A Pilot Study of Dexamethasone Therapy Prior to Rechallenge With Enzalutamide in Men With Metastatic Castration-Resistant Prostate Cancer Dex EXTends Enza Response (The DEXTER Trial)
Phase: NA
Conditions: Hormone-Resistant Prostate Cancer, Metastatic Prostate Carcinoma, Prostate Adenocarcinoma, Stage IV Prostate Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

1 
SKCCC Protocol #: J1548 
 
ClinicalTrials.gov Identifier:  NCT02491411 
 
TITLE:  A Pilot Study of Dexamethasone Therapy Prior to Rechallenge with Enzalutamide in 
Men with Metastatic Castration-Resistant Prostate Cancer 
 
Dex EXTends Enza Response (The DEXTER Trial) 
 
 
Organization: 
 
 
 
Johns Hopkins 
 
Lead Site Principal Investigator: 
 
 
Samuel R. Denmeade, M.D. 
 
 
 
The Sidney Kimmel Comprehensive Cancer 
 
 
 
1650 Orleans St, CRB-1, Room 1M45 
 
 
 
Baltimore, MD 21231 
 
 
 
Phone: 410-955-8875 
 
 
 
Fax: 410-614-8397 
 
 
 
 
 
denmesa@jhmi.edu 
 
Co-Investigator: 
 
  
 
 
Benjamin A. Teply, M.D. 
Statistician: Hao Wang, PhD  
 
Lead Study Coordinator:  
Yan Tian 
Research Study Coordinator/Data Manager 
550 North Broadway/ Suite 827 
Baltimore, MD 21205 
410-502-5101 Office 
410-614-7287 Fax 
yantian@jhmi.edu  
Responsible Research Nurse: Irina Rifkind, RN 
 
 
Coordinating Center: 
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
Samuel R. Denmeade, M.D. 
1650 Orleans St, CRB-1, Room 1M45 
 
Baltimore, MD 21231 
Phone: 410-955-8875 
Email: denmesa@jhmi.edu 
 
Participating Site: The Akron General Medical Center, Akron, OH 
 
Version # / Version Date: #1.0, Date 4/10/15 
Version # / Version Date: #2.0, Date 09/17/2015 
Version # / Version Date: #3.0, Date 08/24/2016 
 

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SYNOPSIS 
 
Title: A Pilot Study of Dexamethasone Therapy Prior to Rechallenge with Enzalutamide in Men 
with Metastatic Castration-Resistant Prostate Cancer 
 
Phase of Study: Pilot 
 
Objectives: To determine if treatment with dexamethasone (Dex) followed by enzalutamide 
(Enza) provides PSA and objective response, in patients who have previously had disease 
progression after Enza.  Prior treatment with docetaxel is allowed but not required. 
 
Study Design: The study is a single arm, open-label study wherein patients with metastatic 
castrate resistant prostate cancer (mCRPC) will be treated with Dex 2mg PO daily until PSA 
progression, then treated with Enza 160mg PO daily. 
 
Treatment Plan: Patients will be prescribed Dex 2mg tablets to take daily by mouth with food.  
All patients will receive a minimum of two months of Dex.  Following PSA or radiographic 
progression of disease, patients will be prescribed Enza 160 mg (40 mg tablets x4) by mouth 
daily.  Dex will be tapered and stopped over a one week period.  Enza will be continued for three 
months, after which time patients will be assessed for response. All patients will come off study 
after 3 months of Enza.  Patients without evidence of response to Enza will be offered other 
standard of care therapy or additional clinical trial.  Patients demonstrating Enza response will 
come off trial and be allowed to continue Enza as standard of care therapy. Blood Samples for 
assessment of AR and AR-V expression will be taken at baseline and at time of initiation of 
Enza. 
 
Assessment of Response: Patients will have monthly PSA measurements.  Disease will be 
assessed with bone scan and CT C/A/P at baseline, prior to initiation of Enza and at study 
conclusion.  Progression will be defined by RECIST 1.1 and PCWG-2 criteria for soft tissue and 
bone metastasis, respectively.  PSA response will be defined as 50% decrease in PSA from 
initiation of Enza.  PSA progression will be defined by PCWG-2 criteria. 
 
Rationale: The treatment options are very limited for patients with metastatic prostate cancer 
whose disease has become resistant to hormonal therapy and chemotherapy.  Initially, the disease 
responds to drugs such as Enza, which block the androgen receptor.  However, prostate cancer 
becomes resistant to this therapy through several mechanisms, including changes in the cancer’s 
expression of the androgen receptor. 
 
Dex and other glucocorticoids are an established treatment for prostate cancer; they can provide 
pain control, relief of other cancer-related symptoms like anorexia and fatigue, as well as have a 
direct anti-cancer effect.  The receptor for glucocorticoids is expressed on many advanced 
prostate cancers, and recent work has theorized that there is interaction between the 
glucocorticoid receptor and androgen receptor pathways.  It is thought that using a drug to affect 
one of the receptors may change the expression patterns and signaling of the other receptor. 
 
Given that Dex has a known benefit, and that there is a likely interaction between the androgen 

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receptor and glucocorticoid receptor, this research aims to treat patients with medicines in 
sequence to attempt to achieve better responses to the therapies.  By giving Dex and then 
transitioning to Enza at time of progression, patients may respond to Enza who may otherwise 
not have been responders to the therapy.  In addition, the study will seek to identify whether 
there are characteristics of the cancer cells (specifically with regard to the androgen receptor 
expression and splicing) that predict response to the sequence of therapies. 
 
Study Population: Men with metastatic castration-resistant prostate cancer with progression after 
prior treatment with Enza. Prior treatment with docetaxel is allowed but not required. 
 
Number of Patients: 20 
 
Treatment Sites:  The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 
Baltimore, MD; The Akron General Medical Center, Akron, OH 
 
Inclusion Criteria: 
 
1. Patients must have histologically or cytologically confirmed adenocarcinoma of the 
prostate 
2.  Patients must have metastatic disease radiographically documented by CT/MRI or bone 
scan; measurable disease is not necessary for inclusion. 
3. Age ≥18 years. 
4. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
5. Life expectancy of greater than 3 months in the opinion of the investigator 
6. Patients must have acceptable organ and marrow function as defined below: 
• absolute neutrophil count ≥1,500/mcL 
• platelets ≥100,000/mcL 
• hemoglobin ≥ 8; transfusion is allowed 
• total bilirubin ≤1.5 × institutional upper limit of normal 
• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal 
• Creatinine clearance ≥30 by Cockcroft-Gault formula 
7. Patients must have progression after prior treatment with Enza at any point in the disease 
course (pre- or post-chemotherapy).   
8. Prior treatment with docetaxel is allowed but not required.   
9. Prior treatment with other second line hormone therapy is allowed (e.g. flutamide, 
bicalutamide, nilutamide, ketoconazole, abiraterone, ARN-509). Patients must be off 
these therapies for at least 4 weeks prior to starting treatment 
10. Prior treatment with Xofigo (223Radium), Provenge, mitoxantrone and cabazitaxel is 
allowed. 
11. Patients must have rising PSA on two successive measurements, at least 2 weeks apart.  
12. Patient must be treated with continuous androgen ablative therapy (e.g. goserelin, 
leuprolide, triptorelin, or degarelix, if he has not had prior surgical castration) and have 
castrate levels of testosterone (<50 ng/dL or  1.7 nmol/L). 
13. Ability to understand and the willingness to sign a written informed consent document. 
 
 

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Exclusion Criteria: 
1. Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the 
study or those who have not recovered from adverse events due to agents administered 
more than 4 weeks earlier (persistent toxicity ≥ Grade 1) . 
2. Patients who are receiving any other investigational agents. 
3. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Dex or Enza. 
4. Any use of systemic corticosteroids in the prior 4 weeks. 
5. Uncontrolled diabetes mellitus 
6. History of seizure, underlying brain injury with loss of consciousness, transient ischemic 
attack within the past 12 months, cerebral vascular accident, brain metastases, and brain 
arteriovenous malformations. 
7. Patients receiving any medications or substances that are inhibitors or inducers of 
CYP2C8 are ineligible (e.g. gemfibrozil, rifampin, trimethoprim, pioglitazone). 
8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations or geographical condition that would limit compliance 
with study requirements. 
 
Study Endpoints: 
 
The primary endpoint: 
• Response rate to Enza after treatment with Dex therapy.  Responses will be determined 
by PSA criteria as defined by Prostate Cancer Working Group (PCWG2) criteria.  The 
baseline will be defined as the initiation of Enza.  The percentage of patients with >50% 
PSA response on rechallenged with Enza will be the primary endpoint. 
 
The secondary endpoints/analysis: 
• Objective response rate to Enza in patients with measurable disease on CT scan using 
RECIST criteria. 
• Time to PSA progression (based upon PCWG2 criteria) for treatment with Dex.  
• Effect of each treatment on quality of life as assessed by patient completion of validated 
instruments.  Quality of life assessments will be taken at study entry, periodically while 
on Dex and Enza, at time of progression on Dex, and at study completion. 
• PSA response rates to Dex for patients who are AR-V7 positive and AR-V7 negative, 
respectively, at study entry. 
• Response rates to Enza for patients who are AR-V7 positive and AR-V7 negative, 
respectively, at study entry. 
• Percentage of patients who are AR-V7 positive at study entry who are AR-V7 negative at 
time of initiation of Enza, and vice-versa. 
 
 
 
 
 
 

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Study Scheme: 
 
 
 
Statistical Plan:  
The primary endpoint will be the PSA response rate with the re-challenge of Enza following 
Dex, which is defined as the proportion of subjects with a ≥50% PSA decline from baseline and 
maintained for ≥4 weeks at any time-point after receiving Enza.  The treatment regimen would 
be considered of insufficient activity for further study in this population if PSA response rate is 
5% or less, and the minimum required level of efficacy that would warrant further study with the 
proposed regimen is a 25% PSA response rate.  The sample size is calculated to detect an 
improved PSA response rate from 5% to 25%. A minimax Simon two-stage design is planned. A 
total of 13 patients will be entered in the first stage. If none of them show PSA response after 
Enza, the treatment regimen will be terminated and we will conclude the regimen is ineffective. 
If >=1 subjects has PSA response, then additional 7 patients will be studied.  If a total of 2 or 
fewer subjects achieve PSA response in stage one and two combined, we consider this regimen 
ineffective. If a total of 3 or more respond, we conclude the regimen is promising and warrant 
further study. The trial could be terminated early also as soon as 3 PSA responses with the post-
Dex Enza treatment are confirmed.  
 
The maximum sample size will be 20. Patients who receive at least one dose of Dex will be 
evaluable for PSA response. This design provides 90% power to reject a 5% PSA response in 
favor of 25% response rate, with a type I error of 0.1. The chance of early stopping is 0.51 when 
the response rate is less than 5%. 
Enroll in trial
•Baseline assessments 
and laboratories
•CTC collection for 
assessment of AR-V 
expression
•Initiation of treatment 
with dex 2mg PO daily
Ongoing assessment:
•PSA monthly
•Study team visits q1-2 
months
•Quality of life, 
symptom, toxicity 
assessments
•CBC, CMP, A1C q 
3months
At progression:
•Obtain second CTC 
sample for AR-V 
expression
•Stop/ taper 
dexamathasone
•rechallenge with Enza 
160mg PO daily
Ongoing assessment:
•PSA monthly
•CT / Bone scans at 3 
months
•Quality of life and 
symptom assessments  
at 3 months
•Complete trial after 3 
months

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TABLE OF CONTENTS 
 
SYNOPSIS .......................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives...................................................................................................8 
1.2 
Secondary Objectives...............................................................................................8 
2. 
BACKGROUND .................................................................................................................8 
2.1 
Study Disease ...........................................................................................................8 
2.2 
Study Agents ............................................................................................................9 
2.3 
Study Rationale ......................................................................................................11 
2.4 
Study Hypothesis ...................................................................................................11 
2.5 
Correlative Studies Background ............................................................................11 
3. 
PATIENT SELECTION ....................................................................................................12 
3.1 
Eligibility Criteria ..................................................................................................13 
3.2 
Exclusion Criteria ..................................................................................................14 
3.3 
Inclusion of Women and Minorities ......................................................................14 
4. 
PATIENT REGISTRATION AND ENROLLMENT PLAN............................................15 
4.1 
Registration Procedures .........................................................................................15 
4.2 
General Guidelines.................................................................................................15 
5. 
TREATMENT PLAN ........................................................................................................16 
5.1 
Study Design ..........................................................................................................16 
5.2 
Study Treatments and Scheme ...............................................................................16 
5.3 
Duration of Follow Up ...........................................................................................17 
5.4 
Criteria for Removal from Study ...........................................................................17 
5.5 
Concomitant Therapy.............................................................................................17 
5.6 
Prohibited Concomitant Medications ....................................................................18 
5.7 
Dosing Delays / Modifications ..............................................................................18 
6. 
STUDY ACTIVITIES .......................................................................................................19 
6.1 
Screening................................................................................................................19 
6.2 
Treatment Period ....................................................................................................19 
6.3 
End of Study ..........................................................................................................20 
6.4 
Early Discontinuation ............................................................................................20 
7. 
SAFETY AND ADVERSE EVENTS ...............................................................................20 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................21 
8.1 
Enza........................................................................................................................21 
8.2 
Dex .........................................................................................................................21 
9. 
STUDY CALENDAR .......................................................................................................22 

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10. 
STUDY ASSESSMENTS .................................................................................................23 
10.1 
Assessing PSA response ........................................................................................23 
10.2 
Assessing response in measurable disease .............................................................23 
11. 
DATA REPORTING / REPORTING REQUIREMENTS................................................23 
11.1 
Adverse Event Monitoring and Reporting .............................................................24 
11.2 
Evaluating Adverse Events ....................................................................................24 
11.3 
Documenting Adverse Events................................................................................24 
11.4 
Serious Adverse Events .........................................................................................25 
11.5 
Expedited Reporting of Serious Adverse Events ...................................................25 
11.6 
Protocol Amendments ............................................................................................26 
11.7 
Informed consent: ..................................................................................................26 
11.8 
Multicenter Guidelines: .........................................................................................26 
12. 
STATISTICAL CONSIDERATIONS...............................................................................28 
12.1 
Study Design/Endpoints.........................................................................................28 
12.2 
Sample Size/Accrual Rate ......................................................................................28 
12.3 
Analysis Method ....................................................................................................28 
12.4 
Reporting and Exclusions ......................................................................................29 
REFERENCES ..............................................................................................................................30 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................32 
APPENDIX B 
NCI COMMON TOXICITY CRITERIA, VERSION 4.0 .........................33 
APPENDIX C  
Response Evaluation Criteria in Solid Tumors (RECIST) ........................34 
APPENDIX D  
Circulating Tumor Cell (CTC) Blood Collection and SHIPPING  ...........39 
APPENDIX E 
Prostate Cancer Working group 2 (PCWG2) Criteria ...............................40 
 
 
 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To determine the PSA response rate to Enza after treatment with Dex (Dex) therapy.  
Responses will be determined by PSA criteria as defined by Prostate Cancer Working 
Group (PCWG2) criteria.  The baseline will be defined as the initiation of Enza.  The 
percentage of patients with >50% PSA response will be the primary endpoint. 
 
1.2 
Secondary Objectives 
 
1.2.1 Objective response rate to Enza in patients with measurable disease on CT scan using 
RECIST criteria. 
 
1.2.2 Time to PSA progression (based upon PCWG2 criteria) for treatment with Dex.  
 
1.2.3 Effect of each treatment on quality of life as assessed by patient completion of 
validated instruments (FACIT-Fatigue Scale, RANDSF-36) Quality of life 
assessments will be taken at study entry, during second on-treatment visits for both 
Dex and after 3 cycles of Enza. 
 
1.2.4 PSA response rates to Dex for patients who are AR-V7 positive and AR-V7 negative, 
respectively, at study entry. 
 
1.2.5 Response rates to Enza for patients who are AR-V7 positive and AR-V7 negative, 
respectively, at study entry. 
 
1.2.6 Percentage of patients who are AR-V7 positive at study entry who are AR-V7 negative 
at time of initiation of Enza, or vice-versa. 
 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
Prostate cancer remains the second leading cause of cancer death among men in the United 
States.  Initially, most patients with metastatic prostate cancer will respond to androgen-
deprivation therapies.  Inevitably, resistance to this therapy develops and patients experience 
progression of disease.  Over the past several years, new treatments have been introduced that 
have prolonged the overall survival for patients with metastatic castration-resistant prostate 
cancer.  After patients develop castration-resistant metastatic disease, options include treatment 
with secondary androgen synthesis suppression, anti-androgens, chemotherapy, radiotherapy, or 
immunotherapy.  The basis for the several of these novel therapies is that prostate cancer remains 
dependent on androgens despite the development of a “castration-resistant” phenotype.  As 
patients are treated with these novel hormonal therapies and chemotherapy, responses are 
transient.  While the treatments have been shown to prolong survival in patients, all are non-

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curative.  Patients eventually are challenged with the available therapies and exhaust their 
treatment options.   
 
A common sequence of treatment for a patient who develops castration-resistant disease, but 
remains minimally symptomatic from his disease, would to first be treated with abiraterone 
acetate and then Enza after progression.  After a patient has progressed on these secondary 
hormonal therapies, chemotherapy with docetaxel is administered.  Patients who then experience 
progression after treatment with both Enza and docetaxel are faced with more limited options.  
For those that are were not treated with abiraterone prior to Enza and docetaxel, it is known that 
response rates are reduced when compared with responses as first- or second-line therapy.1  As 
patients are challenged with subsequent therapies (including Enza as third-line agent), responses 
become increasing limited both in terms of percentage of patients who respond and length of 
progression-free and overall survival. 
 
There is a great need, not only for the development of novel therapeutics, but also for strategies 
to potentially re-sensitize the patients so that they again may respond to the established therapies. 
 
2.2 
Study Agents 
 
2.2.1 Dexamethasone (Dex) 
 
Dex is an FDA-approved corticosteroid that is used for a variety of clinical indications.  
Specifically for oncology patients, it is commonly used as an anti-emetic for prevention of 
chemotherapy-induced nausea and vomiting, as an anti-inflammatory agent to palliate pain due 
to cancer, and as an anti-cancer agent in hematologic malignancies, most commonly multiple 
myeloma.  It is readily bioavailable after oral administration.   
 
In the case of prostate cancer, glucocorticoids such as Dex have long been used in advanced 
cases.2  Beyond the palliative effects of glucocorticoids for relief of pain, studies have repeatedly 
demonstrated PSA responses and clinical benefit.  Clinical trials that use continuous low-dose 
Dex have reported >50% PSA response rates ranging from 32 – 62% (See Table 1).  
 
While some portion of this effect may be attributable to adrenal suppression due to the 
exogenous glucocorticoids, responses are reported even in patients on potent suppressants of 
adrenal androgens.  For example, Lorente et al. recently reported a small trial of patients with 
metastatic castration-resistant disease who were experiencing progression of disease while on 
abiraterone and prednisone.3  By performing the intervention of changing prednisone 5mg twice 
daily to Dex 0.5mg while continuing abiraterone, 25% of patients (5 / 20) had a PSA response.  
Cell-based disease models of prostate cancer have demonstrated downstream effects from 
activation of the glucocorticoid receptor includes arresting cell growth in the G0 phase of the cell 
cycle via activation of TGF-b and suppression of NF-kb and IL6, among other functions.4   
 
 
 
 
 

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Table 1.  Studies of PSA response to Dex and mifepristone in castrastion-resistant prostate 
cancer 
 
Study 
Treatment 
N 
PSA Response (>50%) 
Storlie et al. 19955 
Dex 1.5-2.25mg daily 
38 
61%  
Nishiyama et al. 19986 
Dex 0.5-1.5mg daily 
7 
57% 
Nishimura et al. 20007 
Dex 0.5-1mg daily 
37 
62% 
Saika et al. 20018 
Dex 1.5mg daily 
19 
26% 
Morioka 20029 
Dex 1.5mg daily 
27 
59% 
Venkitaraman et al. 
200710 
Dex 0.5mg daily 
102 
49% 
Attard et al. 200911 
Dex 0.5mg daily 
30 
32% 
Komiya et al. 201012 
Dex 0.5-1.5mg daily 
99 
40% 
Shamash et al. 201113 
Dex 2mg daily 
133 
50% 
Study 
GR antagonist treatment 
 
 
Taplin et al. 200814 
Mifepristone 200 mg/day 
19 
0% 
 
 
It has been postulated that glucocorticoid receptor antagonists may reverse resistance in 
advanced disease,15 yet the only clinical trial in metastatic prostate cancer using mifepristone, an 
anti-progestin that also antagonizes the glucocorticoid receptor, had a 0% response rate (Taplin 
study in Table 1), and mifepristone can offer no palliative effects.  Studies examining use of 
glucocorticoid antagonists in combination with Enza are ongoing. 
 
2.2.2 Enzalutamide (Xtandi) 
 
Enza is a potent small molecule androgen receptor antagonist that was FDA-approved for 
treatment of patients with metastatic castration-resistant prostate cancer in 2012.  The first 
indication for the drug’s use was after treatment with docetaxel chemotherapy.  In the 1199 
patient phase III AFFIRM study, Scher et al. demonstrated increased survival for treatment with 
Enza versus placebo.16  Patients who were treated with Enza had longer overall survival (18.4 vs 
13.6 months), improved median progression free survival (radiographic: 8.3 vs. 2.9 months; 
PSA: 8.3 vs 3.0 months), and improved PSA response rates (54% vs 2%). 
 
The FDA updated the approval for Enza to allow for its use before treatment with chemotherapy 
after the results from the PREVAIL study were released.  In that phase III study, 1717 patients 
were randomized to receive Enza or placebo.17  Those receiving Enza compared to placebo had a 
greater overall survival (32.4 vs 30.2 months), improved median progression free survival 
(radiographic: not reached vs 3.9 months; PSA: 11.2 vs 2.8), and improved PSA response rates 
(78% vs 3%).   
 
Based upon these trials, Enza is increasingly being used as prostate cancer treatment prior to 
docetaxel therapy for castration-resistant disease. 
 
 

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2.3 
Study Rationale 
 
We now understand some of the resistance mechanisms of the cancer to hormonal therapies.    
Prostate cancer develops resistance as it adapts to the low androgen environment.18  Yet, the 
prostate cancer cells remain dependent on the androgen receptor signaling pathway for growth.19  
This ongoing dependence on androgen signaling is the basis for clinical responses to further anti-
androgen therapies even after development of castration-resistant disease.20  These therapies act 
through either direct antagonism (i.e. bicalutamide or Enza) or indirectly through suppression of 
synthesis of non-prostate sources of androgen (i.e. ketoconazole or abiraterone).  Several 
mechanisms have been proposed for resistance to these treatments, including overexpression of 
androgen receptor via increased transcription and gene amplification or expression of ligand-
independent androgen receptor splice variants.21 
 
In addition, the glucocorticoid receptor pathway is thought to interplay with the androgen 
signaling pathway since the glucocorticoid receptor is able to bind to androgen response 
elements.4  Glucocorticoid receptor overexpression has been demonstrated as a common feature 
in heavily treated metastatic prostate cancer.  In one series of 45 patients who underwent prostate 
biopsies after androgen deprivation therapy and / or chemotherapy, 25 (56%) co-expressed 
androgen receptor and glucocorticoid receptor while 5 (11%) expressed only the glucocorticoid 
receptor and exhibited loss of androgen receptor.22  Two studies have examined glucocorticoid 
receptor expression at patients with metastatic prostate cancer, including in response to therapy 
on Enza.15,23  Arora et al. observed up-regulation of glucocorticoid receptor in patients who were 
poor responders to Enza.15   
 
It is postulated that there is interplay between the androgen receptor and glucocorticoid receptor, 
and that the glucocorticoid receptor expression and activation represents an additional resistance 
mechanism for Enza.  Given our expanding knowledge of mechanisms of resistance to anti-
androgen therapy, coupled with the prior observed benefits in a subset of patients of 
glucocorticoid therapy, we are studying treatment with glucocorticoid agonist therapy prior to 
rechallenge with Enza.   
 
2.4 
Study Hypothesis 
 
The hypothesis of the study is that Dex-mediated down-regulation of the glucocorticoid receptor 
could reverse one resistance mechanism to Enza therapy and allow for renewed therapeutic 
sensitivity to Enza.   
 
2.5 
Correlative Studies Background 
 
We will study expression of AR-V7 and its association with response to Dex and subsequent 
response to Enza.   
 
The androgen receptor is a 110-kDa protein with several functional domains.  Anti-androgen 
drugs such as Enza target the highly conserved C-terminal ligand binding domain.  Transcripts 
that are produced by alternative splicing of the androgen receptor mRNA transcript can lead to 
protein products that lack the target for androgen receptor antagonists.  While a total of 15 

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androgen receptor variants have been described, the most important variant is AR-V7.  Our 
institution recently examined associations between AR-V7 status and PSA response rates and 
progression-free survival (PSA and radiographic), using multivariable cox regression analysis to 
determine the independent effect of AR-V7 expression on clinical outcomes.24  In this study, 31 
patients treated with Enza were enrolled, of which 12 (38.7%) were positive for expression of 
AR-V7.  Patients that were positive for AR-V7 had a 0% PSA response rate to Enza compared to 
52.6% for those that were negative.  Other poorer outcomes similarly were associated with AR-
V7 positivity including progression free survival (PSA: 1.4 vs 5.9 months; radiographic/clinical: 
2.1 vs 6.1 months).  The presence of AR-V7 in circulating tumor cells was found to be associated 
with poor response to Enza. 
 
In preclinical cell-based prostate cancer assays performed in our laboratory, AR-V7 expressing 
cell-lines (VCaP and CWR22Rv1) can be growth inhibited by Dex exposure at high doses.  
Given that there is a previously demonstrated benefit to administration of Dex to patients with 
advanced disease, including PSA responses as discussed above, and there is preclinical data 
showing growth inhibition of cell lines, even expressing AR-V7, we will perform the correlative 
study to track AR-V7 expression with response Dex and Enza. 
 
The methods have been previously described and published.  Circulating tumor cells are enriched 
from peripheral blood collected from patients via a modified commercially available AdnaGen 
Prostate Cancer Select kit, wherein circulating prostate cancer cells are isolated with ligand-
coated magnetic beads and lysed yielding mRNA.  The cells are isolated using magnetic beads 
coated with 3 different antibodies (EPCAM and 2 proprietary antibodies).  Quantitative RT-PCR 
is subsequently performed on the samples to evaluate mRNA expression of full length androgen 
receptor and AR-V7. 
 
Technology to assay for changes in glucocorticoid receptor expression and glucocorticoid 
receptor splice variants in circulating tumor cells currently does not exist. 
 
3. PATIENT SELECTION 
 
Eligible patients will have with metastatic castration-resistance prostate cancer who have 
experienced disease progression after treatment with Enza. .  Prior treatment with Enza pre or 
post-chemotherapy is required. Prior treatment with docetaxel is allowed but not required. 
Patients will have been treated with continuous ADT. Patients will continue on ADT with LHRH 
agonist (i.e. Zoladex, Trelstar, Eligard or Lupron) or LHRH antagonist (Degarelix) if not 
surgically castrated throughout the duration of the study to inhibit endogenous testosterone 
production.  Patients will be treated in a single–arm study sequentially with Dex then Enza.  A 
total of 13 patients will be recruited across 2 treatment sites in the initial phase of the trial, after 
which an additional 7 patients will be recruited if initial benchmarks for non-futility are met. 
 
 
 
 
 

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3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed adenocarcinoma of the 
prostate 
 
3.1.2 Patients must have metastatic disease radiographically documented by CT/MRI or 
bone scan; measurable disease is not necessary for inclusion. 
 
3.1.3 Age ≥18 years. 
 
3.1.4 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.5 Life expectancy of greater than 3 months in the opinion of the investigator 
 
3.1.6 Patients must have acceptable organ and marrow function as defined below: 
 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
hemoglobin ≥ 8; transfusion is allowed 
− 
total bilirubin 
≤1.5 × institutional upper limit of normal 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
− 
Creatinine clearance 
≥30 by Cockcroft-Gault formula 
 
3.1.7 Patients must have progression after prior treatment with Enza at any point in the 
disease course (pre- or post-chemotherapy).   
 
3.1.8 Prior treatment with docetaxel is allowed but not required.     
 
3.1.9 Prior treatment with other second line hormone therapy is allowed (e.g. flutamide, 
bicalutamide, nilutamide, ketoconazole, abiraterone, ARN-509). Patients must be off 
these therapies for at least 4 weeks prior to starting treatment. 
 
3.1.10 Prior treatment with Xofigo (223Radium), Provenge, mitoxantrone and cabazitaxel is 
allowed. 
 
3.1.11 Patients must have rising PSA on two successive measurements, at least 2 weeks apart.  
 
3.1.12 Patient must be treated with continuous androgen ablative therapy (e.g. goserelin, 
leuprolide, triptorelin, or degarelix, if he has not had prior surgical castration) and 
have castrate levels of testosterone (<50 ng/dL or  1.7 nmol/L). 
 
3.1.13 Ability to understand and the willingness to sign a written informed consent document. 
 
 
 

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3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering 
the study or those who have not recovered from adverse events due to agents 
administered more than 4 weeks earlier (persistent toxicity ≥ Grade 1) . 
 
3.2.2 Patients who have received any other investigational agents within the last 4 weeks. 
 
3.2.3 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to Dex or Enza. 
 
3.2.4 Any use of systemic corticosteroids in the prior 4 weeks. 
 
3.2.5 Uncontrolled diabetes mellitus 
 
3.2.6 History of seizure, underlying brain injury with loss of consciousness, transient 
ischemic attack within the past 12 months, cerebral vascular accident, brain 
metastates, and brain arteriovenous malformations. 
 
3.2.7 Patients receiving any medications or substances that are inhibitors or inducers of 
CYP2C8 are ineligible (e.g. gemfibrozil, rifampin, trimethoprim, .pioglitazone).  
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; 
medical reference texts such as the Physicians’ Desk Reference may also provide this 
information.  As part of the enrollment/informed consent procedures, the patient will 
be counseled on the risk of interactions with other agents, and what to do if new 
medications need to be prescribed or if the patient is considering a new over-the-
counter medicine or herbal product. 
 
3.2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations or geographical condition that 
would limit compliance with study requirements. 
 
3.3 
Inclusion of Women and Minorities 
 
This study is focused on prostate cancer, therefore is applicable to men only. Women and 
children will not be included on this study. Men from all ethnic and race groups are eligible for 
this study. 
 
 
 
 
 
 
 

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15 
4. PATIENT REGISTRATION AND ENROLLMENT PLAN 
 
4.1 
Registration Procedures 
 
4.1.1 All patients must sign a written informed consent form before study specific screening 
procedures are performed. Screening procedures to evaluate patient eligibility for the 
study will be conducted within 28 days prior to Cycle 1 Day 1. If the patient meets 
eligibility and screening requirements he will initiate on therapy.  All required 
screening, treatment and post-treatment study procedures and assessments must be 
done within 7 days (+/-) of the specified study visit date. 
 
4.1.2 Initial Registration Process: Eligible patients will be registered on study centrally at 
the Sidney Kimmel Comprehensive Cancer Center by the Lead Site Study 
Coordinator. 
 
To register a patient, the following documents must be completed and emailed to the 
Lead Center Program Coordinator at Johns Hopkins, Yan Tian, at yantian@jhmi.edu: 
 
• Signed/dated patient consent form 
• Eligibility checklist 
• Copies of the prostate cancer pathology report 
• Copies of pre hormone therapy/chemotherapy or radiation therapy 
• Screening labs 
• CT and bone scan reports 
• Other materials may also be sent if considered pertinent for confirming patient 
eligibility 
 
The Lead Center (Johns Hopkins) will review the documents to confirm eligibility. To complete 
the registration process the Lead Center will: 
 
• Assign a patient study number 
• Patients found to be ineligible for participation after being consented will be 
considered screen failures, and documented as such in the Screening and 
Enrollment Log 
• Once eligibility is confirmed, all patients must commence treatment within 7 
calendar days. 
 
4.2 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
 

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16 
5. TREATMENT PLAN 
 
5.1 
Study Design 
 
Patients with metastatic castration-resistant prostate cancer who are treated with continuous 
androgen-deprivation therapy and have progressed after prior treatment with Enza  will be 
treated on a single-arm, open-label, multi-site study to determine the response rate of Enza after 
treatment with Dex. Prior treatment with docetaxel is allowed but not required. Secondary 
objectives will be radiographic response rates to Enza for patients with measurable disease, 
response rates to Dex, progression-free survival (PSA and radiographic) for treatment with Dex, 
AR-V7 positivity with correlation to response to Dex and Enza, and any change in AR-V7 
positivity occurs as a result of treatment with Dex.   
 
5.2 
Study Treatments and Scheme 
 
Treatment will be administered on an outpatient basis.  No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the 
patient's malignancy. 
 
5.2.1 Study Treatments 
 
Patients will continue on ADT with LHRH agonist (i.e. Zoladex, Trelstar, Eligard or Lupron) or 
LHRH antagonist (Degarelix) if not surgically castrated throughout the duration of the study.  
 
Patients will be prescribed Dex 2mg tablets to take once daily orally with food for 28 days/cycle 
continuously.  Patients who have PSA progression after one cycle will continue on Dex for a 
second cycle.  Patients with continued increase in PSA (if satisfies progression based upon 
PCWG2 definition) will begin Enza.  Patients with declining PSA after 2 cycles of Dex will 
continue on Dex until PSA progression.  Every 3 cycles patients will have repeat bone/CT scans 
to evaluate treatment response. Patients will remain on treatment with Dex until evidence of PSA 
progression (per the PCWG2 definition) or disease progression on CT scan (per RECIST 
criteria), or progressive bone metastatic disease (per the PCWG2 definition).  
 
At time of progression, Dex will be stopped via a rapid taper over one week if patients were 
treated for >30 days.  Patients will be instructed to take 1 mg Dex for 7days, then stop.  
However, ongoing use of corticosteroids will be allowed if indicated for bone pain or adrenal 
suppression.   
 
Patients will then be prescribed Enza 40 mg tablets and instructed to take 4 tablets per day orally 
with or without food for 28 days/cycle continuously.  Dose adjustments and delays will be 
allowed as per standard of care with treatment with Enza.  Patients will have PSA checked 
monthly. All patients will remain on Enza for 3 cycles regardless of PSA response. At the end of 
3 cycles of Enza all patients will come off study.   Those patients with PSA or radiographic 
progression will come off study and be offered standard of care or another clinical trial. Those 
patients with PSA or radiographic response after 3 cycles will be offered to remain on Enza as 
standard of care therapy. 

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Patient with progression 
after Enzalutamide and 
Docetaxel:
•Screening and enrollment
•Initiation of treatment with 
dexamethasone 2mg PO 
daily
At progression (PSA or 
radiographic):
•Stop dexamathasone
•Initiation of enzalutamide 
160mg PO daily
After 3 months:
•Conclude study
•End of study assessments
Continuous LRHR agonist 
 
 
5.2.2 Treatment Scheme 
 
 
 
 
 
 
 
 
 
 
5.3 
Duration of Follow Up 
 
Patients will be followed for 4 weeks after removal from study or until death, whichever occurs 
first.  Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
5.4 
Criteria for Removal from Study 
 
A patient may be removed from the study for a variety of reasons, including: 
1. 
As defined by the protocol, evidence of disease progression based on radiographic 
progression or worsening symptoms while on Enza. 
2. 
Unacceptable adverse events 
3. 
Intercurrent illness that prevents further participation 
4. 
Experiencing a treatment delay of longer than 2 weeks due to drug toxicity 
attributed to Dex.  Patients who experience treatment delay while on Enza will 
remain on study as per protocol. 
5. 
Patient refuses further treatment through the study and/or withdraws consent to 
participate 
6. 
Need for “stress dose” glucocorticoids due to a life threatening medical condition.   
7. 
Patients is noncompliant with respect to taking drugs, keeping appointments, or 
having tests required for the evaluation of drug safety and efficacy  
8. 
General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in this study in the judgment of the investigator 
9. 
Under no circumstance will care of a withdrawn patient be adversely affected by a 
decision to withdraw or be withdrawn from the study. 
10. 
Ongoing response after 12 cycles of dexamethasone. 
 
5.5 
Concomitant Therapy 
 
The use of any concurrent medication from screening and while on study, prescription or over-
the-counter, is to be recorded on the patient's CRF along with the reason the medication was 
taken. In addition, tobacco and alcohol use will be collected.  Concurrent use of another clinical 
investigational drug or device while on study is prohibited.  Supportive care medications are 

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18 
permitted with their use following institutional guidelines. For patients who did not undergo 
orchiectomy, concurrent treatment with LHRH analogue is mandatory and must be recorded. 
 
The following supportive care medications are considered permissible during the study.  
• Conventional multivitamins, selenium and soy supplements  
• Dutasteride or finasteride if being used to treat BPH and only if patients are on the 
medication for at least 3 months prior to Study Day 1 
• Bisphosphonate and denosumab usage is allowed only if patients are on the medication 
for at least 3 months prior to Study Day 1  
• Transfusions and hematopoietic growth factors per institutional practice guidelines 
5.6        Prohibited Concomitant Medications 
Concomitant therapy during the treatment phase of the study with any of the following listed is 
prohibited:  
• Chemotherapy 
• Immunotherapy  
• Bicalutamide, nilutamide, flutamide  
• Systemic ketoconazole (or other azole drugs such as fluconazole and itraconazole) 
• Abiraterone acetate 
• Prednisone or other glucocorticoids, except if indicated for bone pain or adrenal 
suppression at the time of tapering of dexamethasone 
• Diethylstilbestrol, PC-SPES, and other preparations such as saw palmetto thought to have 
endocrine effects on prostate cancer  
• Radiopharmaceuticals such as xofigo (223Ra), strontium (89Sr) or samarium (153Sm)  
• Other experimental drugs or treatments 
 
5.7 
Dosing Delays / Modifications 
 
During treatment with Dex, any interruption in treatment due to treatment toxicity for greater 
than 2 weeks will result in removal from study.  No dose modifications are otherwise allowed. 
 
During treatment with Enza, patients will remain on study for three months, regardless of dose 
intensity, treatment modifications or delays.  While the standard dose of 160mg by mouth daily 
is initiated, the investigator may dose adjust for toxicities and interactions per standard protocols 
for Enza.  These dose delays and modifications will be tracked and reported. 
 
 
 
 
 
 

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6. STUDY ACTIVITIES 
 
6.1 
Screening 
 
All patients must sign a written informed consent form before study specific screening 
procedures are performed. Screening procedures to evaluate patient eligibility for the study will 
be conducted within 28 days prior to Cycle 1 Day 1. Prior to enrollment, patient must have 
documented insurance coverage demonstrating ability to pay for Enza.  If the patient meets 
eligibility and screening requirements he will be initiated on study.  All required screening, 
treatment and post-treatment study procedures and assessments must be done within 7 days (+/-) 
of the specified study visit date. 
 
6.1.1 Screening studies (Screening assessments must begin within 28 days prior to Cycle 1, 
Day 1) 
 
• Comprehensive medical history and physical exam, including height and weight, and 
medications. 
• ECOG Performance status (PS) 
• CBC (Complete blood count) with differential and platelet count 
• CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, Serum 
Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, Alkaline 
Phosphatase, HCO3) 
• Serum PSA 
• Serum testosterone 
• Hemoglobin A1C 
• Staging imaging with CT  if not already performed within 4 weeks and bone scintigraphy 
if not already performed within 8 weeks 
 
6.2 
Treatment Period 
 
Patients will have continuous treatment of outpatient therapy.  Patients who are not surgically 
castrated will continue to receive ongoing GnRH agonist or antagonist therapy as prior.  Patients 
will be assessed every 1-3 cycles at a clinic visit. 
 
6.2.1 Cycle 1 Day 1 visit: 
• Physical exam, including weight, ECOG performance status, vital signs 
• CBC (Complete blood count) with differential and platelet count (Not needed if 
performed within the last 2 weeks at screening) 
• CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, Serum 
Creatinine, Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, Alkaline 
Phosphatase, HCO3) (Not needed if performed within the last 2 weeks at screening) 
• Serum PSA  
• Hemoglobin A1 (Not needed if performed within the last 2 weeks at screening) 
• Blood drawn for to assess level of full length and androgen receptor variant in circulating 
tumor cells (CTC AR-V7) 

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• Quality of life surveys (FACIT-Fatigue Scale, RANDSF-36) 
 
6.2.2 Ongoing assessments while on Dex 
• Clinic visit after cycle 1 and then every third cycle for patients who are responding after 2 
cycles. 
o Physical exam, including weight, ECOG performance status, vital signs 
o Assessment of toxicity 
o Quality of life surveys 
• PSA every cycle 
• CBC, Comprehensive Metabolic Panel, Hemoglobin A1c every 3 cycles 
• CT scan and bone scan every 3 cycles 
• Blood drawn for research testing to assess level of full length and variant androgen 
receptor at time of progression on Dex (at time of initiation of Enza). 
 
6.2.3 Ongoing assessment while on Enza 
• Clinic visit every cycle. 
o Physical exam, including weight, ECOG performance status, vital signs 
o Assessment of toxicity 
o Quality of life surveys 
• PSA every cycle 
 
6.3 
End of Study 
• Clinic visit 
o Physical exam, including weight, ECOG performance status, vital signs 
o Assessment of toxicity 
o Quality of life surveys 
• PSA 
• CBC, Comprehensive Metabolic Panel, Hemoglobin A1C 
• CT scan and bone scan 
 
6.4 
Early Discontinuation 
• Clinic visit 
• If early discontinuation is due to an adverse event or toxicity of any of the study  
treatments, the patient should be followed until resolution of the adverse event/toxicity or 
at least one month, whichever is later. 
 
7. SAFETY AND ADVERSE EVENTS  
 
Safety will evaluated based on the incidence, severity, duration, causality, seriousness, and type 
of adverse events (AEs), and changes in the patient’s physical examination, vital signs, and 
clinical laboratory results.  Investigators will use the NCI CTCAE version  4.0 published 28 May 
2009 to assess the severity of adverse events and toxicities (see Appendix B).  All observed or 
volunteered adverse events regardless of treatment group or causal relationship to study drug will 
be recorded on the adverse event pages of the case report form. 
 

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8. PHARMACEUTICAL INFORMATION 
 
8.1 
Enza 
 
8.1.1 Administration 
Enza 160 mg daily (the current FDA approved dose), or four 40 mg capsules by mouth daily, 
will be administered. A 30 day supply will be prescribed at the beginning of each month. The 
study will not pay for supply of Enza. 
 
8.1.2 Supply 
Enza, marketed as Xtandi, comes in 40 mg capsules and are supplied as white to off-white 
oblong soft gelatin capsules imprinted in black ink with MDV. Enza capsules are available in 
bottles of 120 capsules (NDC 0469-0125-99).   
 
8.1.3 Storage 
Store Enza capsules at 20°C to 25°C (68°F to 77°F) in a dry place and keep the container tightly 
closed. Excursions permitted from 15°C to 30°C (59°F to 86°F). 
 
8.2 
Dex 
 
8.2.1 Administration 
Dex 2 mg daily by mouth will be administered.   
 
8.2.2 Supply 
Dex, marketed as Decadron, comes in 2 mg tablets in generic formulations.  A 90 day supply 
will be prescribed every 3rd cycle. 
 
8.2.3 Storage 
Store Dex tablets at 20° to 25°C (68° to 77°F). Protect from moisture. 
 
 

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22 
9. STUDY CALENDAR 
 
Baseline screening evaluations are to be conducted within 28 days prior to Cycle 1, Day 1.  
Cycles are 28 days. Return visits after initiation of therapy can be done be done within 7 days 
(+/-) of the specified study visit date. 
 
 
Screening1 
Dex C1 
Dex C2 
Dex C3 
Dex C4 
-> 
ongoing 
Progression 
(post Dex) 
Enza C1 
Enza C2 
Enza C3 (Study 
Conclusion Visit) 
Dex 
 
X 
X 
X 
X 
 
 
 
 
Enza 
 
 
 
 
 
 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts2 
X 
X4 
 
X 
X6 
X 
 
 
X 
Serum chemistry3 
X 
X4 
 
X 
X6 
X 
 
 
X 
Hemoglobin A1C 
X 
X4 
 
X 
X6 
X 
 
 
X 
PSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum testosterone 
X 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
CT Scan (C/A/P) 
X9 
 
 
X5 
X6 
X 
 
 
X 
Bone Scan 
X9 
 
 
 
X6 
 
 
 
X 
QOL (FACIT, 
RAND SF-36) 
 
X 
X 
X 
X 
X 
X 
X 
X 
AR-V7 CTC 
measurement 
 
X7 
 
 
 
X7 
 
 
 
1 Screening assessments must begin within 28 days prior to Cycle 1, Day 1 
2 CBC (Complete blood count) with differential and platelet count 
3 CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, Serum Creatinine, Calcium, Total Protein, Albumin, Total 
Bilirubin, AST, ALT, Alkaline Phosphatase, HCO3) 
4 Not needed if performed within the last 2 weeks at screening 
5 CT scan post-cycle 2 on Dex if evidence of PSA progression 
6 CBC, CMP, Hgb A1C and Radiologic Evaluation (CT scan, bone Scan) will be performed every 3 cycles while responding to Dex.   
7 Blood Samples for assessment of AR and AR-V expression will be taken at baseline and at time of initiation of Enza. 
8 Vital signs: Temperature, blood pressure and pulse rate will be measured. 
9 Screening Radiologic Evaluation with CT of the chest, abdomen and pelvis within 4 weeks and bone scan within 8 weeks prior to C1 D1. 
 
 
 
 
 

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10. STUDY ASSESSMENTS 
 
10.1 
Assessing PSA response 
 
PSA response and progression will be defined per PCWG2 criteria (Appendix E).  PSA response 
is defined as a 50% decline in baseline PSA.  PSA progression is defined as an elevation of 25% 
and an absolute increase of at least 2ng/dl over the nadir, confirmed by a second measurement at 
least 3 weeks apart.  Patients will have PSA measurements taken every cycle of therapy. 
 
10.2 
Assessing response in measurable disease 
 
In patients with measurable disease, tumor response will be evaluated using CT and bone scan. 
Patients will undergo screening CT scan and bone scan. CT scan is repeated after 2 cycles of Dex 
if evidence of PSA progression, otherwise CT and bone scan are performed every 3 months to 
determine disease response/progression to Dex or Enza.  Progression for soft tissue lesions will 
be based on RECIST 1.1 criteria (Appendix C) and for bone lesions based on PCWG2 criteria. 
 
10.2.1 AR-Variant Studies 
 
To determine levels of full length AR and AR-V7, blood will be obtained from patients at 
screening and after 2 cycles of Dex therapy. Blood samples are collected and shipped to the 
Johns Hopkins Laboratory within 24 hrs according to standard procedure (Appendix D). 
 
 
11. DATA REPORTING / REPORTING REQUIREMENTS 
 
Data and safety monitoring will follow SKCCC Data and Safety Monitoring Plan. Additionally, 
scheduled meetings will take place monthly and will include the protocol principal investigator, 
research nurse, data manager, and, when appropriate, the collaborators, sub-investigators, and 
biostatistician involved with the conduct of the protocol. 
During these meetings the investigators will discuss matters related to: safety of protocol 
participants, validity and integrity of the data, enrollment rate relative to expectation, 
characteristics of participants, retention of participants, adherence to protocol (potential or real 
protocol violations), data completeness, and progress of data for secondary objectives. 
This is a DSMP Level I study under the SKCCC Data Safety Monitoring Plan (12/6/2012). The 
Clinical Research Office will perform an audit after the first subject has been treated and then 
periodically depending on the rate of accrual and prior audit results. All trial monitoring and 
reporting will be reviewed annually by the SKCCC Safety Monitoring Committee. The PI is 
responsible for internally monitoring the study. Data must be reviewed to assure the validity of 
data, as well as, the safety of the subjects. The PI will also monitor the progress of the trial, 
review safety reports, and clinical trial efficacy endpoints and to confirm that the safety 
outcomes favor continuation of the study.” 
 
 
 

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11.1 
Adverse Event Monitoring and Reporting 
 
An Adverse Event is defined as any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medical 
treatment or procedure regardless of whether it is considered related to the medical treatment or 
procedure (attribution of unrelated, unlikely, possible, probable, or definite). The PI and/or the 
research nurse will monitor each patient closely for the development of adverse events and 
toxicities and record all such events. Patients will be evaluated for toxicity if they have received 
one dose of Dex. The timely reporting of adverse events (including toxic deaths) is required by 
the Food and Drug Administration (FDA). 
 
11.2 
Evaluating Adverse Events 
 
The grade and severity of the event will be determined using the DCT/NCI Common 
Terminology Criteria, CTCAE v.4.0. Links to CTCAE version 4.0 can be found in Appendix B. 
All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. Study 
staff must use one of the CTCAE criteria to define the event. Adverse events not included in the 
CTCAE v.4.0 should be reported and graded under the “Other” adverse event within the 
appropriate category and grade 1 to 5 according to the general grade definitions, mild, moderate, 
severe, life-threatening, fatal or disabling, as provided in the CTCAE. 
The event will be determined to be expected or unexpected.   
The event will be evaluated for relationship to the medical treatment or procedure. The 
Investigator should document his/her opinion of the relationship of the event to study medication 
as follows: 
 
• Unrelated- The adverse event is clearly not related to the investigational agent(s). 
• Unlikely- The adverse event is doubtfully related to the investigational agent(s). 
• Possible-The adverse event may be related to the investigational agent(s). 
• Probable-The adverse event is most likely related to the investigational agent(s). 
• Definite- The adverse event is clearly related to the investigational agent(s). 
 
Based on this information, a decision will be made whether an adverse event should be reported 
as an expedited report (Serious Adverse Event, section 3.0) in addition to the routinely reported 
clinical data. All expedited adverse event reports should be submitted to the JHM Institutional 
Review Board (IRB) and to the FDA. 
 
11.3 
Documenting Adverse Events 
 
Each individual sign or symptom must be documented separately.  All adverse events (both 
expected and unexpected) will be captured on the appropriate study-specific case report forms 
(CRFs). CRFs must be signed and dated by person conducting evaluation to be used as source 
documentation 
The attribution of all adverse events must be verified by an investigator. Evaluation of laboratory 
toxicities may be documented directly on a printed laboratory report or CRF provided it is signed 
by the investigator. However, if an action was conducted due to this abnormality (e.g. RBC 
transfusion due to low Hgb) this would be recorded on the AE form also. 

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11.4 
Serious Adverse Events 
 
A SAE is any sign, symptom or medical condition that emerges during treatment or during a 
post-treatment follow-up period that (1) was not present at the start of treatment and is not a 
chronic condition that was part of the patient’s medical history, OR (2) was present at the start of 
treatment or as part of the patient’s medical history but worsened in severity and/or frequency 
during therapy, AND that meets any of the following regulatory criteria: 
• is fatal (i.e., results in death from any cause at any time) or life-threatening (i.e., the patient was 
in the view of the investigator, at immediate risk of death from the reaction as it occurred) 
• required or prolonged hospitalization (see exclusions below) 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly or a birth defect 
• is medically significant, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Events not considered to be serious adverse event are hospitalizations for the: 
• Routine treatment or monitoring of the studied indication, not associated with any deterioration 
in condition 
• Treatment, which was elective or pre-planned, for a pre-existing condition that did not worsen 
Any serious adverse event occurring in a patient from the first day of treatment and until 
4 weeks after the last dose of treatment must be reported. The period after discontinuing study 
drug may be extended if there is a strong suspicion that the drug has not yet been eliminated. 
All serious adverse events must be followed to resolution (≤ 1 or baseline) or until considered 
stable or irreversible. 
 
11.5 
Expedited Reporting of Serious Adverse Events 
 
Serious adverse events and protocol problems will be reported in compliance with JHM 
IRB guideline, “Organization Policy on Reports of Unanticipated Problems 
Involving Risks to Participants or Others” [Policy No. 103.6(b)] (most current version).  A copy 
of this document is located at 
http://www.hopkinsmedicine.org/institutional_review_board/guidelines_policies/organization_p
olicies/103_6b.html  
 
All deaths on study regardless of attribution must be reported by the Principal Investigator Dr. 
Denmeade and to the JHM IRB. In addition, all serious adverse events, regardless of causality to 
study drug and/or administration device, will be reported promptly to the Lead Study 
Coordinator within 24 hours of being made aware of the SAE. If the Lead Study Coordinator 
cannot be reached within 24 hours, SAE will be reported promptly to Dr. Denmeade (fax: 410-
614-8397, e-mail: denmesa@jhmi.edu ) within 24 hours of recognition of the serious adverse 
event.If this falls on a weekend or holiday, an email notification is acceptable but must be 
followed by an SAE reporting form on the next business day. 
 
Investigators will be notified by the Principal/Co-Principal Investigator and/or by the CRO of all 
SAEs that are unexpected (ie, not previously described in the Pharmaceutical Characterization of 
each drug in section 9 of this protocol), and definitely, probably, or possibly related to Dex or 
Enza. This notification will be in the form of an expedited safety report (ESR) that is to be faxed 

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26 
to the investigators and the study coordinators within 48 hours. Upon receiving such notices, the 
site investigator must review and retain the notice and where required by local site regulations, 
the site investigator will submit the ESR to the site IRB. The site investigator and IRB will 
determine if the informed consent requires revision. The site investigator should also comply 
with the site IRB procedures for reporting any other safety information. Where required, 
submission of ESRs by the investigator to Health Authorities should be handled according to 
local regulations. 
 
11.6 
Protocol Amendments 
 
 Any changes to the protocol will be made in the form of an amendment and must be approved 
by the site IRB before implementation. 
 
11.7 
Informed consent:   
 
Written informed consent will be obtained by a study investigator or study research nurse 
working on this study. An explanation of the nature of study, its purpose, procedures involved, 
expected duration, potential risks and benefits will be provided to each participant by the 
investigator or the research nurse. Each participant will be informed that participation in the 
study is voluntary and that he may withdraw from the study at any time, and that withdrawal of 
consent will not affect his subsequent medical treatment. Participants will be allowed time 
needed to make an informed decision. Participants will be encouraged to ask questions about the 
study and the consent before signing the consent form. Consent forms will be filed with the 
Clinical Research Office and copies stored securely with the study coordinator. No patient will 
enter the study before his informed consent has been obtained. 
 
11.8 
Multicenter Guidelines:   
 
The Protocol Chair 
The Protocol Chair, Samuel Denmeade, MD, is responsible for performing the following Tasks: 
• Coordinating, developing, submitting, and obtaining approval for the protocol as well as 
its subsequent amendments 
• Assuring that all participating institutions are using the current IRB approved version of 
the protocol 
• Taking responsibility for the overall conduct of the study at all participating institutions 
and for monitoring the progress of the study 
• Reviewing and ensuring reporting of Serious Adverse Events (SAEs) from all sites  
• Reviewing all study data from all sites 
 
Coordinating Center Responsibilities (SKCCC) 
Coordinating Centers must: 
• Verify that each participating institution has a Federal Wide Assurance (FWA) number. 
• Confirm that IRB approval has been obtained at each participating site prior to their first 
patient registration 
• Maintain copies of IRB approvals from each site 
• Implement central patient registration 

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• Prepare all submitted data for review by the Protocol Chair (Samuel Denmeade, MD) 
• Establish procedures for documentation, reporting, and submitting of adverse events to 
the Protocol Chair (Samuel Denmeade, MD) and all applicable parties 
• Facilitate audits by securing selected source documents and research records from 
participating sites for audit, or by conducting audits at participating sites. 
 
Participating Sites: 
Participating sites are responsible for performing the following tasks: 
• Follow the protocol as written and conduct the study within the guidelines of Good 
Clinical Practice. 
• Collect and submit data, and report adverse events according to the schedule specified by 
the protocol. 
• Register all patients with the Lead Center (SKCCC) by submitting patient registration 
forms, and signed informed consents promptly. 
• Provide sufficient experienced clinical and administrative staff; as well as adequate 
facilities and equipment to conduct a collaborative trial according to the protocol. 
• Maintain regulatory binders on site, and provide copies of all required documents to the 
Lead Center (SKCCC) 
 
Case report forms 
Case report forms will be generated by Staff at the Lead Site Coordinating Center at SKCCC for 
the collection of all study data. The data should be entered in eCRF in a timely manner, (within 2 
weeks of the visit). All relevant supporting documentation such as scans, progress notes, nursing 
notes, blood work, pathology reports, etc., will be submitted via email to the Lead Study 
Coordinator, Yan Tian, at yantian@jhmi.edu.  All patient names or other identifying information 
will be removed prior to being sent to the Coordinating Center (SKCCC) or non- redacted source 
documents can be sent via a password -protected/ secured document transfer based on each 
institution’s guidelines.  
Investigators will be responsible for ensuring that the eCRFs are kept up-to-date. 
Authorized representatives of the Coordinating Center (SKCCC) may visit the satellite sites to 
perform audits or inspections, including source data verification. The purpose of these audits or 
inspections is to systematically and independently examine all trial-related activities and 
documents to determine whether these activities were conducted and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP), and 
any applicable regulatory requirements. 
 
Source documents 
Study personnel will record clinical data in each patient’s source documents (ie, the patient’s 
medical record). Source documentation will be made available to support the patient research 
record. Study monitors will review entries on the CRFs at regular intervals, comparing the 
content with source documents. 
 
 
 
 

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12. STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design/Endpoints 
 
We will conduct a single arm trial to determine if treatment with Dex followed by Enza provides 
PSA and objective response in patients who have previously had disease progression after Enza. 
Prior treatment with docetaxel is allowed but not required. 
 
The primary endpoint will be the PSA response rate with the re-challenge of Enza following 
Dex, which is defined as the proportion of subjects with a ≥50% PSA decline from baseline level 
when starting Enza and maintained for ≥4 weeks at any time-point after receiving Enza. 
 
The secondary endpoints will include objective response rate to Enza in patients with measurable 
disease on CT scan, time to PSA progression (based upon PCWG2 criteria) for treatment with 
Dex, quality of life assessment using FACIT-Fatigue Scale and RANDSF-36 surveys, and 
response rate with Dex and Enza by AR-V7 status at study entry. 
 
12.2 
Sample Size/Accrual Rate 
 
The treatment regimen would be considered of insufficient activity for further study in these 
population if PSA response rate is 5% or less, and the minimum required level of efficacy that 
would warrant further study with the proposed regimen is a 25% PSA response rate.  The sample 
size is calculated to detect an improved PSA response rate from 5% to 25%. A minimax Simon 
two-stage design is planned. A total of 13 patients will be entered in the first stage. If none of 
them show PSA response after Enza, the treatment regimen will be terminated and we will 
conclude the regimen is ineffective. If >=1 subjects has PSA response, then additional 7 patients 
will be studied.  If a total of 2 or fewer subjects achieve PSA response in stage one and two 
combined, we consider this regimen ineffective. If a total of 3 or more respond, we conclude the 
regimen is promising and warrant further study. The trial could be terminated early also as soon 
as 3 PSA responses with the post-Dex Enza treatment are confirmed.  
The maximum sample size will be 20.  Patients who receive at least one dose of Dex will be 
evaluable for the primary endpoint of PSA response. Those who do not start Enza subsequent to 
Dex will be considered as non-responders in the analysis. This design provides 90% power to 
reject a 5% PSA response in favor of 25% response rate, with a type I error of 0.1. The chance of 
early stopping is 0.51 when the response rate is less than 5%. 
 
12.3 
Analysis Method 
 
We will determine the PSA response rate with the re-challenge of Enza following Dex as the 
proportion of subjects with a ≥50% PSA decline from baseline level when starting Enza and 
maintained for ≥4 weeks at any time-point after receiving Enza, and its corresponding 95% 
confidence interval.  
 
For the secondary endpoints, we will estimate objective response rate to Enza in patients with 
measurable disease on CT scan and its 95% confidence interval. Time to PSA progression and 
Radiographic Progression for treatment with Dex will be summarized using Kaplan-Meier 

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approach. Quality of life will be assessed via FACIT-Fatigue Scale and RANDSF-36 
questionnaires. Summary statistics of the scores will be reported at baseline before starting Dex 
and each follow-up time during the treatment of Dex and Enza. Changes in quality of life scores 
over the course of the study will be computed and their significance will be evaluated by paired-
sample t-tests.  Response rate to Dex and Enza will also be reported by AR-V7 status at baseline 
of study entry. 
 
 
12.4 
Reporting and Exclusions 
 
12.4.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with Dex. 
 
12.4.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.   
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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REFERENCES 
 
1. 
Caffo O, De Giorgi U, Fratino L, et al. Clinical Outcomes of Castration-resistant 
Prostate Cancer Treatments Administered as Third or Fourth Line Following Failure of 
Docetaxel and Other Second-line Treatment: Results of an Italian Multicentre Study. European 
urology 2014. 
2. 
Fakih M, Johnson CS, Trump DL. Glucocorticoids and treatment of prostate cancer: 
A preclinical and clinical review. Urology 2002; 60(4): 553-61. 
3. 
Lorente D, Weatherstone K, Omlin A, et al. Tumor responses after steroid switch of 
prednisolone (P) to dexamethasone (D) in castration-resistant prostate cancer (CRPC) patients 
(pts) on abiraterone acetate (AA). Eur J Cancer 2013; 49: S703-S. 
4. 
Kassi E, Moutsatsou P. Glucocorticoid receptor signaling and prostate cancer. Cancer 
Lett 2011; 302(1): 1-10. 
5. 
Storlie JA, Buckner JC, Wiseman GA, Burch PA, Hartmann LC, Richardson RL. 
Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-
refractory metastatic prostate carcinoma. Cancer 1995; 76(1): 96-100. 
6. 
Nishiyama T, Terunuma M. Hormone/antihormone withdrawal and dexamethasone 
for hormone-refractory prostate cancer. International journal of urology : official journal of the 
Japanese Urological Association 1998; 5(1): 44-7. 
7. 
Nishimura K, Nonomura N, Yasunaga Y, et al. Low doses of oral dexamethasone for 
hormone-refractory prostate carcinoma. Cancer 2000; 89(12): 2570-6. 
8. 
Saika T, Kusaka N, Tsushima T, et al. Treatment of androgen-independent prostate 
cancer with dexamethasone: a prospective study in stage D2 patients. International journal of 
urology : official journal of the Japanese Urological Association 2001; 8(6): 290-4. 
9. 
Morioka M, Kobayashi T, Furukawa Y, et al. Prostate-specific antigen levels and 
prognosis in patients with hormone-refractory prostate cancer treated with low-dose 
dexamethasone. Urologia internationalis 2002; 68(1): 10-5. 
10. 
Venkitaraman R, Thomas K, Huddart RA, Horwich A, Dearnaley DP, Parker CC. 
Efficacy of low-dose dexamethasone in castration-refractory prostate cancer. BJU international 
2008; 101(4): 440-3. 
11. 
Attard G, Reid AHM, A'Hern R, et al. Selective Inhibition of CYP17 With 
Abiraterone Acetate Is Highly Active in the Treatment of Castration-Resistant Prostate Cancer. J 
Clin Oncol 2009; 27(23): 3742-8. 
12. 
Komiya A, Shimbo M, Suzuki H, et al. Oral low-dose dexamethasone for androgen-
independent prostate cancer patients. Oncol Lett 2010; 1(1): 73-9. 
13. 
Shamash J, Powles T, Sarker SJ, et al. A multi-centre randomised phase III trial of 
Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: 
immediate vs deferred Diethylstilbestrol. Brit J Cancer 2011; 104(4): 620-8. 
14. 
Taplin ME, Manola J, Oh WK, et al. A phase II study of mifepristone (RU-486) in 
castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones. 
BJU international 2008; 101(9): 1084-9. 
15. 
Arora VK, Schenkein E, Murali R, et al. Glucocorticoid receptor confers resistance to 
antiandrogens by bypassing androgen receptor blockade. Cell 2013; 155(6): 1309-22. 
16. 
Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate 
Cancer after Chemotherapy. New Engl J Med 2012; 367(13): 1187-97. 
17. 
Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in Metastatic Prostate 

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Cancer before Chemotherapy. New Engl J Med 2014; 371(5): 424-33. 
18. 
Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to 
antiandrogen therapy. Nature medicine 2004; 10(1): 33-9. 
19. 
Yuan X, Cai C, Chen S, Chen S, Yu Z, Balk SP. Androgen receptor functions in 
castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the 
androgen axis. Oncogene 2014; 33(22): 2815-25. 
20. 
De Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and Increased Survival in 
Metastatic Prostate Cancer. New Engl J Med 2011; 364(21): 1995-2005. 
21. 
Hu R, Denmeade SR, Luo J. Molecular processes leading to aberrant androgen 
receptor signaling and castration resistance in prostate cancer. Expert review of endocrinology & 
metabolism 2010; 5(5): 753-64. 
22. 
Yemelyanov A, Bhalla P, Yang X, et al. Differential targeting of androgen and 
glucocorticoid receptors induces ER stress and apoptosis in prostate cancer cells: a novel 
therapeutic modality. Cell cycle 2012; 11(2): 395-406. 
23. 
Efstathiou E, Titus M, Wen S, et al. Molecular Characterization of Enzalutamide-
treated Bone Metastatic Castration-resistant Prostate Cancer. European urology 2015; 67(1): 53-
60. 
24. 
Antonarakis ES, Lu CX, Wang H, et al. AR-V7 and Resistance to Enzalutamide and 
Abiraterone in Prostate Cancer. New Engl J Med 2014; 371(11): 1028-38. 
 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX B 
NCI COMMON TOXICITY CRITERIA, VERSION 4.0 
 
Version 4.0 of the NCI CTC, dated May 28, 2009, may be viewed and/or downloaded by 
accessing the following websites: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcae_4_with_lay_term
s.pdf 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 
 
 

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APPENDIX C  
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) 
 
Eligibility 
Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint.  
Measurable disease –  
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
Measurable lesions –  
Lesions that can be accurately measured in at least one dimension with longest diameter ≥20 mm 
using conventional techniques or ≥10 mm with spiral CT scan. 
 
Non-measurable lesions –  
All other lesions, including small lesions (longest diameter <20 mm with conventional techniques 
or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic 
lesions, and also abdominal masses that are not confirmed and followed by imaging techniques. 
All measurements should be taken and recorded in metric notation, using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes). For the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Methods of Measurement  
CT and MRI are the best currently available and reproducible methods to measure target lesions 
selected for response assessment.  Conventional CT and MRI should be performed with cuts of 
10 mm or less in slice thickness contiguously.  Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm.  This applies to tumors of the chest, abdomen and pelvis.  
Head and neck tumors and those of extremities usually require specific protocols. 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung.  However, CT is preferable.  
When the primary endpoint of the study is objective response evaluation, ultrasound (US) should 
not be used to measure tumor lesions.  It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules.  
US might also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been 

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fully and widely validated.  Their uses in this specific context require sophisticated equipment 
and a high level of expertise that may only be available in some centers.  Therefore, the 
utilization of such techniques for objective tumor response should be restricted to validation 
purposes in specialized centers.  However, such techniques can be useful in confirming complete 
pathological response when biopsies are obtained. 
Tumor markers alone cannot be used to assess response.   If markers are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete clinical response 
when all lesions have disappeared. 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after 
treatment to differentiate between residual benign lesions and residual malignant lesions in tumor 
types such as germ cell tumors). 
 
Baseline Documentation of “Target” and “Non-Target” Lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or clinically).  
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD.  The baseline sum LD will be used as reference by which to characterize the 
objective tumor. 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence or absence 
of each should be noted throughout follow-up.  
 

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Response Criteria 
Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new 
lesions 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level 
Incomplete Response / Stable 
Disease (SD):  
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, 
the opinion of the treating physician should prevail and the progression status should be 
confirmed later on by the review panel (or study chair). 

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

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

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APPENDIX D  
CIRCULATING TUMOR CELL (CTC) BLOOD COLLECTION 
AND SHIPPING  
 
Blood draws should be scheduled on Monday-Thursday to allow overnight shipping and 
receiving on weekdays before the weekend. 
 
Instructions for Collecting Blood Samples (Circulating Tumor Cells):   
 
1. 
Collect Blood in 2 Becton Dickinson (BD) Vacutainer ACD Solution A tubes (BD 
ACD-A). Product # for the BD ACD-A tube is 364606. 
 
2. 
Ensure that at least 8.5 mL of blood is drawn into each tube.  Avoid low volume to 
minimize agitation during shipping. 
 
3. 
Invert the tubes gently 180 degree and back 3-4 times. 
 
4. 
Store samples until shipping at 4-8oC in a refrigerator. Do not put on ice. Do not leave 
the samples O/N in a refrigerator. 
 
Instructions for Shipping:   
 
1. 
Activate the FEDEX cold box and place the tubes wrapped in bubble wraps (or 
inserted into plastic tube holders) snugly in the shipping box.  
 
2. 
Ship the two tubes by FEDEX to the address below the same day of blood draw. 
Notify the recipient of the tracking number on the day of shipment by email.  
 
The Fedex cold boxes are available at  
 
http://images.fedex.com/us/healthcare/pdf/Cold_Shipping_Info_Sheet.pdf 
  
Bubble wraps can be purchased from Staples or other shipping supply stores. 
Plastic tube holders can be purchased at https://www.therapak.com/catalog/tube_mailers 
 
Jun Luo, Ph.D. 
411 Marburg, Johns Hopkins Hospital 
600 N. Wolfe Street 
Baltimore, MD 21287  
Tel: 443-2875625 
Email: jluo1@jhmi.edu or  denmesa@jhmi.edu 
 
 

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APPENDIX E 
PROSTATE CANCER WORKING GROUP 2 (PCWG2) CRITERIA 
 
 
Pathology response criteria  
 
When evaluating measurable soft-tissue target lesions, the RECIST definitions will apply. The 
first assessment must show an increase in the sum longest diameter (LD) of both preexisting and 
new lesions of ≥ 20% when compared with the smallest sum LD recorded since treatment 
started. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated further (e.g. by aspirate/biopsy) before confirming the 
complete response status. 
 
Evaluating non-target lesions 
 
When assessing non-target lesions, the following RECIST definitions will apply: 
Complete response: 
Disappearance of all non-target lesions, and 
normalization of tumor marker levels. 
Progressive disease: 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions. 
Stable disease: 
Persistence of one or more non-target lesions 
and/or maintenance of tumor marker above the 
normal limits. 
 
Evaluating best overall response 
 
The best overall response is the best response recorded from the start of treatment until disease 
progression/recurrence. The investigator’s determination of best overall response will be based 
on the response criteria and will not require confirmation scans. For defining disease 
progression, confirmation scans will only be required in the case where progression is seen on 
the first follow-up bone scan, but not if progression is shown on CT.  
Patients with global deterioration of health status who require discontinuation of treatment 
without objective evidence of disease progression should be classified as having symptomatic 
deterioration. Every effort should be made to document their objective progression, even after 
discontinuation of treatment. 
The table below summarized the recommendations of the PCWG2 for measuring 
response/progression outcomes in phase II clinical trials of prostate cancer. Although these 
guidelines have been largely followed in the design of the present trial, this table should not be 
used as a substitute for the clinical protocol. 
 
 
 
 
 

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Prostate Cancer Clinical Trials Working Group (PCWG2) Outcome Measures 
 
Variable 
Control/Relieve/Eliminate 
Prevent/Delay 
PSA 
Record the percent change 
from baseline (rise or fall) at 
12 weeks, and separately, the 
maximal change (rise or fall) 
at any time using a waterfall 
plot 
Decline from baseline: Record 
time from start of therapy to 
first PSA 
increase that is ≥ 25% and ≥ 2 
ng/mL above the nadir, and 
which is 
confirmed by a second value ≥ 
3 weeks later (i.e. a confirmed 
rising trend). 
Recording the duration of PSA 
decline of little value 
No decline from baseline: PSA 
progression ≥ 25% and ≥ 2 
ng/mL after 12 weeks 
Soft-tissue 
lesions 
Use RECIST with caveats 
Only report changes in lymph 
nodes that were ≥ 2 cm in 
diameter at baseline 
Record changes in nodal and 
visceral soft tissue sites 
separately 
Record complete elimination 
of disease at any site 
separately 
Confirm favorable change 
with second scan 
Record changes using 
waterfall plot 
Use RECIST criteria for 
progression, with additional 
requirement that progression at 
first assessment be confirmed 
by a second scan 6 or more 
weeks later (particularly 
important for biologic 
therapies) 
Note that for some treatments, a 
lesion may first increase in size 
before it decreases 
Bone 
Record outcome as new 
lesions or no new lesions 
   First scheduled 
reassessment: 
No new lesions: continue 
therapy 
New lesions: perform a 
confirmatory scan 6 or more 
weeks later 
Confirmatory scan: 
No new lesions: continue 
therapy 
Additional new lesions: 
progression 
   Subsequent re-assessments: 
The appearance of ≥ 2 new 
lesions, and, for the first 
reassessment only, a 
confirmatory scan performed 6 
or more weeks later that shows 
a minimum of 2 or more 
additional new lesions 
The date of progression is the 
date of the first scan that shows 
the change 

SKCCC Protocol #:J1548 
Version # 3.0 Version Date: 08/24/2016 
 
42 
No new lesions: continue 
New lesions: progression 
Symptoms 
Consider independently of other outcome measures 
Document pain and analgesia at entry with a lead in period and 
measure repeatedly at 3- to 4-week intervals 
Perform serial assessments of global changes in HRQOL, 
urinary or bowel compromise, pain management, additional 
anticancer therapy 
Ignore early changes (< 12 weeks) in pain or HRQOL in absence 
of compelling evidence of disease progression 
Confirm response or progression of pain or HRQOL end points 
> 3 weeks later 
 
Abbreviations:  PSA, prostate-specific antigen; HRQOL, health-related quality of 
life