DSMB), Medical Monitor and CRA monitoring as specified in the Data Safety Monitoring 
Plan (DSMP) for the study and the DSMB’s charter. 
 
10.0    STUDY MANAGEMENT 
 
10.1    Ethical Considerations 
This study will be conducted in accordance with current Regulatory Authorities regulations, ICH 
GCP guidelines, the principles of the Declaration of Helsinki, and local ethical and legal 
requirements. 
 
 
 
10.2    Informed Consent 
The IRB-approved Informed Consent document (ICD) must be signed by the patient before 
participation in the study. A signed copy of the ICD must be provided to the patient. If necessary, 
the ICD will be provided in a certified translation of the local language. 
 
Signed consent forms must remain in each patient’s file and must be available for verification by 
study monitors or authorized regulatory representatives at any time. 
 
10.3    Institutional Review Board (IRB) Approval and Consent 
The IRB should approve the consent form and protocol prior to any study-related activities. It is 
expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 


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regulations. Once this essential information has been provided to the patient and the investigator 
is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an IRB-approved consent 
form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
 
10.4    Confidentiality 
The information obtained during the conduct of this clinical study is confidential, and disclosure to 
third parties other than regulatory authorities is prohibited. Processing, evaluation or use of the 
information will be performed by a health professional for medical purposes and/or by those 
operating under a duty of confidentiality that is equivalent to that of a health professional. 
 
All investigators and research study personnel who process information from the study must 
agree to take appropriate measures to prevent unauthorized or unlawful processing or disclosure 
of data. 
 
10.5    Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), subjects 
who have provided written informed consent must also sign a subject authorization to release 
medical information to the study investigator and allow a regulatory authority, or Institutional 
Review Board access to subject’s medical information relevant to the study. 
 
 
 
10.6    Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol 
and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that the study investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. Study documents should be kept 
on file until three years after the completion and final study report of this investigational study. 
 
 
 
10.7    Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial The Principal 
Investigator is responsible for personally overseeing the treatment of all study patients. The 
Principal Investigator must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator is responsible for assuring that all the required data will be collected 
and entered onto the Case Report Forms. Periodically, monitoring visits will be conducted and 
the Principal Investigator will provide access to his/her original records to permit verification of 


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proper entry of data. At the completion of the study, all case report forms will be reviewed by the 
Principal Investigator and will require his/her final signature to verify the accuracy of the data. 


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11.0 
REFERENCES 
1. 
Ornstein DK, Colberg JW, Virgo KS et al: Evaluation and management of men whose 
radical prostatectomies failed: results of an international survey. Urology, 52: 1047, 1998 
2. 
Pound CR, Partin AW, Epstein JI et al. Prostate-specific antigen after anatomic radical 
retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am, 
24: 395, 1997 
3. 
Pound CR, Partin AW, Eisenberger MA et al. Natural history of progression after PSA 
elevation following radical prostatectomy. JAMA, 281: 1591, 1999 
4. 
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, 280: 969, 1998 
5. 
D'Amico AV, Whittington R, Malkowicz SB et al. The combination of preoperative 
prostate specific antigen and postoperative pathological findings to predict prostate 
specific antigen outcome in clinically localized prostate cancer. J Urol, 160: 2096, 1998 
6. 
D'Amico AV, Moul J, Carroll PR et al. Cancer-specific mortality after surgery or radiation 
for patients with clinically localized prostate cancer managed during the prostate-specific 
antigen era. J Clin Oncol, 21: 2163, 2003 
7. 
Walsh PC, Partin AW, Epstein JI. Cancer control and quality of life following anatomical 
radical retropubic prostatectomy: results at 10 years. J Urol, 152: 1831, 1994 
8. 
Kupelian PA, Elshaikh M, Reddy CA et al. Comparison of the efficacy of local therapies 
for localized prostate cancer in the prostate-specific antigen era: a large single-institution 
experience with radical prostatectomy and external-beam radiotherapy. J Clin Oncol, 20: 
3376, 2002 
9. 
Amato RJ, Teh BS, Henary H, et al. A retrospective review of combination 
chemohormonal therapy as initial treatment for locally advanced or metastatic 
adenocarcinoma of the prostate. Urol Oncol, 27(2): 165, 2009 
10.  Amato R1, Stepankiw M, Gonzales P. A phase II trial of androgen deprivation therapy 
(ADT) plus chemotherapy as initial treatment for local failures or advanced prostate 
cancer. Cancer Chemother Pharmacol, 71(6): 1629, 2013 
11.  Shannon C, Smith I. Is there still a role for neoadjuvant therapy in breast cancer? Crit 
Rev Oncol Hematol, 45: 77, 2003 
12.  Logothetis C, Swanson D, Amato R et al. Optimal delivery of perioperative 
chemotherapy: preliminary results of a randomized, prospective, comparative trial of 
preoperative and postoperative chemotherapy for invasive bladder carcinoma. J Urol, 
155(4): 1241-5, 1996 
13.  Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2013 Nov 8. [Epub ahead of 
print] 
14.  Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus 
prednisone for advanced prostate cancer. N Engl J Med, 351: 1502, 2004 
15.  Petrylak DP, Tangen CM, Hussain MH. et al. Docetaxel and estramustine compared with 
mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med, 
351: 1513, 2004 
16.  Schmidt JD, Gibbons RP, Murphy GP et al. Adjuvant therapy for clinical localized 
prostate cancer treated with surgery or irradiation. Eur Urol, 29: 425, 1996 
17.  Berry W, Dakhil S, Gregurich MA et al. Phase II trial of single-agent weekly docetaxel in 
hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol, 
28: 8, 2001 
18.  Shelley MD, Kumar S, Wilt T et al. A systematic review and meta-analysis of randomised 
trials of neo-adjuvant hormone therapy for localised and locally advanced prostate 
carcinoma. Cancer Treat Rev, 35: 9, 2009 


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19.  Gleave M, Kelly WK. High-risk localized prostate cancer: a case for early chemotherapy. 
J Clin Oncol, 23: 8186, 2005 
20.  Millikan RE, Wen S, Pagliaro LC et al. Phase III trial of androgen ablation with or without 
three cycles of systemic chemotherapy for advanced prostate cancer. J Clin Oncol, 26: 
5936, 2008 
21.  Dreicer R, Magi-Galluzzi C, Zhou M et al. Phase II trial of neoadjuvant docetaxel before 
radical prostatectomy for locally advanced prostate cancer. Urology, 63: 1138, 2004 
22.  Taplin ME, Montgomery RB, Logothetis C et al. Effect of neoadjuvant abiraterone 
acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response 
(pCR), and near pCR in localized high-risk prostate cancer (LHRPC): Results of a 
randomized phase II study. Presented at the 2012 ASCO Annual Meeting, J Clin Oncol 
30, 2012 (suppl; abstr 4521), 2012 
23.  Narita S, Tsuchiya N, Kumazawa T, et al. Short-term clinicopathological outcome of 
neoadjuvant chemohormonal therapy comprising complete androgen blockade, followed 
by treatment with docetaxel and estramustine phosphate before radical prostatectomy in 
Japanese patients with high-risk localized prostate cancer. World J Surg Oncol, 10: 1 
2012 
24.  National Cancer Institute. NIH-funded study shows increased survival in men with 
metastatic prostate cancer who receive chemotherapy when starting hormone therapy. 
Press release, December 5, 2013. Available at: 
http://www.nih.gov/news/heatlh/dec2013/nci-05.htm 


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Appendix 1:  NCI Common Terminology Criteria for Adverse Eveents, Version 4.03 
 
 
Version 4.03 of the NCI CTCAE, dated 14 June 2010, may be viewed and/or downloaded by 
accessing the following website:  http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06- 
14_QuickReference_5x7.pdf 


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Appendix 2:  Assessment of Performance Status 
 
 
ECOG 
Performance 
Status* 
Criteria 
Karnofsky Score 
0 
Fully active; able to carry on all 
pre-disease performance without 
restriction 
90-100% 
1 
Restricted in physically strenuous 
activity but ambulatory 
70-80% 
2 
Ambulatory and capable of self- 
care, but unable to carry out any 
work activities 
50-60% 
3 
Capable of only limited self-care; 
confined to bed or chair more than 
50% of waking hours 
30-40% 
4 
Completely disabled 
10-20% 
 
* Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, 
E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 


 
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Appendix 3:  Schedule of Assessment 
 
Screening 
Cycle 1 
Cycle 2 
Post-Treatment 
Visit Name 
Day 
-7 to -1 
Day 
1 
Days 
8,15,22 
Day 
29 
Day 
36 
C1D43,50 
(REST) 
Day 1 
Days 
8,15,22 
Day 
29 
Day 
36 
C2 Day 
57 
+ 2 days 
Day 133 
+ 7 days 
Informed Consent 
X 
Comprehensive Physical exam 
X 
X 
Medical History 
X 
Concomitant medication 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete metabolic profile* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrolytes* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with diff. platelet count* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT, INR, PTT 
X 
X 
Urinalysis 
X 
X 
PSA 
X 
X 
X 
X 
Testosterone 
X 
X 
X 
X 
X 
CTC’s 
X 
X 
X 
X 
Bone Scan 
X 
CT Chest and abdomen 
X 
mpMRI pelvis 
X 
X 
X 
ECG 
X 
Echo 
X 
Tissue collection 
X(biopsy) 
X (surgery) 
Interim physical 
X 
X 
X 
X 
X 
X 
X 
X 
IV Chemotherapy 
(2 cycles) 
X 
X 
X 
X 
X 
X 
X 
X 
ADT 
X 
X 
X 
X 
 
 
* If not performed within the previous 72 hours 
 
IRB NUMBER: HSC-MS-14-0424 
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