Clinical trial NCT02560051
Conditions: Prostatic Neoplasms
Keywords: Prostate Cancer Advanced Local Failures
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2015-11-01; Completion date: 2017-09-14
Enrollment: 19 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is for men who have prostate cancer and have failed local therapy or are not a candidate for prostatectomy or radiation therapy. The purpose of this research study is to assess the safety and benefit of androgen deprivation therapy (ADT, blocks hormones) plus chemotherapy. Degarelix is the hormone blocking drug that will be used. Doxorubicin, Ketoconazole, Docetaxel and Estramustine are the chemotherapy drugs that will be used. The drugs used in this study are approved by the Food and Drug Administration (FDA).

Participants will be treated with ADT plus chemotherapy for three, four, or five 8-week cycles (12, 18, or 24 months). The number of cycles of chemotherapy they receive and the number of months they receive ADT will be based on their disease. The current standard treatment is ADT and chemotherapy. What differs in this research study is the cycling and combination of chemotherapy drugs chosen. The drugs chosen for this study have fewer side effects and are believed to provide maximum benefit.

Detailed description:
As a working hypothesis, investigators suspect that the transformation from an androgen-dependent to an androgen-independent phenotype is mediated by expansion of an androgen-independent clone already present at the time of ADT that continues to grow while androgen-sensitive clones are being suppressed. It is thus desirable to bring treatment to bear on the androgen-independent component while the corresponding tumor burden remains minimal and prolong the time to hormone resistance. Investigators view the androgen-independent component as analogous to "microscopic residual" or "micro-metastatic" disease, for which adjuvant chemotherapy has been shown to be effective in other contexts, even when the same drugs had little or no impact on survival in the setting of more advanced disease.

By treating all components of the tumor initially, investigators anticipate that the emergence of androgen-independent growth will be delayed, ultimately prolonging patient survival. Additionally, instead of treating patients empirically with an identical regimen, as in investigator's previous work, these patient subsets were designed to ensure a level of treatment appropriate to their individual disease, thus potentially lessening the burden of treatment (such as the long-term adverse effects of ADT). Investigators have chosen 3, 4, or 5 cycles of chemotherapy to be administered on the basis of tumor burden, a treatment selection method long established in germ cell tumors and used by this PI. Sub-analyses of previous data have raised the concern that treating patients with varying levels of disease the same way does not produce optimal results. Therefore, investigators seek to improve outcomes by tailoring treatment to tumor burden. In this study, patients with less tumor burden will receive 3 cycles of chemotherapy and 12 months of ADT, those with moderate tumor burden will receive 4 cycles and 18 months of treatment, and those with the greatest tumor burden will receive 5 cycles and 24 months of treatment. Additionally, this regimen of administering treatment sequentially, including a 2-week break, reduces toxicity.

Arms: arm 1: 3 cycles of chemotherapy (doxorubicin, ketoconazole, docetaxel and estramustine) + 12 months ADT (degarelix) arm 2: 4 cycles of chemotherapy (doxorubicin, ketoconazole, docetaxel and estramustine) + 18 months ADT (degarelix) arm 3: 5 cycles of chemotherapy (doxorubicin, ketoconazole, docetaxel and estramustine) + 24 months ADT (degarelix)
Interventions: intervention 1: Doxorubicin intervention 2: Ketoconazole intervention 3: Docetaxel intervention 4: Estramustine intervention 5: Degarelix
Intervention descriptions: intervention 1: In weeks 1, 3, and 5 of each 8-week cycle, participants will receive doxorubicin (20 mg/m2 as a 24-hour intravenous infusion on day 1 of each applicable week) intervention 2: In weeks 1, 3, and 5 of each 8-week cycle, participants will receive ketoconazole (400 mg orally 3 times daily for 7 days) intervention 3: In weeks 2, 4, and 6 of each 8-week cycle, participants will receive docetaxel (35 mg/m2 intravenously on day 1 of each applicable week) intervention 4: In weeks 2, 4, and 6 of each 8-week cycle, participants will receive estramustine (280 mg orally 3 times daily for 7 days) intervention 5: The starting dose (240 mg given as two injections of 120 mg each) is followed by maintenance doses of 80 mg administered as a single injection every 28 days

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-14-0949 
IRB APPROVAL DATE: 01/26/2016 
 
 
 
 
 
 
 
 
 
 
 
 
Phase 2 Study of Androgen Deprivation Therapy (ADT) plus Chemotherapy as Initial Treatment 
for Local Failures or Advanced Prostate Cancer 
 
NCT02560051 
 
Version Date: 01/26/2016 
 
 


IRB NUMBER: HSC-MS-14-0949 
IRB APPROVAL DATE: 01/26/2016 
 
 
 
 
 
 
Androgen Deprivation Therapy (ADT) plus Chemotherapy as Initial Treatment for Local Failures 
or Advanced Prostate Cancer 
 
Clinical Protocol No: GU-13-101 
 
 
 
Principal Investigator: 
Robert J. Amato, D.O. 
Director and Professor, Department of Internal Medicine, Division of Oncology 
6410 Fannin, Suite 830 
Houston, TX 77030 
832-725-7702 
 
Collaborators: Varaha 
Tammisetti, M.D. Angel 
Blanco, M.D. 
Nwabugwu S. Ochuwa, Pharm.D., BCOP 
Reynolds Brobey, Ph.D. 
 
Statistician: 
Jessica Williams, M.S. 
 
Center: 
Memorial Hermann Cancer Center 
 
 
 
Version 1: 
February 20, 2015 
Version 2: 
October 1, 2015 
Version 3: 
November 20, 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 J. Amato, D.O. 


IRB NUMBER: HSC-MS-14-0949 
IRB APPROVAL DATE: 01/26/2016 
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Protocol No. GU-13-101 
Page 2 of 57 
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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ...........................................................................................................................................4 
1.0 
OBJECTIVES.................................................................................................................................................9 
2.0 
BACKGROUND ............................................................................................................................................9 
2.1 
Androgen Deprivation Therapy in Prostate Cancer....................................................................................9 
2.1.1. Rationale for use of degarelix...................................................................................................................9 
2.2 
Chemotherapy in Prostate Cancer ............................................................................................................10 
2.2.1 Castration-resistant prostate cancer .........................................................................................................10 
2.2.2 Hormone-sensitive prostate cancer..........................................................................................................10 
2.3 
Rationale for the Present Trial..................................................................................................................10 
3.0 
PATIENT SELECTION...............................................................................................................................11 
3.1 
Inclusion Criteria ......................................................................................................................................11 
3.2 
Exclusion Criteria:....................................................................................................................................12 
4.0 
TREATMENT PLAN ..................................................................................................................................12 
4.1 
ADT plus Chemotherapy..........................................................................................................................12 
4.2 
Chemotherapy...........................................................................................................................................13 
4.3 
Androgen Deprivation Therapy ................................................................................................................13 
4.4 
Prophylaxis against DVT .........................................................................................................................13 
4.5 
Logistic Details Related to Therapy Delivery ..........................................................................................13 
4.6 
Specific Treatment Plan According to Patient Subset ..............................................................................14 
5.0 
PRE-TREATMENT EVALUATION ..........................................................................................................15 
5.1 
Complete history and physical examination.............................................................................................15 
5.2 
Laboratory evaluation...............................................................................................................................15 
5.3 
Diagnostic Imaging ..................................................................................................................................15 
5.4 
Additional Diagnostic Studies ..................................................................................................................15 
6.0 
ON-STUDY EVALUATION.......................................................................................................................15 
7.0 
PROSTATE RADIATION THERAPY FOR THOSE WITH VIABLE CELLS.........................................16 
8.0 
TOXICITY CRITERIA ALTERATION OF THERAPY ............................................................................16 
8.1 
Hematologic Toxicity ...............................................................................................................................16 
8.2 
Specific Non-Hematologic Toxicities ......................................................................................................17 
8.3 
Other Non-Hematologic Toxicities ..........................................................................................................18 
9.0 
CRITERIA FOR RESPONSE ......................................................................................................................18 
10.0 
REASONS FOR DISCONTINUATION OF THERAPY ............................................................................18 
11.0 
STATISTICAL CONSIDERATIONS .........................................................................................................18 
12.0 
SAFETY MONITORING AND REPORTING ...........................................................................................19 
12.1 
Adverse Events .........................................................................................................................................19 
12.2 
Adverse Event Definition .........................................................................................................................19 
12.3 
Evaluating Adverse Events.......................................................................................................................20 
12.4 
Determination of Severity ........................................................................................................................20 
12.5 
Determination of Relatedness...................................................................................................................20 
12.6 
Serious Adverse Events ............................................................................................................................21 
12.7 
Reporting ..................................................................................................................................................22 
12.8 
Unanticipated Problem Reporting ............................................................................................................22 
12.9 
Interim Safety Analysis ............................................................................................................................22 
13.0 
DATA AND PROTOCOL MANAGEMENT .............................................................................................23 
13.1 
Protocol Compliance ................................................................................................................................23 
13.2 
Data Collection .........................................................................................................................................23 
13.3 
Database Management..............................................................................................................................23 
13.4 
Site Monitoring.........................................................................................................................................23 
14.0 
DRUG INFORMATION ..............................................................................................................................23 
14.1 
Degarelix ..................................................................................................................................................23 


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14.2 
Ketoconazole ............................................................................................................................................25 
14.3 
Doxorubicin ..............................................................................................................................................27 
14.4 
Estramustine .............................................................................................................................................29 
14.5 
Docetaxel ..................................................................................................................................................30 
14.6 
Management of Adverse Effects ..............................................................................................................34 
15.0 
ETHICAL CONSIDERATIONS .................................................................................................................36 
15.1 
Ethical Compliance ..................................................................................................................................37 
15.2 
IRB Review ..............................................................................................................................................37 
15.3 
Recruitment ..............................................................................................................................................37 
15.4 
Informed Consent .....................................................................................................................................37 
15.5 
Confidentiality ..........................................................................................................................................37 
15.6 
Publication of Study Results ....................................................................................................................38 
15.7 
Retention of Documents ...........................................................................................................................38 
16.0 
REFERENCES .............................................................................................................................................39 
APPENDIX A: FACT-P Qualify of Life Scale ........................................................................................................42 
APPENDIX B: ECOG Performance Status..............................................................................................................45 
APPENDIX C: NCI Common Terminology Criteria for Adverse Events (CTCAE) ..............................................46 
APPENDIX D: RECIST 1.1 Guidelines ..................................................................................................................48 
APPENDIX E: Schedule of Assessments: ...............................................................................................................52 


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PROTOCOL SYNOPSIS 
 
PROTOCOL 
Androgen Deprivation Therapy (ADT) plus Chemotherapy as Initial Treatment for Local 
Failures or Advanced Prostate Cancer 
 
 
 
PRINCIPAL INVESTIGATOR 
Robert J. Amato, D.O. 
 
 
 
OBJECTIVES 
Primary Objective: 
 Assess the clinical benefit as measured by time to tumor progression of androgen deprivation 
therapy (ADT) plus chemotherapy based on tumor burden, applied to previously untreated 
patients with local failures or patients who were not candidates for prostatectomy or radiation 
therapy. 
Secondary Objective: 
 Soft tissue objective response rate 
 Measure of PSA response 
 Time to PSA progression 
 Overall survival 
 Quality of life measure 
 
 
 
 
PATIENT SELECTION 
 
 Pathologic proof of adenocarcinoma of the prostate. 
 
 Patients must belong to one of the following subsets: 
 
- Prior local therapy 
 
 
 
Patients with PSA recurrence following prostatectomy or radiation therapy who 
have no radiographic involvement. PSA doubling time ≤6 months. 
 Nodal involvement only. 
 Low volume bone disease: ≤3 metastases. 
 Nodal involvement with associated bone involvement. 
 
 High volume bone/visceral disease: Patients with >3 metastatic bone sites or 
visceral metastases. 
- No prior definitive local therapy 
 Tumors felt to be unresectable, not candidates for radiation therapy, and PSA 
elevated with biopsy-proven disease. 
 Metastatic disease at presentation. 


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 Patients may have started ADT within 3 months of study entry. 
 
 
 No previous cytotoxic therapy is allowed, including systemic irradiation  with strontium-89, 
samarium, or radium-223. 
 
 
 Previous definitive radiotherapy to one metastatic site is acceptable, provided that unirradiated 
sites remain. At least 8 weeks must have elapsed since radiation therapy to the pelvis. Patients 
having limited irradiation of a metastatic site are eligible 4 weeks following radiation. 
 
 
 Patients may have had previous exposure to ADT if it was given for ≤6 months to "downstage" 
the primary and provided that such therapy was completed at least 12 months prior to entry into 
this study with a return of serum testosterone to ≥200 ng/dL. 
 
 Patients must be free of serious comorbidity and have a life expectancy of ≥3 years. 
 
 
 
Patients must have adequate physiologic reserves as evidenced by: 
 
- Eastern Cooperative Oncology Group (ECOG) status of ≤2. 
- Patients  must  have  adequate  bone  marrow  function:  Platelets  ≥100,000  cells/mm3, 
Hemoglobin ≥9.0 g/dL, and ANC ≥1,500 cells/mm3. 
- Patients must have adequate renal function: creatinine ≤2 × upper limit of normal (ULN). 
- Patients must have adequate liver function: AST/ALT ≤2.5 × ULN; alkaline phosphatase 
<2.5 × ULN, unless bone metastasis is present in the absence of liver metastasis; and 
bilirubin <2.5 × ULN or 1.5 mg/dl. 
- No evidence of active ischemia on ECG and documentation of EF ≥50%. 
Exclusion criteria 
 
 Patients must not have a second malignancy unless there is confidence of previous curative 
therapy. 
 
 Patients with a recent history of TIA (within 6 months), who are requiring regular antianginal 
therapy, or who are having claudication sufficient to limit activity are not eligible. Patients with 
a previous history of deep venous thrombosis or pulmonary embolism (within 12 months) are 
not eligible. 
 
 Patients must not have a serious intercurrent medical or psychiatric illness, including serious 
active infection. 
 Patients must not have sensory neuropathy > grade 1. 
 
 
 
 
 
TREATMENT PLAN: 
 
Treatment will be ADT plus chemotherapy. 
 
 ADT plus chemotherapy 
 
Patients will be treated with degarelix plus chemotherapy for three, four, or five 8-week cycles 


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according to  their tumor burden.  Each  cycle of  chemotherapy will  consist  of  6  weeks  of 
chemotherapy and 2 weeks of rest. Patients may already be medically castrated at the time of 
study entry, provided such therapy was started within 3 months of initiating chemotherapy. For 
the patients who are on anti-androgen therapy before initiating chemotherapy, the anti-androgen 
therapy will be discontinued. 
 Chemotherapy 
Patients will receive three, four, or five 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). 
Maintenance hydrocortisone (20 mg morning and 10 mg afternoon) will be administered daily 
throughout chemotherapy to counteract potential ketoconazole-induced adrenal complications. 
 Androgen Deprivation Therapy 
Patients will be treated with degarelix. 
Patient Tumor Burden 
Treatment Schedule 
Definitive local therapy: Patients with PSA 
recurrence following prostatectomy or 
radiation therapy who have no radiographic 
involvement. 
3 cycles of chemotherapy 
+ 
12 months of androgen deprivation therapy 
Nodal involvement only. 
4 cycles of chemotherapy 
+ 
18 months of androgen deprivation therapy 
Low-volume bone disease: Patients with ≤3 
bone metastases. 
4 cycles of chemotherapy 
+ 
18 months of androgen deprivation therapy 
Nodal involvement with associated bone 
involvement 
5 cycles of chemotherapy 
+ 
24 months of androgen deprivation therapy 
High-volume bone/visceral disease: Patients 
with >3 metastatic bone sites or visceral 
metastases. 
5 cycles of chemotherapy 
+ 
24 months of androgen deprivation therapy 
No prior definitive local therapy: Tumors felt 
to be unresectable, not candidates for radiation 
therapy, and PSA elevated with biopsy-proven 
disease. 
5 cycles of chemotherapy 
+ 
24 months of androgen deprivation therapy 


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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 
KETO 
1↓ 
TAXOT 
EMCYT 
2↓ 
ADRIA 
KETO 
3↓ 
TAXOT 
EMCYT 
4↓ 
ADRIA 
KETO 
5↓ 
TAXOT 
EMCYT 
6↓ 
i.v. (weekly) 
p.o. (3 times 
daily) 
Androgen Deprivation Therapy 
Degarelix (starting week 1) 
 
 
 
 
 
 
STATISTICAL CONSIDERATIONS: 
 
 
This study is intended to determine the efficacy of determining chemotherapy dose based on tumor burden. 
Time to tumor progression (TTP) is the primary endpoint. The study is designed to have at least 
80% power to detect at least a 4-month increase in the median TTP found in the literature (16-24 
months, two-sided type I error of 0.05), with an exponential distribution. We plan to enroll 224 patients, 
assuming uniform accrual over time, no loss to follow-up, exponentially distributed death times, and the 
use of the exponential MLE test. 
 
Each group will be examined separately in an independent post-hoc subgroup analysis using descriptive 
statistics. TTP may vary among treatment subgroups. The median PFS will be constructed for each subset. 
The 95% confidence intervals will describe the reliability of our results. 
 
An interim safety analysis is planned after 56 patients (25%) have completed the first cycle of treatment. 
During this analysis, enrollment will be stopped, the DSMB will review the safety and toxicity information 
and make their recommendation, and the DSMB report will be given to the IRB for review prior to 
treatment of additional patients. For the interim analysis, the alpha spending function with O‘Brien-
Fleming type boundaries will be used to used preserve the overall type I error rate for safety and 
effectiveness at the 0.025 level. 
 
 
PATIENT EVALUATION: 
ALL SIX SUBSETS 
 
 Complete history and physical examination. 
 
 MRI of the pelvis. 
 
 Complete metabolic panel, electrolytes, CBC with differential and platelet count, testosterone, and 


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PSA. Imaging studies to consist of x-ray or CT of the chest, CT or MRI of the abdomen, and bone 
scan. Blood tests must be obtained within 7 days of study entry and imaging studies within 28 days. 
Additional diagnostic studies, ECG, and echocardiogram must have been obtained within the 
preceding 6 months. 
 
 A CBC with differential and platelet count is required prior to each dose of chemotherapy. The 
PSA will be determined prior to each subsequent cycle. Once chemotherapy is completed, monitoring  
will  continue  as  described  below.  Additional  ECG  and  echocardiograms  will  be obtained before 
each course of chemotherapy. 
 
 Following the completion of chemotherapy, for all patients, PSA will be monitored every 12 weeks, 
and every patient will have a clinical evaluation including a CBC with differential and platelet 
count, complete metabolic panel, electrolytes, and testosterone level. 
 
 Once the PSA response is maximal, patients will have a repeat bone scan if the initial result was 
suggestive of metastatic disease. If a patient was known to have abnormalities on other imaging 
studies at entry, these will be repeated in order to document the full extent of response. 
 
 If the PSA is rising, a repeat determination to confirm an upward PSA trend will be obtained in 2 
weeks. Although repeat imaging studies may help in cases with an equivocal clinical presentation, 
there  is  no  mandate  to  monitor  patients  except  by  PSA,  serum  chemistries,  electrolytes, 
hematologic evaluation, and testosterone level. 
 
 
 
FOR PATIENTS WITHOUT PRIOR SURGERY OR RADIATION THERAPY 
 At month 12, patients will undergo a biopsy of the prostate to determine whether there are viable 
tumor cells. If viable cells are present, patients will be referred for radiation therapy as described in 
section 7.0. 


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x has been 
 
PROTOCOL 
 
1.0 
OBJECTIVES 
 
 
 
Primary Objective: 
o Assess the clinical benefit as measured by time to tumor progression of ADT plus chemotherapy 
based on tumor burden, applied to previously untreated patients with local failures or patients 
who were not candidates for prostatectomy or radiation therapy. 
Secondary Objective: 
o Soft-tissue objective response rate 
o Measure of PSA response 
o Time to PSA progression 
o Overall survival 
o Quality of life measure 
 
 
 
2.0 
BACKGROUND 
 
2.1       Androgen Deprivation Therapy in Prostate Cancer 
Prostate cancer is expected to be diagnosed in 238,590 men in the United States in 2013, and 29,720 
men are expected to die from it.1 Androgen deprivation therapy (ADT) is commonly used for the 
management of patients who develop an increasing serum prostate-specific antigen (PSA) level after 
prostatectomy or radiation therapy. For the management of prostate cancer where localized therapy is 
not an option, ADT is the first-line therapeutic approach. The prostate cancer mortality rate reflects the 
failure of ADT, which eventually occurs in virtually all patients. Despite its essentially palliative and 
short-lasting effects, ADT remains the most common therapy for local failure or for men who were not 
candidates  for  local  therapy.  The  estimated  median  time  to  treatment  failure  is  16-24  months.2 
Alternatives such as salvage radiation therapy after failed radical prostatectomy3,4 and salvage therapy5 
have been tried but still fall short in terms of clinical benefit. 
 
Evidence suggests that PSA levels correspond with clinical disease progression or response to therapy, 
although the magnitude of PSA values indicative of clinically significant improvement and the exact 
relationship between rising PSA levels and tumor burden remains undefined.6 Rising PSA levels often 
precede symptomatic progression by 5 months.7 Elevations can predict clinical relapse in patients who 
had a prostatectomy or radiation therapy, and PSA doubling times after initial treatment may identify 
and stratify patients at high risk of prostate cancer–specific death.8-10 
 
However, clinical pathological evidence shows that long-term ADT is associated with adverse effects that 
have a major impact on patients‘ quality of life. These include fatigue, vasomotor flushing, loss of libido,  
cognitive  dysfunction,  decreased  bone  mineral  density,  loss  of  muscle  mass,  and  mild anemia.11,12 
Long-term ADT can also result in diabetes mellitus, cardiac disease, and metabolic syndrome.13-18 Studies 
have sought strategies to reduce these sequelae, including intermittent and short- term (4-6 months) 
administration, are effective at decreasing prostate cancer-related mortality while minimizing adverse 
effects.19-21 
 
2.1.1. Rationale for use of degarelix 
 
Our  previous  studies  used  leuprolide  for  ADT.22,23   However,  this 
 
 
 
IpRrBojNecUtMwBEilRl : uHsSeC-dMeSg-a1r4e-0li9x4,9 a 
gonadotropin-releasing hormone receptor inhibitor. Degareli 
sIRhoBwAnPPtoROsVupApLreDsAsTtEe:st0o1s/2te6r/2o0n1e6 


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of an andr 
 
more quickly than leuprolide and to cause milder adverse events. Degarelix has a favorable effect on 
PFS and does not require the addition of an androgen receptor inhibitor (such as bicalutamide).12,24-26 
 
2.2       Chemotherapy in Prostate Cancer 
 
2.2.1 Castration-resistant prostate cancer 
 
Chemotherapy in castration-resistant prostate cancer provides PSA reduction and prolongs overall 
survival (OS). Several combination regimens have produced PSA response rates of ~50%. Two of the 
more effective regimens are ketoconazole plus weekly doxorubicin27 and estramustine plus weekly 
vinblastine.28 Alternating administration of ketoconazole plus doxorubicin with estramustine plus 
vinblastine was reported as safe and possibly enhancing OS.29 After the development of taxanes, docetaxel 
was found to have strong activity against advanced prostate cancer.30,31 In 2004, it became the standard of 
treatment.32 
 
2.2.2 Hormone-sensitive prostate cancer 
The present trial builds  upon the results of a  retrospective review22  and a prospective study23  by 
members of our research group that used the same treatment regimen of doxorubicin with ketoconazole 
and docetaxel with estramustine, with the treatment regimen updated to reflect the current docetaxel 
standard. In the previous prospective study, 46 patients were enrolled, 45 of whom were evaluable. Median 
progression-free survival (PFS) was 23.4 months, and median overall survival (OS) was 53.7 months.  Of 
the  45  patients  with  measurable disease,  22  had  an  objective response:  9  achieved  a complete 
response, 2 achieved a partial response, and 10 had stable disease. Frequent grade 3 adverse events 
included elevated ALT (17%), hypokalemia (13%), and hypophosphatemia (13%). Grade 4 adverse events 
were rare and included low bicarbonate (2%), hypokalemia (2%), leukocytopenia (2%), and neutropenia 
(2%). The treatment demonstrated clinical benefit in all patient subsets with minimal 
reversible treatment-related adverse events.23 
 
To further validate the use of combined chemotherapy and ADT in hormone-sensitive prostate cancer, 
Eastern Cooperative Oncology Group researchers conducted a multicenter phase III study among 790 
men with hormone-sensitive, newly metastatic prostate cancer. They found that the combination of 
ADT and docetaxel substantially increased the length of overall survival, particularly in men with 
highly metastatic disease, without notable toxicity.33 Based on the results of that trial, the concept of 
hormone therapy plus chemotherapy has become the recommended standard for prostate cancer treatment. 
 
Another recent study explored the safety of combined ADT and chemotherapy in a similar patient 
population to ours. Although patients receiving the combination experience more serious adverse events 
than those receiving ADT only (25% vs. 9.8%), numbers of patients completing treatment were similar in 
both groups (87% vs. 89%), so they determined that the combination regimen is safe and feasible.34 
 
2.3       Rationale for the Present Trial 
 
Some reports have addressed the potential clinical benefit of chemotherapy in hormone-responsive 
prostate cancer.35-37 The early application of chemotherapy to androgen-dependent prostate cancer cells 
may have clinical benefit, given that the tumor burden would be minimal. Androgen-independent clones 
that have already started proliferating and transforming the tumor into a more hormone-resistant 
phenotype would be treated while, simultaneously, the androgen-sensitive cells would be treated by ADT. 
 
As a working hypothesis, we suspect that the transformation from an androgen-dependent to an androgen-
independent phenotype is mediated by expansion                  ogIReBn-NinUdMepBeEnRd: eHnStCc-lMoSn-e14a-l0r9e4a9dy 


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Metastatic disease at presentation. 
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present at the time of ADT that continues to grow while androgen-sensitive clones are being suppressed. 
It is thus desirable to bring treatment to bear on the androgen-independent component while the 
corresponding tumor burden remains minimal and prolong the time to hormone resistance. We view the 
androgen-independent component as analogous to "microscopic residual" or "micro-metastatic" disease, 
for which adjuvant chemotherapy has been shown to be effective in other contexts, even when the same 
drugs had little or no impact on survival in the setting of more advanced disease. 
 
By treating all components of the tumor initially, we anticipate that the emergence of androgen- 
independent growth will be delayed, ultimately prolonging patient survival. Additionally, instead of 
treating patients empirically with an identical regimen, as in our previous work, our patient subsets were 
designed to ensure a level of treatment appropriate to their individual disease, thus potentially lessening 
the burden of treatment (such as the long-term adverse effects of ADT). We have chosen 3, 4, or 5 
cycles of chemotherapy to be administered on the basis of tumor burden, a treatment selection method 
long established in germ cell tumors and used by our PI.38,39 Subanalyses of previous data,23 have raised 
the concern that treating patients with varying levels of disease the same way does not produce optimal 
results. Therefore, we seek to improve outcomes by tailoring treatment to tumor burden. In our study, 
patients with less tumor burden will receive 3 cycles of chemotherapy and 12 months of ADT, those 
with moderate tumor burden will receive 4 cycles and 18 months of treatment, and those with the 
greatest tumor burden will receive 5 cycles and 24 months of treatment. Additionally, our regimen of 
administering treatment sequentially, including a 2-week break, reduces toxicity. 
 
 
 
3.0 
PATIENT SELECTION 
 
3.1       Inclusion Criteria 
 
3.1.1 Pathologic proof of adenocarcinoma of the prostate. Patients with other histologic subtypes, such 
as pure ductal (e.g., "endometrioid" or "cribriform" histology) or any component of small cell 
carcinoma are not eligible. Patients must have metastatic disease or locally advanced disease that 
either is not appropriately treated with surgery or radiation or has recurred following previous 
"definitive" local therapy. Biopsy of indicator lesions is not required when the clinical presentation 
is characteristic. For example, a patient with visceral involvement without high- volume bone 
disease, especially in the setting of only modest PSA elevation, should be biopsied to exclude a 
variant histology. Pathologic samples must be available for review. 
 
3.1.2    Patients must belong to one of the following subsets: 
 
  Prior local therapy 
 Patients with PSA recurrence following prostatectomy or radiation therapy who have no 
radiographic involvement. PSA doubling time of ≤ 6 months. 
 Nodal involvement only. 
 Low-volume bone disease: ≤3 metastases. 
 Nodal involvement with associated bone involvement. 
 High-volume bone/visceral disease: patients with >3 metastatic bone sites or visceral 
metastases. 
  No prior definitive local therapy 
 Tumors felt to be unresectable, not candidates for radiation therapy, and PSA elevated 
with biopsy-proven disease. 


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3.1.3    Patients may already be medically castrated at the time of study entry, provided that such 
therapy was started within 3 months of study entry. 
 
3.1.3 No previous cytotoxic systemic therapy of any kind is allowed, including systemic irradiation 
with strontium-89, samarium, or radium-223. 
 
3.1.4 Previous definitive radiotherapy to one metastatic site is acceptable. At least 8 weeks must have 
elapsed since radiation therapy to the pelvis. Patients having limited irradiation of a single 
metastatic site are eligible 4 weeks after the completion of radiation. 
 
3.1.5    Patients may have had previous exposure to ADT if it was given for ≤6 months to "downstage" 
the primary tumor and provided that such therapy was completed at least 12 months prior to 
study entry with a return of serum testosterone to ≥200 ng/dL. 
 
3.1.6 Patients must be free of serious comorbidity and have a life expectancy of ≥3 years. 
 
3.1.7 Patients must have adequate physiologic reserves as evidenced by: 
 
  Eastern Cooperative Oncology Group (ECOG) status of ≤2 (Appendix B). 
  Patients   must   have  adequate  bone  marrow   function:   platelets   ≥100,000   cells/mm3, 
hemoglobin ≥9.0 g/dL, and ANC ≥1,500 cells/mm3. 
  Patients must have adequate renal function: creatinine ≤2 × ULN. 
  Patients must have adequate liver function: AST/ALT ≤2.5 × ULN; alkaline phosphatase 
<2.5  ×ULN,  unless  bone  metastasis  is  present  in  the  absence  of  liver  metastasis;  and 
bilirubin <2.5 × ULN or 1.5 mg/dl. 
  No evidence of active ischemia on ECG and documentation of EF ≥50% 
  Patients must not have a second malignancy unless there is confidence of previous curative 
therapy. 
 
 
3.2 
Exclusion Criteria: 
 
3.2.1 Patients must not have a second malignancy unless there is confidence of previous curative 
therapy. 
 
3.2.2 Patients  with  a  recent  history of  TIA  (within  6  months),  are  requiring  regular  antianginal 
therapy, or are having claudication sufficient to limit activity are not eligible. Patients with a 
previous history of deep venous thrombosis or pulmonary embolism (within 12 months) are not 
eligible. 
 
3.2.3 Patients must not have a serious intercurrent medical or psychiatric illness, including serious 
active infection. 
 
3.2.4 Patients must not have sensory neuropathy > grade 1. 
 
 
 
4.0 
TREATMENT PLAN 
 
Treatment will be ADT plus chemotherapy. 
 
4.1 
ADT plus Chemotherapy 
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Patients will be treated with monthly degarelix plus chemotherapy for three, four, or five 8-week 
cycles. Each cycle of chemotherapy will consist of 6 weeks of chemotherapy and 2 weeks of 
rest. Patients may already be medically castrated at the time of study entry, provided that such 
therapy was started within 3 months of initiating chemotherapy. For the patients who are on anti- 
androgen   therapy   before   initiating   chemotherapy,   the   anti-androgen   therapy   will   be 
discontinued. This regimen is summarized below. 
 
4.2 
Chemotherapy 
 
Patients will receive three, four, or five 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). 
 
Maintenance hydrocortisone (20 mg morning and 10 mg afternoon) will be administered daily 
throughout chemotherapy to counteract potential ketoconazole-induced adrenal complications. 
 
4.3 
Androgen Deprivation Therapy 
 
Patients will be treated with monthly degarelix. 
 
 
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 to 56 (hydrocortisone continues) 
Week 
ADRIA 
KETO 
1↓ 
TAXOT 
EMCYT 
2↓ 
ADRIA 
KETO 
3↓ 
TAXOT 
EMCYT 
4↓ 
ADRIA 
KETO 
5↓ 
TAXOT 
EMCYT 
6↓ 
i.v. (weekly) 
p.o. (three 
times daily) 
Androgen Deprivation Therapy 
Degarelix 
 
4.4 
Prophylaxis against DVT 
 
The association between cancer, chemotherapy (particularly estramustine), and venous 
thromboembolic events is long established.40,41 It has been shown that patients with cancer— 
including prostate cancer—have up to a 7-fold greater risk of thrombosis than those without 
cancer.42,43 Warfarin (1 mg) is given during chemotherapy as prophylaxis against thrombosis.44- 
48 
 
 
4.5 
Logistic Details Related to Therapy Delivery 


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drogen depr 
 
 Doxorubicin will be given as a prolonged infusion of 24 hours. Given by prolonged infusion, 
it must be given into a central line. 
 
 Ketoconazole  must  be  taken  with  an  acidic  gastric  environment.27   Patients  are  to  take 
ketoconazole 1 h before or 2 h after eating. Gastrointestinal upset is the most common side 
effect of ketoconazole, and many pharmacies dispense the drug labeled ―TAKE WITH 
FOOD.‖ Patients should be alerted to this. Compliance with the requirement for taking 
ketoconazole apart from meals will be verified at each clinical evaluation. Also, the over- 
the-counter availability of gastric acid secretion inhibitors such as omeprazole, cimetidine, 
ranitidine, and famotidine make it imperative to ask specifically about use of these agents, 
which some patients may not consider ―drugs.‖ 
 
 Docetaxel is given IVPB over 60 minutes. 
 
 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. 
 
 Estramustine absorption is significantly reduced by calcium. Therefore, milk, milk products, 
and other calcium-rich food or drugs (especially calcium containing antacids) must not be 
taken concurrently with estramustine capsules. 
 
 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. 
 
 
 
4.6 
Specific Treatment Plan According to Patient Subset 
 
 
 
Patient Tumor Burden 
Treatment Schedule 
Definitive local therapy: Patients with PSA 
recurrence following prostatectomy or 
radiation therapy who have no radiographic 
involvement. 
3 cycles of chemotherapy 
+ 
12 months of androgen deprivation therapy 
Nodal involvement only. 
4 cycles of chemotherapy 
+ 
18 months of androgen deprivation therapy 
Low-volume bone disease: Patients with ≤3 
bone metastases. 
4 cycles of chemotherapy 
+ 
18 months of androgen deprivation therapy 
Nodal involvement with associated bone 
involvement 
5 cycles of chemotherapy 
+ 
24 months of an 
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High-volume bone/visceral disease: Patients 
with >3 metastatic bone sites or visceral 
metastases. 
5 cycles of chemotherapy 
+ 
24 months of androgen deprivation therapy 
No prior definitive local therapy: Tumors felt 
to be unresectable, not candidates for radiation 
therapy, and PSA elevated with biopsy-proven 
disease. 
5 cycles of chemotherapy 
+ 
24 months of androgen deprivation therapy 
 
 
 
5.0 
PRE-TREATMENT EVALUATION 
 
5.1 
Complete history and physical examination 
 
5.2 
Laboratory evaluation 
 
  Complete metabolic profile 
- BUN, creatinine, alkaline phosphatase, ALT/AST, total bilirubin, LDH, calcium, albumin, 
glucose, magnesium, uric acid, phosphorous 
  Electrolytes 
- Sodium, potassium, chloride, CO2 content 
  Hematology 
- CBC with differential, platelet count 
- PT, INR, PTT 
      PSA 
      Testosterone 
 
5.3 
Diagnostic Imaging 
     X-ray or CT of the chest 
     Bone scan 
     MRI or CT scan of the abdomen 
     MRI of the pelvis 
 
5.4 
Additional Diagnostic Studies 
  ECG 
  Echocardiogram 
 
6.0 
ON-STUDY EVALUATION 
 
These assessments should be performed within ±3 days of the scheduled day of assessment. 
 
6.1 
A CBC with differential and platelet count will be required prior to each dose of chemotherapy. 
The biochemical profile will be required prior to each dose of chemotherapy. An ECG and 
echocardiogram will be obtained prior to each cycle of chemotherapy. The PSA will be repeated 
every 8 weeks. Once the 3, 4, or 5 cycles of chemotherapy are completed, monitoring will continue 
as described in Sections 6.2 and 6.3. 
 
 
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6.2 
Following the completion of chemotherapy, for all patients, PSA will be monitored every 12 
 
weeks, and every patient will have a clinical evaluation including a CBC with differential, 
platelet count, complete metabolic panel, electrolytes, and testosterone level. 
 
6.3 
Quality of life will be assessed using the FACT-P scale (Appendix A), a validated instrument 
specific to prostate cancer, after every cycle of chemotherapy, 12 weeks after the completion of 
chemotherapy, after the completion of ADT, and upon testosterone recovery to normal levels.46 
 
6.4       Once the PSA response is maximal, patients will have a repeat bone scan if the initial study was 
suggestive of metastatic disease. Although not required for study eligibility, if a patient was known 
to have abnormalities on other imaging studies at entry, these should also be repeated in order to 
document the full extent of response. 
 
6.5       If any PSA result is higher than the previous determination, then a repeat determination to 
confirm an upward trend will be obtained within 2 weeks. Repeat imaging studies may be done 
in cases with an equivocal clinical presentation, but there is no mandate to monitor patients except 
by clinical exam, PSA and serum chemistries, and hematologic evaluation. 
 
6.6       The attending physician and/or the assigned oncology research staff must see each patient prior 
to drug administration. All required interim and pretreatment data should be available. Interim 
toxicity will be recorded at each treatment in accordance with the NCI Common Toxicity Criteria, 
Version 4.0, as listed in Appendix C. 
 
6.7       At month 12, patients without surgery or radiation therapy will undergo a biopsy of the prostate 
to determine if there are viable cells. If viable cells are present, they will be referred for radiation 
therapy as described in the next section. 
 
6.8       PSA 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 MRI 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 
PROSTATE RADIATION THERAPY FOR THOSE WITH VIABLE CELLS 
 
These  patients  will  receive  image-guided  intensity-modulated  radiation  therapy  (IG-IMRT).  A 
prescribed dose (76-80 Gy) will be delivered to the prostate in 2 Gy fractions over 38-40 fractions 
depending on bladder and rectal dose constraints. The patients will undergo CT simulation in the prone 
position with rectal balloon in place if tolerated, and a customized vacuum bag will be fabricated for 
optimal immobilization. An MRI will be obtained at the time of treatment planning and fused to the 
treatment planning CT. Dose constraints will be placed for important surrounding normal structures 
including rectum, bladder, and femoral heads according to established QUANTEC guidelines. Daily 
image guidance will be utilized, preferably via cone-beam CT. Patients will be monitored weekly for vital 
signs and side effects related to radiotherapy, including rectal and urinary symptoms. 
 
8.0 
TOXICITY CRITERIA ALTERATION OF THERAPY 
 
8.1 
Hematologic Toxicity 
 
 
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6.2 
Following the completion of chemotherapy, for all patients, PSA will be monitored every 12 
IRB APPROVAL DATE: 01/26/2016 
 
 
>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. Neupogen can be administered as needed 
to increase platelet 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 
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 more than 3 times 
or more than 3 weeks are required for cell count recovery, chemotherapy will be discontinued 
and the patient will proceed directly to androgen deprivation. 
 
 
 
8.2 
Specific Non-Hematologic Toxicities 
 Patients unable to tolerate ketoconazole due to GI upset should be offered carafate, 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  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 
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istribution
 
or grade 1. Liver enzymes should be measured immediately, regardless of when the next 
study visit or monitoring interval is scheduled. 
 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. 
 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. 
 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. 
 
8.3 
Other Non-Hematologic Toxicities 
NCI standard toxicity criteria are included as Appendix C. 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. 
 
9.0 
CRITERIA FOR RESPONSE 
 
Tumor response will be determined according to the Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 (Appendix D),47 and PSA will be evaluated according to the Prostate-
Specific Antigen Working Group's Guidelines.48 
 
10.0 
REASONS FOR DISCONTINUATION OF THERAPY 
 
Patient will continue on therapy until 
 
 Progression of disease 
 Unacceptable toxicity 
 Patient or treating physician wishes to stop 
 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
This study is intended to determine the efficacy of determining chemotherapy dose based on tumor 
burden. Time to tumor progression (TTP) is the primary endpoint. The study is designed to have at least 
80% power to detect at least a 4-month increase in the median TTP found in the literature (16-24 
months, two-sided type I error of 0.05), with an exponential d 
. IW
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ssociated 
 
assuming uniform accrual over time, no loss to follow-up, exponentially distributed death times, and the 
use of the exponential MLE test. 
 
Each group will be examined separately in an independent post-hoc subgroup analysis using descriptive 
statistics. TTP may vary among treatment subgroups. The median PFS will be constructed for each subset. 
The 95% confidence intervals will describe the reliability of our results. 
 
An  interim  safety  analysis  is  planned  after  56  patients  (25%)  have  completed  the  first  cycle  of 
treatment. During this analysis, enrollment will be stopped, the DSMB will review the safety and 
toxicity information and make their recommendation, and the DSMB report will be given to the IRB for 
review prior to treatment of additional patients. For the interim analysis, the alpha spending function 
with O‘Brien-Fleming type boundaries will be used to used preserve the overall type I error rate for 
safety and effectiveness at the 0.025 level. 
 
12.0 
SAFETY MONITORING AND REPORTING 
 
The investigator will monitor each patient for clinical and laboratory evidence of adverse events on a 
routine basis throughout the study following the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.0. A link to the electronic version of the CTCAE can be found in Appendix 
C. Investigators must document their review of laboratory reports by initialing and dating each report, 
as well as addressing the clinical significance (for significant abnormalities). The investigator will 
assess and record any adverse event (serious and non-serious) in detail on the adverse event form including 
the date of onset, description, severity, time course, duration, outcome and relationship to the study drug 
from the time the patient signs the informed consent until 4 weeks after the patient has stopped study 
treatment. 
 
12.1     Adverse Events 
 
All adverse events should be treated appropriately. Such treatment may include interruption or 
discontinuation of study drug, starting or stopping concomitant treatments, changes in the 
frequency or nature of assessments, hospitalization, or any other medically required intervention. 
 
Information about common side effects already known about the study drugs can be found in the 
protocol (section 14) and respective package inserts. Two drugs in the study, doxorubicin and 
docetaxel, have known potential for non-overlapping cumulative toxicities (cardiac for 
doxorubicin and neuropathic for docetaxel). These are well known and are described in the package 
inserts. This information will be included in the patient informed consent and should be discussed 
with the patient during the study as needed. 
 
12.2     Adverse Event Definition 
 
An adverse event (AE) is defined as any unintended or undesirable, noxious, or pathological 
change, compared to pre-existing conditions, experienced by a patient during a clinical study or 
the follow-up period, regardless of relationship to study drug. Adverse events include: 
    Suspected adverse drug reactions. 
    Reactions from drug overdose, abuse, withdrawal, sensitivity, or toxicity. 
 Significant changes or abnormalities, when compared to baseline, in structure (sign), 
function (symptom), clinical laboratory results, or physiological testing. This includes any 
worsening of a pre-existing condition temporally a 
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the patient.
 
 Other medical events, regardless of their relationship to the study drug, such as injury, 
surgery, accidents, extensions of symptomatology, or apparently unrelated illnesses. 
 
12.3 
Evaluating Adverse Events 
 
Each adverse event will be evaluated to determine: 
    the severity grade (mild, moderate, severe) or (grade 1-4) 
    its relationship to the study drug(s) (suspected/not suspected) 
    its duration (start and end dates or if continuing at final exam) 
 action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study drug 
permanently discontinued due to this adverse event; concomitant medication taken; non-drug 
therapy given; hospitalization/prolonged hospitalization) 
    outcome 
    whether it constitutes a serious adverse event (SAE) 
 
12.4 
Determination of Severity 
 
The severity of AEs will be assessed according to CTCAE, Version 4.0. If the AE is not defined 
in the CTCAE, the Investigator will determine the severity of an adverse event based on the 
following definitions: 
 Mild (Grade 1): The AE is noticeable to the patient but does not interfere with routine 
activity. The AE does not require discontinuing administration or reducing the dose of the 
study drug. 
 Moderate (Grade 2): The AE interferes with routine activity but responds to symptomatic 
therapy or rest. The AE may require reducing the dose but not discontinuing administration 
of the study drug. 
 Severe (Grade 3): The AE significantly limits the patient‘s ability to perform routine 
activities despite symptomatic therapy. In addition, the AE leads to discontinuing 
administration or reducing the dose of the study drug. 
    Life-Threatening (Grade 4): The AE requires discontinuing administration of the study drug. 
The patient is at immediate risk of death. 
 
12.5 
Determination of Relatedness 
 
The Investigator will determine the relatedness of an adverse event with the study drug based on 
the following definitions: 
 
Not Related 
This category applies to those adverse events which, after careful medical consideration, are felt 
to  be  due  to  extraneous  causes  (disease,  environment,  etc.)  that  are  not  related  to  the 
administration of study drug. 
 
Probably Not Related (must have first two bullets below) 
This category applies to those adverse events, which, after careful medical consideration, are 
clearly felt unlikely to be related to the administration of the study drug. The relationship of an 
adverse event to the study drug can be considered probably not related if: 
    It does not follow a reasonable temporal sequence from administration of the drug. 
    It could readily have been a result of the patient‘s clinical state, environmental or toxic 
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    It does not follow a known response pattern to the suspected drug. 
    It does not reappear or worsen when the drug is readministered. 
 
Possibly Related (must have first two bullets below) 
This category applies to those adverse events, which, after careful medical consideration, are felt 
unlikely to be related to the administration of the study drug, but the possibility cannot be ruled 
out with certainty. The relationship of an adverse event to the study drug can be considered 
possibly related if: 
    It follows a reasonable temporal sequence from administration of the drug. 
    It could readily have been a result of the patient‘s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient. 
    It follows a known response pattern to the suspected drug. 
 
Probably Related (must have first three bullets below) 
This category applies to those adverse events which, after careful medical consideration, are felt 
with a high degree of certainty to be related to the administration of the study drug. The 
relationship of an adverse event to the study drug can be considered probably related if: 
    It follows a reasonable temporal sequence from administration of the drug. 
    It could not be reasonably explained by the known characteristics of the patient‘s clinical 
state, environmental or toxic factors or other modes of therapy administered to the patient. 
    It disappears or decreases upon cessation of drug or reduction in dose.* 
    It follows a known response pattern to the suspected drug. 
 
Definitely Related (must have first three bullets below) 
This category applies to those adverse events, which, after careful medical consideration, are felt 
to be related to the administration of the drug. The relationship of an adverse event to the study 
drug can be considered definitely related if: 
 It follows a reasonable temporal sequence from administration of the drug or drug levels 
have been established in body fluids or tissues. 
    It could not be reasonably explained by the known characteristics of the patient‘s clinical 
state, environmental or toxic factors or other modes of therapy administered to the patient. 
 It disappears or decreases upon cessation of drug or reduction in dose and, if applicable, 
appears upon rechallenge.* 
    It follows a known response pattern to the suspected drug. 
 
*There are exceptions when an adverse event does not disappear upon discontinuation of the 
drug, yet drug relatedness clearly exists; e.g., 1) tardive dyskinesia, 2) fixed drug eruptions. 
 
12.6 
Serious Adverse Events 
 
Information about all serious adverse events (SAEs) will be collected and recorded. A SAE is an 
undesirable sign, symptom or medical condition which: 
    is fatal or life-threatening 
    results in persistent or significant disability/incapacity 
    constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
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 routine  treatment  or  monitoring  of  the  studied  indication,  not  associated  with  any 
deterioration in condition (specify what this includes) 
 elective or pre-planned  treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
 treatment  on  an  emergency  outpatient  basis  for  an  event  not  fulfilling  any  of  the 
definitions of a SAE given above and not resulting in hospital admission 
 social reasons and respite care in the absence of any deterioration in the patient‘s general 
condition 
 is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
 
12.7 
Reporting 
 
The principal investigator has the obligation to report all serious adverse events to the IRB, DSMB 
and FDA according to their respective requirements. All events reported to the FDA by the 
investigator are to be filed utilizing the Form FDA 3500A (MedWatch Form). 
 
All SAEs should be reported to the DSMB within 5 days of first knowledge by the investigator. 
Deaths should be reported to the IRB within 24 hours of investigator knowledge.   Any unexpected, 
serious, related adverse experiences should be reported within 7 days of investigator knowledge. 
 
 
 
Any pregnancy that occurs during study participation should be reported. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details of 
birth, and the presence or absence of any birth defects, congenital abnormalities or maternal and 
newborn complications. 
 
12.8 
Unanticipated Problem Reporting 
 
The Principal Investigator (PI) must notify the IRB of unexpected problems that might arise during 
the study within 7 days. The PI must make a judgment call regarding the expectedness and 
causality of the problem. 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 
    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 
 
12.9 
Interim Safety Analysis 
 
Enrollment to the study will be halted after 56 patients (25%) have completed the first cycle of 
treatment. A summary of safety and toxicity information for these patients will be prepared and 
provided to the Committee for the Protection of Human Subjects (CPHS) at the University of 
Texas Health Science Center at Houston and Data Safety Monitoring Board (DSMB). In the 
absence of dose-limiting toxicities and safety observations that would prevent subsequent 
administration of the regimen in the opinion of the Investigator, in agreement with the CPHS 
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In the presence of dose-limiting toxicities or safety observations that would prevent subsequent 
administration of the regimen in the opinion of the Investigator, subsequent enrollment to the 
study may continue at a reduced dose level only in agreement with the CPHS and DSMB. 
 
 
13.0 
DATA AND PROTOCOL MANAGEMENT 
 
13.1 
Protocol Compliance 
Written informed consent must be obtained from the patient prior to study specific screening 
tests or procedures.  Results of all baseline evaluations which  assure that all inclusion and 
exclusion criteria have been satisfied, must be reviewed by the Investigator prior to enrollment
of that patient. The investigator and/or research coordinator must see each patient prior to drug
administration. All required interim and pre-treatment data should be available and the investigator
must have made a designation as to tumor response and toxicity grade. 
13.2 
Data Collection 
Investigators or their designee must enter the data required by the protocol onto Case Report
Forms (CRFs). A brief explanation for required but missing data should be recorded as a comment.
The Principal Investigator is ultimately responsible for assuring that data entered into the CRFs
are accurate, authentic / original, attributable, complete, consistent, legible, timely
(contemporaneous), enduring and available when required. 
Entries made in the CRF must be either verifiable against source documents, or have been directly
entered into the CRF, in which case the entry in the CRF will be considered as the source
data. Any corrections to entries made in the CRFs or source documents must be dated, initialed
and explained (if necessary) and should not obscure the original entry. The Investigator will sign
the CRFs to indicate that, to his/her knowledge, they are complete and accurate. 
13.3 
Database Management 
The  data  manager  will  review  the  CRF  data  entered  by  study  staff  for  completeness  and
accuracy. Data queries stating the nature of the problem and requesting clarification will be created
for discrepancies and missing values and sent to the study coordinator. The study coordinator will
respond promptly to queries and make any necessary changes to the CRFs. 
13.4 
Site Monitoring 
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. 
14.0 
DRU G INFORMATION 
14.1 
Degarelix 
Pharmacology 


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Degarelix is a third-generation gonadotropin-releasing hormone (GnRH) receptor antagonist that 
binds reversibly to the pituitary GnRH receptors, leading to a reduction in the release of 
gonadotropins, including testosterone. Degarelix causes a decrease in the plasma concentrations 
of luteinizing hormone and follicle-stimulating hormone and, subsequently, testosterone. 
Degarelix produces a faster suppression of testosterone and PSA with no testosterone surge or 
microsurges. This prevents the risk of clinical flare in advanced disease. In clinical studies, 
degarelix is usually well tolerated with limited toxicity and no evidence of systemic allergic 
reactions. 
 
Plasma protein binding in vitro is ~90%. It is widely distributed throughout total body water. 
Degarelix undergoes peptide hydrolysis in the hepato-biliary system. According to in vitro studies, 
degarelix is not a substrate, inducer, or inhibitor of the CYP450 or p-glycoprotein transporter 
systems. No quantitatively significant metabolites of degarelix were detected in plasma after 
subcutaneous administration. 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. 
 
At least 20%-30% of a given dose of degarelix is excreted unchanged in the urine. 
A population pharmacokinetic analysis of data from the randomized study demonstrated that there 
is no significant effect of mild renal impairment (creatinine clearance [CrCL] 50-80 mL/min) on 
either the degarelix concentration or testosterone concentration. Data on patients with moderate 
or severe renal impairment is limited; therefore, degarelix should be used with caution in patients 
with CrCL <50 mL/min. 
 
 
 
Supplier/How Supplied 
Degarelix  is  available  as  120  mg  and  80  mg  powder  for  injection  (Firmagon,  Ferring 
Pharmaceuticals). It is supplied in a carton that contains the drug and supplies needed for 
preparation. 
 
Starting dose – One carton contains: 
 
 Two vials each with 120 mg of 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 of powder for injection 
 One prefilled syringe containing 4.2 mL of sterile water for injection, USP 
 One vial adapter 
 One administration needle 
 Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). 
 
Dosage and Administration 
Degarelix administration requires an initial subcutaneous starting dose of 240 mg followed by a 
monthly subcutaneous maintenance dose of 80 mg every 28 days. 


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Solution Preparation 
Starting dose 
Given as two 3-mL injections of 120 mg each. One vial of contains 120 mg of degarelix. Each 
vial is to be reconstituted with a prefilled syringe containing 3 mL of sterile water for injection; 
3 mL is withdrawn to deliver 120 mg of degarelix at a concentration of 40 mg/mL 
 
Maintenance dose 
Given as one 4-mL injection. One vial contains 80 mg degarelix. Each vial is to be reconstituted 
with a prefilled syringe containing 4.2 mL of sterile water for injection; 4 mL is withdrawn to 
deliver 80 mg of degarelix at a concentration of 20 mg/mL 
 
During preparation, keep the vial vertical at all times and do not shake the injection. Administer 
within 1 hour of reconstitution 
 
Administration 
 
Degarelix solution is for subcutaneous use only. Do not administer intravenously. Administer 
subcutaneously in the abdominal region, choosing an area that will not be exposed to pressure. 
Injection sites should be varied. 
 
Adverse Effects 
The most frequently reported adverse reactions were injection site reaction (35%-44%), hot sweats 
(26%), mild to moderate increases in transaminase and gamma-glutamyltransferase levels, and weight 
gain (9%-11%). For injection site reactions, the most frequently reported adverse reactions were pain 
(28%) and erythema (17%). These adverse reactions were mostly transient, of mild to moderate intensity, 
occurred primarily with the starting dose, and led to few discontinuations (<1%). Grade 3 injection site 
reactions  occurred  in  ≤2%  of  patients  receiving  degarelix.  Hepatic  laboratory  abnormalities  were 
primarily grade 1 or 2 and were generally reversible. Grade 3 hepatic laboratory abnormalities occurred 
in <1% of patients. Post-marketing data indicates that hypersensitivity reaction may occur. 
 
 
 
14.2 
Ketoconazole 
 
Pharmacology 
Ketoconazole inhibits several adrenal enzymes required for steroid biosynthesis It is a synthetic 
imidazole-derivative antifungal agent. When used in higher doses, ketoconazole has been shown 
to inhibit gonadal and adrenal steroidogenesis by disrupting the P-450–dependent enzyme system. 
Ketoconazole causes a rapid decrease in circulating androgens and is associated with significant 
responses in previously untreated prostate cancer. Dosages of 800-1200 mg daily have been 
reported to have a prolonged effect on testosterone synthesis and to interfere with corticosteroid 
synthesis by the adrenals. 
 
Ketoconazole is rapidly absorbed from the GI tract. Oral bioavailability is similar following 
administration of tablets or suspension but is highest following administration of the ketoconazole 
solution. The bioavailability of oral ketoconazole depends critically on an acid pH in the stomach. 
Thus buffering the gastric pH with food or concomitant administration of drugs that   increase   
gastric   pH   (i.e.,   antacids,   H2    blockers)   decreases   the   bioavailability   of ketoconazole. 
 
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Ketoconazole is available as 200 mg tablets (Nizoral®, Janssen pharmaceuticals). 
 
Dosage and Administration 
The recommended dose/schedule of ketoconazole for the treatment of prostate cancer is 400 mg 
orally three times daily with hydrocortisone replacement given in divided doses. Lower doses of 
ketoconazole have also been given (200 mg t.i.d.); however, the endocrine effects at this dose have 
not been found to be optimal. 
 
Drug Interactions 
Prolongation of the OT interval: Many drugs, including astemizole (Hismanol®), terfinidine 
(Seldane®), omeprazole (Prilosec®), and cisapride (Propulsid®), have known interactions with 
inducers of P-450 such as ketoconazole. Rarely, serious cardiovascular effects, including 
arrhythmia, arrest, palpitations, syncope, and death have been reported in patients receiving 
ketoconazole concomitantly with these drugs. 
 
Antacids/H2-blockers: Gastric acidity is necessary for the dissolution and absorption of 
ketoconazole; thus, any drug that decreases gastric acidity may decrease the absorption of 
ketoconazole. 
 
 
 
Adverse Effects 
Ketoconazole is well tolerated in patients with adverse effects including mineralocorticosteroid 
excess secondary to CYP17 inhibition, which can be managed with oral hydrocortisone 20 mg in 
the morning and 10 mg in the evening. Other common side effects include diarrhea, stomach 
upset, and mild nausea/vomiting (50%). 
 
Endocrine: Ketoconazole inhibits cortisol synthesis, particularly in patients receiving relatively 
high daily dosages or divided daily dosing of the drug. Patients taking 400 mg t.i.d. should be 
assumed to be adrenal suppressed and treated accordingly, with "stress doses" of corticosteroids 
given for serious intercurrent illness. 
 
Bilateral gynecomastia with breast tenderness has occurred in some men during therapy with 
ketoconazole. Limited data suggest that gynecomastia occurs because ketoconazole decreases 
serum testosterone concentrations and to a lesser extent serum estradiol concentrations, resulting 
in an increased estradiol:testosterone ratio. 
 
 
 
Gastrointestinal: The most frequent adverse reactions to ketoconazole are nausea and/or vomiting, 
which have been reported in 3-10% of patients. Abdominal pain, constipation, flatulence, GI 
bleeding, and diarrhea have also been reported. Adverse GI effects appear to be dose related, are 
reported less frequently when ketoconazole is administered with food, and usually subside with 
continued therapy. 
 
Hepatic effects: Transient increases in serum AST (SGOT), ALT (SGPT), and alkaline 
phosphatase concentrations have been reported during ketoconazole therapy. Hepatotoxicity, 
which may be hepatocellular, cholestatic, or a mixed pattern of injury, has been reported rarely. 
Although ketoconazole-induced hepatotoxicity usually is reversible following discontinuance of 
the drug, recovery may take several months, and rarely death has occurred. 
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Dermatologic effects: Pruritus has been reported in ~2% of patients receiving ketoconazole. 
Rash, dermatitis, purpura, and urticaria have been reported in <1% of patients receiving 
ketoconazole,   and   in   some   cases   these   effects   may   have   been   manifestations   of   a 
hypersensitivity reaction to the drug. 
 
14.3 
Doxorubicin 
 
Pharmacology 
Doxorubicin (Adriamycin®) binds to nucleic acids, presumably by specific intercalation of the 
planar anthracycline nucleus with the DNA double helix. The anthracycline ring is lipophilic, 
but the saturated end of the ring system contains abundant hydroxyl groups adjacent to the 
amino sugar, producing a hydrophilic center. The molecule is amphoteric, containing acidic 
functions in the ring phenolic groups and a basic function in the sugar amino group. It binds to 
cell membranes as well as to plasma proteins. Doxorubicin has several proposed mechanisms of 
cytotoxic action, including DNA intercalation, covalent DNA binding, free radical formation, 
and inhibition of DNA topoisomerase I and II. 
 
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. 
 
 
 
Supplier/How Supplied 
Doxorubicin HCl is available as a solution for injection (2 mg/ml) or a lyophilized powder for 
reconstitution. Several manufacturers produce doxorubicin, with Adria Laboratories being the first 
company to market the drug (Adriamycin®). Various vial sizes are also available. 
 
Solution Preparation 
Lyophilized drug may be reconstituted with sterile water for injection, D5W, or normal saline. 
This solution does not need to be further diluted for administration. 
 
Storage & Stability 
The vials of lyophilized powder can be stored at room temperature, away from direct light, for at 
least 2 years. Commercial solutions need to be refrigerated. Reconstituted solutions are stable 
for long periods of time, but, if not used within 8 hours, need to be protected from light. 
 
Administration of doxorubicin 
Doxorubicin can be administered as an intravenous push, a slow infusion over several minutes to 
an hour, or as a continuous infusion for 24-96 hours. Different toxicities are associated with 
different methods of administration (see Adverse Effects below). In general, short infusions or 
bolus  administration  of  doxorubicin  cause  more  myelosuppIrReBssNioUnMBthEaRn: HSmCu-McoSs-i1t4is-0, 94a9nd 


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rrence fro 
 
continuous infusions of doxorubicin cause more mucositis than myelosuppression. There is 
evidence that prolonged infusion schedules are less cardiotoxic. 
 
Doxorubicin is a vesicant and, if extravasated, can cause severe ulceration and necrosis. Therefore, 
it will be administered through a central line for infusion to prevent extravasation. Doxorubicin 
given peripherally as a slow infusion or as a bolus must be infused simultaneously with a running 
intravenous fluid through the same line. The nurse should check often for blood return when giving 
such infusions. Continuous infusions of doxorubicin should never be given through a peripheral 
i.v. site but requires a central line for infusion. 
 
 
 
Drug Interactions: 
Doxorubicin is a major substrate of cytochrome P450 CYP3A4, CYP2D6, and P-glycoprotein 
(P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4, 
CYP2D6, and/or P-gp (e.g., verapamil), resulting in increased concentration and clinical effect 
of doxorubicin. Inducers of CYP3A4 (e.g., phenobarbital, phenytoin, St. John‘s Wort) and P-gp 
inducers may decrease the concentration of doxorubicin. 
 
 
 
Adverse Effects 
Hematologic: Myelosuppression is the dose-limiting side effect for doxorubicin given as a short 
infusion or a bolus. Leukopenia is most common with a nadir of 10-14 days and recovery by day 
21-28. Thrombocytopenia is less common (0.1%) and is rarely dose-limiting. 
 
Cardiac: Doxorubicin is associated with acute and delayed cardiac toxicity. The acute effects on 
the cardiac system manifest as a rare pericarditis-myocarditis syndrome with or without 
electrophysiologic aberrations. The conduction abnormalities are generally transient and are not 
associated with severe morbidity or the need for dose modification. In contrast, the delayed cardiac  
toxicity  is  clearly  dose  related,  generally  associated  with  a  cumulative  dose  of 
~500 mg/m2  of doxorubicin. Cardiac toxicity can take up to 10 years to manifest but is most 
often seen within 2-3 years following administration. The clinical syndrome presents as classic 
congestive  heart  failure  and  is  usually  irreversible  but  manageable.  Patients  with  prior 
mediastinal irradiation (>2000 rad), >70 years old, and a history of preexisting cardiovascular 
disease (e.g., myocardial infarction or long standing hypertension) are at increased risk for delayed 
cardiac toxicity secondary to doxorubicin. 
 
Prolonged (24-96 h) infusions of doxorubicin have been shown to decrease the incidence of cardiac 
toxicity, allowing higher cumulative doses to be given without compromising cardiac function. 
 
Gastrointestinal:  Nausea  and  vomiting  (N/V)  are  moderate  to  severe  with  doxorubicin, 
depending on the dose and the method of administration. N/V are more severe with bolus or 
short administration of doxorubicin compared to continuous infusions at the same dose. N/V 
usually begins 6-12 hours after the start of administration and can last for up to 48 hours after 
administration. 
 
Mucositis is common with continuous infusions of doxorubicin. The lesions often follow the 
leukopenia, peaking at approximately day 10-14 and recovering by day 21-28. If the lesions are 
severe and traverse the entire GI tract, diarrhea might accompanyItRhBemNU. SMhBoErRte:nHinSgC-tMheS-l1e4n-0g9th49of 
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no  effective  treatments  that  will  speed  the  healing  process  once  the  lesions  are  present. 
Leukocyte recovery is the only treatment that effectively heals the ulcers. Granulocyte colony- 
stimulating-factor (G-CSF, filgrastin, Neupogen®) has been shown, in a few studies, to decrease 
the incidence of mucositis. 
 
Vesicant reactions: As mentioned earlier, doxorubicin is a vesicant and, if extravasated, will cause 
ulceration and necrosis, requiring surgical debridement and skin grafting for repair. This reaction 
is a slow process that may continue for several days. Immediate action is required to limit  the 
tissue damage  and  prevent  severe damage of  underlying structures  (e.g.  tendons, nerves, 
muscles). 
 
Radiation recall: Doxorubicin can cause reactivation of soft-tissue reactions in areas previously 
irradiated. The most sensitive area involved is the esophagus. 
 
Other: 
 Alopecia is nearly universal with doxorubicin but usually only includes the hair on the 
head and occasionally the eyebrows or eyelashes to a lesser degree. 
 
 Doxorubicin is dark red and may impart an orange or pink color to the urine. 
 
 Hyperpigmentation   of   nail   beds   and   skin   is  occasionally  seen   with   doxorubicin 
administration, and thin, fragile nails prone to superficial infection are commonly seen 
with weekly administration schedules, including that used in this protocol. 
 
 Secondary malignancies have been reported post-market. Specifically, secondary acute 
myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) have occurred in 
patients receiving doxorubicin. Cumulative incidences were 0.2% at 5 years and 1.5% at 
10  years  in  2  separate  trials  of  breast  cancer  patients  who  received  an  adjuvant 
doxorubicin-containing regimen. These leukemias generally develop within 1-3 years of 
treatment. 
 
 
 Fertility may be affected secondary to therapy. Doxorubicin is toxic to male reproductive 
organs. Subjects may choose sperm banking if desired. 
 
 
 
14.4 
Estramustine 
 
Pharmacology 
Chemically,  estramustine  (Emcyt®)  is  a  combination  of  estradiol  phosphate  and  nitrogen 
mustard linked via a carbamate at the C-3 position of estradiol. Estramustine was designed for use 
in advanced carcinoma of the prostate. Estramustine phosphate has bischloromethyl side chains 
and was presumed to act by chemical alkylation. However, the drug may not act as an alkylating 
agent. The basic steroidal structure also imparts weak estrogenic activity. Recent studies suggest 
that estramustine has antimicrotubule activity. The drug appears to bind to high- molecular-weight 
microtubule-associated proteins to promote microtubule disassembly. Estramustine can kill tumor 
cells in any phase of the cell cycle and causes cells to accumulate in metaphase. 
 
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Estramustine sodium phosphate is a pro-drug administered orally. About 75% of orally 
administered  estramustine  phosphate  is  absorbed.  After  oral  administration,  it  is  rapidly 
converted to estramustine. The major active metabolite is another cytotoxic metabolite, 
estromustine. Estramustine and estromustine are metabolized to estradiol and estrone, respectively.  
The  estrogens  may  cause  the  antigonadotropic  effects  reported  (including decreased  
plasma  concentrations  of  testosterone,  dihydrotestosterone,  gonadotropins, cholesterol, and 17-
hydroxyprogesterone and increased concentrations of prolactin and cortisol). The compound is 
excreted as metabolites of both the alkylating and estrogenic moieties into the bile, urine, and 
feces. Non-renal excretion is the major route of elimination of estramustine. The terminal half-life 
of estramustine is reported to be ~20-24 hours in humans. 
 
Supplier/How Supplied 
Estramustine phosphate is investigationally available as an injectable compound for intravenous 
use and commercially available as hard, off-white capsules containing 140 mg of drug as the 
disodium salt (12.5 mg sodium per capsule) from Roche Laboratories (Estracyte®) and Kabi 
Pharmaceuticals (Emcyt®). Long-term storage requires refrigeration at temperatures of 2-8°C. The 
commercially available capsules may be kept at room temperature for 24-48 h. 
 
Administration 
In a randomized, three-way crossover study of 6 patients with prostate cancer, estramustine 420 
mg administered with a low-calcium breakfast or milk significantly decreased the rate and extent 
of absorption. Thus, doses should be taken 1 h before or 2 h after meals; dairy products should not 
be taken with estramustine. The effect of antacid on estramustine absorption is not known; 
however, decreased drug absorption is possible. 
 
Drug Interactions 
Because of the  estrogenic effect,  patients  may have increased  warfarin  requirements  while 
taking estramustine. Patients receiving a live virus vaccine may have increased risk of infection. 
Common side effects occurring at rate of >10% include mild nausea and, diarrhea, minor 
gastrointestinal upset, edema or exacerbation of peripheral edema, dypnea, breast tenderness, 
and a transient increase in bilirubin, LDH, and AST. 
 
Adverse Effects 
Gastrointestinal:  Dose-limiting  adverse  effects  of  estramustine  have  generally  consisted  of 
extreme gastrointestinal toxicity. The nausea and vomiting from estramustine can occur soon 
after administration. Symptoms are generally transient and responsive to phenothiazines. A similar 
but delayed and often intractable gastrointestinal toxicity is rarely reported. This later 
presentation can occur up to 6-8 weeks after initiation of continuous therapy and usually 
necessitates drug discontinuance. Diarrhea is reported in 15-30% of patients. 
 
Cardiac: Several patients with pre-existing cardiac disease have demonstrated increasing 
symptoms of congestive heart failure during estramustine therapy, presumably because of the 
salt-retaining effects of the estrogenic portion of the drug. Other rare cardiovascular complications 
include thromboembolism, ischemic effects, and cerebral effects. The incidence and severity are 
similar to those with estrogen treatment of prostate cancer. 
 
Endocrine: Gynecomastia has been reported due to the estrogenic effects of estramustine. 
 
 
14.5 
Docetaxel 
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Pharmacology 
 
Docetaxel (Taxotere) is a semisynthetic antimicrotubule agent. It is a taxane derivative similar to 
paclitaxel. Docetaxel is approximately 2 times as potent as paclitaxel and at least 5 times more 
potent against paclitaxel-resistant cells. It binds to free tubulin and promotes the assembly of 
tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads 
the inhibition of mitosis in cells. 
 
In vitro, docetaxel is 94-97% protein bound. It is widely distributed throughout total body water. 
Docetaxel is primarily metabolized through the cytochrome p450 3A4 isoenzyme (CYP3A4) 
system and eliminated primarily through feces. Less than 6% is eliminated renally. Dose 
adjustments are required elevated serum bilirubin. 
 
Common adverse effects include alopecia (56.3%-98%), fluid retention syndrome (6.5%-67%), 
myelosuppression, nausea (38%-81%), vomiting (22%-67%), stomatitis (19%-69%), cutaneous 
reactions (8%-41%), and hypersensitivity reaction (rare). 
 
How Supplied 
Docetaxel is available as single-use vials of 20 mg/mL and 80 mg/4 mL (Taxotere, Sanofi- 
Aventis). 
 
Drug Interactions 
Drugs that induce or inhibit CYP3A4 may lead to decreased efficacy or enhanced toxicity. 
These medications include cyclosporine, terfenadine, ketoconazole, and erythromycin. 
 
Adverse Effects 
Hematologic: Myelosuppression is the dose-limiting side effect for docetaxel given as a short 
infusion or a bolus. Leukopenia is most common, with a nadir of 7, while thrombocytopenia is 
less common. 
 
Gastrointestinal: Mucositis is most common. Other side effects include nausea, vomiting, 
stomatitis, and diarrhea. 
 
Fluid retention syndrome: May be due to decreased colloid osmotic pressure of plasma followed 
by a capillary protein leakage. 
 
Neurologic: Mild to moderate sensory neuropathy has been reported in patients treated with 
cumulative i.v. doses between 50 and 720 mg/m. The onset and severity varies between 
individuals. Dose reductions should be considered if severe neuropathic symptoms develop; 
treatment may need to be discontinued if symptoms do not resolve following a dose reduction 
 
Hypersensitivity reaction: This is a rare side effects and is attributed to the solvent Polysorbate 
80. Dexamethasone administration for 3 days minimizes the incidence. 
 
Cutaneous reactions: Commonly presents as a rash with or without itching. Docetaxel is 
continued for mild to moderate rash but may be discontinued if severe rash occurs despite dose 
adjustments. 
 
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Preparation and Administration Precautions 
 
Docetaxel is a cytotoxic anticancer drug, and, as with other potentially toxic compounds, caution 
should be exercised when handling and preparing docetaxel solutions. The use of gloves is 
recommended. Please refer to Handling and Disposal section. 
 
If docetaxel concentrate, initial diluted solution, or final dilution for infusion should come into 
contact with the skin, immediately and thoroughly wash with soap and water. 
 
If docetaxel concentrate, initial diluted solution, or final dilution for infusion should come into 
contact with mucosa, immediately and thoroughly wash with water. 
 
Docetaxel for injection concentrate requires two dilutions prior to administration. Please follow 
the preparation instructions provided below. Note: Both the docetaxel for injection concentrate and 
the diluent vials contain an overfill. 
 
A.  Preparation of the Initial Diluted Solution 
 
1. If refrigerated, remove the appropriate number of vials of docetaxel for injection concentrate 
and diluent (13% ethanol in water for injection). Allow the vials to stand at room 
temperature for ~5 minutes. 
 
2.   Aseptically withdraw the contents of the appropriate diluent vial into a syringe and 
transfer it to the appropriate vial of docetaxel for injection concentrate. If the procedure 
is followed as described, an initial diluted solution of 10 mg docetaxel/mL will result. 
 
3.  Gently rotate the initial diluted solution for ~15 seconds to assure full mixture of the 
concentrate and diluent. 
 
4.   The initial diluted docetaxel solution (20 mg docetaxel/mL) should be clear; however, 
there may be some foam on top of the solution due to the Polysorbate 80. Allow the 
solution to stand for a few minutes to allow any foam to dissipate. It is not required that 
all foam dissipate prior to continuing the preparation process. 
 
The initial diluted solution may be used immediately or stored either in the refrigerator or at 
room temperature for a maximum of 8 hours. 
 
 
 
B.        Preparation of the Final Dilution for Infusion 
 
1.  Aseptically withdraw the required amount of initial diluted docetaxel solution (20 mg 
docetaxel/mL) with a calibrated syringe and inject into a 250 mL infusion bag or bottle 
of either 0.9% sodium chloride solution or 5% dextrose solution to produce a final 
concentration of 0.3-0.74 mg/mL. 
 
If a dose >200 mg of docetaxel is required, use a larger volume of the infusion vehicle so 
that a concentration of 0.74 mg/mL docetaxel is not exceeded. 
 
2.   Thoroughly mix the infusion by manual rotation. 
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3.  As with all parenteral products, docetaxel should be inspected visually for particulate matter  
or  discoloration  prior  to  administration  whenever  the  solution  and  container permit. 
If the docetaxel for injection initial diluted solution or final dilution for infusion is not 
clear or appears to have precipitation, these should be discarded. 
 
The final docetaxel dilution for infusion should be administered intravenously as a l-hour 
infusion under ambient room temperature and lighting conditions. 
 
Contact of the docetaxel concentrate with plasticized PVC equipment or devices used to prepare 
solutions for infusion is not recommended. In order to minimize patient exposure to the 
plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags 
or sets, the final docetaxel dilution for infusion should be stored in bottles (glass, polypropylene) 
or plastic bags (polypropylene polyolefin) and administered through polyethylene-lined 
administration sets. 
 
Stability: Unopened vials of docetaxel are stable until the expiration date indicated on the 
package when stored from 2-25C (36-77F) and protected from bright light. Freezing does 
not adversely affect the product. 
 
How Supplied 
 
Docetaxel for injection concentrate is supplied in a single-dose vial as a sterile, pyrogen-free, 
non-aqueous, viscous solution with an accompanying sterile, non-pyrogenic, diluent (13% ethanol 
in water for injection) vial. The following strengths are available: 
 
Docetaxel 80 mg 
 
Docetaxel 80 mg concentrate for infusion: 80 mg docetaxel in 2 mL Polysorbate 80 and diluent 
for docetaxel 80 mg; 13% (w/w) ethanol in water for injection. Both items are in a blister pack 
in one carton. 
 
Docetaxel 20 mg 
 
Docetaxel (docetaxel) 20 mg concentrate for infusion: 20 mg docetaxel in 0.5 mL Polysorbate 
80 and diluent for docetaxel 20 mg; 13% (w/w) ethanol in water for injection. Both items are in 
a blister pack in one carton. 
 
 
Storage: Store between 2C and 25C (36-77F). Retain in the original package to protect from 
bright light. 
 
Docetaxel initial dilution solution (10 mg docetaxel /mL) and final dilution for infusion solution 
(in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 4 hours 
(including the 1 hour administration) after preparation. However, the initial dilution solution is 
stable for 8 hours either at room temperature, 15-25C (59-77F), or stored refrigerated, 2-8C (36-
46F). 
 
Handling and Disposal: Procedures for proper handling and disposal of anticancer drugs should 
be considered. Several guidelines on this subject have been published.1-7  There is no general 
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agreement  that  all  of  the  procedures  recommended  in  the  guidelines  are  necessary  or 
appropriate. 
 
Weekly Dosing 
 
Protocols involving the weekly administration of docetaxel are currently utilizing 30-minute or 
15-minute infusion times in addition to a l-hour infusion period. This is due to the fact that the 
infusion solution volume (100 cc) for weekly docetaxel is generally less than that for every 3- 
week treatment (250 mL). 
 
14.6 
Management of Adverse Effects 
 
Any AE/SAE not listed in the CTCAE version 4.0 will be graded as follows 
 
Severity of Event 
Grade 
Definition 
1 
Mild:  Symptoms  which  do  not  interfere  with  patient‘s  daily 
activities 
2 
Moderate:  Symptoms  which  may  interfere  with  patient‘s  daily 
activities 
3 
Severe: Events which interrupt patient‘s usual daily activities 
4 
Life-threatening or disabling 
5 
Death 
 
 
 
Medically significant adverse events considered related to the study treatment by the investigator 
will be followed until resolved or considered stable. 
 
It will be left to the investigator‘s clinical judgment to determine whether an adverse event is 
related and of sufficient severity to require the subject‘s removal from treatment or from the 
study. A subject may also voluntarily withdraw from treatment due to what he or she perceives 
as an intolerable adverse event. If either of these situations arises, the subject should be strongly 
encouraged to undergo medical supervision until symptoms cease or the condition becomes stable. 
 
Management of Abnormal Laboratory Results 
 
All clinically important abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return either to baseline or to a level deemed acceptable by the 
investigator or until a diagnosis that explains them is made. The criteria for determining whether 
an abnormal laboratory test result should be reported as an adverse event are as follows: 
1.         Test result is associated with accompanying symptoms, and/or 
2. 
Test result requires additional diagnostic testing or medical/surgical intervention (merely 
repeating an abnormal test, in the absence of any of the above conditions, does not meet 
criteria for reporting), and/or 
3. 
Test  result  leads  to  a  change  in  study  dosing  or  discontinuation  from  the  study, 
significant additional concomitant drug treatment or other therapy, and/or 
4. 
Test result leads to any of the outcomes included in the definition of a serious adverse 
event, and/or                                                                        IRB NUMBER: HSC-MS-14-0949 


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ersensitivi
 
5.         Test result is considered to be an adverse event by the investigator 
 
Any abnormal test result that is determined to be an error does not require reporting as an 
adverse event, even if it met one of the above conditions except for condition #4. Clinically 
significant laboratory results must be recorded in the patient‘s CRF. 
 
Management of Cardiotoxicity 
 
Baseline echocardiograms and EKG will be conducted prior to therapy initiation. Additional 
ECG and echocardiograms will be obtained before each cycle of chemotherapy. 
 
Management of electrolyte abnormalities 
 
Investigator should manage electrolyte abnormality as medically indicated per local standards 
 
Mucositis: Stomatitis/oral mucositis/mouth ulcers should be treated using local supportive care. 
Examinations will describe whether the examination reveals mouth ulcers rather than general 
inflammation of the mouth. The paradigm below will be followed. 
1. 
For mild toxicity (grade 1), use conservative measures such as non-alcoholic mouthwash 
or salt water (0.9%) mouthwash several times per day until resolution. 
2. 
For more severe toxicity (grade 2, in which patients have pain but are able to maintain 
adequate oral alimentation, or grade 3 in which patients cannot maintain adequate oral 
alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., viscous   
lidocaine   1%,   diphenhydramine,   and   Mylanta®   or   Maalox   [Aluminum Hydroxide 
| Magnesium Hydroxide | Simethicone]). 
3. 
Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen 
mouth ulcers. It is preferable to avoid these agents. 
4.         Oral antifungal agents such as fluconazole and nystatin may be used for oral candidiasis. 
Antiviral agents such as acyclovir should be avoided unless a viral infection is suspected. 
 
Management of Nausea and Vomiting 
 
Investigator should manage nausea and vomiting as medically indicated per local standards. 
 
Management of Anemia 
 
Investigator should manage anemia as medically indicated per local standards 
 
Management of diarrhea 
 
The appearance of diarrhea attributed to treatment may be treated with loperamide 
 
Management of Degarelix Adverse Effects 
Injection site reaction 
After the initial and subsequent degarelix injections, subjects will place ice on the injection site 
to minimize local irritation and erythema. 
 
Hypersensitivity reactions 
Hypersensitivity  reactions,  including  anaphylaxis,  urticarial, 
 
 
IaRnBdNUanMgBioEeRd: eHmSCa,-MhSa-1v4e-09b4e9en 
reported  post-marketing.  In  case  of  a  serious  hyp 
tyIRBreAaPcPtiRoOn,VAdLegDaAreTlEix: 01w/2i6ll/20b1e6 


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15.0 
ETHICAL CONSIDERATIONS 
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immediately discontinued if the injection has not been completed and managed as clinically 
indicated. 
 
Hot flashes 
Hot flashes are frequently reported during the first 3 months, but with no overall difference over 
a 1-year period. Reporting during therapy initiation may be due to higher velocity of testosterone 
suppression. Increased body weight may predispose patients to hot flashes. Weight control may 
minimize the incidence.24 
 
Management of Doxorubicin Adverse Effects 
Vesicant extravasation, anthracycline-induced 
Infusion will be stopped and an initial dose of dexrazoxane (Totect®): 1000 mg/m2 body surface 
area over 1-2 hours on day 1, maximum 2000 mg. Within 6 hours of extravasation, repeat the 
same dose 24 ± 3 hours on day 2, maximum 2000 mg, followed by a 500 mg/m2 dose after 48 ± 
3 hours on day 3, maximum 1000 mg. 
 
Management of Docetaxel Adverse Effects 
Fluid retention syndrome 
Severe fluid retention may occur; pretreatment with oral corticosteroids recommended prior to 
each dose; monitoring recommended with preexisting effusion. This AE  occurs in 50-19% of 
patients treated with docetaxel every 3 weeks. It is characterized by  weight gain, peripheral and/or 
generalized edema, pleural effusions, and ascites. Incidence is increased when total dose 
> 400 mg/m2. This may be due to decreased colloid osmotic pressure of plasma followed by a 
capillary protein leakage. 
 
This AE is managed by premedication with dexamethasone 4-8 mg po bid x 3 days beginning 1 
day prior to docetaxel administration. Patients developing new-onset edema, progression of 
existing edema, or another sign of fluid retention (e.g., 2 pound weight gain) are  treated with 
oral diuretics such as triamterene/hydrochlorothiazide (one capsule orally [PO] once per day up 
to three times daily).  If edema persists despite triamterene/hydrochlorothiazide therapy,  give 
furosemide (40 mg PO daily) with potassium supplementation if needed. If after 2 weeks, 
furosemide 40 mg PO daily is not effective, furosemide (20 mg PO daily) plus metolazone (2.5 
mg PO daily) with potassium supplementation if needed. 
 
Neurologic symptoms 
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 


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or in the loc 
 
15.1 
Ethical Compliance 
 
The study will be conducted in accordance with legal and regulatory (21 CFR 50, 56, 312 as applicable) 
requirements, as well as the general principles set forth in the Guidelines for GCP (ICH 1996) and the 
Declaration of Helsinki (World Medical Association 1996 and 2008). 
 
The principal investigator is responsible for ensuring that all participating staff members are adequately 
trained and competent to perform his/her assigned tasks. 
 
15.2 
IRB Review 
 
Before implementing this study, the protocol, the proposed informed consent form, and other required 
information, must be reviewed and approved by a properly constituted Institutional Review Board (IRB). 
Any amendments to the protocol, other than administrative ones, must be reviewed and approved by this 
committee before implementation. If an immediate change to the protocol is implemented for safety reasons 
by the investigator, the IRB must be informed immediately. The study must be reviewed and approved 
at least annually as well. 
 
15.3 
Recruitment 
 
Recruitment typically occurs from patients treated at the Cancer Center. Recruitment may occur from 
patient self-referral from trials posted on ClinicalTrials.gov. If the investigator wishes to expand 
recruitment, advertisements will be reviewed and approved by the IRB prior to use. 
 
15.4 
Informed Consent 
 
The Investigator will be responsible for obtaining consent, documented on the Informed Consent Form 
(ICF) signed and dated by each patient or his/her legally authorized representative, prior to his/her 
participation in the study, in accordance with ICH GCP guidelines. The ICF will be written in non- technical 
language. The patient should read and be given as much time as they need to consider their participation 
before signing and dating it. 
 
The investigator or study staff designee must explain to each patient the nature of the study, its purpose, 
the procedures involved, the expected duration, the potential risks and benefits involved and any discomfort 
it may entail. Each patient must be informed that participation in the study is voluntary and that he/she 
may withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
 
Participation in the study and date of informed consent should be documented appropriately in the patient‘s 
files. The original ICF will be maintained in the research files and a copy must be maintained in the 
institution‘s medical records. The patient or his/her legally authorized representative will also be given 
a copy of the signed consent form. 
 
15.5 
Confidentiality 
 
All records identifying the patient will be kept confidential and, to the extent permitted by the applicable 
laws and/or regulations, will not be made publicly available. Patient names will not be supplied to third 
parties. A unique study accession number will be assigned to each patient on study and will be used on 
the CRFs. Identifiable data on any document (e.g., pathologist report) must be redacted before a copy of 
the document is supplied to third parties. The study coordinator will maintain a list to enable patients‘ 
records to be identified for verification purposes. 
 
Study data stored electronically will be stored in zone 100, on password-protected, encrypted computers. 


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15.6 
Publication of Study Results 
 
The investigator will assure that the key elements of this protocol will be posted in a publicly accessible 
database such as  www.ClinicalTrials.gov. In addition, upon study completion and finalization of the 
study report the results of this study will be submitted for publication in scientific journals and/or 
scientific  meetings.  If  the  results  of  the  study  are  published,  the  patient‘s  identity  will  remain 
confidential. 
 
15.7 
Retention of Documents 
 
To enable evaluations and/or audits from regulatory authorities or sponsors, the investigator agrees to 
keep records, including the identity of all participating patients (sufficient information to link records, eg, 
CRFs and hospital records), all original signed informed consent documents, copies of all CRFs, safety 
reporting   forms,   source   documents,   detailed   records   of   treatment   disposition,   and   adequate 
documentation of relevant correspondence in a secure storage facility. 
 
Essential documents (written and electronic) should be retained for at least three (3) years after the 
completion of the study. The records should be retained by the investigator according to local regulations 
or as specified in the Clinical Study Agreement (CSA), whichever is longer. 


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16.0 
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45. Hussain, M., Smith, D. C., El-Rayes, B. F., et al. Neoadjuvant docetaxel and estramustine chemotherapy in high- 
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46. Eastham, J. A., Kelly, W. K., Grossfeld, G. D., et al. Cancer and Leukemia Group B (CALGB) 90203: a 
randomized phase 3 study of raidcal prostatectomy alone versus estramustine and docetaxel before radical 
prostatectomy for patients with high-risk localized disease. Urology, 62 Suppl: 55, 2003 
47. Vaughn, D. J., Brown Jr., A. W., Harker, W. G., et al. Multicenter phase II study of estramustine phosphate plus 
weekly paclitaxel in patietns with androgen-independent prostate carcinoma. Cancer, 100: 746, 2004 


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48. Tiffay, N. M., Ryan, C. W., Garzotto, M., et al. High dose calcitriol, docetaxel and estramustine for androgen 
independent prostate cancer: a phase I/II study. J Urol, 174: 888, 2005 
49. Esper, P., Mo, F., Chodak, G., et al. Measuring quality of life in men with prostate cancer using the functional 
assessment of cancer therapy-prostate instrument. Urology, 50(6): 920, 1997 
50. Eisenhauer, E. A., Therasse, P., Bogaerts, J. et al.: New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 45: 228, 2009 
51. Arlen, P. M., Bianco, F., Dahut, W. L. et al.: Prostate Specific Antigen Working Group guidelines on prostate 
specific antigen doubling time. J Urol, 179: 2181, 2008 


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||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  ...... 
0 
1 
2 
3 
4 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
|||||||| 
||||||||||||||||||||||||||||||||||||||||||. 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
 |  
 |  
 |  
 |  
 |  
 
APPENDIX A: FACT-P Qualify of Life Scale 
 
 
 
 
 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||||||||||||||||||||||||||| 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
 
 
 
 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
 
 
 
GP1 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ....................................................... 
0 
1 
2 
3 
4 
 
GP2 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ...................................................................... 
0 
1 
2 
3 
4 
 
GP3 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
0 
1 
2 
3 
4 
 
GP4 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||........................................................................ 
0 
1 
2 
3 
4 
 
GP5 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ......................... 
0 
1 
2 
3 
4 
 
GP6 
|||||||||||||||||||||||||||||||||||||||| ............................................................................... 
0 
1 
2 
3 
4 
 
GP7 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  ........................................ 
0 
1 
2 
3 
4 
 
 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  
 Not 
at all 
A  little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
 
 
 
GS1 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| .................................................... 
0 
1 
2 
3 
4 
 
GS2 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |  ............................ 
0 
1 
2 
3 
4 
 
GS3 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||............................................. 
0 
1 
2 
3 
4 
 
GS4 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| .................................... 
0 
1 
2 
3 
4 
 
GS5 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||| ...................... 0 
1 
2 
3 
4 
 
GS6 
 
 
Q1 
 
 
 
 
GS7 


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|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
 
 
 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
 Not 
at all 
A  little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
 
GE1 
||||||||||||||||............................................................................. 
0 
1 
2 
3 
4 
GE2 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  .......... 
0 
1 
2 
3 
4 
GE3 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  .................. 
0 
1 
2 
3 
4 
GE4 
||||||||||||||||||||||....................................................................... 
0 
1 
2 
3 
4 
GE5 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ............................................................. 
0 
1 
2 
3 
4 
GE6 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  ............................ 
0 
1 
2 
3 
4 
 
 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
 Not 
at all 
A  little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
GF1 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  .......................... 
0 
1 
2 
3 
4 
GF2 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||..................... 
0 
1 
2 
3 
4 
GF3 
||||||||||||||||||||||||||||||||||||||.......................................................... 
0 
1 
2 
3 
4 
GF4 
||||||||||||||||||||||||||||||||||||||||||||||................................................... 
0 
1 
2 
3 
4 
GF5 
|||||||||||||||||||||||||||||| ............................................................... 
0 
1 
2 
3 
4 
GF6 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  ...................... 
0 
1 
2 
3 
4 
GF7 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.............. 
0 
1 
2 
3 
4 


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|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| 
 
 
|||||||||||||||||||||||||||||||||||||||||| 
Not  at 
all 
A  little 
bit 
Some- 
what 
Quite 
a bit 
Very 
muc 
 
C2 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  ............................................................... 
0 
1 
2 
3 
4 
C6 
|||||||||||||||||||||||||||||||||||||| ......................................................... 
0 
1 
2 
3 
4 
P1 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  ................................. 
0 
1 
2 
3 
4 
P2 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.... 
0 
1 
2 
3 
4 
P3 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ............. 
0 
1 
2 
3 
4 
P4 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  ...................... 
0 
1 
2 
3 
4 
P5 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ................................................. 
0 
1 
2 
3 
4 
P6 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||  ....................................... 
0 
1 
2 
3 
4 
P7 
||||||||||||||||||||||||||||||||||||||||||||.................................................... 
0 
1 
2 
3 
4 
BL2 
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| ................................... 
0 
1 
2 
3 
4 
P8 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||.................. 
0 
1 
2 
3 
4 
BL5 
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||......................... 
0 
1 
2 
3 
4 


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APPENDIX B: ECOG Performance Status 
 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 


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APPENDIX C: NCI Common Terminology Criteria for Adverse Events (CTCAE) 
 
Safety and tolerability will be assessed according to Version 4.0 of the National Cancer Institute‘s Common 
Terminology Criteria for Adverse Events (CTCAE). An electronic version may be found at:: 
http://ctep.cancer.gov/reporting/ctc.html 
 
In brief: 
 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each AE based on this general guideline: 
 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; inter- 
vention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
 
A Semi-colon indicates ‗or‘ within the description of the grade. A single dash (-) indicates a grade is not 
available. 
 
Activities of Daily Living (ADL) 
 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the tele-phone, 
managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 


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IRB NUMBER: HSC-MS-14-0949 
IRB APPROVAL DATE: 01/26/2016 
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APPENDIX D: RECIST 1.1 Guidelines 
 
Tumor response and progression will be defined according to RECIST 1.1 criteria. Electronic guidelines may be 
found at:  http://www.eortc.be/recist/documents/RECISTGuidelines.pdf. 
 
Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference: 
 
Eligibility 
 
• 
Only patients with measurable disease at baseline should be included in protocols where objective tumor 
response is the primary endpoint. 
 
Measurable disease - the presence of at least one measurable lesion. If the measurable disease is restricted 
to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
 
Measurable lesions - lesions that can be accurately measured in at least one dimension with longest 
diameter  ≥20 mm using conventional techniques or ≥10 mm with spiral CT scan. 
 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm with 
conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, and 
also abdominal masses that are not confirmed and followed by imaging techniques; and. 
 
• 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 
weeks before the beginning of the treatment. 
 
• 
The same method of assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up. 
 
• 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and 
palpable lymph nodes). For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
 
Methods of Measurement 
 
• 
CT and MRI are the best currently available and reproducible methods to measure target lesions selected for 
response assessment. Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. 
This applies to tumors of the chest, abdomen and pelvis. Head and neck tumors and those of extremities 
usually require specific protocols. 
 
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and surrounded 
by aerated lung. However, CT is preferable. 
 
• 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) should not be 
used to measure tumor lesions. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical examination. 
 
• 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been fully and 
widely validated. Their uses in this specific context require sophisticated equipment and a high level of 
expertise that may only be available in some centers. Therefore, the utilization of such techniques for objective 
tumor response should be restricted to validation purposes in specialized centers. However, such techniques 
can be useful in confirming complete pathological response when biopsies are obtained. 


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• 
Tumor markers alone cannot be used to assess response.  If markers are initially above the upper normal 
limit, they must normalize for a patient to be considered in complete clinical response when all lesions have 
disappeared. 
 
• 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after treatment 
to differentiate between residual benign lesions and residual malignant lesions in tumor types such as germ 
cell tumors). 
 
Baseline documentation of “Target” and “Non-Target” lesions 
 
• 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, representative of 
all involved organs should be identified as target lesions and recorded and measured at baseline. 
 
• 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or clinically). 
 
• 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum 
LD. The baseline sum LD will be used as reference by which to characterize the objective tumor. 
 
• 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded 
at baseline. Measurements of these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up. 
 
 
Response Criteria 
 
 
Evaluation of target lesions 
* Complete Response (CR): 
Disappearance of all target lesions 
* Partial Response (PR): 
At least a 30% decrease in the sum of the LD of 
target lesions, taking as reference the baseline sum 
LD 
* Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD 
recorded since the treatment started or the appearance 
of one or more new lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment 
started 
 
 
Evaluation of non-target lesions 
* Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level 
* Incomplete Response/Stable Disease (SD): 
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the 
normal limits 


IRB NUMBER: HSC-MS-14-0949 
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* Progressive Disease (PD):                                          Appearance  of  one  or  more  new  lesions  and/or 
unequivocal progression of existing non-target 
lesions (1) 
 
(1)     Although a clear progression of ―non target‖ lesions only is exceptional, in such circumstances, the opinion of 
the treating physician should prevail and the progression status should be confirmed later on by the 
review panel (or study chair). 
 
Evaluation of best overall response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence  (taking as  reference  for  PD the  smallest  measurements  recorded  since the  treatment 
started). In general, the patient's best response assignment will depend on the achievement of both measurement and 
confirmation criteria 
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
 Any  
Any  
Yes  
PD  
 
• 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be classified as having ―symptomatic deterioration‖. Every 
effort should be made to document the objective progression even after discontinuation of treatment. 
 
• 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends on this determination, it is recommended that the residual lesion 
be investigated (fine needle aspirate/biopsy) to confirm the complete response status. 
 
 
Confirmation 
 
• 
The main goal of confirmation of objective response is to avoid overestimating the response rate observed. 
In cases where confirmation of response is not feasible, it should be made clear when reporting the outcome 
of such studies that the responses are not confirmed. 
 
• 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first met. 
Longer intervals as determined by the study protocol may also be appropriate. 
 
• 
In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general, not less than 6-8 weeks) that is defined in the study protocol 
 
 
Duration of overall response 
 
• 
The duration of overall response is measured from the time measurement criteria are met for CR or PR 
(whichever status is recorded first) until the first date that recurrence or PD is objectively documented, 
taking as reference for PD the smallest measurements recorded since the treatment started. 
 
Duration of stable disease 


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• 
SD is measured from the start of the treatment until the criteria for disease progression are met, taking as 
reference the smallest measurements recorded since the treatment started. 
• 
The clinical relevance of the duration of SD varies for different tumor types and grades. Therefore, it is 
highly  recommended  that  the  protocol  specify  the  minimal  time  interval  required  between  two 
measurements for determination of SD. This time interval should take into account the expected clinical 
benefit that such a status may bring to the population under study. 
 
Response review 
 
• 
For trials where the response rate is the primary endpoint it is strongly recommended that all responses be 
reviewed by an expert(s) independent of the study at the study‘s completion.  Simultaneous review of the 
patients‘ files and radiological images is the best approach. 
 
Reporting of results 
 
• 
All patients included in the study must be assessed for response to treatment, even if there are major 
protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of the following 
categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early 
death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data). 
 
• 
All of the patients who met the eligibility criteria should be included in the main analysis of the response 
rate.  Patients in response categories 4-9 should be considered as failing to respond to treatment (disease 
progression).   Thus, an incorrect treatment schedule or drug administration does not result in exclusion 
from the analysis of the response rate.  Precise definitions for categories 4-9 will be protocol specific. 
 
• 
All conclusions should be based on all eligible patients. 
 
• 
Subanalyses may then be performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, early discontinuation of 
treatment, major protocol violations, etc.).  However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported. 
 
• 
The 95% confidence intervals should be provided. 


Confidential 
Protocol No. GU-13-101 
Page 52 of 57 
Ver. 3, dated 11/20/2015 
IRB NUMBER: HSC-MS-14-0949 
IRB APPROVAL DATE: 01/26/2016 
 
 
 
APPENDIX E: Schedule of Assessments: 
 
Treatment Group 1: Prior prostatectomy or XRT with no radiographic involvement 
 
Protocol 
Activity 
Pre- 
treatment 
1 cycle = 8 wks 
Cycles 2 
& 3 
D 1,8,15, 
22,29,36 
C2D5 
0 
Every 12 
weeks after 
completion 
of chemo** 
Visit Name -28 
to -1 
-7 to 
-1 
C1D1 
C1D8 C1D15 C1D22 C1D29 C1D36 C1D43 C1D50 
Informed 
Consent 
X 
Physical exam 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
performance 
status 
X 
X 
X 
X 
FACT-P QoL 
measurement 
§ 
§ 
Inclusion/Excl 
usion criteria 
X 
Complete 
metabolic 
profile 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrolytes 
X 
X 
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 
X 
X 
PT, INR, PTT 
X 
X 
X 
X 
X 
PSA 
X 
X 
X 
X 
Testosterone 
X 
X 
Chest X-Ray 
or CT 
X 
* 
Bone Scan 
X 
† 
CT or MRI 
abd 
X 
* 
MRI pelvis 
X 
* 


Confidential 
Protocol No. GU-13-101 
Page 53 of 57 
Ver. 3, dated 11/20/2015 
IRB NUMBER: HSC-MS-14-0949 
IRB APPROVAL DATE: 01/26/2016 
 
 
 
Protocol 
Activity 
Pre- 
treatment 
1 cycle = 8 wks 
Cycles 2 
& 3 
D 1,8,15, 
22,29,36 
C2D5 
0 
Every 12 
weeks after 
completion 
of chemo** 
Visit Name -28 
to -1 
-7 to 
-1 
C1D1 
C1D8 C1D15 C1D22 C1D29 C1D36 C1D43 C1D50 
ECG 
(-180 to -1) 
X 
*** 
Echo 
(-180 to -1) 
X 
*** 
PreTx 
observation 
X 
X 
X 
X 
X 
X 
X 
IV 
Chemotherapy 
(3 cycles) 
X 
X 
X 
X 
X 
X 
X 
ADT Tx (12 
mos) 
C1D1 and monthly for total of 12 months (start date may be adjusted if patients received first dose prior 
to C1D1) 
 
*Repeat imaging if rise in PSA is >0.3 on 2 readings after maximum benefit 
** Every 12 weeks for the first 2 years, then every 6 months for the next 3 years, then annually 
***An ECG and echocardiogram will be obtained prior to each cycle of chemotherapy. 
§ At completion of every cycle; 12 weeks after completion of chemotherapy; after completion of ADT; upon testosterone recovery. 
† Repeat imaging if rise in PSA is >0.3 on 2 readings after maximum benefit and/or if abnormal at baseline. 


Confidential 
Protocol No. GU-13-101 
Page 54 of 57 
Ver. 3, dated 11/20/2015 
IRB NUMBER: HSC-MS-14-0949 
IRB APPROVAL DATE: 01/26/2016 
 
 
 
Schedule of Assessments: 
 
Treatment Group 2: Nodal Involvement Only;  
Treatment Group 3: Low Volume Bone Disease (4 Cycles) 
 
Protocol 
Activity 
Pre- 
treatment 
1 cycle = 8 wks 
Cycles 
2,3,4 
D 1,8,15, 
22,29,36 
C2,4 
D50 
Every 12 
weeks after 
completion 
of chemo** 
Visit Name -28 
to -1 
-7 to 
-1 
C1D1 
C1D8 C1D15 C1D22 C1D29 C1D36 C1D43 C1D50 
Informed 
Consent 
X 
Physical exam 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
performance 
status 
X 
X 
X 
X 
FACT-P QoL 
measurement 
§ 
§ 
Inclusion/Excl 
usion criteria 
X 
Complete 
metabolic 
profile 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrolytes 
X 
X 
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 
X 
X 
PT, INR, PTT 
X 
X 
X 
X 
X 
PSA 
X 
X 
X 
X 
Testosterone 
X 
X 
X-Ray or CT 
Chest 
X 
* 
Bone Scan 
X 
† 
CT abd 
X 
* 
MRI pelvis* 
X 
* 
ECG 
(-180 to -1) 
X 
*** 


Confidential 
Protocol No. GU-13-101 
Page 55 of 57 
Ver. 3, dated 11/20/2015 
IRB NUMBER: HSC-MS-14-0949 
IRB APPROVAL DATE: 01/26/2016 
 
 
 
Protocol 
Activity 
Pre- 
treatment 
1 cycle = 8 wks 
Cycles 
2,3,4 
D 1,8,15, 
22,29,36 
C2,4 
D50 
Every 12 
weeks after 
completion 
of chemo** 
Visit Name -28 
to -1 
-7 to 
-1 
C1D1 
C1D8 C1D15 C1D22 C1D29 C1D36 C1D43 C1D50 
Echo 
(-180 to -1) 
X 
*** 
PreTx 
observation 
X 
X 
X 
X 
X 
X 
X 
IV 
Chemotherapy 
(4 cycles) 
X 
X 
X 
X 
X 
X 
X 
ADT Tx (18 
mos) 
C1D1 and monthly for total of 18 months (start date may be adjusted if patients received first dose prior 
to C1D1) 
 
* Repeat imaging if rise in PSA is >0.3 on 2 readings after maximum benefit 
** Every 12 weeks for the first 2 years, then every 6 months for the next 3 years, then annually 
*** An ECG and echocardiogram will be obtained prior to each cycle of chemotherapy. 
§ At completion of every cycle; 12 weeks after completion of chemotherapy; after completion of ADT; upon testosterone recovery. 
† Repeat imaging if rise in PSA is >0.3 on 2 readings after maximum benefit and/or if abnormal at baseline. 


Confidential 
Protocol No. GU-13-101 
Page 56 of 57 
Ver. 3, dated 11/20/2015 
IRB NUMBER: HSC-MS-14-0949 
IRB APPROVAL DATE: 01/26/2016 
 
 
 
Schedule of Assessments; 
Treatment Group 4: Nodal with Bone Involvement;  
Treatment Group 5: High-Volume Bone/Visceral;  
 
Treatment Group 6: No Prior Definitive Local Therapy (5 Cycles) 
 
Protocol 
Activity 
Pre- 
treatment 
1 cycle = 8 wks 
C 2,3,4,5 
D 1,8,15, 
22,29,36 
C2,4 
D50 
Every 12 
weeks after 
completion 
of chemo** 
Visit Name -28 
to -1 
-7 to - 
1 
C1D1 
C1D8 C1D15 C1D22 C1D29 C1D36 C1D43 C1D50 
Informed 
Consent 
X 
Physical exam 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
performance 
status 
X 
X 
X 
FACT-P QoL 
measurement 
§ 
§ 
Inclusion/Excl 
usion criteria 
X 
Complete 
metabolic 
profile 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrolytes 
X 
X 
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 
X 
X 
PT, INR, PTT 
X 
X 
X 
X 
X 
PSA 
X 
X 
X 
X 
Testosterone 
X 
X 
X-Ray or CT 
Chest 
X 
* 
Bone Scan 
X 
† 
CT abd 
X 
* 
MRI pelvis* 
X 
* 


Confidential 
Protocol No. GU-13-101 
Page 57 of 57 
Ver. 3, dated 11/20/2015 
IRB NUMBER: HSC-MS-14-0949 
IRB APPROVAL DATE: 01/26/2016 
 
 
 
Protocol 
Activity 
Pre- 
treatment 
1 cycle = 8 wks 
C 2,3,4,5 
D 1,8,15, 
22,29,36 
C2,4 
D50 
Every 12 
weeks after 
completion 
of chemo** 
Visit Name -28 
to -1 
-7 to - 
1 
C1D1 
C1D8 C1D15 C1D22 C1D29 C1D36 C1D43 C1D50 
ECG 
(-180 to -1) 
X 
*** 
Echo 
(-180 to -1) 
X 
*** 
PreTx 
observation 
X 
X 
X 
X 
X 
X 
X 
IV 
Chemotherapy 
(5 cycles) 
X 
X 
X 
X 
X 
X 
X 
ADT Tx (24 
mos) 
C1D1 and monthly for total of 24 months (start date may be adjusted if patients received first dose 
prior to C1D1) 
Prostate 
Biopsy for 
viable cells 
Group 6 
only 
At month 12 
Radiation 
therapy if 
viable cells 
Group 6 
only 
At month 12 
 
*Repeat imaging if rise in PSA is >0.3 on 2 readings after maximum benefit 
**Every 12 weeks for the first 2 years, then every 6 months for the next 3 years, then annually 
***An ECG and echocardiogram will be obtained prior to each cycle of chemotherapy. 
§ At completion of every cycle; 12 weeks after completion of chemotherapy; after completion of ADT; upon testosterone recovery. 
† Repeat imaging if rise in PSA is >0.3 on 2 readings after maximum benefit and/or if abnormal at baseline.