Conditions: Breast Cancer
Keywords: Advanced Breast Cancer ER+/Her2 Advanced Breast Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
A phase 2 study to evaluate the tolerability and clinical activity of adding enzalutamide to fulvestrant treatment in women with advanced breast cancer that are ER and/or PR positive and Her2 normal.

Detailed description:
This is a single arm, non-randomized, open-label phase 2 study designed to evaluate the tolerability and clinical activity of adding enzalutamide to fulvestrant treatment in women with advanced breast cancer that are ER and/or PR-positive and Her2 normal. In this study 500 mg of Fulvestrant will be given IM on days 1, 15, 28, then every 4 weeks as per standard of care (SOC) and 160mg of Enzalutamide will be, in conjunction with Fulvestrant, PO daily.

Arms:
arm 1: 500mg of Fulvestrant will be given IM on days 1, 15, 28, then every 4 weeks as per standard of care (SOC) and 160mg of Enzalutamide will be given, in conjunction with Fulvestrant, PO daily.

Interventions: intervention 1: Fulvestrant with Enzalutamide
Intervention descriptions: intervention 1: 500mg of Fulvestrant will be given IM on days 1, 15, 28, then every 4 weeks as per standard of care (SOC) and 160mg of Enzalutamide will be given PO daily. Patients will receive a tumor biopsy at the start of treatment and 4 weeks after the start of treatment, with an optional 3rd biopsy at the end treatment.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Page 1 of 32 
PROTOCOL NUMBER:   
16-1001 
 
 
PROJECT TITLE: 
Phase II trial of fulvestrant plus enzalutamide in 
ER+/Her2- advanced breast cancer 
 
 
VERSION DATE:  
08/27/2019 
 
 
LEAD PRINCIPAL INVESTIGATOR:  
Anthony Elias, MD 
 
COORDINATING CENTER: 
University of Colorado 
Anschutz Medical Campus 
Division of Medical Oncology 
12801 E. 17th Avenue 
Mailstop 8117 
Aurora, CO  80045 
anthony.elias@ucdenver.edu 
 
PARTICIPATING SITES:  
Multiple centers 
 
 
 
 
 
  
FUNDING SUPPORT / 
Department of Defense (DOD) 
STUDY REFERENCE NUMBER:  
W81XWH-13-1-0091 
 
 
ASTELLAS REFERENCE NUMBER: 
ENZA16G07 
 
 
 
 
 
 
 
 
 
 
 


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STATEMENT OF COMPLIANCE 
 
This is an investigator-initiated study.  The lead principal investigator (PI), Anthony Elias, 
MD, is conducting the study and acting as the sponsor.  As the sponsor-investigator, both 
the legal/ethical obligations of a PI and those of a sponsor will be followed. 
 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by 
applicable United States (US) laws and applications, including but not limited to United 
States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
 
The PI will assure that no changes to the protocol will take place without documented 
approval from the Institutional Review Board (IRB). All personnel involved in the conduct of 
this study have completed Human Subjects Protection Training.  
 
 
I agree to ensure that all staff members involved in the conduct of this study are informed 
about their obligations in meeting the above commitments.  
 
 
Sponsor-Lead Principal Investigator:  Anthony Elias, MD 
 
 
 
 
  
 
 
 
 
 
 
                         
                        Print/Type Name  
 
 
Signed:   
 
 
 
 
 
 
 
 
 
Date:    
 
  
 
 
                         Signature 
 
 
Site Principal Investigator:   
 
 
 
 
__________________  
 
 
 
 
 
 
       
 
                Print/Type Name  
 
 
Signed:   
 
 
 
 
 
 
 
 
 
Date:    
 
  
 
 
 
                   Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PARTICIPATING SITES 
 
A complete and current listing of investigators, research personnel, research facilities and other 
study centers (if applicable) participating in this study will be maintained throughout the duration 
of this study on a Protocol Contact List form, incorporated herein by reference.  
 
PROTOCOL/TRIAL SUMMARY 
 
Protocol Title 
Phase II trial of fulvestrant plus enzalutamide in ER+/Her2- 
advanced breast cancer 
Protocol Number 
16-1001 
Trial Phase 
II 
Objectives 
Primary Objective: 
To determine the clinical benefit rate (complete and partial 
response plus stable disease for 24 weeks) of the combination 
of enzalutamide/fulvestrant.  
Secondary Objectives:  
1. To confirm the safety profile of the combination. 
2. Response rate (complete and partial response) at 24 weeks, 
Progression-free survival (PFS) and % of patients remaining 
free from progression at 12 and 24 weeks. 
3. To obtain serial biopsies of breast cancer pretreatment, 
during treatment and at time of tumor progression in order to 
determine the extent of AR expression and signaling in 
breast tissue, to evaluate the effect of enzalutamide on the 
tumor, and to evaluate the relationship of these effects on 
clinical outcomes. 
Endpoints 
Primary Endpoint: Clinical benefit rate at 24 weeks 
Secondary Endpoints: Safety, PFS, PFS12, PFS24, ORR 
Exploratory Endpoint: Tissue studies 
Subject Population  
Clinical Indication:  ER+ Her2- breast cancer 
Gender:  Female 
Age Range:  18-100 years 
Trial Type 
Interventional 
Type of control 
Non-randomized 
Description of Study 
Agents 
Fulvestrant: 500mg given IM on days 1, 15, and 28, and then 
every 4 weeks as per standard of care (SOC) 
Enzalutamide: 160mg given PO daily 
Trial Blinding 
Open-label 
Treatment Groups  
Single arm  


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Number of trial subjects 24 evaluable; up to 45 may be consented to allow for screen 
failures 
Estimated enrollment 
period 
24 months 
Duration of Participation Until disease progression or unacceptable drug-related toxicity 
 
 
SCHEMATIC OF STUDY DESIGN 
 
 
 
 
 
LIST OF ABBREVIATIONS 
 
ACRONYM 
DESCRIPTION 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AR 
androgen receptor 
ASCO 
American Society for Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BC 
breast cancer 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
cGCP 
current good clinical practice 


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CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
central nervous system 
CRF 
case report form 
CRPC 
castration-resistant prostate cancer 
CT 
computed tomography 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient variation 
DHT 
dihydrotestosterone 
DLT 
dose-limiting toxicity 
DSM 
data and safety monitoring 
DSMC 
Data and Safety Monitoring Committee 
eCRF 
electronic case report form 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
G(1/2) 
grade of adverse event 
IB 
investigator’s brochure 
IHC 
immunohistochemistry 
IIT 
investigator-initiated trial 
IM 
intramuscular 
INR 
international normalized ratio 
IRB 
institutional review board 
LOI 
letter of intent 
MBC 
metastatic breast cancer 
mg 
milligram 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NR 
no response 
OS 
overall survival 
PD 
pharmacodynamics 
PFS 
progression-free survival 
PI 
principal investigator 
PK 
pharmacokinetics 
PO 
by mouth 
PR 
progesterone receptor 
PS 
performance status 
PTT 
partial thromboplastin time 
R 
response 
RPMA 
Reverse Phase Protein Microarray 
SAE 
serious adverse event 
SOC 
standard of care 
TNBC 
triple-negative breast cancer 
UAP 
unanticipated problem 
UCCC 
University of Colorado Cancer Center 
USC 
University of Southern California 
ULN 
upper limit of normal 


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TABLE OF CONTENTS 
 
1. 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE: ......................... 8 
1.1 
Background Information ................................................................................................................ 8 
1.2 
Summary of Relevant Clinical Experience with Enzalutamide ..................................................... 9 
1.3 
Preliminary Studies/Progress Report .......................................................................................... 10 
1.3.1 
Preliminary Data Points ........................................................................................................... 11 
1.4 
Hypothesis ................................................................................................................................... 11 
2. 
OBJECTIVES AND OUTCOMES: ....................................................................................................... 12 
2.1 
Hypotheses and Specific Aims.................................................................................................... 12 
2.2 
Primary Objective ........................................................................................................................ 12 
2.3 
Secondary Objectives ................................................................................................................. 12 
2.4 
Laboratory Hypotheses (From Serial Tissue Biopsies) .............................................................. 12 
3. 
STUDY DESGIN AND RESEARCH METHODS: ................................................................................ 13 
3.1 
Study Design ............................................................................................................................... 13 
3.2 
Study Schema ............................................................................................................................. 13 
3.3 
Study Periods .............................................................................................................................. 13 
3.4 
Sample Size ................................................................................................................................ 13 
4. 
STUDY ENROLLMENT AND WITHDRAWL: ...................................................................................... 14 
4.1 
Inclusion Criteria ......................................................................................................................... 14 
4.2 
Exclusion Criteria ........................................................................................................................ 14 
4.3 
Withdrawal ................................................................................................................................... 15 
5. 
STUDY AGENT: .................................................................................................................................. 15 
5.1 
Enzalutamide............................................................................................................................... 15 
5.1.1 
General Information ................................................................................................................ 15 
5.1.2 
Enzalutamide Product Characteristics .................................................................................... 15 
5.1.3 
Enzalutamide Packaging ......................................................................................................... 15 
5.1.4 
Enzalutamide Storage ............................................................................................................. 15 
5.1.5 
Directions for Administration of Enzalutamide ........................................................................ 15 
5.1.6 
Directions for Dose Modification of Enzalutamide .................................................................. 16 
5.1.7 
Treatment Compliance ............................................................................................................ 16 
5.1.8 
Drug Inventory and Accountability .......................................................................................... 16 
5.1.9 
Effects of Enzalutamide on Exposure to Other Drugs ............................................................ 16 
5.1.10 
Drugs That May Affect Exposure to Enzalutamide ............................................................. 16 
5.2 
Fulvestrant ................................................................................................................................... 17 
5.3 
Investigational Product Accountability ........................................................................................ 18 
6. 
STUDY PROCEDURES AND SCHEDULE: ........................................................................................ 19 
6.1 
Study Procedures ........................................................................................................................ 19 
6.2 
Drug Dispensing .......................................................................................................................... 20 
6.3 
Laboratory Procedures/Evaluations ............................................................................................ 20 
6.3.1 
Blood ....................................................................................................................................... 20 
6.3.2 
Serial Biopsies ......................................................................................................................... 20 
7. 
RISKS AND BENEFITS: ...................................................................................................................... 21 
7.1 
Risks of This Protocol ................................................................................................................. 21 
7.2 
Knowledge to Be Gained ............................................................................................................ 21 
7.3 
Justification of Risks .................................................................................................................... 21 
8. 
ASSESSMENT OF SAFETY: .............................................................................................................. 22 
8.1 
Serious Adverse Events .............................................................................................................. 22 
8.2 
Serious Adverse Event Reporting ............................................................................................... 22 
8.3 
Adverse Events ........................................................................................................................... 23 
8.4 
Procedure in Case of Pregnancy ................................................................................................ 23 
8.5 
In Case of Injury .......................................................................................................................... 24 
8.6 
Safety Monitoring and Reporting................................................................................................. 24 


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9. 
STUDY OVERSIGHT:.......................................................................................................................... 24 
9.1 
Data Safety and Monitoring Oversight ........................................................................................ 24 
9.2 
Clinical Monitoring ....................................................................................................................... 25 
9.3 
Auditing ....................................................................................................................................... 25 
10. 
STATISTICAL CONSIDERATIONS: ............................................................................................... 26 
10.1 
Clinical Data ................................................................................................................................ 26 
10.2 
Sample Size ................................................................................................................................ 26 
10.2.1 
Determination of Sample Size ............................................................................................. 26 
10.2.2 
Power Consideration ........................................................................................................... 27 
10.3 
Research Laboratory Data .......................................................................................................... 27 
10.4 
Research (Statistical) Methods ................................................................................................... 27 
10.4.1 
Analysis Populations ........................................................................................................... 27 
10.4.2 
Analysis Methods ................................................................................................................ 27 
10.5 
Data Analysis Plan ...................................................................................................................... 28 
10.5.1 
Toxicity ................................................................................................................................ 28 
10.5.2 
Response & Progression Free Survival (PFS) .................................................................... 28 
10.5.3 
Receptor Expression ........................................................................................................... 29 
11. 
SOURCE DOCUMENTATION AND RETENTION OF RECORDS: ............................................... 29 
11.1 
Data and CRFs............................................................................................................................ 29 
11.2 
Data Accessibility and Record Keeping ...................................................................................... 29 
12. 
POTENTIAL SCIENTIFIC PROBLEMS: ......................................................................................... 30 
12.1 
Enzalutamide may not have sufficient anti-breast cancer activity in the clinic ........................... 30 
12.2 
Inadequate collection of tissues and inadequate serial samples ................................................ 30 
12.3 
Inadequate tissue biopsy samples in more than 10% of individuals........................................... 30 
13. 
ETHICS: .......................................................................................................................................... 30 
14. 
CONFLICT OF INTEREST: ............................................................................................................ 30 
15. 
REFERENCES: ............................................................................................................................... 31 
 


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1. 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE: 
1.1 
Background Information 
Breast cancer is considered a genetically heterogeneous and biologically diverse 
disease.  We currently subdivide breast cancer by ER and Her2 status, in part because 
these markers represent important predictive biomarkers that guides treatment with 
discernible survival benefits.  Endocrine therapies that target estrogen receptor (ER) 
signaling pathways play a critical role in the treatment of patients with ER+ disease, 
even in the advanced setting (1).   The androgen receptor (AR) is expressed in most 
breast cancer specimens, though its functional role in initiating or driving malignancy is 
not yet well understood. In a study of 3093 breast cancers, AR expression (10% or more 
nuclear staining by immunohistochemistry [IHC]) was observed in 77% of invasive 
breast tumors and across all molecular phenotypes, but is expressed in up to 91% of 
ER+ BC (1-3). 
 
In ER+ BC, AR expression is associated with resistance to anti-estrogen therapy.  
Tamoxifen-resistant breast tumors have a high ratio of AR-to-ER expression, while 
tumors that respond to tamoxifen express approximately equal amounts of AR and ER, 
as does adjacent uninvolved epithelium (4). Furthermore, a high ratio of percent cells 
positive for nuclear AR versus ER, a ratio of AR:ER ≥2.0 indicated an over four fold 
increased risk for failure while on tamoxifen (HR = 4.43) and had an independent effect 
on risk for failure above ER % staining alone. AR:ER ratio is also an independent 
predictor of disease-free survival (HR = 4.04, 95% CI: 1.68, 9.69; p = 0.002).  One 
explanation for this is that AR signaling, which overlaps considerably with ER signaling, 
may take over from ER if ER signaling is blocked (5).  This would lead to tumor cell 
survival and proliferation.  In addition, the mechanism of action of an aromatase inhibitor 
is to block the conversion of androstenedione to estrogen, thereby increasing the 
concentrations of androgens that could, in turn, potentially stimulate the AR on tumor 
cells to enhance growth (6). 
 
The anti-AR therapy enzalutamide blocks not only dihydrotestosterone (DHT)-mediated 
growth of BC cells, but also estradiol-mediated growth. In addition, in preclinical models 
of ER+/AR+ breast cancer enzalutamide is just as effective as tamoxifen in blocking 
estradiol-mediated growth in vivo (4). These findings suggest that AR influences breast 
tumor biology and is an independent predictor of response to anti-estrogen therapies, 
but perhaps even more importantly, that those patients who relapse on anti-ER therapies 
may benefit from anti-AR therapies, either up-front in combination with ER-targeted 
therapies, or following disease progression. New evidence is arising that nuclear-
translocated AR serves as an important co-factor regulating DNA binding of activated 
ER, and that AR signaling may become important for tumor cell survival in the absence 
of estradiol (5). 
 
In summary, although effective hormonal therapies are available for the treatment of 
ER+/PgR+ advanced breast cancer, advanced disease remains incurable and currently 
approved treatments have significant side effects. Taken together, nonclinical and 
clinical data suggest a potential role of AR signaling in the development of resistance to 
hormonal treatment. Improvements in the identification of biomarkers that predict benefit 


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from a given therapy are needed to ensure that patients receive the agents from which 
they are most likely to benefit and to minimize their exposure to toxic agents unlikely to 
provide benefit. The phase 2 study described herein is designed to address these 
needs. 
1.2 
Summary of Relevant Clinical Experience with Enzalutamide 
Medivation and Astellas Pharma, Inc. are co-developing enzalutamide for the treatment 
of cancer. Enzalutamide is an AR inhibitor that acts on different steps in the AR signaling 
pathway.  Enzalutamide has been shown to competitively inhibit androgen binding to 
ARs and inhibit AR nuclear translocation and interaction with DNA. The United States 
(US) Food and Drug Administration (FDA) approved Xtandi (enzalutamide) capsules in 
August 2012 based on a benefit in overall survival for men with metastatic castration-
resistant prostate cancer (CRPC) who previously received docetaxel therapy (14).  In 
men with prostate cancer, the maximum tolerated dose (MTD) was determined to be 240 
mg daily, but after review of the safety and efficacy data available, the optimal dose of 
enzalutamide was determined to be 160 mg/day.  More than 4200 subjects and patients 
have been enrolled worldwide in complete and ongoing clinical trials evaluating 
enzalutamide as of October 2012. 
 
The most common adverse reactions (drug-related) (≥ 5%) in patients treated with 
enzalutamide (N = 800) in the phase 3 study CRPC2 (AFFIRM) (N = 1199) were 
asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, 
musculoskeletal pain, headache, upper respiratory infection, muscular weakness, 
dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda 
equina syndrome, hematuria, paresthesia, anxiety, and hypertension (12). 
Discontinuations due to adverse events were reported for 16% of enzalutamide-treated 
patients and 18% of placebo-treated patients. The most common adverse event leading 
to treatment discontinuation was fatigue (0.6% of enzalutamide-treated patients and 
0.3% of placebo-treated patients). The most common adverse reaction leading to 
treatment discontinuation was seizure, an identified risk and a targeted medical event, 
which occurred in 0.9% of the enzalutamide-treated patients and none (0%) of the 
placebo-treated patients. 
 
The use of enzalutamide in women with breast cancer is under investigation. In the 
completed study, MDV3100-08 (NCT01597193), 160 mg/day was determined to be the 
recommended phase 2 dose. The PK and safety profile in women was found to be 
similar to that observed in men.  The dose-expansion portion of this study found 
evidence of some activity of enzalutamide at 160 mg/day as a single agent in women 
with AR+ breast cancer in all subtypes of breast cancer. Enzalutamide was combined 
with either anastrozole or exemestane in women with ER+ breast cancer. Enzalutamide 
was found to be a potent CYP3A4 inducer and reduced the AUC of anastrozole by 80% 
and reduced the AUC of exemestane by about 50%.  Double dose exemestane, ie, 50 
mg/day was found to be safe in combination and provided full suppression of estradiol.  
This dosing was then used for a randomized double blind phase II trial of exemestane 
+/- enzalutamide in ER+ AR+ MBC Protocol MDV3100-12.  This trial has been 
completed, but is currently maturing for efficacy endpoints. No new safety signals were 
found.  In addition, the use of enzalutamide in women with advanced AR+ TNBC was 
evaluated in a single-arm, open-label phase 2 study, MDV3100-11 (NCT01889238).  


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Results have been reported at ASCO 2015.  A trial of enzalutamide plus trastuzumab is 
ongoing in Her2+ AR+ BC. (See preliminary studies). 
 
As part of the phase I study, enzalutamide was combined with full dose fulvestrant.  
Preclinical modeling showed synergistic inhibitory effects on tumor cell growth (13).  
Fulvestrant is not significantly metabolized by CYP3A4.  In this substudy, 11 patients 
with ER+ AR+ BC had loading doses of fulvestrant 500 mg every 2 weeks for one 
month, then were treated with fulvestrant 500 mg IM every 4 weeks as standard of care 
(13).  Open label enzalutamide at 160 mg po daily was added.  PK was done for both 
drugs to look for interactions.  The median age of these patients was 59 (53-78) years, 
and 64% had prior treatment for metastatic disease.  No significant PK interaction was 
found and no new safety signals were found.  Several patients remained on this 
combination treatment for over a year. 
 
1.3 
Preliminary Studies/Progress Report 
Drs. Richer and Elias received a Department of Defense Clinical Translation Research 
Award to study the role of AR signaling and the effect of inhibiting that signal in breast 
cancer in both the preclinical and clinical setting.  Given a long-standing relationship with 
Medivation, both Medivation and Astellas agreed to collaborate in these efforts.  The 
current LOI addresses the need to obtain serial biopsies from patients receiving 
enzalutamide for breast cancer.  We plan to do these clinical trials at multiple selected 
sites. 
 
Preclinical modeling demonstrated that enzalutamide blocked the ability of AR to 
translocate to the nucleus with or without ligand (4-OH testosterone) and that this 
caused significant cytotoxicity both in vitro and in vivo in a variety of breast cancer cell 
lines and patient-derived xenografts (7).  Despite the fact that enzalutamide does not 
bind ER, it blocked ER signaling and estradiol growth stimulation in ER+BC cells.  
Further laboratory investigation has now shown that AR binds directly with ER and 
regulates the DNA binding sites for ER (8).   
 
Thus far, trials sponsored by Medivation and/or Astellas have established: 
 
• 
Phase I evaluation of single agent enzalutamide (9, 10): PK of enzalutamide not 
different in women; RP2D 160 mg po daily.  Toxicities similar to that of men – largely 
G1/2 fatigue, nausea, hot flashes, and occasional mild transaminitis.  Because of 
concern over possible seizure risk (men with prostate cancer ~6/3000 had seizures, 
but most of these had had brain metastases or CNS surgery), women with brain 
metastases have been excluded from all enzalutamide trials. 
• 
Phase I/PK studies (11-13):  enzalutamide with anastrozole, single dose 
exemestane, double dose exemestane, and fulvestrant – AUC of anastrozole 
reduced by ~80%; AUC of exemestane reduced by ~50%; AUC of double dose 
exemestane with concurrent enzalutamide was equivalent to single dose 
exemestane when given alone; and the AUC of fulvestrant was not obviously 
affected by enzalutamide.  Anti-tumor efficacy is documented in each of these trials. 
• 
Phase II enzalutamide in AR+ TNBC (12):  29% clinical benefit rate at 24 weeks. 


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• 
Phase II randomized trial of double dose exemestane +/- enzalutamide in AR+ ER+ 
BC: results maturing. 
• 
The phase I of fulvestrant/enzalutamide combination established safety and lack of 
PK interaction, but only included 11 patients (13).  Preclinical modeling of this 
combination showed synergy (13). 
1.3.1 Preliminary Data Points 
Our preliminary data points to AR expression as being a prerequisite for targeting 
AR.  For our studies, we have set a low bar for AR expression:  positive is 
defined as 1% of cells staining with strong intensity (analogous to the Allred 
score for ER and PR).  Clearly other cutoffs may be worth exploring.  We define 
our outcome, lack of response, as no response or PFS<12 weeks (NR group). 
The following molecular characteristics at baseline will be explored among 
others:  1) nuclear to cytoplasmic localization of AR staining.  2) strength of AR 
signaling as measured by the expression of downstream AR-regulated genes, 
which should reflect dependence of the tumor cell on AR function.  3) AR:ER 
ratio with resistance to anti-estrogen therapy.  The strength of other pathways 
signals that bypass the need for AR or ER signaling may be a harbinger for 
resistance to enzalutamide, hence our interest in examining the PI3K/mTOR 
pathway as that pathway integrates many of the signals emanating from other 
growth factor receptor pathway activations.  These are expected findings, but we 
will also conduct unsupervised analyses to discover other potential associations.  
Because we will not reliably have normal breast tissue from the patients, we will 
not be able to compare gene expression and functional protein pathway 
activation mapping in the tumor vs. normal at baseline; hence, the analysis will 
be restricted to relative gene expression or protein expression or the presence of 
mutations in the tumor vs. the PFS.  Adding strength to our analysis will be our 
ability to parallel the clinical tissue with preclinical tissue, and evaluate the most 
promising of the potential predictive biomarkers in both systems.  Consistent and 
biologically plausible putative biomarkers would then require confirmation using 
more quantitative and specific assays. 
1.4 
Hypothesis 
Enzalutamide with fulvestrant, by blocking both AR and ER signaling, will synergize in 
patients with ER+ AR+ metastatic breast cancer.  It may prevent AR from taking over 
from ER when ER signaling is blocked.  The extent of AR expression that correlates with 
enzalutamide efficacy is unknown and is an objective of this study; therefore, all patients, 
including those with “AR-negative” breast cancer (although this is expected to be fewer 
than 10%), will be enrolled to receive standard of care fulvestrant with enzalutamide. 
We hypothesize that 1) AR localization (a shift from nuclear to cytoplasmic) when 
comparing the pretreatment to the ~4 week tissues will represent a pharmacodynamics 
(PD) marker of enzalutamide activity.  In tumors that respond to treatment, we would not 
only expect such a shift in AR localization, but also 2) a reduced expression in AR-
regulated genes as well as subsequent changes in downstream processes.  Thus, 
comparison of pre- vs during treatment tissues should allow us to identify PD markers as 
well as predictive biomarkers that indicate no response to enzalutamide (such as no 


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change in Ki67 or TUNEL).  We will be able to measure Ki67 using standard IHC assays 
as well as a quantitative measurement by Reverse Phase Protein Microarray (RPMA). 
Multivariate analysis will be required to attempt to classify protein, gene, or TUNEL 
markers associated with PFS as predictive (of therapeutic impact), prognostic (of 
intrinsic tumor biology), or mixed as discussed above.   A similar plan to compare the 
preclinical with the clinical analyses should facilitate the discovery and validation of 
putative biomarkers.  The evaluation of Ki67 and TUNEL will provide the preliminary 
data necessary to mount our preoperative trial proposed in Years 3-5.Sample size and 
power consideration: 24 baseline samples will provide 80% power to detect a mean 
difference in change (baseline-during treatment) of 1 (or 1.3) standard deviation between 
the two groups (NR vs R) using one-sided 2-group t-test with a significance level of 0.05, 
assuming the response is 50% (or 20%).  Statistical analysis plan: the same analysis 
approaches described in aim 1 will be used here, with the changes (baseline –during 
treatment) instead of the baseline values. Coefficient variation (CV) will be calculated for 
each potential biomarkers and biomarkers with smaller CV will be particularly interesting.    
 
2. 
OBJECTIVES AND OUTCOMES: 
2.1 
Hypotheses and Specific Aims 
This phase II study is designed to evaluate the tolerability and clinical activity of adding 
enzalutamide to fulvestrant treatment in women with advanced breast cancer that is ER 
positive and Her2 normal. 
2.2 
Primary Objective 
To determine the clinical benefit rate (complete and partial response plus stable disease 
for 24 weeks) of the combination of enzalutamide/fulvestrant. 
2.3 
Secondary Objectives 
1. To confirm the safety profile of the combination. 
2. Response rate (complete and partial response) at 24 weeks, Progression-free 
survival (PFS) and % of patients remaining free from progression at 12 and 24 
weeks. 
3. To obtain serial biopsies of breast cancer pretreatment, during treatment and at time 
of tumor progression in order to determine the extent of AR expression and signaling 
in breast tissue, to evaluate the effect of enzalutamide on the tumor, and to evaluate 
the relationship of these effects on clinical outcomes. 
2.4 
Laboratory Hypotheses (From Serial Tissue Biopsies) 
1. In the luminal (ER+/AR+) tumors, decrease in Ki67 after ~4 weeks of treatment to 
below 10% is associated with response to therapy and will correlate with 
progression-free survival (PFS). 
2. Pretreatment molecular characteristics (such as AR:ER ratio in ER+ tumors, Her2 
status, PI3K pathway mutations, or others based on further profiling of sensitive 
versus resistant cell line and patient samples) will be associated with lack of 
response and/or prolonged PFS.  


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3. Tissue at time of disease progression will be enriched for genes/proteins 
representing resistance mechanisms.  Timing of such progression (early vs. late) 
may yield different hypotheses for resistance, and resistance mechanisms will likely 
vary with subtype, since we already have found that the mode of action by which 
enzalutamide inhibits tumor growth differs in ER+/AR+ as compared to ER-/AR+ 
tumors. 
 
3. 
STUDY DESGIN AND RESEARCH METHODS: 
3.1 
Study Design  
Single arm, non-randomized, open-label treatment consisting of: 
• 
Fulvestrant 500 mg IM given days 1, 15, 28, then every 4 weeks as per 
standard of care (SOC).  Fulvestrant may have already been started. 
• 
Enzalutamide 160 mg daily. 
If pre- or perimenopausal, patients will also receive goserelin 3.6 mg sq every 4 weeks 
(or equivalent) as per standard of care (SOC). 
 
3.2 
Study Schema 
            
      
3.3 
Study Periods  
The study periods will be as follows for all patients: 
• 
Screening: Up to 28 days before treatment; 
• 
Treatment: Day 1 of treatment through discontinuation of enzalutamide 
treatment; 
• 
Safety follow-up: Approximately 30 days after the last dose of enzalutamide 
or before initiation of a new antitumor treatment, whichever occurs first. 
3.4 
Sample Size  
Twenty-four (24) evaluable patients will be recruited for this study. Up to 45 patients may 
be consented to allow for screen failures. The 24 evaluable patients will receive serial 


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tumor biopsies – pre-enzalutamide treatment and at ~4 weeks on therapy.  Patients will 
be asked to allow an optional biopsy upon progression of disease.   
 
4. 
STUDY ENROLLMENT AND WITHDRAWL: 
4.1 
Inclusion Criteria 
1. ER+ Her2- breast cancer 
2. Metastatic  
3. Female, at least 18 years of age 
4. Candidate for fulvestrant therapy – patients who have started  fulvestrant may 
enter this trial if within 3 months of starting fulvestrant 
5. Measurable or evaluable by RECIST 1.1 
6. ECOG PS 0-2 
7. Able to swallow study drug and comply with study requirements 
8. Tumor available for fresh biopsy (two biopsies – pretreatment as regards 
enzalutamide, and during treatment at 4 weeks).  The patient will be also be 
asked if they would be willing to provide a third biopsy at time of progression. 
9. If patient is pre- or peri- menopausal, then will need to have concurrent 
ovarian suppression. Patients may have already gotten the loading dose of 
ovarian suppression. Pre- or peri- menopausal subjects must have a negative 
urine pregnancy test confirmed at screening. 
10. ANC >1000/uL and platelets >75,000/uL at screening visit 
11. Total bilirubin < 1.5 times upper limit of normal (ULN) at the screening visit 
unless an alternate nonmalignant etiology exists (eg, Gilbert’s disease) 
12. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 
times ULN or < 5 times ULN if patient has documented liver metastases 
13. Creatinine < 1.5 times ULN 
14. INR < 1.5 times ULN, or if on warfarin, can safely transition off for biopsy 
15. Willing to donate blood for research at 4 time points 
16. Written informed consent obtained prior to biopsies and blood samples 
17. Agreement to exercise appropriate use of contraception. Subjects should use 
2 acceptable methods of birth control (one of which must include a condom 
as a barrier method of contraception) starting at the time of screening for an 
enzalutamide study and continuing throughout the course of treatment and 
for at least three months after enzalutamide is discontinued. 
4.2 
Exclusion Criteria 
1. Current or previously treated brain or leptomeningeal metastases 
2. History of seizures 


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3. Prior treatment with an anti-androgen (abiraterone, ARN-509, bicalutamide, 
enzalutamide, ODM-201, TAK-448, TAK-683, TAK-700, VT-464) 
4. Systemic estrogens or androgens within 14 days before initiating therapy.  
Vaginal estrogens are allowed if necessary for patient comfort. 
4.3 
Withdrawal 
The participants may withdraw consent at any time throughout the course of the trial. A 
copy of the informed consent document will be given to the participants for their records. 
The rights and welfare of the participants will be protected by emphasizing to them that 
the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
 
An investigator may also terminate a participant’s enrollment in the study if any clinical 
adverse event, laboratory abnormality, non-compliance, lost to follow-up, or other 
medical condition or situation occurs such that continued participation in the study would 
not be in the best interest of the participant. 
 
5. 
STUDY AGENT: 
5.1 
Enzalutamide 
 
5.1.1 General Information 
The study drug, enzalutamide, is approved in the US to treat men with metastatic 
CRPC who previously received docetaxel.  
5.1.2 Enzalutamide Product Characteristics 
Enzalutamide, also known as MDV3100, has the chemical name 4-{3-[4-cyano-3-
(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-
fluoro-Nmethylbenzamide. The drug substance is formulated in the surfactant 
caprylocaproyl polyoxylglycerides, also known as Labrasol. The product will be 
supplied as white to off-white soft gelatin capsules containing 40 mg of 
enzalutamide. 
5.1.3 Enzalutamide Packaging 
Enzalutamide is packaged in bottles with induction-sealed child-resistant caps 
labeled with the study protocol number, contents, directions for use, storage 
directions, clinical trial statement, and sponsor name. Each bottle contains 120 
capsules (30-day supply).   
5.1.4 Enzalutamide Storage 
Enzalutamide study drug is to be handled and stored safely and properly in 
accordance with the study drug label. 
5.1.5 Directions for Administration of Enzalutamide 
The daily dose of enzalutamide is 160 mg/day in 4 capsules (40 mg each) given 
by mouth.  Patients should self-administer enzalutamide study drug by mouth 
once daily, with or without food, starting on day 1. The capsules should be 
swallowed whole without chewing, dissolving, or opening them. Patients will self-


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administer the study drug at home. Patients should not make up missed or 
vomited doses; dosing should resume on the next calendar day unless otherwise 
instructed. 
5.1.6 Directions for Dose Modification of Enzalutamide 
Patients who experience a grade 3 or higher toxicity that is attributed to 
enzalutamide study drug and cannot be ameliorated by the use of adequate 
medical intervention may interrupt treatment with enzalutamide. Subsequently, 
the enzalutamide dosing may be restarted at the original dose (160 mg/day, 4 
capsules) or a reduced dose (80 mg/day, 2 capsules). Treatment interruption and 
re-initiation should be discussed with the principal investigator. 
5.1.7 Treatment Compliance 
Study drug accountability will be performed to document compliance with the 
dosing regimen. Patients will be asked to return all bottles of study drug at study 
visits. Patients who forget to return bottles will be asked to return them at the 
next study visit. 
5.1.8 Drug Inventory and Accountability 
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/pharmacist.  Used or unused study drug may be destroyed at the 
study site according to standard institutional procedures if the sponsor agrees 
with the procedure, and after drug accountability has been conducted by the 
sponsor or representative, unless otherwise approved. 
5.1.9 Effects of Enzalutamide on Exposure to Other Drugs 
Clinical data indicate that enzalutamide is a strong inducer of CYP3A4 and a 
moderate inducer of CYP2C9 and CYP2C19. Concomitant use of enzalutamide 
with drugs with a narrow therapeutic index that are metabolized by CYP3A4 (eg, 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus), CYP2C9 (eg, phenytoin, warfarin), and 
CYP2C19 (eg, S-mephenytoin) should be avoided if possible as enzalutamide 
may decrease their exposure. If coadministration with warfarin cannot be 
avoided, additional INR monitoring should be conducted. 
5.1.10 Drugs That May Affect Exposure to Enzalutamide 
5.1.10.1 
Drugs That Inhibit or Induce CYP2C8 
Coadministration of a strong CYP2C8 inhibitor (eg, gemfibrozil) increased 
the composite AUC0-∞ of enzalutamide plus its active metabolite in 
healthy volunteers by 2.2-fold; therefore, coadministration of 
enzalutamide with strong CYP2C8 inhibitors should be avoided if 
possible. If coadministration of enzalutamide with strong CYP2C8 
inhibitors cannot be avoided, the enzalutamide dose should be reduced to 
80 mg once daily. If coadministration of the strong inhibitor is 
discontinued, the enzalutamide dose should be returned to the dose used 
prior to initiation of the strong CYP2C8 inhibitor. 
 


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The effects of CYP2C8 inducers on the PK of enzalutamide have not 
been evaluated in vivo.  Coadministration of enzalutamide with strong or 
moderate CYP2C8 inducers (eg, rifampin) may alter the plasma exposure 
of enzalutamide and should be avoided if possible. Selection of a 
concomitant medication with no or minimal CYP2C8 induction potential is 
recommended. 
5.1.10.2 
Drugs That Induce CYP3A4 
The effects of CYP3A4 inducers on the PK of enzalutamide have not 
been evaluated in vivo.  Coadministration of enzalutamide with strong 
CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, 
rifabutin, rifampin, rifapentine) may decrease the plasma exposure of 
enzalutamide and should be avoided if possible. Selection of a 
concomitant medication with no or minimal CYP3A4 induction potential is 
recommended. Moderate CYP3A4 inducers (eg, bosentan, efavirenz, 
etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce the 
plasma exposure of enzalutamide and should be avoided if possible. 
5.1.10.3 
Precautions Regarding Concomitant Medications 
Refer to the following websites for updated lists of CYP inhibitors, 
inducers, and substrates. 
• 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Development
Resources/DrugInteractionsLabeling/ucm093664.htm#potency    
• 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
5.2 
Fulvestrant 
Fulvestrant is an ER antagonist indicated for the treatment of postmenopausal 
women with hormone receptor-positive advanced breast cancer. Unlike the 
selective ER modulator tamoxifen, which displays mixed antagonist/agonist 
properties, fulvestrant has no agonist effects.  Fulvestrant binds, blocks, and 
increases degradation of the ER, leading to an inhibition of estrogen signaling. 
This distinctive mode of action may overcome tumor resistance to previous 
endocrine agents. The increased degradation of the ER by fulvestrant may also 
limit cross-talk between growth factor receptor and ER-mediated signaling 
pathways and thus increase the duration of response observed with fulvestrant 
treatment.  
 
Per the USPI8, the recommended dose of fulvestrant is 500 mg administered by 
IM injection on days 1, 15, and 29 and once monthly thereafter. The most 
common clinically significant adverse reactions occurring in ≥ 5% of patients 
receiving fulvestrant 500 mg are injection site pain, nausea, bone pain, arthralgia, 
headache, back pain, fatigue, pain in extremity, hot flush, vomiting, anorexia, 
asthenia, musculoskeletal pain, cough, dyspnea, and constipation. In addition, ≥ 
grade 1 elevations in AST, ALT or alkaline phosphatase were observed in > 15% 
in pooled analysis of fulvestrant trials, with grade 3 to 4 increases observed in 
1% to 2% of patients.  Clinical data show that fulvestrant does not affect the 
pharmacokinetics of midazolam (a sensitive CYP3A4 substrate) and rifampin and 


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enzalutamide (a potent CYP3A4 inducer) had no effect on the pharmacokinetics 
of fulvestrant.  
5.3 
Investigational Product Accountability  
The Investigator must maintain accurate records (including dates and lot 
numbers) of all study drug supplies received. All study drug supplies issued to, 
used by, and returned by each patient must be recorded on a Drug Accountability 
Log completed by the Investigator or designee. All remaining study supplies, 
opened or unopened, must be returned to the Sponsor (or designee) at the end 
of the study or destroyed on site according to the site’s standard operating 
procedures only after study drug accountability has been completed and with 
approval of the Study Monitor. All records must be made available to the Sponsor 
(or designee) and appropriate regulatory agencies upon request. 
 
 
 


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6. 
STUDY PROCEDURES AND SCHEDULE: 
6.1 
Study Procedures 
 
Study Phase 
Screening 
Treatment 
Progression 
Follow-up 
Study Week 
-4 to -1 
1 
5 
9 
13 [1] 
varies 
varies [10] 
Window (Days) 
28 
n/a 
+/- 7 
+/- 7 
+/- 7 
n/a 
+/- 7 days 
Informed Consent 
x 
 
 
 
 
 
 
Eligibility 
x 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
Archived Tissue 
Collection [2] 
x 
 
 
 
 
 
 
Tumor Imaging [3] 
x 
 
 
x 
 
 
 
Physical Exam 
x 
x 
x 
x 
x 
x 
 
Adverse Events 
x 
x 
x 
x 
x 
x 
x 
Concomitant 
Medications 
x 
x 
x 
x 
x 
x 
 
Study Drug 
Dispensing [4] 
 
x 
 
x 
 
 
 
Fulvestrant [9] 
 
x 
x 
x 
x 
 
 
Tumor Biopsy 
 
x [5] 
x 
 
 
optional 
 
Hematology, Serum 
Chemistry [6] 
x 
x [8] 
x 
x 
x 
x 
 
PT/INR, PTT [11] 
x 
 
x  
 
 
x  
 
Urine Pregnancy Test 
[12] 
x 
 
 
 
 
 
 
Circulating Tumor 
Biomarkers 
x 
x [8] 
x 
x 
x 
x 
 
CTCs [7] 
x 
x [8] 
x 
x 
 
x 
 
Survival & 
Recurrence Follow-up 
 
 
 
 
 
 
 
x 
 
[1] Continue every 4 weeks until progression. 
[2] From primary lesion and/or metastatic sites previously biopsied. If tissue is available, archival blocks 
from both sites (primary and metastatic) should be collected, however, the top priority is the primary tissue.  
[3] Within approximately 28 days before study entry and includes CT with contrast (unless medically contraindicated) 
of chest, abdomen, and pelvis. Bone assessments as clinically indicated. Thereafter, perform assessments every 8 
weeks up to week 49 and then every 12 weeks thereafter until progression is documented per RECIST 1.1 or 
permanent treatment discontinuation.  MRI is acceptable if CT not possible.  Use the same testing across time. 
[4] Refill every 8 weeks as long as patient remains on active treatment. 
[5] Before treatment, but after eligibility determined. 
[6] Hematology: hematocrit, hemoglobin, platelet count, red blood cell count, total neutrophils (absolute), white blood 
cell count with differential. Chemistry:  albumin, alkaline phosphatase, ALT (alanine aminotransferase), AST 
(aspartate transaminase), blood urea nitrogen and creatinine; Ca++, Cl-, K+, Na+; glucose (non-fasting), total 
bilirubin, total CO2 (bicarbonate), total protein. 
[7] CTCs will be collected at all participating sites, coded to remove patient identifiers, and shipped to UCCC 
and USC for processing as outlined in the lab manual. 
[8] Only one sample is needed pretreatment (either during screening or prior to treatment on C1D1). 
[9] Given IM on days 1, 15, and 28 (C2D1), and then every 4 weeks as per standard of care (SOC). 
[10] 30 days after the last dose of enzalutamide or before initiation of a new antitumor treatment, whichever occurs 
first. May be done by telephone. 
[11] Collected at screening, tumor biopsy time points if clinically required for biopsy, and as required per institutional 
standard. 
[12] If woman of child bearing potential only. 
Bold represents non-SOC events. 


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6.2 
Drug Dispensing 
An 8 week supply of enzalutamide will be provided to each patient at a time (provided by 
Astellas/Medivation) and dispensed by the research pharmacy.  Additional bottles may 
be dispensed to accommodate necessary windows for subsequent visits or for 
accidental wastage. 
6.3 
Laboratory Procedures/Evaluations 
6.3.1 Blood 
Routine blood tests (chemistries, hematology) will be obtained every month as 
clinically indicated.  Tumor markers to be followed every 1-2 months as clinically 
indicated. 
 
Blood for potential pharmacogenomics testing will be obtained at baseline. The 
white cell pellet required for this sample will be obtained from the baseline 
plasma vacutainer. 
 
Plasma for tumor related exosomes and other circulating tumor products will be 
obtained each cycle on day 1 (10 ml).  
 
Blood for circulating tumor cells will be obtained day 1 of cycles 1, 2, and 3 (up to 
30ml each time). 
Baseline: 
1 plasma vacutainer (green top, lithium heparin, 10ml) 
1 serum vacutainer (red top, 10ml) 
2-3 tubes for CTC sample collection (up to 30ml) 
~Week 5: 
1 plasma vacutainer (green top, lithium heparin, 10ml) 
2-3 tubes for CTC sample collection (up to 30ml) 
~Week 9: 
1 plasma vacutainer (green top, lithium heparin, 10ml) 
2-3 tubes for CTC sample collection (up to 30ml) 
~Week 13: 
1 plasma vacutainer (green top, lithium heparin, 10ml) 
End of study: 
1 plasma vacutainer (green top, lithium heparin, 10ml) 
2-3 tubes for CTC sample collection (up to 30ml) 
6.3.2 Serial Biopsies 
At each time point described above, subject will have a biopsy obtained (up to 3 
cores), divided into a formalin fixed, paraffin embedded specimen and a fresh 
frozen specimen to be analyzed. Biopsy can be either needle biopsy or 
excisional biopsy, depending on the site of the tumor, according to physician’s 


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preference. Tissue will be used for future studies, if subjects consent to tissues to 
be banked. See study procedure manual for shipping and other instructions.  The 
purpose of the baseline pre-enzalutamide tumor tissue is to gather an 
understanding of ER+ breast cancers that may or may not benefit from AR 
signaling inhibition.  The biopsy 4 weeks into treatment is taken at the time that 
both drugs are at their steady state concentrations (eg, following the loading 
doses of fulvestrant, and at least 4 half-lives of exposure to enzalutamide (T1/2 = 
5.7 days).  This will examine the subacute effects of this treatment on the tumor 
tissue, on AR and ER signaling.  The purpose of the biopsy at time of 
progression is to obtain insights as to the mechanism of resistance to this 
treatment.  We expect about half the patients to allow us to do this biopsy (based 
on previous experience). 
 
7. 
RISKS AND BENEFITS: 
7.1 
Risks of This Protocol 
• 
Clinical toxicities of fulvestrant (standard agent) plus enzalutamide as outlined in 
package insert and investigator brochure. 
• 
Biopsies (each one is requested of the patient). 
• 
Misuse or inadvertent release of information. 
• 
Identification of the patient by release of comprehensive genomic information. 
o Pharmacogenomic analysis typically does not identify a genetic 
predisposition to a disease since its analysis typically is restricted to 
enzymes that metabolize the therapeutically administered agents. 
• 
Low white blood cell count, which may increase risk of infection. 
• 
Blood clot in the lungs (also known as pulmonary embolism). 
7.2 
Knowledge to Be Gained  
• 
The relationship between the clinical efficacy measures (response, clinical 
benefit rate, PFS) and AR signaling will be examined. 
• 
Characteristics of breast cancers that are resistant to enzalutamide with or 
without other targeted agents.  A set of putative biomarkers will be identified. 
• 
Mechanisms of resistance to enzalutamide-based treatment that arise in the 
clinic. 
7.3 
Justification of Risks  
The clinical impact of enzalutamide in breast cancer is not yet determined.  If the tumor 
appears to progress, the patient can be taken off study and treated accordingly as per 
the treating physician.   
 
The extent of AR expression that correlates with enzalutamide efficacy is unknown and 
is an objective of this study; therefore, all patients, including those with “AR-negative” 
breast cancer, will be enrolled to receive standard of care fulvestrant with enzalutamide.  


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The choice of this combination was to take advantage of the lack of PK interaction 
between the two agents and conduct a phase II trial. 
 
8. 
ASSESSMENT OF SAFETY: 
8.1 
Serious Adverse Events 
A serious adverse event or reaction is any untoward medical occurrence that at any 
dose:  
 
• 
Results in death (death solely as a result of disease progression is not a serious 
adverse event);  
• 
Is life threatening (i.e., the patient was at immediate risk of death at the time of 
the event). “Life threatening” does not include an event that hypothetically might 
have caused death if it were more severe. For example, drug induced hepatitis 
that resolved without evidence of hepatic failure would not be considered life 
threatening even though drug induced hepatitis can be fatal;  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization;  
• 
Results in persistent or significant disability/incapacity (i.e., a substantial 
disruption of the patient’s ability to carry out normal life functions);  
• 
Is a congenital anomaly/birth defect;  
• 
Is a medically important event, including seizure.  
8.2 
Serious Adverse Event Reporting 
NCI CTCAE 4.03 will be used for adverse event reporting. 
 
Within 24 hours of awareness of a serious adverse event, whether or not related to the 
study drug, the Investigator or delegated personnel will complete and submit a 
Medwatch 3500A Form to the sponsor investigator and Astellas, containing all required 
information (reference 21 CFR 312.32).  The sponsor investigator will submit the SAE to 
any additional regulatory authorities as required. If submission of this SAE to the 
sponsor investigator or Astellas is not possible within 24 hours, the Investigator’s local 
drug safety contact (IRB, etc.) should be informed by phone.  
 
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained. Non-serious AEs will be recorded until 30 days after the last day of 
study treatment or until initiation of new therapy, whichever comes first. SAEs will be 
followed until resolution or stabilization. 
 
Notification of the Principal investigator, Dr. Anthony Elias:   
Anthony.elias@ucdenver.edu 
Cell 303-638-2018 
ACP 5310, MS 8117 


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1665 North Aurora Court 
Aurora, CO 80045 
 
The SAE documentation, including the Medwatch 3500A Form and available source 
records should be emailed or faxed to: 
Astellas Pharma Global Development – United States 
Email: Safety-us@us.astellas.com 
Fax number: (847) 317-1241 
 
The following minimum information is required: 
• 
Study number/IIT regulatory identifier 
• 
Subject number, sex and age 
• 
The date of report 
• 
A description of the SAE (event, seriousness of the event) 
• 
Causal relationship to the study drug 
Follow-up information for the event should be sent promptly (within 7 days) as 
necessary. 
 
The Principal Investigator, Dr. Anthony Elias, will ensure prompt reporting of the SAE to 
all investigators and co-PIs of the study. 
8.3 
Adverse Events 
• 
An adverse event is defined as any untoward medical occurrence in a patient or 
clinical investigation patient administered a pharmaceutical product and which 
does not necessarily have to have a causal relationship with study drug. 
• 
An adverse event observed after starting administration of the study drug or 
comparator drug is called a “treatment-emergent adverse event.” Treatment-
emergent adverse events will be analyzed and discussed in the clinical study 
report for this study. 
8.4 
Procedure in Case of Pregnancy 
• 
The effect of enzalutamide in pregnant and lactating women is not known, and 
the exposure of a fetus or nursing infant is considered a potential risk. 
Enzalutamide can cause fetal harm when administered to a pregnant woman 
based on its mechanism of action. Subjects receiving enzalutamide are advised 
to use 2 acceptable methods of birth control (one of which must include a 
condom as a barrier method of contraception) starting at the time of screening for 
an enzalutamide study and continuing throughout the course of treatment and for 
at least three months after enzalutamide is discontinued.  
 
• 
The Investigator should report the outcome of the pregnancy (independent of 
outcome, eg. full term delivery, pre-term delivery, spontaneous abortion, induced 
abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 


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miscarried fetus, etc.]  in accordance with the same reporting procedure as for 
SAEs.  The date of outcome of the pregnancy, gestational age, date of birth and 
neonatal data etc., should be included in this information.  
8.5 
In Case of Injury 
In the event of a side effect or injury, appropriate medical care as determined by the 
Investigator or his/her designated alternate will be provided. No other compensation of 
any type will be provided by the study Sponsor. 
8.6 
Safety Monitoring and Reporting 
A monthly teleconference will be held amongst the institutional investigators to review 
patients and adverse events. 
 
9. 
STUDY OVERSIGHT: 
9.1 
Data Safety and Monitoring Oversight  
The sponsor investigator will be responsible for monitoring the trial per the trial 
monitoring plan, in addition to overseeing the safety and efficacy of the trial including any 
specimens collected, executing the data and safety monitoring (DSM) plan, and 
complying with all reporting requirements to local and federal authorities. This oversight 
will be accomplished through additional oversight from the Data and Safety Monitoring 
Committee (DSMC) at the University of Colorado Cancer Center (CU Cancer Center).  
The DSMC is responsible for ensuring data quality and study participant safety for all 
clinical studies at the CU Cancer Center, which is the coordinating institution of this trial.  
   
A summary of the DSMC’s activities is as follows: 
 
• 
Conduct of internal audits 
• 
Ongoing review of all serious adverse events (SAEs), unanticipated 
problems (UAPs) and reportable adverse events (AEs) 
• 
Has the authority to close and/or suspend trials for safety or trial conduct 
issues 
• 
May submit recommendations for corrective actions to the CU Cancer 
Center’s Executive Committee 
 
Per the CU Cancer Center Institutional DSM Plan, SAEs, UAPs and reportable AEs are 
reported to the DSMC, IRB and the sponsor investigator per protocol.  All SAEs, UAPs 
and reportable AEs are to be reported to the DSMC within 5 business days of the 
sponsor investigator receiving notification of the occurrence. 
 
Each subject’s treatment outcomes will be discussed by the site PI and appropriate staff 
at regularly scheduled meetings.  Data regarding number of subjects, significant 
toxicities, dose modifications, and treatment responses will be discussed and 
documented in the meeting’s minutes. 
 


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The sponsor investigator is responsible for organizing and conducting regularly 
scheduled teleconferences with all participating sites.  The sponsor investigator will also 
be responsible for including data from all of the participating sites to include the minutes 
from these regularly scheduled teleconferences between the sponsor investigator and 
the sites within the overall trial’s six month DSM report. 
 
The sponsor investigator will provide a DSM report to the CU Cancer Center DSMC on a 
six month basis. The DSM report will include a protocol summary; current enrollment 
numbers; summary of toxicity data to include specific SAEs, UAPs and AEs; any dose 
modifications; all protocol deviations; and protocol amendments. The DSM report 
submitted to the DSMC will also include, if applicable, the results of any efficacy data 
analysis conducted.  Results and recommendations from the review of this six month 
report by the DSMC will then be provided to the sponsor investigator in a DSMC review 
letter.  The sponsor investigator is then responsible for ensuring this letter is submitted to 
the site’s IRB of record at the time of IRB continuing review. 
9.2 
Clinical Monitoring  
Clinical site monitoring will be conducted to ensure that the rights and well-being of 
human participants are protected, that the reported trial data are accurate, complete, 
and verifiable, and that the conduct of the trial is in compliance with the currently 
approved protocol/ amendment(s), with GCP, and with applicable regulatory 
requirement(s).  
 
The Research Monitor, Elaine Lam, MD is responsible to oversee the safety of the 
research and report observations/findings to the IRB or a designated institutional official. 
The Research Monitor will review all unanticipated problems involving risks to subjects 
or others associated with the protocol and provide an independent report of the event to 
the IRB. The Research Monitor may discuss the research protocol with the investigators; 
shall have authority to stop a research protocol in progress, remove individual human 
subjects from a research protocol, and take whatever steps are necessary to protect the 
safety and well-being of human subjects until the IRB can assess the monitor's report; 
and shall have the responsibility to promptly report their observations and findings to the 
IRB or other designated official and the HRPO.  Dr. Lam is a member of the University of 
Colorado Cancer Center and is a medical oncologist specializing in prostate cancer.  
She is a member of the UCCC Data Monitoring and Safety Committee. 
 
Monitoring for this study will be performed by CU Cancer Center Clinical Monitor in 
accordance with the clinical monitoring plan (CMP), incorporated herein by reference. 
The CMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of the monitoring reports. As necessary, requests for data clarification or 
correction will be sent to the appropriate site PI. 
9.3 
Auditing  
Independent audits will be conducted by the CU Cancer Center DSMC. Independent 
auditors from the sponsor investigator’s authorized representative will be allowed by the 
site’s PI.  In addition, audits may be conducted at any time by appropriate regulatory 
authorities and/or the IRB. During the course of the study and after it has been 


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completed it is likely that 1 or more study site visits will be undertaken by authorized 
representatives of the Sponsor.  
 
The purpose of the audit is to ensure that the study is being, or has been, conducted and 
monitored in compliance with the protocol as well as recognized cGCP guidelines and 
regulations, to ensure monitoring practices are performed consistently across all 
participating sites and that monitors are following the CMP, as defined herein. These 
audits will also increase the likelihood that the study data and all other study 
documentation can withstand a subsequent regulatory authority inspection.  
 
If such audits are to occur, they will be arranged for a reasonable and agreed time.  
 
All reports and patient samples will be identified only by the patient’s ID number and the 
patient’s initials in order to maintain patient confidentiality. Additional patient 
confidentiality issues are covered in the Clinical Trial Agreement and in the informed 
consent form signed by the patient. 
 
10. 
STATISTICAL CONSIDERATIONS: 
10.1 
Clinical Data  
Age, ethnicity, race, gender, breast cancer histology (ductal, lobular, other), breast 
cancer subtype (ER, PR, Her2, Ki67, AR), detailed prior treatment history, selected 
comorbidities (especially insulin, metformin use), clinical response, CBR, PFS at 12 
weeks, TTP.  Details of treatment, including AE, SAE, and compliance.   
10.2 
Sample Size 
10.2.1 Determination of Sample Size 
The primary outcome is the clinical benefit rate. Assuming the undesirable rate of 
10% and desirable rate of 30%, a sample size of 24 provides 89% power to 
detect this 25% rate difference using an exact binomial test with a one-sided 
alpha of 0.085. If 5 or more patients show clinical benefit the drug combination 
warrants further evaluation.  During treatment period, patients might withdraw 
due to toxicity or loss to follow-up before on treatment for 24 weeks. Table below 
summarize the statistical power and the decision rule for sample size from 24 to 
20, a 20% loss in the total sample size, which is the upper bound for loss seen in 
practice.  
 
Statistical 
Power 
n 
Actual 
Alpha 
Reject 
H0 
If R ≥ 
0.89 
24 
0.085 
5 
0.86 
23 
0.073 
5 
0.84 
22 
0.062 
5 
0.80 
21 
0.052 
5 
0.76 
20 
0.043 
5 


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R is the response as the clinical benefit 
 
10.2.2 Power Consideration 
For the outcome lack of response, 24 samples gathered during years 1-2 provide 
80% power to detect a minimum mean difference at baseline of 1.2 (or 1.5) 
standard deviation between the NR group vs all others (Response group, R), 
using a two-sided t-test with a significance level 0.5, assuming 50% (or 20%) 
response rate. Due to the exploratory nature of this aim, the type I error rate will 
not be adjusted for exploring multiple biomarkers. 
10.3 
Research Laboratory Data  
AR IHC quantitation, AR pathway activation, AR localization (nuclear/cytoplasmic), Ki67 
and response, cleaved caspase 3, AR mRNA, AR mutational status, AR splice variants, 
ER IHC quantitation, ER mRNA, RNAseq, whole exome sequencing, proteomic analysis. 
10.4 
Research (Statistical) Methods 
Data collected in this study will be presented using summary tables, patient data listings, 
and figures. Disease evaluations will be performed by investigators per the RECIST __ 
criteria. Each enrolled patients will provide tumor tissues at baseline (0 week) and during 
treatment (4 weeks) and at disease progression. 24 pre- and treatment- biopsy pairs are 
planned for this study. Patients lacking pre- or treatment- biopsies will be replaced. 
10.4.1 Analysis Populations  
Patients who received at least 4 weeks of enzalutamide treatment will be 
included in the efficacy analyses. Patients who received at least one dose of 
enzalutamide will be included for the safety evaluation.  
10.4.2 Analysis Methods  
10.4.2.1 
Summary Statistics  
Summary statistics will be used for the primary outcome clinical benefit 
rate as well as the response rate. Clinical benefit rate is defined as the 
proportion of subjects with complete response or partial response or 
stable disease.  Response rate is defined as the proportion of subjects 
with complete response or partial response. 95% exact confidence 
intervals will be provided. Kaplan-Meier product limit survival plots will be 
generated and median survival time and associated 95% CI will be 
estimated, the PFS percentage at 12 and 24 weeks will be calculated. 
Descriptive statistics will be used to summarize the safety data such as 
the DLT for both hematologic and non-hematologic toxicity per type and 
grade, as well as all collected AE data, which will be listed per patient, 
and cycle. For the biopsy samples, exploratory analyses such as 
multivariable logistic regression, linear regressions and survival analyses 
will be required to attempt to classify protein, gene, or TUNEL markers 
associated with clinical outcomes such as response, clinical benefit and 
PFS as predictive (of therapeutic impact) or prognostic (of intrinsic tumor 


COMIRB 16-1001 
 
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biology).   Bio-informatics tools such as unsupervised pathway analysis 
will also be explored. The following molecular characteristics at baseline 
will be explored among others:  1) Nuclear to cytoplasmic localization of 
AR staining.  2) Strength of AR signaling as measured by the expression 
of downstream AR-regulated genes, which should reflect dependence of 
the tumor cell on AR function.  3) AR:ER ratio with resistance to anti-
estrogen therapy. 
The same summary statistics will be used for the response rate and 
clinical benefit rate. Response rate is defined as the proportion of 
subjects with complete response or partial response. Clinical benefit rate 
is defined as the proportion of subjects with complete response or partial 
response or stable disease.  Kaplan-Meier product limit survival plots will 
be generated and median survival time and associated 95% CI will be 
estimated for each arm.  Combined and separate data for patients with 
AR+ and AR- BC and those with one prior endocrine therapy and those 
with more than one prior endocrine therapy for metastatic breast cancer. 
 
10.4.2.2 
Descriptive Statistics  
Descriptive statistics will be used to summarize the DLT for both 
hematologic and non-hematologic toxicity per type and grade. The same 
summary statistics will be used for the response rate and clinical benefit 
rate. Response rate is defined as the proportion of subjects with complete 
response or partial response. Clinical benefit rate is defined as the 
proportion of subjects with complete response or partial response or 
stable disease.  Kaplan-Meier product limit survival plots will be 
generated and median survival time and associated 95% CI will be 
estimated for each arm. 
Descriptive statistics will be used to summarize the AEs and SAEs for 
both hematologic and non-hematologic toxicity per type and grade. Safety 
follow-up: Approximately 30 days after the last dose of both study drugs 
or before initiation of a new antitumor treatment, whichever occurs first. 
10.5 
Data Analysis Plan 
10.5.1   Toxicity 
The study populations will include the following:  
• 
The Safety Population, which will include all patients who received at 
least 1 dose of enzalutamide;  
• 
The Response Population, which will include all patients who received 
enzalutamide. 
10.5.2 Response & Progression Free Survival (PFS) 
 
10.5.2.1 
Tumor Response  
Tumor response will be assessed using RECIST 1.1.  
 


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10.5.2.2 
Overall Response, Target Lesion Response, Non-
Target Lesion Response:  
Overall Response: If measurable disease, then confirmed by repeat 
assessments 4 or more weeks after initial documentation of the response.  
 
If evaluable but not measurable, response will be assessed either 
quantitatively, in the case of patients with elevated tumor markers, or 
descriptively (e.g., resolution of bone scan findings, decrease in tumor 
related pain symptoms).  
 
10.5.2.3 
Progression Free Survival 
For all patients enrolled, PFS will be defined as the time from the first day 
of enzalutamide treatment (Study Day 1) until documented disease 
progression or death on study, whichever occurs first. For patients who 
do not die or experience disease progression on study, PFS will be right 
censored at the day of the last information available for progression 
assessment. Kaplan-Meier methods will be used to describe PFS by dose 
level and overall.  
 
10.5.3 Receptor Expression  
The degree of ER, PR, and AR expression in the nucleus will be reported by IHC 
strength of staining (0-3+) and % nuclei stained.  The relationship between tumor 
response and degree of AR expression, and/or AR signaling, will be examined. 
Additional assays for AR signaling, (e.g., gene expression array analyses, 
mutation analyses, or other immunohistochemistry evaluations) may be 
performed on remaining tissue to evaluate for molecular phenotypes and 
patterns associated with activated AR signaling. 
 
11. 
SOURCE DOCUMENTATION AND RETENTION OF RECORDS: 
11.1 
Data and CRFs 
The clinical data will be collected on eCRFs and stored in a secure, encrypted RedCap 
file. 
11.2 
Data Accessibility and Record Keeping 
The Investigator must make study data accessible to the Study Monitor or other 
authorized representatives of the Sponsor (or designee) and Regulatory Agency (e.g., 
FDA) inspectors upon request. A file for each patient must be maintained that includes 
the signed informed consent form and copies of all source documentation related to that 
patient. The Investigator must ensure the reliability and availability of source documents 
from which the information on the case report form was derived.  
 
Investigators must maintain all study documentation for a period of 2 years following the 
approval date of the drug in breast cancer, or until 2 years after the investigational drug 
program is discontinued. Study documentation includes the Investigator’s Brochure, 
signed protocol and amendments; signed informed consents; notifications of serious 


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PI: Dr. Elias 
 
 
 
Page 30 of 32 
 
 
adverse events and related reports; any dispensing and accountability logs; shipping 
records of investigational product and trial related materials; documentation of the 
financial aspects of the trial, insurance statement, and signed agreement between 
involved parties; dated and documented IRB approval, and approval of regulatory 
authority(ies); normal laboratory values; decoding procedures for blinded trials; initiation 
visit report; curricula vitae; and all correspondence pertaining to the conduct of the study. 
The Sponsor will notify the Study Investigator when any records may be discarded. 
 
12. 
POTENTIAL SCIENTIFIC PROBLEMS:   
12.1 
Enzalutamide may not have sufficient anti-breast cancer activity in the 
clinic  
Subsequent studies would then focus on defining the tumor characteristics that most 
likely would be sensitive to this or other AR signaling inhibitors and identifying rational 
combinations with enzalutamide to overcome this intrinsic resistance. 
12.2 
Inadequate collection of tissues and inadequate serial samples  
We anticipate inadequate specimens in up to 10% of individuals.  Each investigator is 
determined to collect these samples and is experienced in obtaining such specimens.  
Handling of these tissues is routine in all institutions.  All participating sites are 
experienced NCI designated cancer centers, and have well developed phase I and 
breast cancer multidisciplinary programs. All sites see a large number of new breast 
cancer patients per year, and have high clinical trial accruals. All of the sites lead 
investigators are accomplished medical oncologists with experience with phase I/II and 
III trials.  Dr. Elias in collaboration with Dr. Richer, conducted the preoperative hormone 
trial that established the potential importance of AR and enzalutamide in ER+ breast 
cancer.    University of Colorado has well-established core facilities to perform Nextgen 
sequencing, tissue banking and processing, and CLIA certified IHC. 
12.3 
Inadequate tissue biopsy samples in more than 10% of individuals 
We would then consider increasing the patient enrollment to obtain 20 matched serial 
samples (pre-enzalutamide and after 4 weeks). 
 
13. 
ETHICS: 
The PI will ensure that this study is conducted in full conformity with regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR 
Part 56. ICH E6 may also be followed to the extent it has been adopted by and is in accordance 
with FDA regulations. 
 
14. 
CONFLICT OF INTEREST: 
Independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Any actual conflict of interest of persons who have a role in 


C O MI R B  1 6 -1 0 0 1  
 
V er si o n D at e 0 8 -2 7 -2 0 1 9  
PI: Dr. Eli a s  
 
 
 
P a g e 3 1  of 3 2  
 
 
t h e  d e si g n,  c o n d u ct,  a n al y si s,  p u bli c ati o n,  or  a n y  a s p e ct  of  t hi s  tri al  will  b e  di s cl o s e d  a n d 
m a n a g e d. b y  t h e  U ni v er sit y  of  C ol or a d o  D e n v er’ s  ( U C D)  Offi c e  of  R e g ul at or y  C o m pli a n c e 
C o nfli ct  of  I nt er e st  a n d  C o m mit m e nt  M a n a g e m e nt  ( C OI C)  pr o gr a m.  P er s o n s  wit h  a  p er c ei v e d 
c o nfli ct  of  i nt er e st  will  h a v e  s u c h  c o nfli ct s  m a n a g e d  i n  a  w a y  t h at  i s  a p pr o pri at e  t o  t h eir 
p arti ci p ati o n  i n  t h e  tri al.  C o nfli ct  of  I nt er e st  m a n a g e m e nt  pl a n s  ar e  pr oj e ct -s p e cifi c  a n d  ar e 
r e vi e w e d at l e a st a n n u all y. U C D h a s i nt e gr at e d t h e i n stit uti o n al c o nfli ct of i nt er e st m a n a g e m e nt 
pr o gr a m wit h it s e xi sti n g pr o gr a m.  
 
1 5.  
R E F E R E N C E S : 
1. C olli n s L C, C ol e K S, M ar otti J D, H u R, S c h nitt S J, T a mi mi R M. A n dr o g e n r e c e pt or e x pr e s si o n 
i n br e a st c a n c er i n r el ati o n t o m ol e c ul ar p h e n ot y p e: r e s ult s fr o m t h e N ur s e s' H e alt h St u d y. M o d 
P at h ol. 2 0 1 1; 2 4: 9 2 4 -3 1.  
2. El e br o K, B or g q ui st S, Si m o n s s o n M, M ar k k ul a A, Jir str o m K, I n g v ar C, et al. C o m bi n e d 
A n dr o g e n a n d E str o g e n R e c e pt or St at u s i n Br e a st C a n c er: Tr e at m e nt Pr e di cti o n a n d Pr o g n o si s 
i n a P o p ul ati o n-B a s e d Pr o s p e cti v e C o h ort. Cli n C a n c er R e s. 2 0 1 5; 2 1: 3 6 4 0 -5 0.  
3. H u R, D a w o o d S, H ol m e s M D, C olli n s L C, S c h nitt S J, C ol e K, et al. A n dr o g e n r e c e pt or 
e x pr e s si o n a n d br e a st c a n c er s ur vi v al i n p o st m e n o p a u s al w o m e n. Cli n C a n c er R e s. 
2 0 1 1; 1 7: 1 8 6 7 -7 4.  
4. C o c hr a n e D R, B er n al e s S, J a c o b s e n B M, Citt ell y D M, H o w e E N, D' A m at o N C, et al. R ol e of 
t h e a n dr o g e n r e c e pt or i n br e a st c a n c er a n d pr e cli ni c al a n al y si s of e n z al ut a mi d e. Br e a st C a n c er 
R e s. 2 0 1 4; 1 6: R 7  P MI D: 2 4 4 5 1 1 0 9 D e si g n at e d a s Hi g hl y Cit e d b y t h e j o ur n al Br e a st C a n c er 
R e s e ar c h.  
5. D’ A m at o N C, J a c o b s e n B M, G or d o n M A, et al.  A n dr o g e n r e c e pt or s u p p ort s Er a a cti vit y a n d 
g e n o mi c bi n di n g i n br e a st c a n c er.  S u b mitt e d 2 0 1 6.  
6. T a k a gi K, Mi ki Y, N a g a s a ki S, Hir a k a w a H, O n o d er a Y, A k a hir a J. et al. I n cr e a s e d 
i ntr at u m or al a n dr o g e n s i n h u m a n br e a st c ar ci n o m a f oll o wi n g ar o m at a s e i n hi bit or e x e m e st a n e 
tr e at m e nt. E n d o cr R el at C a n c er. 2 0 1 0 A pr 2 1; 1 7( 2): 4 1 5-3 0.  
7. C o c hr a n e D R, B er n al e s S, J a c o b s e n B M, Citt ell y D M, H o w e E N, D’ A m at o N C, S p o el str a N S, 
E d g ert o n S M, J e a n A, G u err o er o J, G ó m e z F, M e di c h erl a S, Alf ar o I E, M c C ull a g h E, J e dli c k a P, 
T or k k o K C, T h or A D, Eli a s A D, Pr ott er A A, Ri c h er J K.  R ol e of t h e A n dr o g e n R e c e pt or i n Br e a st 
C a n c er a n d Pr e cli ni c al A n al y si s of E n z al ut a mi d e.  Br e a st C a n c er R e s e ar c h 2 0 1 4  J a n 
2 2; 1 6( 1): R 7. d oi: 1 0. 1 1 8 6/ b cr 3 5 9 9.  P MI D: 2 4 4 5 1 1 0 9  
8.  D’ A m at o N C, J a c o b s e n B M, G or d o n M A, B art o n V N, R o g er s T J, S p o el str a N S, B a b b s B L, 
S art ori u s C A, Eli a s A D, G ert z J, Ri c h er J K.  A n dr o g e n r e c e p t or s u p p ort s E R a cti vit y a n d 
g e n o mi c bi n di n g i n br e a st c a n c er.  2 0 1 6, s u b mitt e d.  
9. Eli a s A, Ri c h er J K, L o R u s s o P, P et er s o n A C, St ei n b er g J, M or d e nti J, L o p e z C, H u di s C, 
Tr ai n a T.  M D V 3 1 0 0 -0 8:  A p h a s e 1 o p e n -l a b el, d o s e-e s c al ati o n st u d y e v al u ati n g t h e s af et y, 
t ol er a bilit y, a n d p h ar m a c o ki n eti c s of M D V 3 1 0 0 i n w o m e n wit h i n c ur a bl e br e a st c a n c er.  A S C O 
2 0 1 2, T P S 6 6 8.  
1 0. Tr ai n a T A, Y ar dl e y, D A, P at el M, S c h w art z b er g L, Eli a s A , G u c al p A, P et er s o n A C, H a n n a h 
A, Gi b b o n s J, K h o n d k er Z, H u di s C A, L o R u s s o P.  A p h a s e 1 o p e n -l a b el, d o s e-e s c al ati o n st u d y 
e v al u ati n g t h e s af et y, t ol er a bilit y, a n d p h ar m a c o ki n eti c s of e n z al ut a mi d e ( pr e vi o u sl y M D V 3 1 0 0) 


COMIRB 16-1001 
 
Version Date 08-27-2019 
PI: Dr. Elias 
 
 
 
Page 32 of 32 
 
 
alone or in combination with an aromatase inhibitor in women with advanced breast cancer.  
SABCS 2013 PD3-6 (A938), accepted, poster discussion. 
11. Traina TA, Yardley DA, Patel MR, Schwartzberg LS, Elias A, Gucalp A, Blaney ME, Gibbons 
J, Hudis CA, LoRusso P.  A phase 1 open-label study evaluating the safety, tolerability, and 
pharmacokinetics of enzalutamide alone or combined with an aromatase inhibitor in women with 
advanced breast cancer.  IMPAKT 2014 Breast Cancer Conference May 2014, Abstract 214. 
12. Schwartzberg LS, Yardley DA, Elias A, Patel MR, Gucalp A, Burris HA, Peterson AC, 
Hannah AL, Blaney ME, Gibbons J, Tudor IC, Steinberg JL, LoRusso P, Infante JR, Hudis CA, 
Traina TA.  Enzalutamide plus exemestane: a pilot study to assess safety, pharmacokinetics, 
and effects on circulating estrogens in women with advanced hormone-positive breast cancer.  
Proc ASCO 2014. 
13. Elias AD, Burris HA, Patel MR, Schwartzberg LS, Richer JK, Kavalerchik E, 
Stopatschinskaja S, Gibbons J, Markova D, Steinberg JL, Traina TA. MDV3100-08: A phase 1 
study evaluating the safety and pharmacokinetics of enzalutamide plus fulvestrant in women 
with advanced hormone receptor-positive breast cancer. [abstract]. In: Proceedings of the 
Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; 
San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-16-05. 
Poster presentation. 
14. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with 
enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012 Sep 27; 
367(13):1187-97. 
15. Wyatt AW, Azad AA, Volik SV, Annala M, Beja K, McConeghy B, Haegert A, Warner EW, 
Mo F, Brahmbhatt S, Shukin R, Le Bihan S, Gleave ME, Nykter M, Collins CC, Chi KN.  
Genomic Alterations in Cell-Free DNA and Enzalutamide Resistance in Castration-Resistant 
Prostate Cancer.  JAMA Oncol. 2016 May 5. doi: 10.1001/jamaoncol.2016.0494. [Epub ahead 
of print]. 
16. Fujii T, Reuben JM, Krupa R, Graf R, Johnson C, Dugan L, Louw J, Lim B, Barcenas CH, 
Marx AN, Tripathy D, Want Y, Dittamore R, Ueno NT.  Androgen receptor expression on 
circulating tumor cells (CTCs) in metastatic breast cancer.  Proc SABCS 2015. 
 
 
 
 

ICF_001.pdf: 
Consent and Authorization Form
Page 1 of 14
Initials______
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
Principal Investigator:
Anthony Elias, MD
COMIRB No:
16-1001
Version Date:
August 27, 2019
Study Title: Phase II trial of fulvestrant plus enzalutamide in ER+/ Her2- advanced 
breast cancer
You are being asked to be in a research study.  This form provides you with information about 
the study. A member of the research team will describe this study to you and answer all of your 
questions. Please read the information below and ask questions about anything you don’t 
understand before deciding whether or not to take part. 
Why is this study being done?
This study plans to learn more about a combination of drugs called fulvestrant and enzalutamide 
and how they work together to treat your type of cancer. Fulvestrant is a standard treatment for 
your type of cancer. It works by blocking a hormone receptor on the cancer cells. Enzalutamide 
has been approved to treat other types of cancer and works to block a different hormone 
receptor. This study is looking at whether the two drugs can work together to help prevent the 
growth of cancer cells better than each drug could by itself.
You are being asked to be in this research study because you have ER+/ Her2- breast cancer 
that has spread to other areas of your body and you are a candidate for treatment with 
fulvestrant. 
Throughout the rest of this consent form when referenced together, fulvestrant and 
enzalutamide will be called the “study drugs”.
Other people in this study
Up to 45 people from your area and around the country will participate in this study.
What happens if I join this study?
If you join the study, you will be asked to sign this consent form before you receive any study 
related tests or procedures. You will be given a copy of this form to keep and the original form 
will be kept at the clinic. Some of these procedures are the same as you would receive as 
standard of care treatment even if you did not take part in this trial. You can withdraw from the 
study at any time and this will not affect the standard medical care you receive. 
There are three main parts to this study:
1.
Screening (before treatment)
2.
Treatment (during the study)
3.
Follow-up (after treatment)
COMIRB
APPROVED
For Use
05-Sep-2019
20-Aug-2020


Consent and Authorization Form
COMIRB 16-1001
PI:  Anthony Elias, MD
Version Date: 08/27/2019
2
There are also optional parts of this study. These optional procedures are voluntary and are not 
required. You can still take part in the main study if you choose not to take part in the optional 
study procedures.
This next section is an overview of what will be expected of you, and what you can expect if you 
take part in this study. 
Study visits and procedures
While you are taking part in this study, many of the tests and procedures that will be 
performed are standard of care for your disease. Some “research” procedures are 
performed just for this study and are identified below. This study also has both required 
and optional procedures, which will be listed here. 
Screening 
(Weeks -4 to -1)

Sign informed consent – research

Review medical history

Collect archived tumor tissue – research 

Tumor imaging scan, such as a CT or MRI

Physical exam

Review adverse events

Review medications

Blood draw:
o
Standard of care tests including complete blood count, blood chemistry, and 
blood clotting
o
Tumor biomarkers test – research
o
Circulating tumor cells test– research

Urine test for pregnancy if applicable
If you are pre- or peri-menopausal, you will receive injections of goserelin throughout the 
study as a standard part of treatment for your disease.
Treatment 
(Each cycle is 4 weeks long)
Cycle 1/ Week 1/ Day 1

Physical exam

Review adverse events

Review medications

Fulvestrant injection (into your muscle). You may have already started this 
treatment.

Receive 8 weeks of enzalutamide (pills) – research. You will take 4 capsules by 
mouth every day during this study. 

Tumor biopsy – research

Blood draw (if not collected at screening):
o
Standard of care tests including complete blood count, blood chemistry, 
and blood clotting


Consent and Authorization Form
COMIRB 16-1001
PI:  Anthony Elias, MD
Version Date: 08/27/2019
3
o
Tumor biomarkers test – research 
o
Circulating tumor cells test – research 
Cycle 1/ Day 15

Fulvestrant injection (into your muscle). Unless you have previously started this 
treatment.
Cycle 2/ Week 5

Physical exam

Review adverse events

Review medications

Fulvestrant injection (into your muscle)

Tumor biopsy – research

Blood draw:
o
Standard of care tests including complete blood count, blood chemistry, and 
blood clotting
o
Tumor biomarkers test – research
o
Circulating tumor cells test– research
Cycle 3/ Week 9

Tumor imaging scan, such as a CT or MRI

Physical exam

Review adverse events

Review medications

Fulvestrant injection (into your muscle)

Receive 8 weeks of enzalutamide (pills) – research

Blood draw:
o
Standard of care tests including complete blood count and blood chemistry
o
Tumor biomarkers test – research
o
Circulating tumor cells test– research
Cycle 4/ Week 13
The procedures at this visit will be repeated in each successive cycle (every four weeks) 
as long as you are benefiting. You will continue to receive 8-week supplies of 
enzalutamide at every other visit as long as you are benefiting. . You will also receive 
tumor imaging scans, such as a CT or MRI, every 8 weeks up to week 49 and then 
every 12 weeks thereafter until progression.

Physical exam

Review adverse events

Review medications

Fulvestrant injection (into your muscle).

Blood draw:
o
Standard of care tests including complete blood counts and blood chemistry
o
Tumor biomarkers test – research
End of Treatment/Progression

Physical exam


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COMIRB 16-1001
PI:  Anthony Elias, MD
Version Date: 08/27/2019
4

Review adverse events

Review medications

Tumor biopsy – optional research

Blood draw:
o
Standard of care tests including complete blood count, blood chemistry, and 
blood clotting
o
Tumor biomarkers test – research
o
Circulating tumor cells test– research
Follow-up
You will be followed 30 days after the last dose of enzalutamide or before initiation of a 
new antitumor treatment, whichever occurs first. Staff will follow-up with you at a 
scheduled clinic visit or may contact you by telephone.
Optional study procedures
Here are the optional parts of this study. Remember, no matter what you decide to do 
about this optional part of the study, you may still take part in the main study. If you 
decide to withdraw your consent for the optional parts, you can continue to take part in the 
main study, unless you withdraw your consent for the main study as well.  
Following each optional procedure is a statement asking if you want to participate in the 
optional procedure. Please read the statement and think about your choice. After reading 
the sentence, please check “Yes” or “No” and initial next to your choice. If you have any 
questions, please talk to your doctor or nurse. 
1.
Optional consent for biopsy
We would like your permission to allow us to take a biopsy of your tumor at the 
end of the study, when and if it is determined that your disease has progressed.
I give my permission for an additional biopsy of my tumor to be taken at the end 
of study.
   Yes
   No
_________Initials
2.
Optional Consent for Future Contact
We would like your permission to allow us to contact you in the future to inform 
you about findings from this research and updates on this study on a periodic 
basis, when available.  
I give my permission for my study doctor (or someone he or she chooses) to 
contact me to inform me about findings from this research and updates on this 
study on a periodic basis, when available. 
   Yes
   No
_________Initials


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COMIRB 16-1001
PI:  Anthony Elias, MD
Version Date: 08/27/2019
5
3.
Optional Consent for Data and Specimen Banking for Future Research
Dr. Elias would like to keep some of the data, blood and tissue that is taken 
during the study but is not used for other tests. If you agree, the data and 
samples will be kept and may be used in future research to learn more about 
breast cancer. Your samples will be stored in the Breast Cancer Tissue Bank at 
the University of Colorado Denver. The research that is done with your data and 
samples is not designed to specifically help you. It might help people who have 
breast cancer and other diseases in the future. Reports about research done with 
your data and samples will not be given to you or your doctor. These reports will 
not be put in your health records. The research using your data and samples will 
not affect your care.
The choice to let Dr. Elias keep the data and samples for future research is up to 
you. No matter what you decide to do, it will not affect the care that you will 
receive as part of the study. If you decide now that your data and samples can be 
kept for research, you can change your mind at any time and contact your study 
doctor to let him or her know that you do not want Dr. Elias to use your samples 
any longer, and they will no longer be used for research. Otherwise, they may be 
kept until they are used up, or until Dr. Elias decides to destroy them.
When your data and samples are given to other researchers in the future, Dr. 
Elias will not give them your name, address, phone number or any other 
information that will let the researchers know who you are. 
Sometimes data and samples are used for genetic research (about diseases that 
are passed on in families). Even if your data and samples are used for this kind 
of research, the results will not be told to you and will not be put in your health 
records. Your data and samples will only be used for research and will not be 
sold. The research done with your data and samples may help to develop new 
products in the future, but there is no plan for you to be paid.
The possible benefits of research from your data and samples include learning 
more about what causes breast cancer and other diseases, how to prevent them 
and how to treat them. The greatest risk to you is the release of your private 
information.  Dr. Elias will protect your records so that your name, address and 
phone number will be kept private. The chance that this information will be given 
to someone else is very small. There will be no cost to you for any data or 
sample collection and storage by Dr. Elias.
Please read each sentence below and think about your choice. After reading 
each sentence, check “yes” or “no” and initial next to your choice. If you have 
questions, please talk to your doctor or nurse. Remember, no matter what you 
decide to do about the storage and future use of your data and samples, you 
may still take part in the study.


Consent and Authorization Form
COMIRB 16-1001
PI:  Anthony Elias, MD
Version Date: 08/27/2019
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1.
I give my permission for my data, blood and tissue to be kept by Dr. 
Elias and stored in a central tissue bank at the University of Colorado 
Denver for future use by the study investigators.
   Yes
   No
_________Initials
2.
I give my permissions for my data, blood and tissue samples to be 
used for research about other health problems (for example: causes 
of heart disease, osteoporosis, diabetes).
   Yes
   No
_________Initials
3.
I give my permission for my study doctor (or someone he or she 
chooses) to contact me to inform me about findings from this research 
and updates on this study on a periodic basis, when available
   Yes
   No
_________Initials
At the end of this consent form, you will also be asked to allow information collected from your 
specimens to be used. You need to agree to have information from these optional procedures to 
be used, or you cannot take part in these optional study procedures.
How long will I be on the study?
You will continue to receive treatment with the study drugs as long as you are benefiting or until 
you have an unacceptable drug-related side effect. There is no maximum duration of this 
treatment.
What are the possible discomforts or risks?
As with any study drug, side effects may occur while taking these study drugs. While taking part 
in this study, and being treated with the study drugs, you will be watched carefully for any side 
effects. Some side effects may go away after you stop taking the study drug. Some side effects 
can be long lasting and may never go away or may even lead to death.
You should talk to your study doctor about any side effects or discomfort you may have. The 
study doctor may give you some medicine that will help with some side effects. The study doctor 
may also interrupt or discontinue the study drug.
You will be notified by your study doctor of any new side effects seen in other patients that 
occur during the time you are on the study. This may affect you wanting to continue in this 
research study.


Consent and Authorization Form
COMIRB 16-1001
PI:  Anthony Elias, MD
Version Date: 08/27/2019
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Discomforts you may experience while in this study include:
Risks of Study Drugs:
Enzalutamide:
Likely:

Diarrhea

Nausea

Vomiting

Fatigue or weakness

Headache

Feeling hot or flushed

Increase in blood pressure
Less likely:

Dizziness

Memory impairment

Restless leg syndrome

Anxiety

Nose bleeds

Dry skin

Itchy skin

Skin rash
Rare, but serious:

Low white blood cell count, which may increase your risk of infection

Seizures

Epileptic seizures

Hallucination
Fulvestrant:
Likely:

Fatigue or weakness

Pain, including generalized, back, stomach, and injection site pain

Headache

Decrease in blood pressure

Feeling hot or flushed

Nausea

Vomiting

Constipation

Diarrhea

Bone pain

Sore throat

Cough
Less likely:

Pelvic and chest pain


Consent and Authorization Form
COMIRB 16-1001
PI:  Anthony Elias, MD
Version Date: 08/27/2019
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
Flu-like symptoms

Fever

Loss of appetite

Anemia (low red blood cell count), which may cause tiredness or weakness

Swelling in the hands and feet

Joint swelling

Dizziness

Difficulty sleeping

Numbness or tingling in the hands and feet

Depression

Anxiety

Skin rash

Sweating

Urinary tract infection
Rare, but serious:

Blood clots in your arms or legs that may reach the lungs

Vaginal bleeding

Low white blood cell count, which may increase your risk of infection

Blood clot in the lungs (also known as pulmonary embolism)
Risks of having blood taken:
In this study, we plan to take about 3-4 tablespoons of blood from you at screening/week 1, 
week 5, week 9, week 13, and when your disease progresses. You may feel some pain 
when the needle goes into your vein, and you could have a bruise over the next few days.
Risks of biopsy:
In this study, we will take 2 or 3 biopsies from you. There are some risks to taking a biopsy. 
There is a small chance that you could get an infection where the needle goes in. You may 
also experience redness, swelling, minor bleeding or bruising at the site where the cut was 
made or the needle inserted. You may experience mild to moderate pain at the site of the 
needle puncture. There is also a small chance that you could have an allergic reaction to the 
numbing medicine. After your skin heals up, you may have a small scar where we take the 
samples. 
Archival tumor tissue:
A section will be taken from tumor tissue samples you may have had in the past. Since this 
has already been removed from you, there are no additional risks to you. 
Risks of loss of confidentiality:
There is a risk that people outside of the research team will see your research information. 
We will do all that we can to protect your information, but it cannot be guaranteed.
Other possible risks include:


Consent and Authorization Form
COMIRB 16-1001
PI:  Anthony Elias, MD
Version Date: 08/27/2019
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The particular treatment or procedures involved in this study may involve risks to the embryo 
or fetus which are currently unclear. Women of child-bearing potential should avoid getting 
pregnant while on this study.
This study may include risks that are unknown at this time.
What are the possible benefits of the study?
This study is designed for the researcher to learn more about your cancer and how the study 
drugs affect this type of cancer. However, there is no guarantee that your health will improve if 
you join this study. Also, there could be risks to being in this study. If there are risks, these are 
described in the section describing the discomforts or risks.
Are there alternative treatments? 
There may be other ways of treating your cancer. You have the following choices available to 
you:

Getting treatment or care for your cancer without being in a study.

Taking part in a different study.

Get treatment only for your pain and symptoms, but no treatment for the cancer itself.

You could also choose to get no treatment at all.
You should talk to your doctor about your choices. Make sure you understand all of your 
choices before you decide to take part in this study. You may leave this study and still have 
these other choices available to you. 
Who is paying for this study? 
This research is being paid for by The University of Colorado Cancer Center and the 
Department of Defense. The study drug Enzalutamide is furnished without charge by the 
manufacturer, Astellas.
Will I be paid for being in the study?  
You will not be paid to be in the study. 
Will I have to pay for anything?
There are some medical treatments that you would get for your condition whether you were in 
this study or not, such as a biopsy or blood draw. You or your insurance will have to pay for 
these. There are other medical treatments that you will get because you are in this research 
study. We will pay for those. We will pay for biopsies and blood collection when they are not 
needed for your normal care. Otherwise, these procedures may be combined and charges will 
be sent to your insurance.  You or your insurer would also be responsible for paying for the 
study drug, Fulvestrant.  However, the study drug, Enzalutamide, is provided without charge by 
its manufacturer.


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COMIRB 16-1001
PI:  Anthony Elias, MD
Version Date: 08/27/2019
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Is my participation voluntary?
Taking part in this study is voluntary. You have the right to choose not to take part in this study. 
If you choose to take part, you have the right to stop at any time. If you refuse or decide to 
withdraw later, you will not lose any benefits or rights to which you are entitled. 
In addition, you have the right to change your mind at any point and write to the study doctor to 
not use your samples for research any longer.
If you leave this study, you will still receive your normal medical care.  The only medical care 
that you will lose is the medical care you are getting as part of this study.  You might be able to 
get that same kind of medical care outside of the study.  Ask your study doctor. 
If there are any new findings during the study that may affect whether you want to continue to 
take part, you will be told about them.
Can I be removed from this study? 
The study doctor may decide to stop your participation without your permission if the study 
doctor thinks that being in the study may cause you harm, or for any other reason. You can still 
receive the study drug, if your doctor thinks that it is safe for you.
If you are taken out of the study, you will still receive your normal medical care.
 
What happens if I am injured or hurt during the study? 
If you have an injury while you are in this study, you should call Dr. Anthony Elias immediately. 
His phone number is 720-848-1030 or 303-266-2059.
We will arrange to get you medical care if you have an injury that is caused by this research.  
However, you or your insurance company will have to pay for that care. 
Who do I call if I have questions?
The researcher carrying out this study is Dr. Anthony Elias. You may ask any questions you 
have now. If you have questions, concerns, or complaints later, you may call Dr. Elias at 720-
848-1030 or 303-266-2059.You will be given a copy of this form to keep.  
You may have questions about your rights as someone in this study. You can call Dr. Elias with 
questions.  You can also call the responsible Institutional Review Board (COMIRB).  You can 
call them at 303-724-1055. 
A description of this clinical trial will be available on http://www.Clinical Trials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. You can search this 
Web site at any time.


Consent and Authorization Form
COMIRB 16-1001
PI:  Anthony Elias, MD
Version Date: 08/27/2019
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Who will see my research information?
The University of Colorado Denver (UCD) and its affiliated hospital(s) have rules to protect 
information about you. Federal and state laws including the Health Insurance Portability and 
Accountability Act (HIPAA) also protect your privacy. This part of the consent form tells you 
what information about you may be collected in this study and who might see or use it.  
The institutions involved in this study include:

University of Colorado Denver

University of Colorado Hospital
We cannot do this study without your permission to see, use and give out your information.  You 
do not have to give us this permission.  If you do not, then you may not join this study.  
We will see, use and disclose your information only as described in this form and in our Notice 
of Privacy Practices; however, people outside the UCD and its affiliate hospitals may not be 
covered by this obligation.
We will do everything we can to maintain the confidentiality of your personal information but 
confidentiality cannot be guaranteed. 
The use and disclosure of your information has no time limit.  You can cancel your permission to 
use and disclose your information at any time by writing to the study’s Principal Investigator (PI), 
at the name and address listed below.  If you do cancel your permission to use and disclose 
your information, your part in this study will end and no further information about you will be 
collected.  Your cancellation would not affect information already collected in this study.  
Anthony Elias, MD
Mailstop 8117
12801 E. 17th Ave.
Aurora, CO 80045
Both the research records that identify you and the consent form signed by you may be looked 
at by others who have a legal right to see that information, such as:

Federal offices such as the Food and Drug Administration (FDA) and the Office of 
Human Research Protections (OHRP) that protect research subjects like you.

People at the Colorado Multiple Institutional Review Board (COMIRB)

The study doctor and the rest of the study team.

The Independent Research Monitor, Dr. Elaine Lam, who is responsible for overseeing 
the safety of this research, and to report observations or findings to the IRB or 
designated institutional officials.

Medivation and Astellas, the companies providing the drug, will see only coded 
information.

Officials at the institution where the research is conducted and officials at other 
institutions involved in this study who are in charge of making sure that we follow all of 
the rules for research.
We might talk about this research study at meetings.  We might also print the results of this 
research study in relevant journals.  But we will always keep the names of the research 
subjects, like you, private. 


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PI:  Anthony Elias, MD
Version Date: 08/27/2019
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You have the right to request access to your personal health information from the Investigator. 
The investigator (or staff acting on behalf of the investigator) will use your information 
for the research outlined in this consent form. They will also make all or some of the 
following health information about you collected in this study available to other sites 
participating in this study.
Information about you that will be seen, collected, used and disclosed in this study: 

Name and Demographic Information (age, sex, ethnicity, address, phone number, etc.

Portions of your previous and current Medical Records that are relevant to this study, 
including but not limited to Diagnosis(es), History and Physical, laboratory or tissue 
studies, radiology studies, procedure results

Research Visit and Research Test records

Tissue samples and the data with the samples.

Billing or financial information 
 
Genetic Information Nondiscrimination Act (GINA)
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. This law will generally protect you in the 
following ways:

Health insurance companies and group health plans may not request your genetic 
information that we get from this research.

Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums.

Employers with 15 or more employees may not use your genetic information that we 
get from this research when making a decision to hire, promote, or fire you, or when 
setting the terms of your employment.
All health insurance companies and group health plans must follow this law by May 21, 2010. All 
employers with 15 or more employees must follow this law as of November 21, 2009.
Be aware that this new Federal law does not protect you against genetic discrimination by 
companies that sell life insurance, disability insurance, or long-term care insurance.
What happens to Data, Tissue, Blood and Specimens that are collected in this study?
Scientists at the University of Colorado Denver and the hospitals involved in this study work to 
find the causes and cures of disease.  The data, tissue, blood and specimens collected from 
you during this study are important to this study and to future research.  If you join this study:

The data, tissue, blood, or other specimens given by you to the investigators for this 
research no longer belong to you.  

Both the investigators and any sponsor of this research may study your data, tissue, 
blood, or other specimens collected from you.


Consent and Authorization Form
COMIRB 16-1001
PI:  Anthony Elias, MD
Version Date: 08/27/2019
13

If data, tissue, blood, or other specimens are in a form that identifies you, UCD or the 
hospitals involved in this study may use them for future research only with your 
consent or Institutional Review Board (IRB) approval.

Any product or idea created by the researchers working on this study will not belong 
to you.

There is no plan for you to receive any financial benefit from the creation, use or sale 
of such a product or idea. 
HIPAA Authorization for Optional Additional Study Procedures
In this form, you were given the option to agree to additional, optional research procedures. You 
must also give us your permission, under HIPAA rules, to use and disclose the information 
collected from these optional procedures, as described above.  
Some of these optional procedures may involve genetic testing or the use of your genetic 
information. Your genetic information will not be released to others.
If you decline to give us permission to use and disclose your information, you cannot take part in 
these optional procedures, but you can still participate in the main study. Please initial next to 
your choice:
_____ I give permission for my information, from the optional procedures I have agreed 
to above, to be used and disclosed as described in this section.
_____ I do not give permission for my information for any optional procedures to be 
used and disclosed; I understand that I will not participate in any optional 
procedures.
Agreement to be in this study and use my data
I have read this paper about the study or it was read to me. I understand the possible risks and 
benefits of this study. I understand and authorize the access, use and disclosure of my 
information as stated in this form. I know that being in this study is voluntary. If I choose to be in 
this study, I will get a signed and dated copy of this consent form.
Signature: 
Date: 
Print Name: 
Consent form explained by: 
Date: 
Print Name: 
If applicable, the signature line for witness is required for
consent of non-reading subjects and consent using a short form.


Consent and Authorization Form
COMIRB 16-1001
PI:  Anthony Elias, MD
Version Date: 08/27/2019
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Witness Signature: 
Date: 
Witness Print Name:  
Witness of Signature
Witness of consent process


Version 08.05.2016 
 
 
 
 
UCCC Informed Consent Process Documentation 
 
COMIRB# ________             Patient Initials ________   Subject Number __________ 
 
Type of ICF (i.e. screening, main, optional) ______________________________ 
 
Version date: __________________IRB Approval date: ________________ 
(CIRB = protocol version) 
 
  (CIRB = ICF version date) 
 
The clinical investigator or trained delegate has: 
 
 
Date 
Initials 
Thoroughly reviewed the study treatments, procedures, risks, 
schedules and expenses with the patient and/or legal guardian. 
Provided adequate opportunity to read the IRB approved 
consent and HIPAA form. 
Provided adequate opportunity to consider all options. 
Exchanged information and responded to questions. 
Verified understanding of this information. 
Obtained voluntary agreement to participate in the clinical 
trial. 
Verified the date of signature on the consent document. 
Consent was obtained before the subject began participation in 
the study. 
Provided the patient and/or legal guardian with a copy of the 
consent document that was given to subject to obtain consent.   
Provided the patient and/or legal guardian with the CCTO 
Internal Patient Card (If Applicable).  If N/A, write N/A next to 
initials. 
Retained the original signed consent document in the study 
records. 
This consent form has been sent to Health InforMatics to be 
added to the participant’s medical chart.