Clinical trial NCT03069937
Conditions: Metastatic Prostatic Adenocarcinoma
Sponsor: Medical University of South Carolina
Start date: 2017-03-01; Completion date: 2024-12-11
Enrollment: 52 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to look at patient outcomes when docetaxel is started prior to ADT with degarelix.

Detailed description:
This study will look at two drugs, docetaxel and degarelix, which are both FDA approved for the treatment of prostate cancer. Docetaxel is a standard chemotherapy treatment for metastatic prostate cancer. Degarelix is an androgen deprivation therapy (ADT) agent that decreases the amount of testosterone in the body, which helps to fight tumor growth. Usually, docetaxel is given after ADT. This study will look at how your cancer changes when docetaxel is started before ADT. You are being asked to participate in this study because you have metastatic prostate cancer that can be treated with docetaxel and ADT.

Arms: arm 1: Docetaxel (TAXOTERE) will be given for up to 6 cycles every 21 days. During the 5th and 6th cycles, degarelix (Firmagon) will be administered on Cycle 5 day 1 and cycle 6 day 8. After cycle 6, degarelix will continue to be given every 28 days for a 5 more doses, for a total of 7 doses.
Interventions: intervention 1: Docetaxel intervention 2: Degarelix
Intervention descriptions: intervention 1: The docetaxel dose is a 75mg/m2 intravenous (given through the vein) injection. intervention 2: Degarelix will be given as a subcutaneous (given under the skin) injection in the abdomen. The first dose will be a 240mg dose; all other doses will be 80 mg.

Protocol documents:
Prot_SAP_001.pdf: 
Protocol version 6.0 dated  April 3, 2020 
1 
NCT #:NCT03069937 
 
MUSC CTO #: 102509 
 
A PHASE II STUDY OF DOCETAXEL BEFORE MEDICAL CASTRATION WITH 
DEGARELIX IN PATIENTS WITH NEWLY DIAGNOSED METASTATIC 
PROSTATIC ADENOCARCINOMA. 
 
PRINCIPAL INVESTIGATOR  
Theodore Gourdin, MD 
 
CO-INVESTIGATORS 
Thomas Keane, M.B.B.Ch., FACS 
Michael Lilly, M.D. 
David Marshall, M.D. 
 
Charleston, SC 29425  
Phone: 843-792-4895 
FAX: 843-792-1445 
E-mail: gourdith@musc.edu 
 
COORDINATING OFFICE: 
Sponsor-Investigator Support Unit (SIS Unit) 
Hollings Cancer Center 
Medical University of South Carolina 
86 Jonathan Lucas Street, Suite 373 
Charleston, SC 29425 
 
PROTOCOL VERSTION HISTORY 
Version 6.0 dated April 3, 2020 
Version 5.0 dated February 19, 2019 
Version 4.0 dated September 18, 2018 
Version 3.2 dated July 6, 2018 
Version 2.1 dated March 27, 2017 
Version 1.1 dated 12/13/2016 
Version 1 dated 11/30/16 
 
 
 
 
 
 
 


Protocol version 6.0 dated  April 3, 2020 
2 
TABLE OF CONTENTS 
1 
SCHEMA ............................................................................................................................................ 6 
2 
OBJECTIVES .................................................................................................................................... 7 
2.1 Primary Objective .............................................................................................................................. 7 
2.2 Secondary Objectives ......................................................................................................................... 7 
2.3 Exporatory Objectives ....................................................................................................................... 7 
3 
BACKGROUND................................................................................................................................. 7 
3.1 Metastatic Prostate Cancer ............................................................................................................... 7 
3.2 Docetaxel Based Chemotherapy for Prostate Cancer ..................................................................... 8 
3.3 Risk Groups/Volume of Mestastatic Disease ................................................................................. 12 
3.4 Androgen Deprivation Therapy ...................................................................................................... 13 
3.5 Genomic Analysis in Metastatic Prostate Cancer ......................................................................... 13 
3.6 Trial rationale and Hypothesis ........................................................................................................ 14 
3.7 Explanation of Primary Endpoint .................................................................................................. 15 
3.8 Explanation of Select Secondary Endpoints .................................................................................. 16 
4 
SUBJECT SELECTION.................................................................................................................. 16 
4.1 Inclusion Criteria ............................................................................................................................. 16 
4.2 Exclusion Criteria ............................................................................................................................ 17 
4.3 Inclusion of Women and Minorities ............................................................................................... 18 
4.4 Subject Registration ......................................................................................................................... 18 
5 
STUDY INTERVENTION .............................................................................................................. 19 
5.1 Agent Administration ...................................................................................................................... 19 
5.2 Pre- and Post- Medications .......................................................................................................... 2019 
6 
DOSE MODIFICATIONS .............................................................................................................. 20 
6.1 Docetaxel ........................................................................................................................................... 20 


Protocol version 6.0 dated  April 3, 2020 
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6.2 Degarelix ........................................................................................................................................... 23 
7 
CONCOMITANT THERAPY .................................................................................................... 2423 
7.1 Permitted Medications – Use with Caution ............................................................................... 2423 
7.2 Prohibited Medications .................................................................................................................... 24 
8 
STUDY ASSESSMENTS ................................................................................................................. 24 
8.1 General Considerations ................................................................................................................... 24 
8.2 History and Physical ........................................................................................................................ 24 
8.3 Concomitant Medications ................................................................................................................ 24 
8.4 Laboratory Assessments .................................................................................................................. 24 
8.5 Radiographic Assessments .............................................................................................................. 25 
8.6 Study Calendar.a ............................................................................................................................... 26 
8.7 Criteria for Removal from Protocol Treatment ............................................................................ 28 
8.8 Duration of Follow Up ..................................................................................................................... 28 
9 
DRUG INFORMATION ................................................................................................................. 28 
9.1 Docetaxel ........................................................................................................................................... 28 
9.2 Degarelix (Firmagon®) .................................................................................................................... 31 
10 
MEASURES OF EFFECT .............................................................................................................. 33 
10.1 
Definitions: ................................................................................................................................... 33 
10.2 
PSA evaluation and Response criteria ....................................................................................... 34 
10.3 
Radiographic Evaluation and Response Criteria ..................................................................... 35 
10.4 
Symptomatic Deterioration ......................................................................................................... 37 
10.5 
Progression-Free Survial ............................................................................................................. 37 
10.6 
Overall Survival ........................................................................................................................... 37 
11 
DEFINITION OF ENDPOINTS ..................................................................................................... 37 
11.1 
Primary Endpoint ........................................................................................................................ 37 


Protocol version 6.0 dated  April 3, 2020 
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11.2 
Secondary Endpoints ................................................................................................................... 38 
11.3 
Tertiary/Exploratory Endpoints ................................................................................................. 39 
12 
STATISTICAL CONSIDERATIONS AND DETERMINATION OF SAMPLE SIZE ............ 39 
12.1 
Study Design Overview................................................................................................................ 39 
12.2 
Statistical Justification of Sample Size for Primary Objective ................................................ 39 
12.3 
Analysis Approaches .................................................................................................................... 40 
12.4 
Interim Analyses .......................................................................................................................... 41 
13 
CORRELATIVE STUDIES ............................................................................................................ 41 
13.1 
Genomics/Guardant®AnaLysis .................................................................................................. 41 
14 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................... 43 
14.1 
Purpose ......................................................................................................................................... 43 
14.2 
Definition of Adverse Event ........................................................................................................ 43 
14.3 
Definition of Serious Adverse Event .......................................................................................... 44 
14.4 
Definition of Severity ................................................................................................................... 44 
14.5 
Definition of Relationship to Study Drug .................................................................................. 45 
14.6 
Documentation of Adverse Events.............................................................................................. 45 
14.7 
Expected Adverse Events ............................................................................................................ 45 
14.8 
Follow up of Patients with Adverse Events ............................................................................... 46 
14.9 
Notification of Sponsor of Serious Adverse Events ................................................................... 46 
15 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................. 46 
15.1 
Informed Consent ........................................................................................................................ 47 
15.2 
Institutional Review ..................................................................................................................... 47 
15.3 
Drug Accountability..................................................................................................................... 47 
15.4 
Patient Privacy ............................................................................................................................. 47 
15.5 
Publication Policy......................................................................................................................... 48 


Protocol version 6.0 dated  April 3, 2020 
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15.6 
Record Retention ......................................................................................................................... 48 
16 
MONITORING ................................................................................................................................ 48 
16.1 
Protocol Deviations ...................................................................................................................... 48 
16.2 
Data Safety Monitoring Board ................................................................................................... 48 
17 
REFERENCES ................................................................................................................................. 50 
APPENDIX A:  CALCULATION OF CREATININE CLEARANCE................................................ 53 
APPENDIX B:  ADVERSE EVENTS ASSOCIATED WITH THE USE OF DOCETAXEL IN THE 
TAX327 TRIAL ........................................................................................................................................ 54 
 
 
 


Protocol version 6.0 dated  April 3, 2020 
6 
1 SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
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Protocol version 6.0 dated  April 3, 2020 
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2 OBJECTIVES 
2.1 PRIMARY OBJECTIVE 
 The primary objective of this study is to determine the proportion of men with newly 
diagnosed metastatic hormone sensitive prostate cancer who obtain and maintain a PSA 
complete response (less than or equal to 0.2 ng/ml) at 10 months (40 weeks) after 
initiation of trial therapy (7 months of androgen deprivation therapy) with four cycles of 
upfront docetaxel chemotherapy without androgen deprivation therapy followed by two 
additional cycles of docetaxel concurrent with androgen deprivation therapy with LHRH 
antagonist degarelix and then ongoing degarelix. 
2.2 SECONDARY OBJECTIVES 
 To determine the proportion of men with newly diagnosed metastatic hormone sensitive 
prostate cancer who obtain and maintain a PSA complete response (less than or equal to 
0.2 ng/ml) at 6 months (28 weeks) after initiation of trial therapy with four cycles of 
upfront docetaxel chemotherapy without androgen deprivation therapy followed by two 
additional cycles of docetaxel concurrent with androgen deprivation therapy with LHRH 
antagonist degarelix and then ongoing degarelix. 
 To assess the toxicity of administering four cycles of docetaxel chemotherapy without 
androgen deprivation therapy followed by two additional cycles of docetaxel concurrent 
with androgen deprivation therapy with degarelix in non-castrate men with newly 
diagnosed metastatic hormone-sensitive prostate cancer. 
 To determine the frequency of disease progression (clinical, radiographic, or PSA as 
outlined in this protocol), if any, during the four cycles of upfront docetaxel.     
 To determine the frequency of PSA response during the four cycles of upfront docetaxel. 
 To determine the time to development of castration resistance after initiation of ADT 
with degarelix for the cohort as a whole during the entire course of therapy. 
To determine the progression-free survival and overall survival of the patients treated 
with upfront docetaxel followed by ADT. 
2.3 EXPORATORY OBJECTIVES 
 To determine whether baseline tumoral genomic changes assessed via a serum assay of 
cell-free tumor DNA correlate with responses to trial therapy.  
 To evaluate PSA kinetics over time over the duration of study therapy. 
 
3 BACKGROUND 
3.1 METASTATIC PROSTATE CANCER 
Prostate cancer is the second-leading cause of cancer-related death in men in the United 
States.  The American Cancer Society estimates that 220,800 cases of prostate cancer were 
diagnosed in the U.S. in 2015 with 27,540 deaths from the disease.(1) Prostate cancer with 
metastases, whether diagnosed as metastatic at presentation or progressing after previous 


Protocol version 6.0 dated  April 3, 2020 
8 
local therapy, is an incurable disease.  A majority of patients with metastatic prostate cancer 
achieve an initial response to androgen deprivation therapy (ADT) and traditionally have 
been treated with LHRH agonist or orchiectomy plus or minus an antiandrogen.  
Unfortunately, castration resistant disease almost inevitably develops at an average of 18-24 
months (2).  Upon development of castration resistance, patients are eligible for palliative 
docetaxel chemotherapy or recently approved second-line hormonal therapies.  It is only in 
the last few years that evidence has emerged to show a survival benefit to earlier initiation of 
docetaxel chemotherapy in combination with ADT before a patient’s metastatic prostate 
cancer develops castration resistance.(3)  We intend to evaluate the safety and potential 
efficacy of treating patients with newly diagnosed metastatic prostate cancer even earlier 
with docetaxel, before they are even exposed to ADT. 
3.2 DOCETAXEL BASED CHEMOTHERAPY FOR PROSTATE CANCER 
3.2.1 The Established Role for Docetaxel 
Based on two randomized controlled trials showing an associated overall survival benefit, 
Docetaxel (Taxotere®), a taxane microtubule inhibitor, has become the standard 
chemotherapy for metastatic castration resistant prostate cancer (mCRPC).  In the 
Southwest Oncology Group (SWOG) 9916 trial, docetaxel 60 mg/m2 every 3 weeks plus 
estramustine 280 mg three times daily on days 1-5 was compared to mitoxantrone 12 
mg/m2 every 3 weeks plus prednisone 5 mg twice daily in men with mCRPC. (4) Median 
overall survival, time to disease progression, and PSA response were all statistically 
improved with the docetaxel-based therapy.  In the TAX327 trial, men with mCRPC 
were randomized to mitoxantrone 12mg/m2 every three weeks, docetaxel 75 mg/m2 
every three weeks, or docetaxel 30 mg/m2 for five of every six weeks with all arms also 
receiving prednisone 5 mg twice daily.(5)  Both docetaxel arms of the TAX327 trial 
demonstrated statistically significant increases in number of patients achieving a greater 
than 50 percent PSA response as compared to mitoxantrone. Docetaxel 75 mg/m2 every 
three weeks was the only arm to demonstrate a statistically significant overall survival 
benefit, 18.9 months, as compared to mitoxantrone, helping to firmly establish this drug 
and dosing schedule as the standard of care chemotherapy for mCRPC. 
3.2.2 A Role for Docetaxel in Castration Sensitive Prostate Cancer 
Three recent randomized controlled trials have evaluated the role of docetaxel for men 
with metastatic prostate cancer before the disease becomes castration-resistant.  E3805 
randomized 790 men with newly diagnosed metastatic hormone-sensitive prostate cancer 
to androgen deprivation therapy alone or ADT plus 6 cycles of docetaxel 75mg/m2 
initiated within four months of initiation of ADT.(3) After a median follow-up of 28.9 
months, median survival was significantly longer in the chemotherapy plus ADT group at 
57.6 months vs. 44.0 months with ADT alone (HR for death in the combination group of 
0.61; 95% confidence interval, 0.47-0.80; p<0.001).  Patients were stratified 
prospectively into low-volume and high-volume disease with “high-volume” defined for 
that protocol as the presence of visceral disease or 4 or more bony lesions including at 
least one bony lesion outside of the vertebral column and bony pelvis.  The increase in 
overall survival was even more significant in the combination therapy arm when analysis 
was restricted to patients with high-volume disease at 49.2 months as compared to 32.2 
months in high volume patients who received ADT alone. (HR = 0.60; 95% CI, 0.45-


Protocol version 6.0 dated  April 3, 2020 
9 
0.81; p=0.0006).(3)  A statistically significant difference in overall survival has not yet 
been reached in low volume patients although HR for death in the combination therapy 
patients with low volume disease was remarkably similar to high volume patients at 0.63 
( 95 % CI 0.34-1.17; p = 0.1398.)  Median time to disease progression for the E3805 
cohort as a whole (based on radiographic criteria, PSA, or symptoms) was also 
significantly increased in the combined therapy group at 20.2 months as compared to 
11.7 months in the ADT alone arm. (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001).  
Finally, percentage of patients with PSA level less than 0.2 ng/ml at twelve months was 
increased in the combination therapy group at 27.7% as compared to 16.8% in the ADT 
alone group. (p<0.001). 
 
A similar European trial, GETUG-AFU 15, randomized 385 men with newly diagnosed 
hormone-sensitive metastatic prostate cancer at centers in France and Belgium to ADT 
plus Docetaxel 75 mg/m2 every three weeks for up to nine cycles or ADT alone. (6).  The 
docetaxel was initiated within 60 days after starting ADT.  Biochemical progression free 
survival (lack of PSA progression, clinical progression, or death) was statistically 
increased in the ADT plus docetaxel arm at 22.9 months vs. 12.9 months in the ADT 
alone arm (HR 0.72, 0.57-0.91; p = 0.005).  Median overall survival was not statistically 
increased at 58.9 months in the combination therapy group versus 54.2 months in the 
ADT arm (HR 1.01, 95% CI 0.75-1.36; p=0.955).  Differences in relative survival benefit 
between E3805 and GETUG-AFU 15 may be driven by differences in baseline volume of 
metastatic disease between the two cohorts.    Recent updated analysis of the GETUG-
AFU 15 data at median follow-up of 82.9 months was performed with retrospective 
assessment of tumor volume using the definitions of high and low volume disease set 
forth in E3805. (7) 47.5% of GETUG-AFU 15 patients had high volume disease at 
presentation by E3805 criteria as opposed to 65.1% of patients in E3805.  In 183 high 
volume patients in the GET-AFU 15 study, median overall survival was 39 months in the 
ADT plus docetaxel arm and 35.1 months in the ADT alone arm (HR 0.80; 95% CI 0.6-
1.2; p=.35), thus not yet reaching statistical significance but in an underpowered subset 
analysis.   
 
The recently conducted STAMPEDE trial used an ambitious randomized multi-arm, 
multistage design to analyze the effect of adding one or a combination of several agents 
to standard ADT in hormone-sensitive advanced prostate cancer. (8).  One arm of the trial 
added 6 cycles of docetaxel 75 mg/m2 every 3 weeks plus prednisone 10 mg daily to 
ADT in patients with locally advanced or metastatic hormone-sensitive disease.  Recently 
published data summarizing a pre-planned subset analysis of metastatic patients showed a 
statistically significant increase in median survival in the M1 patients receiving docetaxel 
plus ADT of 60 months as compared to 45 months in M1 patients receiving ADT alone( 
HR = 0.76, 95% CI 0.62-0.92; p= 0.005).  With these three recent data sets available, 
many practitioners have begun to treat patients with metastatic hormone-sensitive 
prostate cancer, especially with high volume disease, with upfront ADT plus docetaxel. 


Protocol version 6.0 dated  April 3, 2020 
10 
3.2.3 Toxicity of Docetaxel Chemotherapy in Hormone Sensitive versus 
Castration-Resistant Prostate Cancer 
Cytotoxic chemotherapy inevitably has potential toxicity and docetaxel is no exception.  
In the TAX 327 study, 332 mCRPC patients were on the arm receiving docetaxel 75 
mg/m2 every 3 weeks plus prednisone, and 32% of these patients had Grade 3 or 4 
neutropenia with 3% febrile neutropenia and 0.3% treatment-related death.  (5)  
Interestingly, there is a suggestion that perhaps toxicity was higher in both E3805 and 
GETUG-AFU 15 with patients newly initiated on ADT.  Because data regarding 
prophylactic use of G-CSF or antibiotics on E3805 and GETUG-AFU 15 are incomplete, 
the relative toxicity observed on the trials is somewhat difficult to interpret.  That said, 
the drug-related death rate on GETUG-AFU 15 was 2.1%, higher than the 0.3% observed 
during TAX 327.  After 56% accrual to GETUG-AFU 15, there had been 41% Grade 3 or 
4 neutropenia with 8% febrile neutropenia and four treatment related deaths prompting an 
addendum to the protocol from the data safety monitoring committee mandating G-CSF 
administration from days 5-10 of each cycle.  This modification yielded a subsequent 
drop in the febrile neutropenia rate to 6% and no further treatment-related deaths. In 
E3805, the Grade 3 or 4 neutropenia rate was only 12% with 0.3% deaths, but the febrile 
neutropenia rate was 6% and 2% (8/397) of the patients on the combined treatment arm 
died with “cause unknown.”(3). 
 
It is problematic to compare toxicities across trials, but there are data to suggest a 
hypothetical mechanism for increased hematologic toxicity with docetaxel in men who 
are more naïve to medical castration.  Franke, RM et al. examined the relative clearance 
of docetaxel in ten non-castrated and twenty castrated men with prostate cancer. (9) 
Docetaxel pharmacokinetics were significantly altered in the castrated men with an 
approximately 100% increase in docetaxel clearance and accordingly two-fold reduction 
in AUC as compared to the men who were not castrated.  Human and rat-model data 
were presented to suggest a mechanism for this difference in clearance as increased 
hepatic uptake of docetaxel via increased anion transporter expression in the setting of 
castration.  This study suggests greater systemic exposure to drug as a possible 
explanation for increased hematologic toxicity from docetaxel in the non-castrated or 
newly castrated state as compared to the castrated state, but it also suggests one possible 
rationale for greater efficacy of earlier docetaxel administration. 
3.2.4 Evidence to Support Administering Docetaxel Independently from Androgen 
Deprivation 
3.2.4.1 
Breast Cancer Model 
Hormone-receptor positive breast adenocarcinoma invokes similarities in 
management to prostatic adenocarcinoma in that both disease states are generally 
responsive to both hormonal manipulation and cytotoxic chemotherapy.  As opposed 
to prostate cancer, the established paradigm in breast cancer is generally 
administering cytotoxic chemotherapy independently from hormonal manipulation.  
Pre-clinical data suggest a possible antagonistic effect of tamoxifen on chemotherapy 
cytotoxicity in breast cancer cell lines(10, 11) including evidence that tamoxifen 
places more tumor cells in G1 phase of the cell cycle when they would theoretically 


Protocol version 6.0 dated  April 3, 2020 
11 
be less sensitive to cytotoxic therapy.(12).  A randomized phase III trial of 1558 
postmenopausal women with resected node-positive hormone-receptor positive breast 
cancer prospectively evaluated disease-free survival with adjuvant 
cyclophosphamide, doxorubicin, and fluorouracil followed by 5 years of daily 
tamoxifen versus the same adjuvant chemotherapy given concurrently with 
tamoxifen. After a median 9 years of follow-up, the sequential therapy showed a 
strong trend toward improved DFS with HR of 0.84 (95% CI 0.70-1.01; p = 0.061). 
(13). 
3.2.4.2 
Evidence from Prostate Cancer Cell Lines 
In vitro studies of androgen dependent prostate cancer cell lines have shown 
increased sensitivity to taxane-mediated cell death in response to androgen 
stimulation of the androgen receptor.  In one series, androgen-dependent LNCaP 
prostate cancer cells showed decreased survival when cultured with steroid hormones 
and paclitaxel (25% survival) as compared to cells depleted of steroid hormone and 
then cultured with paclitaxel (55-60% survival).  The mechanism for this finding was 
outlined as likely increased caspase-dependent apoptosis in the presence of p53 
activation and cellular proliferation. (14).  In a separate trial in LNCaP-bearing severe 
combined immunodeficient mice, tumor volume and tumor apoptosis were measured 
in response to castration alone, docetaxel alone, both interventions administered 
concurrently, and both interventions administered in different sequences.  Docetaxel 
administered prior to castration yielded the longest delay in tumor growth of the 
studied interventions including a statistically significant improvement as compared to 
castration followed by docetaxel. (p=0.0003) (15). 
3.2.4.3 
Evidence in Prostate Cancer Trials 
Building on animal models, there has been limited exploration of docetaxel 
administration in prostate cancer in the non-castrate state.  Rathkopf et al. performed 
a phase II trial in 102 non-castrate men with progressive biochemically recurrent or 
metastatic hormone sensitive prostate cancer evaluating the concept of androgen 
cycling.  Patients were treated prospectively in two cohorts with different dosing 
strategies of concurrent docetaxel and LHRH agonist plus testosterone administered 
toward the end of each cycle of docetaxel to facilitate each subsequent dose of 
docetaxel being given in the non-castrate state.  Cohort one received six cycles of 
docetaxel 75 mg/m2 administered every 28 days with leuprolide 7.5 mg IM given on 
each Day 1 and topical testosterone administered on days 21-27.  Cohort two received 
nine cycles of docetaxel 70 mg/m2 administered every 21 days with leuprolide 22.5 
mg IM given every 12 weeks and topical testosterone administered on days 18-20 of 
each cycle of docetaxel.  Only two patients had disease progression during the 
chemo-hormonal therapy. One of the endpoints on the trial was undetectable PSA at 
18 months.  None of the patients in cohort one met this endpoint but 13% of the 
patients in cohort two did.  The febrile neutropenia rate was 14% and 18% in 
respective cohorts, higher than the rate traditionally seen in castrate-resistant disease 
and attributed to the approximately 50% reduction in docetaxel clearance measured in 
these non-castrate patients as compared to historical controls.  The authors of this 
study concluded that the efficacy results of this trial and the high febrile neutropenia 


Protocol version 6.0 dated  April 3, 2020 
12 
rate did not warrant further study of androgen cycling.  Of note, the patients on this 
trial did have median trough testosterone levels that were in the castrate range during 
portions of each cycle of docetaxel.  In terms of toxicity, only eleven patients 
received growth factor support and only in response to neutropenic fever or recurrent 
grade 3 or 4 neutropenia. (16) 
 
In a model similar in many ways to our proposed study, Hussain et al. treated 39 men 
with non-castrate level testosterone and increasing PSA after definitive therapy for 
localized prostate cancer (prostatectomy or radiation) with up to six cycles of 
docetaxel 70 mg/m2 every three weeks. (17)  The cytotoxic chemotherapy was 
followed by total androgen blockade with LHRH agonist and bicalutamide for 12-20 
months.  Serum PSA decreased > 50% in 48.5% of patients and > 75% in 20% of 
patients with the docetaxel alone, and only one patient had increased PSA at the end 
of the docetaxel therapy.  The majority of patients had PSA progression shortly after 
stopping ADT but 5/33 (15%) patients continued to have undetectable PSA at a 
median of 18.9 months after stopping ADT.  Of note, only seven of the men on this 
study had radiographic evidence of metastatic disease at study enrollment but three of 
these men were in the group who continued to have undetectable PSA for a lengthy 
period of time despite regaining non-castrate level testosterone post-ADT.  Grade 3 or 
4 neutropenia occurred in 61.5% of the patients on this trial with five episodes of 
febrile neutropenia.  This study demonstrates a series of patients with progressive 
prostate cancer treated with docetaxel before ADT with only a minimal rate of 
progressive disease during the chemotherapy.  It also raises the question of potential 
efficacy of this intervention in a larger cohort of patients with overt metastatic 
disease. 
3.3 RISK GROUPS/VOLUME OF MESTASTATIC DISEASE 
Multiple attempts have been made to develop prognostic criteria for newly diagnosed 
metastatic prostate cancer.  Glass et al. developed a prognostic model in 2003 using recursive 
partitioning of data from SWOG 8894, a randomized trial comparing orchiectomy plus 
flutamide versus orchiectomy plus placebo in men with newly diagnosed metastatic prostate 
cancer.(18, 19) Four factors had a major impact on outcome and could be used to divide 
patients into good, intermediate, and poor risk with 5 year survivals of 42%, 21%, and 9% 
respectively.  These factors were appendicular versus axial disease, performance status 0 
versus 1 to 3, prostate specific antigen less than 65 versus 65 ng/ml or greater and Gleason 
score less than 8 versus 8 or greater.  As noted previously, E3805 stratified patients 
prospectively into low-volume and high-volume disease with “high-volume” defined for that 
protocol as the presence of visceral disease or four or more bony lesions including at least 
one bony lesion outside of the vertebral column and bony pelvis.  Although a statistically 
significant difference in overall survival has not yet been reached in the subset of low volume 
patients receiving ADT plus chemotherapy versus ADT alone, the hazard ratio for death was 
remarkably similar in low volume patients at 0.63 as compared to 0.60 in the high-volume 
patients.(3)  For purposes of this trial, we will not restrict chemotherapy to “high-volume 
disease” but will require the presence of imaging evidence of metastatic disease. 


Protocol version 6.0 dated  April 3, 2020 
13 
3.4 ANDROGEN DEPRIVATION THERAPY 
Until the last decade, the most common means of obtaining castrate levels of testosterone in 
men with prostate cancer have been bilateral orchiectomy and administration of LHRH 
agonist therapy.  Most men prefer to pursue medical castration, but LHRH agonists generally 
produce a testosterone spike before subsequent drop in testosterone values creating a need for 
lead-in therapy with an anti-androgen in men with high-volume disease where there is 
concern for potential “tumor flare.”  LHRH agonists do not generally produce castrate level 
testosterone until sometime between 15 and 28 days post-administration. (20).  Newer direct 
LHRH antagonists such as degarelix (Firmagon®) do not produce a testosterone flare.  In a 
randomized phase III study of 610 men with prostatic adenocarcinoma in varying disease 
states, patients were randomized to ADT with degarelix vs. leuprolide for a 12 month period.  
Suppression of testosterone to less than 0.5 ng/ml occurred at 3 days after a loading dose of 
240 mg Degarelix in 96.1% of patients and no patients in the leuprolide group. (21).  A 
subsequent extension trial was created where patients on leuprolide were re-randomized to 
two different degarelix doses.  Analysis of data from this extension trial demonstrated that in 
patients with baseline PSA greater than 20 ng/ml, time for 25% of patients to achieve PSA 
failure (TTP25%) was significantly longer with degarelix than leuprolide at 407 versus 303 
days; p=0.085.(22).  LHRH antagonists thus represent an attractive option for rapid medical 
castration in a proposed cohort of patients with metastatic prostate cancer who will initially 
receive cytotoxic therapy without direct manipulation of the hormonal axis. 
3.5 GENOMIC ANALYSIS IN METASTATIC PROSTATE CANCER 
3.5.1 Tumor Heterogeneity in Prostate Cancer 
As our ability to more quickly assess genomic changes in neoplastic tissue improves via 
next generation sequencing, the heterogeneity of genomic aberrations in advanced 
prostate cancer has been revealed.  A variety of examinations of series of prostate cancer 
specimens have been performed all speaking to this heterogeneity.(23-25).  A recent 
multi-institution protocol led by Robinson et al. conducted prospective whole exome and 
transcriptome sequencing from bone or soft tissue tumor specimens from a cohort of 150 
men with mCRPC.  89% of examined patients had tumors with at least one clinically 
actionable genetic aberration including 62.7% of samples with alterations in the androgen 
receptor, 53.3% with mutations in TP53, and 49% with aberrations in the PI3K pathway. 
(26).  Direct sequencing of tumor tissue is probably the most sensitive assay for genetic 
alterations but invasive.   Several studies have looked at the role of analyzing circulating 
tumor DNA or cell free tumor DNA as an alternative less invasive technique for 
analyzing tumor genetic aberrations.(27, 28) 
3.5.2 Guardant® Analysis 
Guardant 360 is a commercial platform for digital sequencing of cell-free circulating 
tumor DNA (ctDNA) developed by Guardant Health®. The test is run on peripheral 
blood samples and analyzes circulating tumor DNA for 70 known cancer-related genes 
identifying missense mutations, amplifications, and a particular set of gene fusions.  (29).  
In our own series of 79 patients with metastatic prostate cancer analyzed with this ctDNA 
platform and presented in recent abstract form, we detected genetic abnormalities in 
92.5% of patients including 48% of patients with TP53 mutations, 47% with androgen 


Protocol version 6.0 dated  April 3, 2020 
14 
receptor alterations, and 19% with BRAF alterations.  These were similar percentages to 
earlier data discussed based on a series of tumor biopsies.(26)  We then retrospectively 
analyzed progression free survival during taxane chemotherapy (predominantly 
docetaxel) for 38 of the patients who had the taxane administered within one year of 
Guardant 360 analysis.  Patients who had a TP53 genetic alteration detected on ctDNA 
analysis had improved PFS with taxane chemotherapy as compared to patients with wild-
type TP53 (p= 0.032) while patients with PI3KCA missense mutations had decreased 
PFS with taxane chemotherapy as compared to patients with wild-type 
PI3KCA(p=0.0244).(30).  This was not prospective data but suggests a role for 
incorporating genomic analysis of prostate cancer ctDNA in future clinical trials 
including this one looking at taxane-based therapy. 
 
For our proposed trial, we will run Guardant assays, when feasible, on all patients at 
baseline.  We will then see if baseline genomic signature can be correlated with responses 
to docetaxel alone and to the overall trial therapy.  If possible, repeat Guardant assays 
could be run on patients as part of standard of care management after completion of trial 
therapy. 
 
3.6 TRIAL RATIONALE AND HYPOTHESIS  
As discussed in the above background, recent randomized trials have suggested an overall 
survival benefit to moving docetaxel therapy into the setting of hormone-sensitive metastatic 
prostate cancer. (3) While a statistically significant difference in survival in the E3805 trial in 
particular has at this point only been detected for patients with “high-volume disease,” 
similar hazard ratios were present for lower volume disease, and it is very possible that a 
statistically significant survival difference will be detected as these patients are followed 
further.  We hypothesize that an even greater survival benefit may be detected when 
administering docetaxel before androgen deprivation therapy in men with newly diagnosed 
metastatic disease.  We hope to further this benefit by using a potentially superior means of 
androgen deprivation in degarelix.  In this trial, we will evaluate PSA complete response at 
10 months (7 months on ADT) among other efficacy endpoints as there are historical 
comparators for these endpoints and some precedent that they serve as surrogates for overall 
survival. (3, 31)  See detailed explanation of endpoints starting in Section 3.8. 
 
Our hypothesis that upfront docetaxel before ADT may improve outcomes is supported, as 
outlined above, by research in animal models and prostate cancer cell lines where prostate 
cancer death is increased when docetaxel is given in the non-castrate state.(15)  Clinical data 
from the hormone receptor positive breast cancer setting also suggests a benefit to 
administering cytotoxic chemotherapy separately from manipulation of the hormonal 
access.(13)  There appears to be greater hematologic toxicity from docetaxel when given in 
the recently castrated or non-castrate state as compared to with castrate level testosterone due 
to increased clearance of the drug in the castrate state, but this finding raises the question of 
whether greater exposure to the drug in the non-castrate state with G-CSF support might 
actually increase efficacy.(9)  There have been studies primarily in the setting of biochemical 
recurrence proving the ability to give docetaxel without castration fairly safely without 
significant disease progression before ADT is ultimately initiated. (17)  We hope to further 


Protocol version 6.0 dated  April 3, 2020 
15 
improve patient outcomes by employing a potentially better form of androgen deprivation 
therapy in degarelix. We will hopefully supplement the knowledge gained from this trial by 
exploring the genomic signature of ctDNA in subjects over the course of their therapy to gain 
insight into the serial changes that may occur and possibly correlate particular genetic 
aberrations with tumor response to early docetaxel chemotherapy and degarelix. 
3.7 EXPLANATION OF PRIMARY ENDPOINT 
The primary endpoint for this trial will be the percentage of patients at 10 months from start 
of trial therapy with undetectable PSA(less than or equal to 0.2 ng/ml).  Using undetectable 
PSA as an endpoint is derived from earlier work suggesting this endpoint as prognostic of 
overall survival. Hussain et al. analyzed results from the SWOG/Intergroup-0612 trial which 
was a randomized phase III trial looking at continuous versus intermittent androgen 
deprivation in men with newly diagnosed metastatic prostate cancer after a lead-in of 7 
months of ADT consisting of goserelin plus bicalutamide.  Patients with PSA nadir less than 
4 ng/ml were eligible for randomization, but the trial recorded the percentage of patients who 
achieved PSA nadir at 7 months less than or equal to  4 ng/ml and less than or equal to 0.2 
ng/ml.  Of 1395 enrolled patients who received induction ADT, 604 patients (43%) obtained 
a PSA nadir less than or equal to 0.2 ng/ml and maintained this at 7 months.  Furthermore, an 
undetectable PSA (less than or equal to 0.2 ng/ml) at 7 months was a significant predictor of 
longer survival (HR 0.34; 95% CI 0.29-0.40; p< 0.001) as compared to not obtaining and 
maintaining such a value.  The median overall survival was 13 months for 383 men with a 
PSA nadir of more than 4 ng/ml at the end of induction (95% CI, 11-16 months), 44 months 
for  360 men who had a PSA nadir of more than 0.2 ng/mL but 4.0 ng/mL or less at months 6 
and 7 (95% CI, 39 to 55 months), and 75 months for 602 men with undetectable PSA (≤ 0.2 
ng/mL) at months 6 and 7 (95% CI, 62, 91 months).(31) 
 
Subsequent SWOG trials including S0925 published in 2015 have used undetectable PSA, 
also defined as < 0.2 ng/ml, at 7 months of ADT as a primary endpoint.  SWOG 0925 
randomized 210 patients with newly diagnosed metastatic prostate cancer to ADT (LHRH 
agonist plus bicalutamide) with or without the investigational agent cixutumumab.  The trial 
did not detect a significantly different undetectable PSA rate between the two arms, but the 
control arm of 105 patients who received ADT alone provide another historical comparator 
with 34 patients (32.3%) having an undetectable PSA at 28 weeks.(32)   
 
In an era of patients being treated with earlier chemotherapy, E3805, which as discussed 
earlier randomized men with newly diagnosed metastatic disease to ADT alone versus ADT 
plus 6 cycles of Docetaxel, did include as secondary endpoints the percentage of patients at 6 
months and 12 months with undetectable PSA (less than 0.2 ng/ml).  This trial, because of its 
initial design, likely contained higher volume patients than SWOG/Intergroup-0612, but the 
results of E3805 also suggest undetectable PSA at both 6 and 12 months as potential 
surrogates for overall survival.  At 6 months, rate of undetectable PSA was 19.6% with ADT 
alone and 32% with ADT plus docetaxel (p<0.001). At 12 months, the rate was 16.8% in the 
ADT arm and 27.7% in the ADT plus docetaxel arm (p<0.001)(3).  
 
It is difficult to find a historical time point for looking at undetectable PSA rate that is 
directly comparable to our trial since our treatment design is novel with chemotherapy 


Protocol version 6.0 dated  April 3, 2020 
16 
initially given independently from ADT.  We have elected to have percentage of patients 
with undetectable PSA (less than or equal to 0.2 ng/ml) after 10 months on all therapy (7 
months on ADT) as the primary endpoint.  This endpoint could be compared to the 
“undetectable PSA rate at 6 months” on CHAARTED/E3805 since the “6 months” time point 
for the CHAARTED trial was calculated from time of randomization but the majority of 
patients were on ADT before randomization for an average of 1.2 months.(3) Thus the “6 
month undetectable PSA rate” for the average patient on E3805 represented the effect of 7.2 
months of ADT.  The PSA at 10 months on all therapy (7 months on ADT) endpoint for our 
proposed trial would also be comparable to the SWOG/Intergroup-0612 undetectable PSA 
rate at 7 months of ADT exposure.(31). 
3.8 EXPLANATION OF SELECT SECONDARY ENDPOINTS 
3.8.1 Six-Month Undetectable PSA Rate 
We propose evaluating patients on this trial for the secondary endpoint of proportion of 
men with newly diagnosed metastatic hormone sensitive prostate cancer who obtain and 
maintain a PSA complete response (less than or equal to 0.2 ng/ml) at 6 months after 
initiation of trial therapy. Although our trial design means that this endpoint will only 
represent 12 weeks on ADT, we speculate that the earlier docetaxel and more rapid 
castration with Degarelix as compared to LHRH agonists will yield an improvement in 
undetectable PSA rate even with this more limited ADT exposure as compared to the “6 
month” time point on E3805.  
 
4 SUBJECT SELECTION 
4.1 INCLUSION CRITERIA 
Patients eligible for study participation must meet all of the following criteria. 
 
1. Histological or cytological diagnosis of adenocarcinoma of the prostate.  
 
2. Metastatic disease identified via radiographic assessment by CT scans of the chest, 
abdomen, pelvis, and nuclear bone scan.  MRI may be used if deemed necessary by the 
investigator. The CT portion of PET-CT can be used for inclusion in place of dedicated 
CT chest, abdomen, and pelvis as long as any non-bony lesions of concern are felt by the 
investigator to be adequately assessed with this imaging.  Subsequent imaging on 
protocol should be with dedicated CT chest, abdomen, pelvis unless there are convincing 
rationale for repeat PET-CT (a bone scan is still required).  See Section 8.5 for more 
details about radiographic assessment requirements.   
 
More specifically, patients must have at least one of the following at time of study 
enrollment: 
 
a) Any visceral metastases identified by CT scans,MRI or PET-CT. 
b) Site(s) of bony metastasis identified by nuclear bone scan, MRI, PET-CT and/or 
CT scan. 


Protocol version 6.0 dated  April 3, 2020 
17 
c) Lymph node based disease not considered to be within a single radiation therapy 
port (e.g. at or above the aortic bifurcation.) 
 
3. Non-castrate testosterone level, >50 ng/dl, at study enrollment. 
 
4. Age greater than or equal to 18 years. 
5. ECOG performance status 0-2. 
 
6. Meet the following hematologic criteria within 14 days of enrollment to trial: 
 
a) Absolute neutrophil count > 1,500/mm3 
b) Hemoglobin > 8.0 g/dl (may be transfused) 
c) Platelet count > 100,000 mm3 
 
7. Have adequate end-organ function as defined by the following parameters.  All lab values 
must be obtained within 14 days of enrollment to trial: 
a) Creatinine clearance of > 30 ml/min.  Creatinine clearance should be determined 
by the Cockcroft-Gault formula (Appendix A) 
b) AST < 2 x institutional ULN 
c) ALT < 2 x institutional ULN 
d) Total bilirubin ≤ institutional ULN 
 
8. Agree to use barrier methods of birth control during the docetaxel portion of the protocol 
and for at least one month after last docetaxel administration. 
 
9. Informed and must sign and give written informed consent in accordance with 
institutional and federal guidelines. 
 
4.2 EXCLUSION CRITERIA 
Patients eligible for study participation CANNOT meet any of the following criteria: 
 
1. CNS metastases (brain or leptomeningeal).  
 
2. Osseous metastases felt in the opinion of the clinician to be high-risk for impending 
pathologic fracture or spinal cord compression. 
 
3. Active cardiac disease defined as symptomatic congestive heart failure, history of NYHA 
Class III or IV Heart Failure, uncontrollable supraventricular arrhythmias, any history of 
a ventricular arrhythmia, active angina pectoris, myocardial infarction or coronary 
intervention within 6 months of registration. 
 
4. Prior malignancy requiring systemic therapy within the last 5 years except for treated 
basal or squamous cell skin cancer.  History of low-grade malignancies with limited 
potential to progress as determined by the primary investigator may be enrolled. 


Protocol version 6.0 dated  April 3, 2020 
18 
 
5. Subjects must not have received any previous androgen deprivation therapy (LHRH 
agonist or LHRH antagonist) or cytotoxic therapy for prostate cancer in the metastatic 
setting.   
 
 
Exception 
Patients may have received no more than 30 days of anti-androgen (e.g. bicalutamide) in 
the metastatic setting prior to the start of study treatment.   
 
6. Subjects must not have had more than 36 months of hormonal therapy in combination 
with prostatectomy or radiation in the setting of localized disease and must not have 
shown any evidence of disease recurrence within 12 months after stopping hormonal 
therapy.  Disease recurrence after hormonal therapy is defined as PSA > 0.2ng/dl after 
prostatectomy + hormonal therapy or PSA that is 2.0ng/dl more than the PSA nadir after 
radiotherapy + hormonal therapy.  Previous hormonal therapy to the prostate must have 
stopped at least 12 months prior to enrollment.     
 
7. Subjects must not have been treated with prior docetaxel in the setting of metastatic 
prostate cancer.  Subjects may have been treated with docetaxel in the setting of localized 
prostate cancer (likely as a trial-based neoadjuvant or adjuvant approach to prostatectomy 
or radiation.)  Subjects treated with this approach must not have shown any evidence of 
disease recurrence within 12 months after stopping docetaxel. Disease recurrence after 
docetaxel is defined as PSA > 0.2ng/dl after prostatectomy + docetaxel or PSA that is 
2.0ng/dl more than the PSA nadir after radiotherapy +docetaxel.  Previous docetaxel in 
the setting of localized prostate cancer must have stopped at least 12 months prior to 
study enrollment.     
 
8. Palliative radiation therapy may have been received but not within the 30 days prior to 
study treatment. 
 
9. Presence of peripheral neuropathy > Grade 1. 
 
10. Known HIV-positive 
 
11. Presence of any severe or uncontrolled concurrent medical condition felt in the opinion of 
the investigator to increase the risk of serious toxicity from the study therapy. 
 
12. Prior hypersensitivity to any of the components of the study drugs. 
4.3 INCLUSION OF WOMEN AND MINORITIES 
Men of all races and ethnic groups are eligible for this trial.   
4.4 SUBJECT REGISTRATION 
The SIS Unit will provide patient registration services for the study.  The SIS Unit will 
conduct a patient eligibility audit review of all eligibility source documents prior to patient 


Protocol version 6.0 dated  April 3, 2020 
19 
registration.  These procedures are outlined in the CTO # 102509 Operations Manual.  After 
obtaining signed informed consent and completion of required baseline assessments, eligible 
subjects will be registered upon the SIS Unit’s verification of study eligibility.  A unique 
subject number will be assigned to each patient.  The SIS Unit will issue a registration 
confirmation email to the enrolling study team at the time of registration.  This confirmation 
will include the patient’s assigned study number.  Subjects may not begin study drug until 
after this confirmation is issued.   
 
5 STUDY INTERVENTION 
5.1 AGENT ADMINISTRATION 
5.1.1 Docetaxel 
Patients will receive docetaxel 75 mg/m2 intravenously over 60 minutes (+/- 15 minutes) 
every 21 days for six cycles.  The first four cycles of docetaxel will be without concurrent 
hormonal therapy of any kind.  The last two cycles will be after initiation of degarelix 
(Firmagon®).  Dose modifications for docetaxel are outlined in Section 6. 
5.1.2 Degarelix 
ADT for this trial will be with the direct LHRH antagonist degarelix (Firmagon®).  
Degarelix will be administered per the product label.   
 
Degarelix will be administered for the first time on Day 1 +/- 2 days of cycle 5 of 
docetaxel.  The first dose will be the standard loading dose of 240 mg SubQ.  The drug is 
given as a deep subcutaneous injection into the abdominal region per product label.   
 
The second dose will be 28 days later on Day 8 of cycle 6 of docetaxel.  The second and 
subsequent doses of degarelix will be given at 80 mg SubQ q 28 days.  Degarelix will be 
continued for the first 28 weeks of ADT (40 weeks of total trial therapy).  At that point, 
the subject may continue degarelix or switch to LHRH agonist versus orchiectomy 
according to investigator/patient preference. 
5.1.3 Regimen Description 
REGIMEN DESCRIPTION
Agent 
Dose 
Route 
Schedule 
Docetaxel 
75 mg/m2 
IV over 60 
minutesa
Day 1 of Cycle 1 – Cycle 6b  
Degarelix 
Dose 1:  240mg  
Dose 2:  80 mg  
Subsequent Doses:  80 mg 
SubQc 
Dose 1:  Cycle 5 Day 1 
Dose 2:  Cycle 6 Day 8 
Subsequent Doses:  Q 28 Days until 10 
months(40 weeks) of trial therapy is completed
a. 
 +/- 15 minutes 
b. Cycle is 21 days  
c. 
Degarelix should be administered as a SubQ injection in the abdomen.  


Protocol version 6.0 dated  April 3, 2020 
20 
 
5.2 PRE- AND POST- MEDICATIONS 
5.2.1 Pre-Medications for Docetaxel 
Patients will receive standard pre-medication prior to docetaxel to help prevent 
anaphylactic reaction and help mitigate later swelling.  The premedications listed in this 
section are recommended, but may be modified per institutional guidelines and 
investigator discretion: 
 Dexamethasone, 8mg PO twice daily the day before, day of, and day after 
docetaxel or 20 mg IV prior to docetaxel infusion  
 Ondansetron 8 mg IV is recommended prior to docetaxel infusion 
 Famotidine 20 mg IV is recommended prior to docetaxel infusion.   
 Benadryl may be given at investigator discretion. 
5.2.2 Post-Chemotherapy G-CSF 
Patients will receive prophylactic GCSF with each cycle of docetaxel.  This G-CSF may 
be given as pegfilgastrim(Neulasta®) 6 mg SubQ 24-72 hours after each dose of 
docetaxel, filgastrim(Neupogen ®) 5 mcg/kg/day SubQ on days 5-10 of each cycle, or as 
per institutional/investigator preference. G-CSF may be omitted if a patient has a history 
of reaction or develops anaphylactic reaction to the drug.  G-CSF may also be omitted per 
investigator discretion or if a patient experiences side effects (bone pain, dyspnea, etc.) 
which in the best judgement of the investigator are attributable to the GCSF and not 
easily manageable 
 
6 DOSE MODIFICATIONS 
This study will utilize the CTCAE Version 4.0 for toxicity and Serious Adverse Event reporting. 
A copy of the CTCAE Version 4.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov).  All appropriate treatment areas should have access to a copy of the 
CTCAE Version 4.0. 
 
Subjects must have ANC  > 1,500/mm3 and platelet count > 100,000/mm3on day of therapy to be 
treated with docetaxel.  If a dose reduction is made, this reduced dose will be maintained for all 
subsequent cycles (no dose re-escalation).  If a planned docetaxel dose must be delayed for three 
consecutive weeks, docetaxel will be discontinued and degarelix initiated immediately (and 
given every 28 days thereafter) or continued without docetaxel.   
6.1 DOCETAXEL 
6.1.1 Docetaxel Dose Levels 
A subject may only have two dose reductions over the course of study drug 
administration.  A need for a third dose reduction will require discontinuation of 
docetaxel and immediate initiation of degarelix (and given every 28 days thereafter) or 
continuation of degarelix without docetaxel. 
 
Dose levels of docetaxel for this trial are as follows: 
Dose Level 
Docetaxel (mg/m2) 


Protocol version 6.0 dated  April 3, 2020 
21 
Level   0
75 mg/m2
Level  -1
65 mg/m2
Level  -2
55 mg/m2
6.1.2 Hematologic Toxicity 
Dose adjustments on Day 1 of each cycle for myelosuppression should be made 
according to the following algorithm.   
 
Event 
Docetaxel Dose 
Granulocyte decreased 
> 1,500/mm3
No change
1,000/mm3-1,499/mm3 
Reduce one dose level and treat at investigator 
discretion.  May also delay one week and reduce 
one dose level.
< 1000/mm3 
Delay until recovery of neutrophil counts to > 
1,500/mm3 and reduce one dose level. 
afebrile Neutropenia G4 for > 7 daysa 
Or 
Neutropenia G3 with feverb > G3b 
Delay until recovery of neutrophil counts to > 
1,500/mm3 and reduce one dose level. 
 
Any active infection must have been actively 
treated and clinically resolved before restarting 
docetaxel.
Thrombocytopenia 
> 100,000/mm3
No Change
75,000-99,000 
Reduce one dose level and treat at investigator 
discretion.  May also delay one week and reduce 
one dose level.
< 74,999 
Delay dosing by one week then reduce by one dose 
level upon recovery of platelet counts to > 100,000
a. 
ANC < 500/mm3 
b. Single temperature > 38.3°C or three oral temperatures > 38.0°C in a 24-hour period. 
6.1.3 Hepatic Dysfunction/Toxicity 
ALT and bilirubin will be examined pre-study and prior to Day 1 of cycles 1-6 of 
docetaxel chemotherapy.  Eligibility criteria in terms of hepatic studies are as defined in 
Section 4.1.  Patients who develop hepatic dysfunction during docetaxel therapy will 
have the docetaxel adjusted according to the following algorithm: 
 
Bilirubin 
 
ALT 
Docetaxel Dose 
> ULN 
or 
> 5 x ULN 
Delay dosing one week and then re-check.  If Bilirubin 
recovers to < ULN AND AST < 3 x ULN, reduce 
docetaxel by one dose level and treat.  If patient does 
not meet treatment criteria at 3 week delay, discontinue 
docetaxel and start Degarelix.
< ULN
and
>3 x ULN but < 5 ULN
Reduce docetaxel by one dose level and treat.
 


Protocol version 6.0 dated  April 3, 2020 
22 
A patient may only have two dose reductions over the course of therapy.  A need for a 
third dose reduction will require discontinuation of docetaxel and immediate initiation of 
degarelix every 28 days. 
6.1.4 Hypersensitivity Reactions for Docetaxel 
Subjects should be monitored closely during all infusions of docetaxel to monitor for 
hypersensitivity reaction presenting as generalized rash, hypotension, bronchospasm, or 
severe anaphylaxis. Subjects should be pre-medicated to help prevent hypersensitivity 
reactions as in 5.2.1.     Flushing or localized rash during infusion may be treated with 
Benadryl without stopping the docetaxel infusion.  Any hemodynamic instability should 
prompt immediate stoppage of docetaxel and aggressive supportive care. 
Subjects with Grade 4 hypersensitivity (life threatening reaction requiring pressors or 
ventilator support) should never be re-challenged with docetaxel.  Subjects with episodes 
of Grade 3 hypersensitivity (prolonged reaction not initially responsive to stopping the 
infusion/supportive meds but not requiring pressors/ventilator support) can be re-
challenged at a later date if agreed upon by the subject and investigator.  Subjects with 
two Grade 3 hypersensitivity reactions should not be re-challenged with docetaxel. 
6.1.5 Peripheral Neuropathy 
Neuropathy 
Docetaxel Dose 
> Grade 3 Neuropathy (severe symptoms 
limiting self-care ADL’s)
Discontinue docetaxel 
Grade 2 Neuropathy (moderate 
symptoms limiting instrumental ADL’s) 
Hold docetaxel until resolves to < Grade 1. At 
that point, reduce one dose level and treat.  If not 
recovered to < Grade 1 at 3 weeks, discontinue 
docetaxel.
6.1.6 Other Docetaxel Related Toxicities 
Subjects with other toxicities thought to be docetaxel-related that are < Grade 2 may be 
managed supportively and treated on schedule without dose reductions. 
 
Subjects who develop other toxicities that are > Grade 3 and thought to be docetaxel-
related should have docetaxel held until toxicity resolved to < Grade 1.  At that point, 
docetaxel may be re-instituted at investigator discretion with a one level dose-reduction.  
A patient may only have two dose reductions over the course of therapy.  A need for a 
third dose reduction will require discontinuation of docetaxel and immediate initiation of 
ADT.   
 
6.1.7 Investigator Concern for Clinical Progression 
PSA progression on docetaxel will not firmly be established as a measurable endpoint 
until after 4 cycles of docetaxel as in Section 10.2.2.  It is the right of the investigator to 
determine that radiographic or clinical progression has occurred at any point during 
therapy or that docetaxel without ADT is no longer in the best interest of the patient for 
any reason at any point during the first four cycles of docetaxel.  If a decision is made 
that docetaxel without ADT is no longer in the best interest of the patient, the patient may 
be immediately administered loading dose (dose#1) of degarelix and remain on trial.  An 


Protocol version 6.0 dated  April 3, 2020 
23 
attempt should be made to obtain repeat imaging (CT scans and a bone scan) as would 
have been done after the 4 cycles of upfront docetaxel, but obtaining this imaging does 
not need to hold up initiation of ADT.  The decision as to whether to continue a total of 6 
doses of docetaxel will be between the investigator and the patient, but in either case the 
patient may remain on the trial.  Any subsequent docetaxel cycles would be administered 
at dosing as per protocol.  Subsequent degarelix injections would be q 28 days as per 
protocol. 
6.2 DEGARELIX 
6.2.1 Hypersensitivity 
If a subject develops a significant hypersensitivity reaction to degarelix (anaphylaxis), the 
drug should be discontinued and the subject should not be re-challenged with degarelix.  
A subject who has had degarelix discontinued for hypersensitivity reaction should be 
switched four weeks later to alternative LHRH agonist or bilateral orchiectomy per 
investigator/patient discretion. 
6.2.2 Cutaneous Site Reactions 
Temporary erythema and pain at the injection site are common with degarelix.  Attempts 
to minimize site reactions should be made by rotating injection sites in the abdomen and 
avoiding sites under constant pressure such as at the beltline.  Patients who develop 
Grade 1 or 2 Injection Site Reactions (ISR’s) can be retreated with Degarelix at the 
standard dosing and interval.  Patients who develop  Grade 3 ISR’s should not receive 
any additional degarelix and should subsequently be switched to LHRH agonist or 
undergo orchiectomy per patient/investigator preference. 
6.2.3 Monitoring Testosterone Level 
Subjects will have their serum testosterone level monitored serially during therapy.  
Subjects will have their serum testosterone level drawn at Point A (screening), Point B 
(before the first dose of degarelix), Point C (before their second dose of degarelix), and 
then every twelve weeks.  Interventions for non-castrate levels of testosterone will be as 
follows: 
 
Time Point 
Testosterone Level 
Intervention 
Point C (before second dose of 
degarelix) 
> 100 ng/dl or > 50 ng/dl and 
less than 50% decline from 
Point B(pre-degarelix)
Re-load the patient with 240 mg 
SC x1 and then recheck 
testosterone level in four weeks.
Four weeks after a degarelix re-
load 
> 50 ng/dl 
Discontinue degarelix and 
switch to alternative LHRH 
agonist or bilateral orchiectomy 
per investigator/patient 
discretion.
Any subsequent testosterone 
check 
> 50 ng/dl 
Re-load the patient with 240 mg 
SC x1 and then recheck 
testosterone level in four weeks.
Any subsequent testosterone 
check
< 50 ng/dl 
Continue degarelix 80 mg SC 
every 4 weeks.


Protocol version 6.0 dated  April 3, 2020 
24 
7 CONCOMITANT THERAPY 
7.1 PERMITTED MEDICATIONS – USE WITH CAUTION 
Docetaxel is a substrate and moderate inhibitor of CYP3A4.  Concomitant drugs that are 
strong CYP3A4 inhibitors should be used with caution. 
7.2 PROHIBITED MEDICATIONS 
Anti-androgens (e.g. bicalutamide) may have been used for no more than 30 days before trial 
enrollment.  At enrollment, all anti-androgens must be stopped.  LHRH-agonists or LHRH-
antagonists may not have been administered in the metastatic setting as outlined in Section 
4.2 (bullet point 3).  LHRH agonists/agonists are only allowed on this trial as outlined in 
Section 4.2 (bullet point 3). 
8 STUDY ASSESSMENTS 
8.1 GENERAL CONSIDERATIONS 
 Screening and baseline evaluations will be performed within 14 days of study 
enrollment.   
 Screening radiologic assessments will take place within 28 days of study enrollment. 
 Physical exam and laboratory testing will be conducted prior to drug administration 
on days when drug is administered.  Safety labs can be drawn up to 3 days prior to 
scheduled dose. 
 Study drug may be administered +/- 3 days.  If holidays or inclement weather cause a 
greater than +/- 3 day delay, this will not be considered a protocol deviation. 
8.2 HISTORY AND PHYSICAL 
History and physical exam, including ECOG performance status should be performed at 
baseline and prior to drug administration.  The physical exam should include at least vital 
signs, height, weight, evaluation of cardiovascular system, lungs, abdomen, extremities, 
neurologic system to include assessment of any baseline peripheral neuropathy, and skin.  
Height will be collected prior to day 1 drug administration.   
8.3 CONCOMITANT MEDICATIONS 
Concomitant medications will be reported at baseline and each subsequent clinic evaluation. 
8.4 LABORATORY ASSESSMENTS 
8.4.1 Safety Labs 
CBC-Diff and CMP (complete metabolic profile) will be conducted at baseline and prior 
to each drug administration.  A CMP includes sodium, potassium, creatinine, total 
bilirubin, AST, ALT, Alkaline phosphatase, calcium and albumin. 
 
Testosterone level will be assessed at baseline and followed as in Section 6.2.3. (C6D8 
testosterone can be done at a non-MUSC facility if necessary - MUSC lab is preferred) 


Protocol version 6.0 dated  April 3, 2020 
25 
8.4.2 PSA 
PSA will be drawn at baseline, before each dose of docetaxel (Day 1 of each cycle before 
drug administration), on Cycle 4 Day 8 of docetaxel (C4D8 PSA can be done at a non-
MUSC facility if necessary - MUSC lab is preferred), before each monthly dose of 
degarelix, and at end of study.  
8.4.3 Cell-Free Circulating Tumor DNA analysis 
Whole blood samples will be drawn for Guardant360® cell-free circulating tumor DNA 
analysis upon enrollment to the trial before study drug administration.  
8.5 RADIOGRAPHIC ASSESSMENTS 
Subjects will have screening nuclear bone scan (Technetium-99) and CT imaging of the 
chest, abdomen, and pelvis (with or without contrast per investigator discretion). CT, PET-
CT and/or MRI may be done within 28 days prior to enrollment.  The bone scan may be 
completed no more than 56 days before study enrollment.  MRI may take the place of CT 
scan if deemed necessary by the investigator, but every attempt should be made to keep the 
modality of follow-up imaging consistent throughout the study. The CT portion of PET-CT 
can be used for inclusion/screening in place of dedicated CT chest, abdomen, and pelvis as 
long as any non-bony lesions of concern are felt by the investigator to be adequately assessed 
with this imaging.  Subsequent imaging on protocol should be with dedicated CT chest, 
abdomen, pelvis unless there are convincing rationale for repeat PET-CT (a bone scan is still 
required). 
 
Subjects will have repeat nuclear bone scan and CT imaging of the chest, abdomen, and 
pelvis (or MRI) after 4 cycles of docetaxel (between cycle 4 Day 8 and Cycle 5 day 1 before 
degarelix).  An attempt should be made to repeat radiographic imaging after any upfront 
docetaxel if the decision is made to abort this approach early and initiate degeralix as in 
Section 6.1.7. These radiographic tests will also be repeated at the end of study or, if before 
10 months, at time of PSA progression or time of concern for clinical progression as 
determined by the investigator. If a patient stops therapy for any reason during the degarelix-
only portion of the trial, an attempt should be made to repeat the baseline radiographic 
imaging if deemed acceptable to the patient and treating physician.   
 
 


Protocol version 6.0 dated  April 3, 2020 
26 
8.6 STUDY CALENDARa   
 
 
 
Screening 
b  
 
C1 
Day 
1 
C2 
Day 
1 
C3 
Day 
1 
C4 
Day 
1  
C4 
Day 
8 
C5 
Day 
1 
C6 
Day 
1 
C6 
Day 
8 
 
 
 
 
 
End of 
Study  
Follow Up 
(Q 3 months)m 
 
 
 
 
 
 
 
Deg. 
dose 
#1
 
Deg. 
dose 
#2
Deg. 
dose 
#3
Deg. 
dose 
#4
Deg. 
dose 
#5
Deg. 
dose 
#6
Deg. 
dose 
#7
 
 
Day on Study 
 
1 
22 
43 
64 
71 
85 
106 
113 
141 
169 
197 
225 
253 
281 
 
Test or Procedurec 
 
REGISTRATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam, ROS 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signsl, Weight 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications Assessment 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
X 
X 
CMP 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
CBCD 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
PSA 
Xb 
Xb 
X 
X 
X 
Xn 
X 
X 
 
X 
Xg 
X 
X 
X 
X 
X 
Serum Testosterone 
X 
 
 
 
 
 
X 
 
Xn 
 
 
X 
 
 
Xj 
X 
AE Assessment 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Radiographic Tumor 
Assessmentf 
X 
 
 
 
 
 
Xe 
 
 
 
 
 
 
 
Xk 
 
Follow Up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xh 
Study Drug 
Administrationc, d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Docetaxel 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Degarelix 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Correlatives 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Guardant Analysis 
 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
 
a. 
Docetaxel cycle is 21 days.  C=cycle; D=day; W=week 
b. 
Screening and baseline evaluations to be performed within 14 days of study enrollment.  Informed consent and CT/MRI/PET-CT will take place within 28 days of study 
enrollment (Note: the use of the CT portion of the PET-CT is only permissible for inclusion/screening as long as any non-bony lesions of concern are felt by the 
investigator to be adequately assessed with this imaging.  Subsequent imaging on protocol should be with dedicated CT chest, abdomen, pelvis unless there are 
convincing rationale for repeat PET-CT. A bone scan is still required). Bone scan may be done within 56 days of study enrollment.  Assessments completed within 3 
days prior to Cycle 1 Day 1 do not need to be repeated. PSA collected within 7 days prior to cycle 1 day 1 does not need to be repeated.  
c. 
Study drugs and study procedures may be completed +/- 3 Days.  All labs must be completed before drug administration.   
d. 
If docetaxel is held > 3 weeks (1 cycle), docetaxel will be permanently stopped and degarelix administration will begin or continue without docetaxel. 
e. 
The radiologic response assessment to be completed AFTER Cycle 4 Day 8 but BEFORE the initiation of degarelix/docetaxel on Cycle 5 Day 1.  If Docetaxel stopped 
because of toxicity before Cycle 5 Day 1, this imaging is to be completed before administration of degarelix.  If decision made per investigator discretion to administer 
degarelix before finishing four cycles docetaxel, an attempt should be made to obtain repeat CT scans/bone scan but imaging does not need to hold up degarelix 
administration. 


Protocol version 6.0 dated  April 3, 2020 
27 
f. 
Radiographic assessments should also be repeated at PSA progression or at time of concern for clinical progression as determined by the investigator. 
g. 
PSA at 24 weeks on study will analyzed as > 0.2 ng/ml or < 0.2 ng/ml 
h. 
ADT modality after 10 months (LHRH agonist vs. antagonist) would be per investigator/patient discretion but should be continued if clinically indicated.    PSA, 
disease status and current therapy will be collected every three months for up to two years after the end of study visit.   
i. 
See Section 13 for details.  The post-study Guardant analysis is not required per the protocol, but if completed, results of the Guardant analysis will be included in the 
data set. 
j. 
If radiographic disease progression is noted at end of study, serum testosterone should also be measured if not already done.   
k. 
If patient comes off study prior to completion of study, scans should be repeated at the end of study visit as clinically indicated. 
l. 
Vital signs include pulse, temperature, and blood pressure. 
m. Follow up will be done every 3 months +/- 15 days. 
n. 
C4D8 PSA and C6D8 testosterone can be done at a non-MUSC facility if necessary (MUSC lab is preferred) 
 
 


Protocol version 6.0 dated  April 3, 2020 
28 
 
8.7 CRITERIA FOR REMOVAL FROM PROTOCOL TREATMENT 
Subjects may discontinue study treatment at any time.  Any subject who discontinues 
treatment will be asked to return to the study center to undergo end of treatment assessments 
as outlined within Study Calendar (Section 8.6).  The primary reason for discontinuation will 
be recorded. In the absence of treatment delays due to adverse events, study drug 
administration may continue for 10 months or until one of the following criteria applies: 
 
 Radiographic disease progression  
o NOTE:  If this occurs during the first 4 cycles of docetaxel or on imaging 
after 4 cycles before initiation of degarelix, the patient may start on 
degarelix per protocol if acceptable to the patient/investigator) 
 Clinical disease progression   
o NOTE:  If this occurs during the first 4 cycles of docetaxel or on imaging 
after 4 cycles before initiation of degarelix, the patient may start on 
degarelix per protocol if acceptable to the patient/investigator) 
 Inter-current illness that would, in the judgment of the investigator, affect 
assessments of clinical status to a significant degree or require discontinuation of 
study drugs 
 Completion of protocol treatment. 
 Unacceptable toxicity 
 Death 
 Subject may withdraw from the study at any time for any reason. 
 Concomitant treatment with a prohibited medication 
 Subject non-compliance 
8.8 DURATION OF FOLLOW UP 
After the end of study, subjects will be followed as clinically indicated thereafter at least 
every 3 months for progression while continuing ADT.  PSA, current therapy, and disease 
status will be recorded at these visits at least out 2 years post end of study therapy. 
 
9 DRUG INFORMATION 
9.1 DOCETAXEL 
Docetaxel is available through commercial supply.  To supplement the information below, 
please see product package insert for complete pharmacologic, stability, preparation and 
safety information.(33) 
9.1.1 Description 
Docetaxel (TAXOTERE ®), a semisynthetic analog of paclitaxel, is chemically described 
as (2R, 3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5β-20-epoxy-
1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate.; 
Empirical formula, C43H53NO14; Molecular weight: 861.9.  


Protocol version 6.0 dated  April 3, 2020 
29 
 
9.1.2 Pharmacology 
Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable 
microtubules, leading to pre-mature mitosis and then apoptosis.  Docetaxel has been 
evaluated in a variety of dosing schedules up to 100 mg/m2 every 3 weeks.  Docetaxel is 
widely distributed in tissues with a linear relationship between dose and area under the 
plasma concentration-time curve. (34) Docetaxel is greater than 90% bound in plasma.  
Metabolism is primarily via the cytochrome p450 (CYP)3A4 system with biliary 
excretion into feces.  The drug is less than 5% renally cleared.(35) 
9.1.3 Mechanism of Action 
Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in 
cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free 
tubulin and promotes the assembly of tubulin into stable microtubules while 
simultaneously inhibiting their disassembly. This leads to the production of microtubule 
bundles without normal function and to the stabilization of microtubules, which results in 
the inhibition of mitosis in cells. (36) 
9.1.4 Product Identification, Packaging and Labeling 
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: 80 mg 
and 20 mg. 
9.1.5 Handling 
Docetaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, 
caution should be exercised when handing and preparing docetaxel solutions. The use of 
gloves is recommended. 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. 
9.1.6 Storage 
Store between 2°C and 25°C (33°F and 77°F). Retain in the original package to protect 
from bright light. Freezing does not adversely affect the product. 
9.1.7 Preparation for Injection 
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 overfill. 
 
Preparation of the initial diluted solution: Gather the appropriate number of vials of 
docetaxel for Injection Concentrate and diluent (13% Ethanol in Water). If the vials were 
refrigerated, allow them to stand at room temperature for approximately 5 minutes. 
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. 


Protocol version 6.0 dated  April 3, 2020 
30 
 
Gently rotate the concentrate and diluent. The initial diluted docetaxel solution (10 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 dissipates 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. 
 
Preparation of the final dilution for infusion: Aseptically withdraw the required amount 
of initial diluted docetaxel solution (10 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 to 0.74 mg/ml. If a dose greater 
than 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. Thoroughly mix the infusion by 
manual rotation. 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. 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. 
9.1.8 Stability of Docetaxel  
The initial diluted solution may be used immediately or stored either in the refrigerator or 
at room temperature for a maximum of 8 hours. Docetaxel infusion, if stored between 
2oC and 25oC (36oF and 77oF) is stable for 4 hours. Fully prepared docetaxel infusion 
solution (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be 
used within 4 hours (including the 1 hour IV administration). 
9.1.9 Toxicity 
The following events are expected in greater than 10% of patients:  CNS toxicity, 
including neuropathy; alopecia; dermatological reaction; nail disease; fluid retention; 
stomatitis; diarrhea; nausea; vomitingneutropenia; leukopenia; anemia; 
thrombocytopenia; febrile neutropenia; increased serum transaminases; hypersensitivity; 
infection; weakness; myalgia; neuromuscular reaction; pulmonary reaction; and fever.   
 
The following events are expected in 1-10% of patients:  decreased left ventricular 
ejection fraction; hypotension; peripheral motor neuropathy; dysgeusia; increased serum 
bilirubin, increased serum alkaline phosphatase; infusion site reactions including 
hyperpigmentation, inflammation, redness, dryness, phlebitis, extravasation, and swelling 
of the vein; and arthralgia. 
 
The following events are expected in <1% of patients or are the result of postmarketing 
and/or case reports:  abdominal pain, acute myelocytic leukemia, acute respiratory 
distress, alopecia, anaphylactic shock, anorexia, ascites, atrial fibrillation, atrial flutter, 


Protocol version 6.0 dated  April 3, 2020 
31 
 
back pain, bronchospasm, cardiac arrhythmia, cardiac tamponade, chest pain, chest 
tightness, chills, colitis, confusion, conjunctivitis, constipation, cystoid macular edema, 
deep vein thrombosis, dehydration, duct obstruction, disseminated intravascular 
coagulation, drug fever, duodenal ulcer, dyspnea, ECG abnormality, epiphora, erythema 
multiforme, esophagitis, flushing, gastrointestinal hemorrhage, gastrointestinal 
obstruction, gastrointestinal perforation, hearing loss, hemorrhagic diathesis, hepatitis, 
hypertension, hyponatremia, intestinal obstruction, interstitial pulmonary disease, 
ischemic colitis, lacrimation, localized erythema of the extremities, loss of consciousness 
(transient), lymphedema (peripheral) multi-organ failure, myelodysplastic syndrome, 
myocardial infarction, neutropenic enterocolitis, ototoxicity, pain, palmar-plantar 
erythrodysesthesia, pneumonia, pneumonitis, pruritus, pulmonary edema, pulmonary 
embolism, pulmonary fibrosis, renal failure, renal insufficiency, respiratory failure, skin 
changes, seizure, sepsis, sinus tachycardia, skin rash, Stevens-Johnson syndrome, 
subacute cutaneous lupus erythermatosus, syncope, tachycardia, thrombophlebitis, toxic 
epidermal necrolysis, unstable angina pectoris, visual disturbance.   
9.1.10 Particular Toxicities of Note 
9.1.10.1 
Neutropenia 
Neutropenia is commonly encountered with Docetaxel.  Patients on this trial will 
receive prophylactic G-CSF but should still be monitored for neutropenia and 
associated infection. 
9.1.10.2 
Hypersensitivity 
Steroid pre-medication is required as in Section 5.2.1.  Severe hypersensitivity has 
been reported even with steroid medication and patients must be managed closely 
during infusion as in Section 6.1.4. 
9.1.10.3 
Neurologic Effects 
Severe neurosensory changes with docetaxel including paresthesias, dysesthesia, and 
pain have been observed.  Dose modifications for peripheral neuropathy should be 
made as in Section 6.1.5. 
9.1.10.4 
Fluid Retention 
Severe fluid retention has been reported following docetaxel and is partially mitigated 
by steroid pre-medication.  In a trial of 92 breast cancer patients pre-medicated with 
3-day steroids, moderate fluid retention occurred in 27.2% of patients and severe 
retention in 6.5%.  Patients who develop edema should be treated with supportive 
measures including salt restriction and/or diuretics as per investigator discretion. 
 
Adverse events associated with the use of docetaxel in the TAX327 trial are shown in 
Appendix B. 
9.2 DEGARELIX (FIRMAGON®) 
Degarelix will be provided by Ferring USA. 


Protocol version 6.0 dated  April 3, 2020 
32 
 
9.2.1 Description 
Degarelix (Firmagon®) is a synthetic linear decapeptide containing seven unnatural 
amino acids.  The chemical name is D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-
alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-
2,6-dioxo-4-pyrimidinyl]carbonyl]amino]-L phenylalanyl-4-[(aminocarbonyl)amino]-D-
phenylalanyl-L leucyl-N6-1-methylethyl)-L-lysyl-L-prolyl.  Empirical formula is 
C82H103N18O16Cl with a molecular weight of 1632.3 Da.  Firmagon® comes as a sterile 
lyophilized powder for injection containing degarelix as the acetate and mannitol.  
9.2.2 Mechanism of Action 
Degarelix is a GnRH receptor antagonist.  It binds reversibly to the pituitary GnRH 
receptors, thereby reducing the release of gonadotrophins and consequently testosterone.   
9.2.3 Packaging 
Degarelix is available as: 
 
Starting dose – one carton contains:  
 Two vials each with 120 mg powder for injection 
 Two prefilled syringes containing 3 mL of sterile water for injection, USP 
 Two vial adapters 
 Two administration needles 
Maintenance dose – one carton contains: 
 One vial with 80 mg powder for injection 
 One prefilled syringe containing 4.2 mL of sterile water for injection, USP 
 One vial adapter 
 One administration needle 
9.2.4 Handling 
Discard all components safely in an appropriate biohazard container. 
9.2.5 Storage 
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F).  Reconstituted drug 
must be administered within one hour after addition of sterile water for injection. 
9.2.6 Administration 
Degarelix is administered as a subcutaneous injection in the abdominal region only.  The 
drug is supplied as a powder to be reconstituted with Sterile Water for Injection.  Package 
insert/diagram for administration must be read prior to drug administration. 
 
For starting dose: 
One starting dose comprises 240 mg given as two 3 mL injections of 120 mg each. 
Powder for injection 120 mg: 


Protocol version 6.0 dated  April 3, 2020 
33 
 
One vial of FIRMAGON 120 mg contains 120 mg 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 degarelix at a concentration of 40 mg/mL. 
 
For maintenance doses: 
One maintenance dose comprises 80 mg given as one 4 mL injection.  
Powder for injection 80 mg:  
One vial of FIRMAGON 80 mg 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 degarelix at a concentration of 20 mg/mL. 
9.2.7 Toxicity 
The following events are expected in greater than 10% of patients: Fatigue, hot flashes, 
increased GGT, weight loss, weight gain, increased serum transaminases, and fever.  
Injection site reactions including pain, erythema, swelling, induration, nodules and 
infections were also seen in greater than 10% of patients. 
 
The following events are expected in 1%-10% of patients:  hypertension, chills, 
dizziness, headache, insomnia, diaphoresis, hypercholesterolemia, gynecomastia, 
constipation, nausea, diarrhea, UTI, erectile dysfunction, testicular atrophy, increased 
ALT and AST, antibody development, back pain, arthralgia, weakness and night sweats.   
9.2.8 Particular Toxicities of Note 
9.2.8.1 
Hypersensitivity Reactions 
Hypersensitivity reactions, including anaphylaxis, urticaria, and angioedema have 
been noted post-marketing of Degarelix.  If this occurs during injection, stop 
immediately and manage supportively.  If hypersensitivity occurs, subsequent ADT 
should be as in Section 6.2.1. 
9.2.8.2 
QT Prolongation 
Androgen deprivation therapy may prolong the QT/QTC interval.  Although 
prolonged QT interval is not an exclusion for this trial, investigators should consider 
periodic monitoring of ECG in patients with congenital long QT syndrome or known 
ventricular dysrhythmia.  
 
10 MEASURES OF EFFECT 
10.1 DEFINITIONS: 
 
 Evaluable for objective response:  Only those subjects who have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These subjects will have their response classified according 


Protocol version 6.0 dated  April 3, 2020 
34 
 
to the definitions in Sections 10.2 and 10.3 (Note:  Subjects who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Subjects must have at least one measurable lesion to qualify for radiographic response 
analysis.  Subjects do not have to have measurable disease to enroll to the study. 
 
 Evaluable for toxicity:  All subjects will be evaluable for toxicity from the time of 
first dose of study drug until the end of study visit.  Toxicity assessment will be based 
on NCI CTCAE v. 4.0.  AEs and SAEs will be reported as outlined in Section 14.   
 
10.2 PSA EVALUATION AND RESPONSE CRITERIA  
10.2.1 Methods for Evaluation of PSA Response 
Serum PSA will be obtained at baseline and then before each dose of docetaxel.  PSA 
will also be drawn on Cycle 4 Day 8 of docetaxel to help facilitate calculation of PSA 
response to chemotherapy.  Once docetaxel has been completed or stopped, PSA will be 
obtained every four weeks before each dose of degarelix.  After 10 months, PSA will be 
measured every 3 months. 
 
Because there are no defined criteria for PSA progression before initiation of ADT, we 
will employ the following criteria modified from Prostate Cancer Working Group 
Criteria.(37) 
10.2.2 PSA Response Criteria during Docetaxel Chemotherapy: 
 
PSA Response Criteria will be defined as: 
 
 PSA Complete Response: PSA level less than or equal to 0.2 ng/ml for two 
consecutive measurements at least two weeks apart.  Date of complete response will 
be defined as the date of first recorded value less than 0.2 ng/ml.   
 
 PSA Partial Response: Decline of PSA from trial baseline of > 50% for two 
consecutive measurements at least two weeks apart.  Date of partial response will be 
defined as the date of first recorded decline of > 50% baseline. 
 
 PSA Progression: PSA progression will be defined as > 25% increase from the PSA 
nadir (lowest PSA value recorded since trial enrollment) and > 2 ng/dl above the 
nadir.  Two consecutive increases must be recorded at least two weeks apart.  Date of 
PSA progression will be defined as the first recorded PSA value that is a > 25% 
increase from the PSA nadir and > 2 ng/dl above the nadir.  PSA progression will not 
be established during the first 12 weeks of therapy (4 cycles of docetaxel) as defined 
by PCWG2 criteria.  Thus subjects with no PSA decline from baseline during therapy 
will have date of PSA progression defined as first PSA value after 12 weeks that is a 
> 25% increase from the PSA nadir and > 2 ng/dl above the nadir.  Patients whose 
PSA level meets the criteria for progression on Cycle 4 Day 8 and Cycle 5 Day 


Protocol version 6.0 dated  April 3, 2020 
35 
 
1(before ADT) will be defined as having had progressive disease during the docetaxel 
only portion of the trial. 
10.2.3 PSA Response/Progression Criteria After ADT Initiated 
PSA Response Criteria after ADT Initiated will be defined as: 
 
 PSA Complete Response: PSA level less than or equal to 0.2 ng/ml for two 
consecutive measurements at least three weeks apart.  Date of complete response will 
be defined as the date of first recorded value less than 0.2 ng/ml.   
 
 PSA Partial Response: Decline of PSA from trial baseline of > 50% for two 
consecutive measurements at least three weeks apart.  Date of partial response will be 
defined as the date of first recorded decline of > 50% baseline. 
 
 PSA Progression: PSA progression will be defined as > 25% increase from the PSA 
nadir (lowest PSA value recorded since trial enrollment) and > 2 ng/dl above the 
nadir.  Two consecutive increases must be recorded at least three weeks apart.  Date 
of PSA progression will be defined as the first recorded PSA value that is a > 25% 
increase from the PSA nadir and > 2 ng/dl above the nadir. PSA progression will not 
be established during the first 12 weeks of therapy (4 cycles of docetaxel) as defined 
by PCWG2 criteria.  Thus subjects with no PSA decline from baseline during therapy 
will have date of PSA progression defined as first PSA value after 12 weeks that is a 
> 25% increase from the PSA nadir and > 2 ng/dl above the nadir.   
10.3 RADIOGRAPHIC EVALUATION AND RESPONSE CRITERIA 
Radiographic Response will be determined by RECIST 1.1 Response Criteria.  Baseline 
tumor burden of measurable and non-measurable disease will be measured and then 
compared on subsequent imaging.  See RECIST criteria in Section 10.3.3. 
10.3.1 Methods for Evaluation of Radiographic Response 
Subjects will have a nuclear bone scan and CT imaging of the chest, abdomen and pelvis 
as outlined in Section 8.5.  Scans will be completed at baseline and repeated after 4 
cycles of docetaxel, prior to the initiation of degarelix.  Radiographic assessment should 
also be repeated at PSA progression or at time of concern for clinical progression, as 
determined by the investigator.   
10.3.2 Disease Parameters 
 
Measurable non-lymphatic disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as >10 
mm with CT scan.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the lesion has been radiated in the metastatic setting, it will 
not count as measurable disease.  If the patient has disease recurrence after previous 


Protocol version 6.0 dated  April 3, 2020 
36 
 
definitive radiation to the prostate/pelvis and new disease in the previously radiated field, 
this tumor can count as measurable disease.  
 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
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), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.   
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  If lymph 
nodes are to be included in the sum, then only the short axis is added into the sum.  The 
baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up if the information is available. 
10.3.3 Radiographic Response Criteria 
The evaluation of target lesions will be based on the RECIST 1.1 criteria as summarized 
in the table below. 
 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in 
short axis to <10 mm.
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study).  In 


Protocol version 6.0 dated  April 3, 2020 
37 
 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.   
 
Note:  the appearance of one or more new lesions is also 
considered progression.
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study
 
The evaluation of non-target lesions will be based on the RECIST 1.1 criteria as 
summarized in the table below. 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis)
Non-CR/Non-PD: 
 
Persistence of one or more non-target lesion(s).
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It 
must be representative of overall disease status change, not a 
single lesion increase.    
10.4 SYMPTOMATIC DETERIORATION  
Subjects with global deterioration of health requiring discontinuation of all therapy will be 
classified as having symptomatic deterioration. 
10.5 PROGRESSION-FREE SURVIAL 
PFS is defined as the duration of time from start of treatment to time of disease progression 
or death, whichever comes first. 
10.6 OVERALL SURVIVAL 
Overall survival is defined as the time interval from trial enrollment to death due to any 
cause. Survival times will be censored for patients lost to follow-up or still alive at the trial’s 
termination.   
 
11 DEFINITION OF ENDPOINTS 
11.1 PRIMARY ENDPOINT  
11.1.1 Undetectable PSA at 10 months 
The Primary endpoint for this trial is a binary indicator of PSA less than or equal to 0.2 
ng/dl at 10 months (40 weeks) on study.  This also represents 7 months (28 weeks) on 
androgen deprivation therapy with degarelix. 


Protocol version 6.0 dated  April 3, 2020 
38 
 
11.2 SECONDARY ENDPOINTS 
11.2.1 Undetectable PSA at 6 months. 
Undetectable PSA at 6 months is a binary indicator for each patient of PSA less than or 
equal to 0.2 ng/dl at 6 months (24 weeks) on study.  This also represents 3 months (12 
weeks) on androgen deprivation therapy with degarelix. 
11.2.2 Toxicity 
Toxicity for all evaluable patients will be defined by CTCAE (NCI Common 
Terminology Criteria for Adverse Events) Version 4.0. 
11.2.3 Disease Progression During First four cycles of Docetaxel 
Disease Progression during the first four cycles of Docetaxel will be defined as any 
manner of disease progression that occurs before degarelix is administered, either after 
four cycles of docetaxel or if stoppage of docetaxel is required before four cycles 
administered.  Specifically, disease progression during docetaxel will include any subject 
who meets criteria for: 
 
a) PSA Progression during Docetaxel: This will be defined as in Section 10.2.2. PSA 
progression will not be defined until after 4 cycles of docetaxel are administered 
(Cycle 5 day 1 before degarelix administration) unless clinical 
progression(symptomatic deterioration), radiographic progression, toxicity, or 
investigator/patient discretion requires stoppage of docetaxel before four cycles 
administered.  For example, if a subject’s docetaxel is discontinued after two cycles 
because of toxicity, and PSA before what would have been cycle 3 meets criteria for 
PSA progression, this will be defined as PSA and disease progression during 
docetaxel. 
 
b) Radiographic Progression during Docetaxel: This will be defined by RECIST 1.1 
criteria as in Section 10.3.3.  Re-imaging will take place after four cycles docetaxel or 
at time that docetaxel is stopped if clinical progression(symptomatic deterioration), 
toxicity, or  investigator/patient discretion requires stoppage of docetaxel before four 
cycles administered. For example, if a subject’s docetaxel is discontinued after two 
cycles because of toxicity, radiographic imaging will be repeated at that point.  If the 
new images meet criteria for radiographic progression, this will be defined as 
radiographic and disease progression during docetaxel. 
 
c) Symptomatic Deterioration – If investigator discretion is that the patient is clinically 
deteriorating because of progressive disease, docetaxel will be stopped and ADT 
started.  This will be defined as clinical/disease progression but effort should be made 
to ensure that the clinical deterioration is in fact from progressive neoplastic disease 
and not treatment-related toxicity or other separate medical event.  
11.2.4 PSA Response uring Docetaxel 
The frequency of PSA response during docetaxel will be determined after four cycles of 
docetaxel (Cycle 4 Day 8 and Cycle 5 Day 1 before degarelix).  The definitions of partial 
and complete PSA response will be defined as in Section 10.2.2.  If clinical progression 


Protocol version 6.0 dated  April 3, 2020 
39 
 
(symptomatic deterioration), radiographic progression, toxicity, or investigator/patient 
discretion requires stoppage of docetaxel before four cycles administered, PSA at time of 
docetaxel stoppage can be evaluable for response. 
11.2.5 Time to Development of Castration Resistance 
This will be defined as the time from initial Degarelix injection to the time of disease 
progression (clinical, radiographic (as in Section 10.3.3), or PSA as in Section 10.2.3).  
Determination of castration resistant disease status will require disease progression and a 
measured serum testosterone level less than 50 ng/dl.  Thus, if disease progression is 
noted, serum testosterone level should be measured if not already done so. 
11.2.6 Progression Free Survival 
Progression free Survival (PFS) will be defined as the duration of time from start of study 
treatment to time of disease progression or death, whichever comes first. 
11.2.7 Overall Survival 
OS is defined as the time interval from trial enrollment to death due to any cause. 
Survival times will be censored for patients lost to follow-up or still alive at the trial’s 
termination. 
11.3 
TERTIARY/EXPLORATORY ENDPOINTS 
See Section 13 - “Correlative Studies.” 
 
12 STATISTICAL CONSIDERATIONS AND DETERMINATION OF SAMPLE SIZE 
12.1 STUDY DESIGN OVERVIEW 
This will be a single-arm non-blinded interventional Phase II study enrolling a maximum of 
50 patients at up to 4 sites.  The primary endpoint is PSA less than or equal to versus greater 
than 0.2 ng/ml at 10 months after initiation of treatment. 
 
Patients will be considered evaluable for efficacy if they complete at least one cycle of 
docetaxel  Any patient who receives study therapy will be evaluable for toxicity.  Patients 
who discontinue treatment will still be followed for clinical outcomes. Only patients who 
leave the study and are lost to follow-up, or leave the study and do not agree to have their 
clinical data included in the study would be considered inevaluable and replaced.   
12.2 STATISTICAL JUSTIFICATION OF SAMPLE SIZE FOR PRIMARY 
OBJECTIVE 
The sample size of 50 is based on undetectable PSA (i.e., PSA <0.2 ng/mL) at 10 months (7 
months on ADT).  Our null hypothesis is based on an assumed rate of undetectable PSA of 
32% (CHAARTED/E3805 “6 month” PSA rate for the chemotherapy plus ADT arm as 
discussed in Section 3.8).(3)  We hypothesize that our study treatment approach has a 50% 
rate of undetectable PSA at 10 months.  With 50 patients, we have 83.9% power to detect this 
difference based on a one-sided alpha of 0.0503 based on a Fisher’s exact binomial test.  That 
is, if the one-sided alpha level is less than 0.0503, we will reject the null hypothesis.  If we 
observe 22 or more patients with undetectable PSA at 10 months out of 50 patients (i.e. an 
observed undetectable rate of 0.44 or greater), we will reject the null hypothesis.  We propose 


Protocol version 6.0 dated  April 3, 2020 
40 
 
a single stage design due to the length of follow-up required to assess this outcome.  Patients 
who are inevaluable (defined in Section 12.1) will be replaced up to a possible total 
enrollment of 53 patients.   
12.3 
ANALYSIS APPROACHES 
Primary objective:  We will perform a one-sided exact binomial test based on a null 
undetectable rate of 0.32.  If the p-value is less than 0.0503, we will reject the null 
hypothesis.  With a sample size of 50, this corresponds to at least 22 patients with 
undetectable PSA at 10 months.  The proportion of patients with undetectable PSA at 10 
months will be estimated with a 90% confidence interval.  
 
Secondary objectives: 
 
Undetectable PSA at 6 months.  The proportion of patients with undetectable PSA at 6 
months will be estimated with a 90% confidence interval. 
 
Toxicity:  All adverse events will be tabulated by type and grade.  Those that are possibly or 
probably related to study treatment.  We will also tabulate possibly and probably related 
events that occur in the first 4 cycles docetaxel.  Proportions of grade 3 and 4 events will be 
calculated with 95% confidence intervals.  
 
Frequency of disease progression within the first four cycles of docetaxel:  The proportion of 
patients with disease progression (defined in Section 11.2.3) will be calculated with a 95% 
confidence interval. Kaplan-Meier curves will be used to describe time to disease 
progression.   
 
Frequency of PSA response:  The proportion of patients with a PSA response within the four 
cycles of upfront docetaxel will be calculated with its exact 95% confidence interval. 
 
Progression-free survival, Overall survival, and Time to development of castration 
resistance:  All time to even outcomes will be described using Kaplan-Meier curves.  The 
median time-to-event will be reported with its 95% confidence interval.  If the median is not 
reached at the time of data analysis, a landmark time will be selected and the estimated 
survival fraction at the landmark time will be reported with its 95% confidence interval. 
 
Exploratory objectives:  
 
Serial genomic changes:  Changes in genomic measures will be calculated and evaluated in 
relation to detectable PSA at 10 months using proportions.  Regression approaches (e.g. 
logistic and Cox regression) will evaluate association between patients with genomic changes 
binary outcomes (e.g. undetectable PSA at 6 months) and time to event endpoints (e.g. PFS). 
 
PSA kinetics:  PSA will be evaluated over time using graphical displays (‘spaghetti plots’) 
and to determine if there are patients that hover just above or below the PSA = 0.2 ng/mL 
limit.  Longitudinal linear modeling, estimated using GEE, will be used to describe trends in 
PSA over time.  Additionally, we will consider (as sensitivity analyses) different PSA cutoffs 


Protocol version 6.0 dated  April 3, 2020 
41 
 
(e.g. 0.1 or 0.4 ng/mL) to determine the effects in inferences.  Our hypothesis is that the 
inferences will not be sensitive to the cutoff.  
12.4 
INTERIM ANALYSES 
The primary endpoint is evaluated at 10 months.  As such, the time it takes to measure the 
events makes an interim analysis for futility or efficacy infeasible.  With an anticipated 
uniform accrual within 24 months, corresponding to about two patients per month, at 75% of 
accrual (18 months), only about 16 patients will have been followed for 10 months.  As such 
including an interim look for early stopping of accrual for futility is not feasible.  
 
Accrual and evaluability of patients (e.g. drop-out) will be monitored continuously 
throughout the trial. Plans are in place for recruiting additional sites if accrual performs 
significantly worse than expected within the first 6 months of accrual. Specifically, accrual 
rates will be evaluated every 6 months by the study team.  If the accrual rate is less than 70% 
of anticipated, corrective actions will be taken.   
 
13 CORRELATIVE STUDIES 
13.1 
GENOMICS/GUARDANT®ANALYSIS 
13.1.1 Description of the Assay 
Guardant360 is a cell-free circulating tumor DNA (ctDNA) targeted next-generation 
sequencing (NGS) panel. It is an advanced diagnostic laboratory test (ADLT) offered by 
a sole source Clinical Laboratory Improvement Amendments (CLIA)-certified and 
College of American Pathology (CAP)-accredited laboratory. This solid tumor profiling 
panel sequences 70 clinically actionable genes for single nucleotide variants and copy 
number variations in 16 genes with a simple blood test.  The genes are selected because 
mutations in these genes have FDA-approved matched therapies or are eligible for late 
phase clinical trials. The panel also includes genomic markers of acquired resistance that 
may require a change in pharmacotherapy. 
 
13.1.2 Assay Methodology 
The Guardant360 ctDNA next generation sequencing assay identifies single nucleotide 
variants (SNVs) in 70 genes and includes complete exon coverage of 30 genes and 
coverage of partial exons (“hot exons”) in 40 genes, including copy number variants in 
16 genes. The gene list was selected to focus on those genomic alterations that are 
currently actionable defined as being targets of sensitivity or resistance to an FDA-
approved matched therapy and/or a targeted therapy in clinical trials. The test 
simultaneously sequences the 70 cancer-related genes to an average depth of coverage of 
greater than 10,000X. To summarize, cell-free DNA is extracted from plasma and 
genomic alterations are analyzed by massively parallel paired end synthesis-by-
sequencing of amplified target genes utilizing an Illumina Hi-Seq 2500 platform 
complemented by systematic end-to-end process optimization including conversion of 
cell-free DNA fragments into digital sequences, improvements in the Illumina next 
generation sequencing process itself, followed by bioinformatics algorithms which enable 
ctDNA to be measured as a quantitative percentage of total cell-free DNA.  
Two 10mls of whole blood are collected in Streck Cell-Free DNA Blood Collection 


Protocol version 6.0 dated  April 3, 2020 
42 
 
(Streck) tubes, which contain a proprietary formaldehyde-free preservative in that 
stabilizes white blood cells, preventing the release of genomic DNA and allowing 
shipping and stability for seven days without need for refrigeration, cold bricks or 
preliminary centrifugation prior to shipping.  
 
After digital libraries are produced, the sample is sequenced and post-sequencing data is 
processed using bioinformatics algorithms to quantify the absolute number of unique 
DNA fragments at a given nucleotide position. This proprietary process is referred to as 
Digital SequencingTM and enables reporting of the fractional concentration (mutant allele 
frequency) of a given SNV. Circulating cell-free DNA is mostly derived from leukocyte 
lysis (germline) and generally a much smaller amount of tumor DNA is derived from 
cancer cell apoptosis/necrosis. All of the cell-free DNA fragments, including leukocyte-
derived and tumor-derived, are simultaneously sequenced with up to single molecule 
sensitivity. In other words, both tumor DNA and “normal”/germline DNA are sequenced 
and measured in the same sequencing assay. The fractional concentration or mutant allele 
frequency for a given mutation is calculated as the fraction of circulating tumor DNA 
harboring that mutation in a background of wild-type cell-free DNA fragments. The 
analytic sensitivity reaches detection of 1-2 single mutant fragments from a 10 ml blood 
sample.  
 
Leveraging the ability of Digital Sequencing™ to absolutely quantify the number of 
unique DNA fragments in a sequenced sample, the copy number of a given gene in 
plasma may be ascertained. To determine the copy number variant (CNV) or 
amplification of a given gene, the total number of unique fragments covering each gene 
are first measured. The mode of the normalized number of fragments covering each gene 
is calculated to estimate the fragment number corresponding to 2 copies to derive a 
baseline diploid value. All values of unique fragments for each gene are then normalized 
by this baseline value. The same procedure is employed using a large set of normal 
samples from healthy donors (Normal Set). The normalized concentration of a given gene 
in the sample is compared to its concentration in the Normal Set. The numerical result of 
the above procedure expresses the absolute copy number of a gene in plasma-derived 
cfDNA samples, which is a combination of both normal cell-free DNA (mainly 
leukocyte-derived) and tumor-derived gene copy number.  Because most of the cell-free 
DNA is typically germline-derived, a small elevation in the gene copy number in plasma 
may reflect a much higher copy number in the tumor. For example, if the ERBB2 (HER2 
protein) gene copy number in the tumor was 10.0, and 5% of the DNA in cell-free DNA 
was tumor-derived and 95% was leukocyte-derived (germline copy number 2.0), then the 
ERBB2 copy number in plasma would be 2.3. 
13.1.13 Sample Acquisition 
Patients will have two 10ml tubes of whole blood collected at baseline.  This blood would 
be placed in two Streck Cell-Free DNA Blood Collection (Streck) tubes provided by 
Guardant in specimen kits.  These kits will then be returned to Guardant at the address 
listed on the kit label.   
   


Protocol version 6.0 dated  April 3, 2020 
43 
 
14 ADVERSE EVENT REPORTING REQUIREMENTS 
The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be utilized 
for AE reporting.  In addition, SAEs have special reporting requirements. AE and SAE criteria 
and reporting requirements are outlined in this section. For both serious and non-serious adverse 
events, the investigator must determine the severity of the event, “expectedness” of the event, 
and the relationship of the event to study treatment administration. 
 
The study period during which all AEs must be reported begins at time of informed consent and 
ends at end of study treatment.  All SAEs, including death due to disease progression, must be 
reported up to 30 days after the end of study treatment.   After this period, investigators should 
only report AEs that are attributed to Degarelix. SAEs should be monitored until they are 
resolved or are clearly determined to be due to the patient’s stable or chronic condition or 
intercurrent illness(es).  Patients removed from study for unacceptable AE(s) will be followed for 
AE(s) for 24 weeks or until resolution or stabilization of the AE if that takes more than 24 weeks. 
 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel 
during questioning, or detected through physical examination, laboratory test, or other 
means will be reported appropriately. Each reported AE or SAE will be described by its 
duration (i.e., start and end dates), regulatory seriousness criteria if applicable, suspected 
relationship to the study treatment, and actions taken.  All AEs should be recorded and 
described in the AE database in REDCap.   
14.1 PURPOSE 
AE data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents. AE are reported in a routine manner at scheduled times during a 
trial. Additionally, certain AEs must be reported in an expedited manner to allow for more 
timely monitoring of patient safety and care. The following guidelines prescribe routine and 
expedited AEs reporting for this protocol.  
 
Throughout the study, the Investigator will be required to provide appropriate information 
concerning any findings that suggest significant hazards, contraindications, side effects, or 
precautions pertinent to the safety of the drug under investigation.  
 
Note:  All deaths on study require both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
14.2 DEFINITION OF ADVERSE EVENT 
An AE is defined as any illness, sign or symptom which has appeared or worsened during the 
course of the study, regardless of causal relationship to the drug under study, experienced by 
a patient.   
 
All adverse events should be recorded and described in the adverse event database in the 
REDCap data capture system.   
 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in 
the frequency, duration or severity, or a change in the quality, of the disease or condition.  


Protocol version 6.0 dated  April 3, 2020 
44 
 
Only grade 3 or 4 abnormal lab values that were not noted during the Screening Phase should 
be recorded; however, any clinical consequences of the abnormality, regardless of grade 
should be reported as AEs.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an 
AE (e.g., surgical insertion of central line) need not be considered AEs and should not be 
recorded as an AE.  Progression of cancer also will not be considered an AE. 
 
Death should only be entered as the outcome for an AE when the patient’s death is at least 
probably related to the AE (Note: the causal relationship of the AE to the test article is not to 
be considered in making this decision). If more than one AE is possibly related to the 
patient's death, the outcome of death should be indicated for each such AE. 
14.3 DEFINITION OF SERIOUS ADVERSE EVENT 
An SAE is defined by regulatory agencies as one that suggests a significant hazard or side 
effect, regardless of the investigator or sponsor’s opinion on the relationship to 
investigational product.  This includes, but may not be limited events that result in the 
following outcomes: 
 
 Death 
 Life-threatening.  Patient was at substantial risk of dying at the time of the event 
or use or continued use of the medical product may have resulted in the death of 
the patient. 
 Hospitalization (initial or prolonged).  Report hospital admissions or prolongation 
of hospitalization.  Emergency room visits that do not result in admission should 
be evaluated for one of the other serious outcomes.   
 Disability or Permanent Damage.  Report is the adverse event resulted in a 
substantial disruption of a person’s ability to conducts normal life functions. 
 Congenital anomaly/birth defect.  Report if it is suspected that the exposure to the 
medical product prior to conception or during pregnancy may have resulted in an 
adverse outcome for the child. 
 Other Serious or important medical events.  If the event does not fit other 
outcomes, but may jeopardize the patient and may require intervention to prevent 
one of the other outcomes.  
14.4 DEFINITION OF SEVERITY 
Adverse events will be graded according to the NCI CTCAE.  If toxicities are not defined by 
the NCI CTCAE v. 4.0, the intensity of each adverse event should be graded as outlined 
below:   
 
GRADE 1 
MILD:  Sign or symptom noticeable, but does not interfere with normal daily 
activities. 
GRADE 2 
MODERATE:  Sign or symptom sufficient to interfere with normal daily 
activities. 


Protocol version 6.0 dated  April 3, 2020 
45 
 
GRADE 3 
SEVERE:  Sign or symptom is incapacitating, with inability to perform daily 
activities. 
GRADE 4 
LIFE-THREATENING:  sign or symptom poses immediate risk of death to this 
patient. 
14.5 DEFINITION OF RELATIONSHIP TO STUDY DRUG 
The categories for classifying the Investigator’s opinion regarding the relationship of an AE 
to the study drug are listed below. 
 
Definitely related: 
An adverse event occurring in a plausible time relationship to drug 
administration, and which cannot be explained by concurrent disease or 
other drugs or chemicals.  The response to withdrawal of the drug should 
be clinically plausible.  The event must be definite pharmacologically or 
phenomenologically, using a satisfactory rechallenge procedure if 
necessary and feasible.
Possibly related: 
An adverse event with a reasonable time sequence to administration of the 
drug, but which could also be explained by concurrent disease or other 
drugs or chemicals.  Information on drug withdrawal may be lacking or 
unclear.
Not related: 
An adverse event with a temporal relationship to drug administration 
which makes a causal relationship improbable, and in which other drugs, 
chemicals or underlying diseases provide plausible explanations. 
14.6 DOCUMENTATION OF ADVERSE EVENTS 
The Investigator will monitor and/or ask about or evaluate AEs using non leading questions 
at each visit or evaluation. The occurrence of all AEs will be documented in the CRF with 
the following information, where appropriate: 
 
 
AE name or term 
 
When the AE first occurred (start date) 
 
When the AE stopped (stop date), (or an indication of “ongoing”) 
 
How long the AE persisted (optional) 
 
Severity of the AE 
 
Seriousness  
 
Actions taken 
 
Outcome 
 
Investigator opinion regarding the relationship of AE to the study drug(s) 
14.7 EXPECTED ADVERSE EVENTS 
Expected adverse events are those events known to be associated with study treatment.  
Expected adverse events are listed in the protocol, investigator brochure, package insert or 
product label.  Events should be classified as unexpected, expected or more frequent than 
expected. 


Protocol version 6.0 dated  April 3, 2020 
46 
 
14.8 FOLLOW UP OF PATIENTS WITH ADVERSE EVENTS 
The Investigator will follow patients with AEs, even if the patient was withdrawn from the 
study due to the AE, until the adverse event has: 
 
 
resolved 
 
the patient has returned to baseline state of health, 
 
the patient is lost to follow-up, 
 
the event is otherwise explained, 
 
the Investigator does not expect any further improvement or worsening of the adverse 
event. 
 
Medically significant AEs considered related to the investigational product by the 
investigator or the sponsor will be followed until resolved or considered stable.   
 
Any AEs not related to study drug ongoing at the time of completion of study drug should be 
considered unresolved.   
14.9 NOTIFICATION OF SPONSOR OF SERIOUS ADVERSE EVENTS 
Any serious adverse events which occur during the clinical study or within 30 days of 
receiving the last dose of study medication, whether or not related to the study drug, must be 
reported by the investigator.  
 
Adverse events classified as serious require expeditious handling and reporting to IRBs and 
designated IRB or ethics board policies should be followed.   
 
Within 24 hours of becoming aware of a SAE, the investigator must file an SAE report to 
MUSC AND Ferring Pharmaceuticals, Inc. .   
 
The SAE report should comprise a full written summary, detailing relevant aspects of the 
adverse events in question. Where applicable, information from relevant hospital case 
records and autopsy reports should be included. Follow-up information should be submitted 
to MUSC and Ferring Pharmaceuticals within 24 hours of receipt. 
 
SAEs will be submitted to MUSC via the 102509 (Gourdin) SAE Submission Form.  A copy 
of that report should be downloaded and sent to Ferring Pharmaceuticals: 
 
Fax:  1-877-243-8120 or  
Email:  safety.mailboxUS@ferring.com  
15 ETHICAL AND REGULATORY CONSIDERATIONS 
The following must be observed to comply with Food and Drug Administration regulations 
for the conduct and monitoring of clinical investigations; they also represent sound research 
practice. 


Protocol version 6.0 dated  April 3, 2020 
47 
 
15.1 INFORMED CONSENT 
The investigator or other designated personnel will obtain written informed consent from all 
participating patients or their authorized representatives.  The principles of informed consent 
are described by Federal Regulatory Guidelines (Federal Register Vol. 46, No. 17, January 
27, 1981, part 50) and the Office for Protection from Research Risks Reports:  Protection of 
Human Subjects (Code of Federal Regulations 45 CFR 46).  These federal guidelines as well 
as ICH GCP must be followed when obtaining informed consent.    
Copies of the signed document will be given to the patient and filed in the Investigator’s 
study file, as well as the patient’s medical record if in conformance with the institution’s 
Standard Operating Procedures.  
15.2 INSTITUTIONAL REVIEW 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 
56) and the Office for Protection from Research Risks Reports:  Protection of Human 
Subjects (Code of Federal Regulations 45 CFR 46) 
The trial will not be initiated without approval of the appropriate IRB.  All administrative 
requirements of the governing body of the institution will be fully complied with.  This 
protocol, consent procedures, and any amendments must be approved by the IRB in 
compliance with current regulations of the FDA.  A letter of approval will be sent to the 
institution(s) funding the study prior to initiation of the study and when any subsequent 
modifications are made.  The IRB will be kept informed by the Investigator as to the progress 
of the study as well as to any serious or unusual adverse events. 
15.3 DRUG ACCOUNTABILITY 
For each drug supplied for a study, an accountability ledger containing current and accurate 
inventory records covering receipt, dispensing, and the return of study drug supplies must be 
maintained.  Drug supplies must be kept in a secure, limited access storage area under the 
recommended storage conditions.  These Accountability Forms must be readily available for 
inspection and are open to FDA or NCI inspection at any time. 
15.4 PATIENT PRIVACY 
In order to maintain patient confidentiality, all case report forms, study reports and 
communications relating to the study will identify patients by initials and assigned patient 
numbers.  The FDA may request access to all study records, including source documentation 
for inspection. The Investigator/Institution will permit direct access to source data and 
documents by Ferring, its designee, the FDA and/or other applicable regulatory authority.  
The access may consist of trial-related monitoring, audits, IRB, and FDA inspections. 
Subject medical information obtained as part of this study is confidential, and must not be 
disclosed to third parties, except as noted below.  The subject may request in writing that 
medical information be given to his/her personal physician. 
 


Protocol version 6.0 dated  April 3, 2020 
48 
 
Release of research results should preserve the privacy of medical information and must be 
carried out in accordance with Department of Health and Human Services Standards for 
Privacy of Individually Identifiable Health Information, 45 CFR 164.508. 
15.5 PUBLICATION POLICY  
The Investigators plan to publish and present the information obtained from the study.  
15.6 RECORD RETENTION  
The Sponsor-Investigator must ensure maintenance of all study records per applicable federal 
regulations.  
 
16 MONITORING 
The SIS Unit will be responsible for the monitoring of study patient data and records; monitoring 
will be performed centrally. The SIS Unit will be responsible for forwarding any applicable 
reports to the HCC DSMC for review. 
The SIS Unit will conduct patient eligibility audit reviews for all patients at each participating 
center prior to patient registration.  During the course of the study, each site will be selected for 
an audit approximately once a year.  Progress reports will be submitted to the HCC DSMC 
approximately twice a year. 
The SIS Unit will maintain a shadow regulatory binder for all participating centers.  Required 
regulatory documents, including those needed for site initiation, during activation, and study 
closure, are outlined in the operations manual for this study. 
16.1 PROTOCOL DEVIATIONS  
For the purposes of this study, a protocol deviation is any variance from the protocol 
involving a subject or subjects that is not approved by the IRB prior to its initiation or 
implementation, and occurs when a member of the study team departs from the IRB-
approved protocol in any way without the investigator first obtaining IRB approval. Protocol 
Deviations have special reporting requirements.   
 
Any protocol deviation and any supporting documentation will be submitted to the SIS Unit 
by the site within 10 days of notification as outlined in the IIT SOP for this study.  Local IRB 
reporting requirements should be followed.  Any IRB approvals or acknowledgments should 
be submitted to the SIS Unit. 
16.2 DATA SAFETY MONITORING BOARD 
The HCC DSMC will have oversight of the protocol. The HCC DSMC will meet at a 
minimum on a semi-annual basis to review the audits and progress reports for this IIT.  
In addition, all protocol deviations and SAEs as defined above will be reviewed by the HCC 
DSMC at monthly meetings. As new protocol deviations or serious adverse events are 
reported to the SIS Unit, the SIS Unit will review these reports for form completion and 
follow up if more information is warranted. The SIS Unit will forward the event report to the 
HCC DSMC so that the information can be reviewed at the next available DSMC meeting. 
During the DSMC review, the DSMC can make recommendations for any further study 
action. The SIS Unit will maintain a copy of the DSMC approval letters for each event 


Protocol version 6.0 dated  April 3, 2020 
49 
 
reviewed for this study within the site’s central study file and will distribute to the 
participating site, if applicable. 
 
 
 
 


Protocol version 6.0 dated  April 3, 2020 
50 
 
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Protocol version 6.0 dated  April 3, 2020 
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APPENDIX A:  CALCULATION OF CREATININE CLEARANCE 
 
Estimation of creatinine clearance using Cockroft and Gault method: 
 
ClCR for males (mL/min) = 
 
[140 - age (years)] X [weight (kg)] 
 
 
 
                        (72) X [Serum creatinine (mg/dL)] 
 
 
 
 
 
 
 
 
 


Protocol version 6.0 dated  April 3, 2020 
54 
 
APPENDIX B:  ADVERSE EVENTS ASSOCIATED WITH THE USE OF 
DOCETAXEL IN THE TAX327 TRIAL 
 
 
Tannock IF et al. N Engl J Med 2004;351:1502-1512