Conditions: Breast Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 47
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the uptake of a radioactive tracer 21-18F-fluoro-16α,17α-\[(R)-(1'-α-furylmethylidene)dioxy\]-19-norpregn-4-ene-3,20-dione (FFNP) uptake, which binds to breast cancer progesterone receptors (PgRs) on a PET/CT scan before and after administration of estradiol for one day (estrogen challenge) to determine if the change in uptake is a predictor of response to endocrine therapy (ET) in patients with hormone-sensitive estrogen receptor positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Estradiol is the most potent of the naturally occurring estrogens, and can be administered to treat menopausal symptoms and also sometimes to treat metastatic breast cancer. The investigators propose to study patients with biopsy-proven newly diagnosed, locally advanced, metastatic, or recurrent breast cancer who are going to be treated with endocrine therapy (ET) (tamoxifen,aromatase inhibitors or fulvestrant as standard of care therapy.

Subjects will undergo a total of two FFNP-PET/CT scans; one before and a second one immediately following the one day estradiol challenge before the start of standard of care ET. The estradiol challenge will consist of administering a total of 6 mg of estradiol orally (three doses of 2 mg each) given at approximately 8 hour intervals and over a 24 hour period.

Detailed description:

Arms:
arm 1: * (2) 18F-FFNP-PET/CT scans

  * First one prior to estradiol challenge test
  * Second one immediately following one day of estradiol challenge test
* (1) FDG-PET/CT scan at screening
* The estradiol challenge test will consist of administering a total of 6 mg of estradiol dosed orally as three 2 mg tablets with each tablet being administered approximately 8 hours apart and within a 24 hour period. This estradiol medication will be provided to the patient by the study.

Interventions: intervention 1: 18F-FFNP intervention 2: CTI/Siemens Biograph 40 PET/CT Scanner intervention 3: Estradiol intervention 4: 18F-FDG
Intervention descriptions: intervention 1: None intervention 2: * Will include (1) 18-FDG-PET/CT scan
* Will include (2) 18F-FFNP-PET/CT scans intervention 3: None intervention 4: None

Protocol document:
Prot_SAP_000.pdf: 
Version 02/01/2019 
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ASSESSMENT OF FUNCTIONAL STATUS OF ESTROGEN RECEPTORS IN BREAST 
CANCER BY POSITRON EMISSION TOMOGRAPHY 
 
Principal Investigator 
Farrokh Dehdashti, M.D. 
Washington University School of Medicine 
Department of Radiology / Nuclear Medicine 
Phone: 314-362-1478 
Email: dehdashtif@mir.wustl.edu 
 
Protocol #: 13 
HRPO #: 201411005 Version date: 02/01/2019 
 
Sub-Investigator 
 
 
 
Modality 
Naugthon, Michael, M.D.  
 
 
Medical Oncology 
Cynthia Ma, M.D., Ph.D. 
 
 
Medical Oncology 
Barry A Siegel, M.D.  
 
 
Radiology 
Ningying Wu, Ph.D.  
 
 
Department of Statistics 
 
 
 
Consultant 
John A. Katzenellenbogen, Ph.D. 
 
Department of Chemistry 
University of Illinois 
 
 
 
Study Drug:  PET imaging tracer 18F-FFNP 
Applicable IND(s):  18F-FFNP IND # 76,214 Investigator Initiated Dr. Farrokh Dehdashti 
Clinical Trials.gov #:  NCT02455453 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 
 
 


Version 02/01/2019 
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Protocol Revision History  
 
 
Initial Approval Version 
12/03/2014 
 
Description of Change 
Protocol Location 
20 August 2014 Summary of Changes after PRMC Initial Review 
Added description of who is providing estradiol 
5.3  Estradiol Challenge Test 
Added description of risks associated with the study 
amount of estradiol 
5.4  Risks Related to Estradiol 
Challenge Test. 
Clarified that the changes in SUV and T/N after 
treatment will be compared in responders and 
nonresponders between the baseline and post 
estradiol challenge FFNP-PET/CT images. 
6.4  Image Analysis 
Clarified that clinical response using RECIST 
version 1.1 by an oncologist will be used. 
6.6  Evaluation of Tumor Response 
Added blood draws to study calendar 
STUDY CALENDAR 
Updated Data Submission schedule to match source 
document labels 
Data Submission Schedule 
Updated protocol version date 
Bottom of each page 
 
 
08 December 2014 Summary of Changes IRB Initial Review 
Added exclusion criteria for subjects with spinal 
lesions at risk for cord compression in the opinion 
of the Principal Investigator and treating medical 
oncologist.   
3.2  Exclusion Criteria 
Added HRPO #, updated version date and protocol 
# 
Title Page 
28 April 2015 Amendment 1 
Added study title to schema and clarified in 
treatment with endocrine therapy should be planned 
for a minimum of 6 months  
SCHEMA 
Updated table of contents 
Page 4  
Clarified inclusion of pre-menopausal patients, 
clarified inclusion criterion to include locally 
advanced / metastatic patients, added endocrine 
therapy should be planned to be administered for at 
least 6 months, clarified prior therapy is allowed if 
≥ 12 months since last treatment 
3.1 Inclusion Criteria 
Clarified both FFNP-PET/CT scans are completed 
prior to the start of standard of care endocrine 
therapy  
5.2 Patient Population 
Added expected toxicities to estradiol challenge 
6.6 Toxicities Related to Estradiol 
Challenge 


Version 02/01/2019 
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Clarified assessments will include adverse events 
related to estradiol administration as part of the 
estradiol challenge  
8.0 
REGULATORY 
AND 
REPORTING REQUIREMENTS 
27 August 2015 Amendment 2 Version 4 
Title page: add clinicaltrials.gov number, update 
version number and date   
Page 1 
Footer – updated to current date  
All pages of document  
Update inclusion criteria to allow for newly 
diagnosed patients and some subjects with hepatic 
disease and to clarify inclusion criteria 
3.1 Inclusion Criteria 
Update exclusion criteria to remove exclusion for 
hepatic disease  
3.2 Exclusion Criteria 
Section 5.2 clarified that any subjects enrolled on 
study whose images are considered non-evaluable 
for any reason may be replaced  
5.2 Patient Population 
Section 5.3  created a larger window for time 
between administration of estradiol and repeat 18F-
FFNP imaging  
Estradiol Challenge Test 
26 October 2015 Study Renewal Version 5  
Update protocol title page and protocol 
footer to current date  
All pages of document  
24 November 2015 Amendment 3 
Update eligibility criteria to include surgery 
as option for determining response regardless 
of amount of time for neoadjuvant therapy  
 
01 April 2016 Amendment 4 Version 7 
Update protocol title page and protocol 
footer to current date for regulatory renewal  
All pages of document  
12 July 2016 Amendment 5 Version 8 
Update schema to remove metastatic this 
should have occurred with Amendment 3 
when newly diagnosed patients were added 
as eligible to participate on study 
STUDY SCHEMA 
Update study schema to clarify that a 
minimum of 6 months of therapy or until 
response assessment should be planned  
STUDY SCHEMA 
Section 3.1 Inclusion Criteria: clarify that 
pathology for eligible breast cancer type can 
be from metastatic or primary pathology 
report  
3.1 Inclusion Criteria 
Section 5.3 Estradiol challenge add 
clarification statement “Whenever possible” 
to description of collecting blood sample for 
estradiol measurement.  
5.3 Estradiol Challenge Test 
Section 5.2 Clarify premenopausal subjects 
are eligible if ovarian suppression is planned. 
5.2 Patient Population 


Version 02/01/2019 
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Protocol Formatting remove extra spaces, 
duplicate words, add page breaks as needed 
for overall format of the protocol  
As needed on all protocol pages  
01-March-2017 Amendment 6 Version 9 
Update protocol title page and protocol 
footer to current date  
Title Page 
Added FDG-PET/CT to Study  
SCHEMA 
Updated table of contents  
Table of Contents 
Updated study objectives  to include FDG-
PET/CT imaging at baseline 
Section 2.0 OBJECTIVES  
Added FDG-PET/CT imaging to study 
related scans  
5.2 Patient Population 
Add FDG-PET/CT imaging to Section 6.0 
Imaging parameters and Analysis  
6.0 IMAGING PARAMETERS AND 
ANALYSIS 
Add additional information FFNP-PET/CT 
imaging and use of port-a-caths 
Section 6.3 18F-FFNP-PET/CT Imaging 
Parameters 
Expected toxicities Section  6.6 added FDG-
PET/CT  
Section 6.0 Toxicities Related to 18F-FDG 
&-18F-FFNP PET/CT Imaging 
Update study calendar section 7.0 to add 
FDG-PET/CT 
Section 7.0 STUDY CALENDAR 
Add FDG-PET/CT to regulatory and 
reporting requirements section 8.0 
Section 8.0 REGULATORY AND 
REPORTING REQUIREMENTS 
16 June 2017 Amendment 7 Version 10  
Fix typographical error 2 weeks is noted 
instead of 4 weeks for time between imaging 
sessions  
Section 5.3 Estradiol Challenge Test 
Clarify and update normal ranges for vital 
sign assessment section 6.0  
Section 6.0 Vital Sign Assessments 
05Feb2018 Renewal Version 11 
Update title page and footer of protocol to 
match date of renewal submission 
Title Page 
25May2018 Amendment 8 Version 12 
Clarify study schema standard of care 
metabolic imaging is acceptable in place of 
baseline FDG PET/CT scanning if it has 
already been performed.   
SCHEMA 
Revise time frame for which follow up chart 
review should occur  
Section 6.8 Evaluation of Tumor Response 
Section 6.9 FOLLOW UP PROCEDURES 
01February2019 Version 13 Annual renewal 
Update title page and footer of protocol to 
match date of renewal submission 
Title Page 


Version 02/01/2019 
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ASSESSMENT OF FUNCTIONAL STATUS OF ESTROGEN RECEPTORS IN BREAST 
CANCER BY POSITRON EMISSION TOMOGRAPHY 
 
SCHEMA 
 
 
 
Standard of Care Diagnosis and Staging of Hormone-Sensitive  
Breast Cancer: 
 
 
 
 
Scheduled to Receive: 
Standard of Care Endocrine Therapy  
 
 
 
 
Research Scan: 
Pre-Treatment: 18F-FDG PET/CT or confirmation of  
acceptable metabolic imaging done per SOC & 
 18F-FFNP PET/CT Scan 
 
 
 
 
Research (Estrdiol Challenge): 
Total of 6 mg of estradiol administered (2 mg TID) over approximately 24 hours 
 
 
 
 
Research Scan: 
Repeat 18F-FFNP PET/CT Scan 
 
 
 
 
 
 
 
 
Planned Standard of Care Endocrine Therapy for a minimum of 6 months or 
response assessment is available  
Standard Chart Review 
For Clinical Response to Planned Treatment  


Version 02/01/2019 
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Table of Contents 
SCHEMA ........................................................................................................................................ 5 
1.0 
BACKGROUND ................................................................................................................. 8 
1.1 
ENDOCRINE THERAPY AND BREAST CANCER .................................................... 8 
1.2 
IMAGING  ER and PR in BREAST CANCER USING PET: FES and FFNP ............... 9 
1.3 
ASSESSMENT of ER FUNCTION WITH PET: .......................................................... 12 
2.0 
OBJECTIVES .................................................................................................................... 14 
3.0 
PATIENT SELECTION .................................................................................................... 15 
3.1 
Inclusion Criteria ............................................................................................................ 15 
3.2 
Exclusion Criteria ........................................................................................................... 16 
3.3 
Inclusion of Men and Minorities .................................................................................... 17 
4.0 
PATIENT REGISTRATION ............................................................................................. 17 
4.1 
Confirmation of Patient Eligibility ................................................................................. 17 
4.2 
Patient Registration in the Siteman Cancer Center Database ........................................ 17 
4.3 
Assignment of UPN ....................................................................................................... 17 
5.0 
METHODS ........................................................................................................................ 17 
5.1 
Study Design .................................................................................................................. 18 
5.2 
Patient Population .......................................................................................................... 18 
5.3 
Estradiol Challenge Test ................................................................................................ 18 
5.4 
Risks Related to Estradiol Challenge Test. .................................................................... 19 
6.0 
IMAGING PARAMETERS AND ANALYSIS ................................................................ 19 
6.1 
Drug Preparation ............................................................................................................ 19 
6.1.1 
18F-FFNP ................................................................................................................. 19 
6.1.2 
18F-FDG .................................................................................................................. 20 
6.2 
18F-FDG-PET/CT Imaging Parameters......................................................................... 20 
6.3 
18F-FFNP-PET/CT Imaging Parameters ........................................................................ 21 
6.4 
Vital Sign Assessments .................................................................................................. 22 
6.5 
Image Analysis ............................................................................................................... 22 
6.6 
Toxicities Related to 18F-FDG &-18F-FFNP PET/CT Imaging ..................................... 23 
6.7 
Toxicities Related to Estradiol Challenge ...................................................................... 24 
6.8 
Evaluation of Tumor Response ...................................................................................... 25 


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6.9 
FOLLOW UP PROCEDURES ...................................................................................... 26 
7.0 
STUDY CALENDAR ....................................................................................................... 27 
7.1 
Data Submission Schedule ............................................................................................. 27 
8.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 27 
8.1 
Adverse Events (AEs) .................................................................................................... 28 
8.2 
Unanticipated Problems ................................................................................................. 28 
8.3 
Noncompliance............................................................................................................... 28 
8.4 
Serious Noncompliance.................................................................................................. 29 
8.5 
Protocol Exceptions........................................................................................................ 29 
8.6 
Reporting to the Human Research Protection Office (HRPO) and the Quality Assurance 
and Safety Monitoring Committee (QASMC) at Washington University ................................ 29 
8.7 
Timeframe for Reporting Required Events .................................................................... 30 
9.0 
DATA AND SAFETY MONITORING PLAN ................................................................ 30 
10.0 STATISTICAL CONSIDERATIONS............................................................................... 31 
10.1 Study Objectives and Endpoints .................................................................................... 31 
11.0 REFERENCES .................................................................................................................. 33 
 
 
 
 


Version 02/01/2019 
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1.0 
BACKGROUND 
 
1.1 
ENDOCRINE THERAPY AND BREAST CANCER  
 
Breast cancer remains the leading cause of cancer mortality among women in Western countries. 
Current estimates suggest one in eight American women will be diagnosed with breast cancer 
during their lifetime. Distinct characteristic of breast cancer can be exploited to help determine 
the overall prognosis and the likelihood of response to specific therapy. It is well established that 
several factors including steroid receptors, peptide growth factors, oncogenes, and tumor 
suppressor genes, play crucial roles in determining tumor response to various endocrine therapies 
(ETs) and the development of resistance to these treatments in breast cancer (Weigel MT. 
Endocr Relat Cancer 2010;17:R245-262).  The majority of patients with breast cancer have 
disease that is estrogen-receptor positive (ER+), and in general this form of breast cancer is a less 
aggressive disease than estrogen receptor-negative (ER-) disease. ER+ disease occurs more 
commonly in postmenopausal women and is characterized by longer disease-free and overall 
survival. Even with metastatic disease, the median survival in patients with estrogen-receptor-
positive (ER+) tumors is three times longer than in those with estrogen-receptor-negative (ER-) 
breast cancer (Keen JC. Cancer 2003;97:825-83).  
 
In treating metastatic breast cancer, the hormone-receptor status directs systemic therapy. ER+ 
disease will respond to first-line endocrine therapy (ET) in 55-60% of patients (Goldhirsch A. 
Ann Oncol. 2002;13(suppl 4):61–68). Nevertheless, nearly half of the patients with ER+ disease 
still fail to respond to ET. Because ER is a key transcription factor for the production of the 
progesterone receptor (PgR), the presence of PgR in ER+ cells is thought to indicate that the 
estrogen-response pathway is functional in these tumors and, thus able to mediate the benefits of 
ETs. The In fact, the presence of PgR in ER+ disease does presence of PgR increases the 
likelihood of hormone responsiveness to some degree (Keen JC. Cancer 2003;97:825-833). The 
presence of the progesterone receptor (PgR) increases the likelihood of hormone responsiveness 
to some degree (Keen JC. Cancer 2003;97:825-83). Progesterone-receptor negative (PgR–) 
tumors are less responsive to therapy, perhaps suggesting that PR may be necessary for positive 
therapeutic outcome with ET. Alternatively, because ER is a key transcription factor for the 
activation of PgR, lack of PgR expression in these ER+/PgR– cells also could suggest that 
estrogen response pathway may not be functional in these tumors. Only a small fraction of 
tumors are ER– and progesterone-receptor positive (PgR+) (< 5%) and they demonstrate an 
intermediate response to ET (Keen JC. Cancer 2003;97:825-83). It has been suggested that PgR 
loss may be a surrogate marker of excessive growth factor receptor signaling and consequently 
poor response to ET (Osborne CK. Breast. 2005 Dec;14(6):458-65). It is also possible that low 
PgR levels in ER+ disease might indicate that estradiol levels are insufficient to induce through 
ER significant PgR levels or that ER is not functional. 
 
Challenges in selecting the best treatments for breast carcinoma.  
ER positivity by immunohisto¬chemistry (IHC) is a prerequisite for ET. However, up to 50% of 
patients with ER+ breast cancer do not benefit from hormonal therapy as a result of intrinsic or 
acquired resistance mechanisms (EBCTCG. The Lancet 2011, 378(9793):771-784; Dowsett M. J 
Clin Oncol 2010, 28(3):509-518; Mouridsen H. J Clin Oncol 2003, 21(11):2101-2109). In the 
early-stage setting, multi-gene assays such as Oncotype Dx, Mammaprint and Prosigna, have 


Version 02/01/2019 
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been developed as prognostic tools to assess the need for chemotherapy; however, their value in 
predicting ET efficacy has not been established. While over 20% of patients with ER+ breast 
cancer develop recurrent disease because of ineffectiveness of hormonal therapy (Cuzick J. The 
Lancet Oncology 2010, 11(12):1135-1141), a large number of patients suffer from treatment-
related adverse events leading to treatment discontinuation (Crew KD. J Clin Oncol 2007, 
25(25):3877-3883). For patients with ER+ metastatic breast cancer, ET is often offered as the 
front-line treatment; however, this approach delays appropriate treatment in up to 50% of 
patients in whom ET is ineffective. In addition, ER status can change over time and be variable 
among metastatic sites within the same patient. It is not practical, however, to biopsy all sites of 
metastatic disease to characterize fully the ER status of a patient’s tumor burden. Our proposed 
PET-imaging strategy, described below, would allow for functional assessment of the ER 
pathway non-invasively and in all macroscopic tumor foci, and, if successful, has the potential to 
improve treatment decisions in patients with ER+ breast cancer. 
 
In vitro assessment of hormone-responsive breast cancer: Immunohistochemical (IHC) assays of 
ER and PgR have numerous shortcomings; better predictive assays are needed. Selection of ET 
is based on hormone receptor status of the breast cancer, which is routinely assessed by in vitro 
IHC assays that have increasingly replaced quantitative radioligand binding assays. IHC 
determinations of hormone receptor status in breast carcinoma are equally sensitive, and more 
specific than biochemical determinations by ligand binding (Rhodes A. J Clin Pathol 
2000;53:292-301; Hammond ME. Arch Pathol Lab Med 2010;134:e48-72.). However, while the 
results of IHC assays provide some predictive value in selecting the best follow up therapies, as 
noted above, even in ER+ disease, response rates to ETs are only approximately 50%. 
Furthermore, IHC assays of ER and PgR have a number of other shortcomings: (a) Most notably, 
they provide limited information about the functional status of the receptors and the 
responsiveness of tumor to ET, as described above. (b) The evaluation criteria to establish the 
positivity of ER and PgR are also not uniform in different laboratories, and widely ranging cutoff 
values for distinguishing positive from negative results have been used in IHC assays for both 
receptors. For example, a positive result can be considered the presence of greater than 1% or 
5%, or even 10%, IHC-positive cells (Elledge RM. Int J Cancer 2000;89:111-117). (c) A recent 
systematic review of the literature on the use of IHC for evaluation of ER and PgR found that up 
to 20% of current IHC test results worldwide may be inaccurate (false negatives or false 
positives) (Hammond ME. Arch Pathol Lab Med 2010;134:e48-72). (d) Also, tumors are 
heterogeneous, and fine needle or core biopsies may miss important regions of the tumor. (e) 
Finally, in recurrent or metastatic breast cancer, the ER or PgR status of the lesions may not 
always be the same as that of the original primary tumor. Indeed, the receptor status of recurrent 
or metastatic disease may be more predictive of response to ET. However, because metastatic 
lesions often are not amenable to biopsy and because the biopsy of multiple lesions is 
impractical, the receptor status of individual lesion(s) cannot be easily determined. 
 
1.2 
IMAGING  ER and PR in BREAST CANCER USING PET: FES and FFNP 
 
Non-invasive assays of prognostic and predictive biomarkers by PET: advantages of in vivo 
assessment of ER and PgR. The in vivo measurement of the ER and PgR expression in breast 
cancer could offer several advantages over current in vitro methods. These include (a) assessing 
ER and PgR expression of the entire tumor volume rather than just a part of the tumor 


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(addressing the intrinsic heterogeneity of receptor expression and limited sampling by needle 
biopsy), (b) directly assessing the binding of the receptors to the imaging agent, a hormone 
analogue, rather than their antigenic properties as measured by IHC, and (c) evaluating the 
effects of therapy on receptor expression of the tumor, as ER and PgR expression may change 
during therapy. Finally, (d) in vivo imaging can simultaneously assess the receptor expression of 
primary and metastatic sites, which may vary across lesions within any given patient.  
 
Positron emission tomography (PET) is a highly sensitive functional imaging technique that 
provides high-resolution images and enables subnanomolar concentrations of receptor targets to 
be quantified. PET using radiolabeled agents is a novel option for non-invasive identification of 
the presence of specific targets throughout the body, tracing and quantifying the distribution of 
imaging agent binding to the target and ultimately helping to better understand the in vivo 
behavior and effectiveness of ET of individual patients. Significant efforts have been made to 
develop imaging agents labeled with positron-emitting radionuclides for noninvasive evaluation 
of ER and PgR expression, and localization of ER and PgR-overexpressing tumors. However, 
while several radiopharmaceuticals for imaging ER-positive lesions have been developed, 
including [18F]-fluoroestradiol (FES), which is now widely used in many medical centers 
worldwide, the development and evaluation of PgR-imaging based tracers has lagged behind 
(See below) (Linden, HM & Dehdashti F. Semin Nucl Med. 2013 Jul;43(4):324-9).  
 
The focus of this project is to investigate the use of PgR-PET to improve selection of those 
patients with advanced breast cancer who will benefit from endocrine therapies.  
 
Assessment of functional status of ER with FES-PET.  To assess in vivo ER availability and 
functional status, efforts have been ongoing for over two decades to identify and evaluate 
radioligands with high affinity and selectivity for binding to ER and with properties suitable for 
imaging. Several steroidal and non-steroidal estrogens labeled with 77Br, 75Br, 123I, and 18F 
have been synthesized (Katzenellenbogen JA. J Nucl Med. 1995 Jun;36(6 Suppl):8S-13S; ; 
Jonson SD. Q J Nucl Med. 1998 Mar;42(1):8-17). One of the most promising positron-emitting 
radiolabeled estrogen analogs identified is FES. This radioligand has high specific activity, high 
selective ER binding in vitro, and high affinity for ER+ target tissues (e.g., uterus and mammary 
tumors) in animal models (Kiesewetter DO. J Nucl Med. 1984 Nov;25(11):1212-21; Mathias Ci., 
Intl Radi4ppl Instiwn [B] 1987;14:15â; Brodack JW., Int J Rad Appl Instrum A. 
1986a;37(3):217-21;  Brodack JW J Nucl Med. 1986b May;27(5):714-21). We and others have 
utilized FES to assess the functional status of tumor ERs in women with breast cancer, and we 
have shown that tumor uptake of FES correlates with ER levels measured in vitro and may be 
more predictive of response to hormonal therapy than knowledge of the tumor ER status (Mintun 
MA Radiology 169:45-48, 1988,; Mortimer JE Clin Cancer Res 2:933-939, 1996; Linden HM. . 
J Clin Oncol. 2006 Jun 20;24(18):2793-9; Linden HM. Clin Cancer Res. 2011 Jul 
15;17(14):4799-805; Peterson LM1. Mol Imaging Biol. 2014 Jun;16(3):431-40; Currin El. Curr 
Breast Cancer Rep. 2011 Dec;3(4):205-211). FES is currently being studied in a number of 
clinical research centers in the US (most notably by us at Washington University in St. Louis, but 
also at the University of Washington, Memorial Sloan Kettering Cancer Center and Harvard 
Medical School) and internationally (Korea, Japan, Europe) to evaluate its predictive value in 
selecting patients for different endocrine therapies. Through this work, FES has been shown to 
have a high negative-predictive value (NPV), i.e., absence of FES uptake in tumor means that 


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response to ET is unlikely, but its positive-predictive value (PPV) has been limited in identifying 
patients who are likely to respond to ET. 
 
As stated above, ER status may be discordant within the same patient; thus, a single biopsy may 
not be representative of the ER characteristics of the entire tumor burden in the patient. Several 
studied evaluated within patient heterogeneity of FES uptake (Mortimer JE Clin Cancer Res 
2:933-939, 1996; Kurland BF J Nucl Med. Oct 2011; 52(10): 1541–1549 and Yang Z Clinical 
Breast Cancer, Vol. 13, No. 5, 359-63 2013). We found heterogeneity (discordance) in FES 
uptake in 4 of the 17 (24%) patients with breast cancer who had multiple metastatic lesions; each 
patient had a single discordant site (Mortimer JE Clin Cancer Res 2:933-939, 1996). Yang et al. 
reported discordance in FES uptake in 9 of 32 (28%) of their patients with metastatic breast 
cancer (Yang Z Clinical Breast Cancer, Vol. 13, No. 5, 359-63 2013). The difference was 8.2-
fold in FES uptake among lesions within the same individual. In a subgroup analysis of the 
patients who had prior ET, 9 of the 24 patients (37.5%) showed within patient heterogeneity in 
FES uptake. It is possible that ER heterogeneity plays an important role in determining response 
to ET in those with substantial within patient heterogeneity in receptor expression. As a 
noninvasive tool, PET as a noninvasive tool has the potential to provide this important 
information on disease heterogeneity, which may be crucial in selection of the mode of therapy 
in the patients with metastatic breast cancer, an aspect that we plan to explore in Specific Aim 2 
in this project.  
 
PgR imaging with PET in breast cancer patients: 18F-FFNP, an imaging agent of great promise.  
As stated above, the combination of ER and PgR expression is a stronger predictor of response to 
ET than either alone. The search for a more suitable progesterone-based imaging compound was 
continued by the Katzenellenbogen group, and they have described several new F-18 labeled 
radioligands. One of these, 21-[18F]fluoro-16α,17α-[(R)-1’-α-furylmethylidene)dioxy]-19-
norpregn-4-ene-3,20 dione (18F-FFNP), a radioligand with high affinity and selectivity for PgR 
and improved imaging characteristics, has been developed. 18F-FFNP showed very marked and 
selective uptake in target tissues in rodents. In addition, only low levels of 18F-FFNP 
accumulated in the liver and fat, because its decreased lipophilicity translated into low in vivo 
non-specific binding. This compound is considered to be the most promising progestin derivative 
for PET imaging (Kochanny et al., J Med Chem. 1993; 36(9):1120-7; Buckman et al., J Med 
Chem. 1995; 38(2): 328-37; Kym et al., J Med Chem. 1993; 36(9):1111-9; Vijaykumar et al., J 
Org Chem. 2002; 67(14):4904-10). 
 
A first in human study that evaluated the safety and dosimetry of 18F-FFNP has been completed 
at Washington University. Twenty patients with 22 primary breast cancers (2 patients each had 
two cancers in different quadrants of the same breast) were evaluated.  We showed that a 
significantly higher tumor uptake (p = 0.001) in PgR+ than PgR- breast cancer. The study also 
showed that 18F-FFNP-PET imaging is a safe method for evaluating tumor PgR non-invasively 
in patients with breast cancer (Dehdashti et al, 2012 J Nucl Med. 2012 Mar;53(3):363-70). In 
addition, human radiation doses calculated from the PET images indicated an effective dose of 
0.02 mSv/MBq, a value that is comparable to that reported for 16-[18F]fluoro-17-estradiol 
(18F-FES) (0.022 mSv/MBq), an estrogen-receptor imaging tracer (see below). 
 


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1.3 
ASSESSMENT of ER FUNCTION WITH PET: 
 
ER and PgR IHC assays, and clinical flare have very limited predictive value. The initial choice 
of agents for treating advanced disease is based on the status of the ER; typically: Patients with 
hormone -sensitive receptor-positive disease are treated with hormone manipulation, whereas 
those with hormone -resistant receptor-negative disease receive chemotherapy.  Although most 
breast cancer is ER+, ET is underutilized in this country in favor of more toxic chemotherapy 
regimens. In part, this is because ETs do not always succeed, even in ER+/PgR+ cancers,. Also, 
many oncologists believe that response to chemotherapy occurs more rapidly and is easier to 
assess than the response to ETs.  
 
A so-called “clinical flare reaction” occurs in 5-20% of women with breast cancer who receive 
certain hormonal therapies. Within 7-10 days after starting ET (particularly with tamoxifen), 
patients who experience a flare reaction have subjective and objective findings suggesting 
disease progression. It is postulated that this transient flare reaction is caused by initial agonist 
effects when tamoxifen levels are low; however, with continued treatment, tamoxifen becomes 
antagonistic, frequently causing subsequent tumor regression in a patient who had an initial flare 
(Vogel J Clin Oncol 1995; 13:1123–1128). Thus, the flare reaction, when it occurs, is an 
indicator of functioning ERs and is a predictor of therapeutic responsiveness, as 80% of these 
patients will respond with continuation of the hormonal agent (Vogel J Clin Oncol 13:1123–
1128). Clinically, however, it is difficult to distinguish a flare reaction from disease progression 
and this, as well as its low frequency, makes it an insensitive and unreliable predictive index of 
ET response. 
 
A hormone-challenge paradigm using tamoxifen or estradiol: an indirect assessment of ER 
function by a “metabolic flare”. We studied women with advanced hormone-sensitive breast 
cancer by serial PET imaging with 18F-fluorodeoxyglucose (FDG) and FES before and 7-10 
days after tamoxifen therapy was initiated to investigate whether the metabolic correlates of a 
subclinical flare reaction, due to the initial agonist effects of the drug, could be documented by 
functional imaging (Mortimer, JE. J Clin Oncol. 2001; 19(11):2797-803). This study 
demonstrated that PET provides unique information about tumor response at the biochemical 
level early during therapy (within 10 days) that could be used to predict ultimate therapeutic 
response (Dehdashti, F. Eur J Nucl Med. 1999 Jan;26(1):51-6, Mortimer, JE. J Clin Oncol. 2001; 
19(11):2797-803). Our findings supported our hypothesis that tumor receptor levels and 
hormone-induced metabolic flare reactions could be assessed by imaging in vivo with FES-PET 
and FDG-PET. The most important single predictors of response to tamoxifen were high baseline 
FES uptake (P=0.0007) and an increase in FDG uptake after tamoxifen (P=0.0002). The latter 
measure gave PPV and NPV of about 90%, which considering that all patients were ER+ by IHC 
assays, represented significantly improved predictive accuracy, notably obtained after only 10 
days of treatment. This study, which concluded some time ago, included only patients who 
received tamoxifen as the initial treatment for their advanced disease. Now, many women who 
present with metastatic disease have already been treated with tamoxifen in the adjuvant setting. 
In such patients, additional second-line and third-line hormonal therapies include aromatase 
inhibitors (AIs) and the full estrogen antagonist, fulvestrant.  


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Because the mechanisms of action of these new endocrine therapy agents are different than that 
of tamoxifen, they do not typically cause clinical flare. Accordingly, we investigated the 
induction of a “metabolic flare reaction” using a brief treatment with estradiol, a more potent 
estrogen than tamoxifen, seeking to find a more robust response. Once again, we found that both 
baseline tumor FES uptake and metabolic flare, assessed by serial FDG-PET, after a 1-day 
estradiol challenge, were predictive of responsiveness to endocrine therapy in ER+ breast cancer 
(Dehdashti F. Breast Cancer Res Treat. 2009 Feb;113(3):509-17). We found that with an 
increase in tumor FDG uptake ≥ 12% as the criterion for defining estradiol-induced metabolic 
flare based on ROC curve analysis, the PPV for response to endocrine therapy was 100% (all 15 
of such patients responded) and the NPV was 94% (only 2 of 36 such patients responded). The 
baseline FES uptake (using a cutoff SUV of ≥ 2 as the criterion for defining functional ER based 
on our prior experience) had PPV and NPV for response to therapy of 50% (12 of 24 FES+ 
patients responded) and 81% (5 of 27 FES‒ patients responded), respectively. Thus, metabolic 
flare assessed by FDG-PET was again a stronger predictor of response to ET than a direct 
measure of ER level by FES-PET. 
 
Subsequently, we studied another group of patients with hormone-sensitive metastatic breast 
cancer treated with an AI, with at least 24 weeks of progression-free survival, or relapse after 
two or more years of adjuvant AI, again using serial FDG-PET and estradiol challenge. An 
estradiol stimulated increase in FDG uptake of ≥ 12% (prospectively defined from the prior 
study) was predictive of response (PPV of 80%; 95% CI: 61%–92%). (Ellis MJ. JAMA 2009 
Aug 19;302(7):774-80). This compares with PPV of 100% on the prior study.  
 
While the results from this FDG-PET hormone challenge test were promising, the increase in the 
SUV for FDG after estradiol was relatively modest in responders, with increases rarely 
exceeding 40%. Consequently, many values lie within 5% of the cutoff, indicated by the fact that 
25% of all the values lie within the gray area.  Thus, this hormone-challenge test lacks the level 
of robustness needed to be truly useful at different clinical sites. Consequently, to make the best 
prediction of potential benefit from ETs, there is a need for a more sensitive and robust test for 
the functional status of ER in breast tumors by PET  
 
A direct assessment of the functional status of ER with FFNP-PET as a predictor of response to 
ET. PgR is a gene highly regulated by ER at the RNA and protein level, and the presence of PgR 
in ER+ breast cancer was proposed to indicate that ER was functional and therefore that the 
likelihood of benefit from endocrine therapy would be greater. While reasonable, this idea has 
not been uniformly accepted, and PgR levels in breast cancer are often not considered in therapy 
decisions (Davies C, Godwin J, Gray R, et. al. Lancet. 2011, 378, 771-784. PMCID: 3163848). 
The conclusion that PgR levels are not of predictive importance, however, represents a serious 
oversight: One should expect PgR levels to be high only if ER is functional and the stimulating 
hormone, estradiol, were present at sufficient levels. PgR assay results, however, are not 
controlled for endogenous estradiol levels, which in most cases (post-menopausal patients) 
would be very low! Thus, we believe that using 18F-FFNP -PET to measure whether PgR levels 
in tumors change upon estrogen stimulation will prove to be a very sensitive way to demonstrate 
that tumor ERs are functional and thus likely to mediate response to ETs 
 


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We have established the efficacy of this “hormone-challenge test for functional ER” in new 
mammary cancer models derived from STAT1-/- mice (Fowler A. J Nucl Med. 2012; 53:1119-
26). In ovary-intact mice, SSM2 tumors, which are ER+ but ET non-responsive, show no 
decrease in PgR (PgR-A and PgR-B) levels upon antiestrogen with Fulvestrant treatment, 
whereas SSM3 tumors, which are ER+ and ET responsive, show a great reduction in PgR levels. 
More notably, in the SSM3 ER+/ET-responsive tumors, both a large decrease in 18F-FFNP 
uptake after Fulvestrant treatment and a large increase in 18F-FFNP uptake are observed after 
estradiol. The average tumor-muscle (T/M) ratios increased from 3.6 for the untreated mice to 
6.9 in SSM3 mice after 24 hours of estrogen stimulation. Therefore, an up or down change in 
18F-FFNP T/M ratio in mammary tumors accurately predicted sensitivity to estrogen addition or 
deprivation therapy, respectively, and was able to distinguish between ER+/endocrine-responsive 
and ER+/endocrine non-responsive disease.  
 
More recently, Chan et al. (manuscript in preparation) used the same model to follow the 
decrease in 18F-FFNP mammary tumor uptake in response to estrogen deprivation therapy by 
ovariectomy, which reduces tumor PgR levels. Notably, in this study, they compared PET 
imaging using 18F-FDG (to measure glucose uptake), 18F-FES (to measure ER levels), or 18F-
FFNP (to measure PgR levels) to see which probe would best predict response to estrogen 
deprivation therapy. Uptake in endocrine-sensitive and -resistant mammary tumors (both of 
which were ER+) was measured by PET in mice before ovariectomy, and on days 3 and 4 after 
this form of estrogen deprivation therapy. Specificity of 18F-FFNP uptake in ER+ mammary 
tumors was determined by competition assays using unlabeled ligands for PgR and confirmed by 
IHC. The levels of 18F-FES and FDG tumor uptake remained unchanged in endocrine-sensitive 
or resistant tumors after estrogen deprivation therapy compared to those at pre-treatment. By 
contrast, estrogen deprivation therapy led to a reduction in PgR expression and 18F-FFNP uptake 
in endocrine-sensitive tumors, but not in endocrine-resistant tumors, as early as 3 days post-
treatment, importantly demonstrating that PgR-PET provides a more sensitive and robust 
measure of tumor response than 18F-FES- or 18F-FDG-PET.  
 
This type of hormone-challenge paradigm was validated by us in human breast cancer patients, 
as described above, using 18F-FDG-PET to measure changes in tumor metabolism after estradiol, 
and although it was highly predictive of ET response, the 18F-FDG changes were mostly quite 
small and were less predictive of response to ET in patients who had been heavily treated with 
ET (Dehdashti F. Breast Cancer Res Treat. 2009 Feb;113(3):509-17; Ellis MJ. JAMA 2009 Aug 
19;302(7):774-80). Because PgR is more acutely regulated by estrogen, it should offer a much 
greater dynamic range of response.  
 
2.0 
OBJECTIVES 
Our hypothesis is that change in 18F-FFNP uptake following 1-day of estradiol is a strong 
predictor of response to ET in patients with hormone-sensitive (ER+/± PgR+)/HER2- breast 
cancer.  We believe the increase in tumor PgR after 1-day estradiol will be more reliable than a 
decrease after estrogen deprivation, particularly because most breast cancer patients are 
postmenopausal and basal PgR levels will be low due to the low endogenous, menopausal 
estrogen levels. Thus, we propose to use a hormone-challenge test for assessment of functional 


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ER based on the change in 18F-FFNP uptake before and after a 1-day estradiol challenge in 
patients with ER+ metastatic breast cancer. We expect that the changes in 18F-FFNP uptake to be 
a highly reliable means to predict a favorable response of ER+ breast cancer to ET.  We propose 
to study patients with biopsy-proven  new diagnosis of ER+ metastatic/recurrent breast cancer 
 who are going to be treated with ET (tamoxifen, AI agents or faslodex) according to standard of 
care. 
2.1. 
Evaluate whether the change in tumor uptake of 18F-FFNP following a 1-day estradiol 
challenge differs among patients who respond to ET versus those who do not respond. 
 
2.1.1 Determine the optimum cutoff value for change in tumor 18F-FFNP uptake after 
estradiol to distinguish responders from nonresponders.  
 
2.1.2 Evaluate whether the change in tumor uptake of FFNP can identify patients with 
hormone-sensitive disease who will respond to ET with greater sensitivity and selectivity 
than tumor PgR measured by IHC.  
 
2.2 
Evaluate the heterogeneity of tumor 18F-FFNP uptake at baseline and after estradiol 
challenge in patients with multiple metastatic foci.  
2.2.1. Explore whether response is related to 18F-FFNP uptake heterogeneity.  To assess 
the heterogeneity at the baseline, a comparison with FDG-PET/CT will be performed to 
map the metabolically active disease. Once the metabolically active disease is 
determined, FDG+/FFNP- will be considered as discordant lesions.  At follow-up, the 
baseline FFNP-PET/CT will be correlated with follow-up FFNP-PET/CT to assess 
heterogeneity in response to estradiol.  
 
3.0 
PATIENT SELECTION  
 
3.1 Inclusion Criteria 
 
1. Patient must be postmenopausal defined as meeting one or more of the 
following: 
a. Age ≥ 60 years 
b. Amenorrheic for at least 12 months 
c. Surgically sterile- having undergone bilateral oophorectomy,  
d. FSH laboratory test level in postmenopausal range according to institutional 
standards (note FSH lab test must be ordered as standard of care to 
determine best treatment option and should not be ordered simply to confirm 
eligibility to this study)  


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e. OR Pre-menopausal for whom standard ET is planned with ovarian 
suppression (imaging on study should be completed prior to start of ovarian 
suppression) 
2. Patient must have histological or cytological confirmed breast cancer and fall 
into one of the following categories: 
a. New diagnosis with plans for at least 6 months of neoadjuvant ET or any 
amount of neoadjuvant ET if surgery is planned as this will be used for 
response assessment .   
b. Patients with newly diagnosed metastatic breast cancer or patient with 
known metastatic disease who has progressed while on therapy (no washout 
period is needed if the patient was treated with AIs or chemotherapy, but 2 
months washout period is needed if the patient was treated with tamoxifen) 
who are going to be treated with ET.   
3. Patient must have any one of the following types of breast cancer (primary or 
metastatic): ER+/PgR+/HER2– or ER+/PgR–/HER2–.  
a. ER+ is defined as Allred score of at least 4 and greater.  
b. PgR+ is defined as Allred score of at least 4 and greater. 
c. IHC is the primary assay methodology for HER2. HER2– refers to HER2 of 
0, 1+ by IHC or negative by fluorescence in situ hybridization (FISH) 
4. Patient must have at least one measurable lesion according to RECIST 1.1 by 
radiological evaluation (ultrasound, mammography, MRI, CT, PET) or physical 
examination.  
a. Patients with evaluable osseous metastasis that are lytic or mixed lytic-sclerotic 
are eligible.  
b. Patients with hepatic lesions may be eligible provided the location of the lesion is 
peripheral or not too close to hepatic ducts.  Decision on hepatic lesion eligibility 
will be made by the principal investigator or sub-investigator after careful review 
of all available imaging to ensure evaluation of the lesion will not be obscured by 
normal hepatobiliary excretion of 18F-FFNP.   
5. Patient must be able to understand and willing to sign a written informed 
consent document. 
6. Prior chemotherapy or endocrine therapy is allowed  
7. The patient must have an ECOG performance status of 0-2 or, based on the 
judgment of the treating medical oncologist,  can tolerate imaging and at least 6 
months of ET  
8. The patient should have a life expectancy of > 6 months.  
 
3.2 Exclusion Criteria 
 
1. Patient with other invasive malignancies, with the exception of non-melanoma 
skin cancer or cervical carcinoma in-situ, who had (or have) any evidence of the 
other cancer present within the last 5 years 
2. Unable to tolerate up to 60 min of PET imaging per imaging session.   
3. Patients with non-measurable non-evaluable lesions such as pleural effusion are 
not eligible to participate. 


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4. Patients with vertebral lesions that, in the opinion of the Principal Investigator 
and the treating medical oncologist, pose an imminent risk for cord 
compression.    
 
3.3 Inclusion of Men and Minorities 
Because breast cancer occurs most often in women, and the receptor 
status of breast cancer in women has been studied more often, men will 
not be eligible for this trial.  The trial is open to members of all races and ethnic 
groups and participation will be encouraged. 
 
4.0 
PATIENT REGISTRATION 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility collecting the information listed below: 
 
1. The registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center Database 
 
All patients must be registered through the Siteman Cancer Center database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  
Patients will also be identified by first, middle, and last initials.  If the patient has no 
middle initial, a dash will be used on the case report forms (CRFs).  All data will be 
recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
METHODS 
 


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5.1 
Study Design 
 
A single center, open-label, baseline controlled diagnostic imaging study designed to 
assess the predictive value of 18F-FFNP-PET/CT imaging women who complete an 
estradiol challenge test.   
 
5.2 
Patient Population  
 
Fifty postmenopausal women OR Pre-menopausal for whom standard ET is planned with 
ovarian suppression (imaging on study should be completed prior to start of ovarian 
suppression) with newly diagnosed, metastatic or recurrent breast cancer which is ER+ 
disease (ER+/PgR+/HER2–, ER+/PgR–/HER2–) will undergo one FDG PET/CT scan to 
map the metabolically active disease plus two 18F-FFNP-PET/CT; one prior to estradiol 
challenge test and a second one immediately following one day of estradiol challenge test 
(2 mg tid).  All scans will be completed prior to the start of standard of care ET.  Patients 
who have had an FDG-PET/CT scan (or other functional studies such as bone scan in 
patients with bone dominant disease or a contrast CT scan for hepatic dominant disease) 
done within 8 weeks of study entry may not need to repeat the scan at the discretion of 
the Principal Investigator and Co-Investigator Medical oncologists.  Any subject whose 
imaging is deemed not evaluable for any reason or any subject who does not complete 
both FFNP-PET/CT imaging sessions for any reason may be replaced on study.  The 
study ID assigned to the subject being replaced will not be re-used.    
 
5.3 
Estradiol Challenge Test  
 
The estradiol challenge test will consist of administering a total of 6 mg of estradiol 
dosed orally as three 2 mg tablets with each tablet being administered approximately 8 
hours apart and within a 24 hour period. This estradiol medication will be provided to the 
patient by the study. Dosing will be such that the third dose of estradiol will be 
administered at a minimum 8 hours (8 ± 2 hours) and a maximum 48 hours prior to the 
scheduled injection of 18F-FFNP for the repeat 18F-FFNP-PET/CT imaging session.  
Timing of the estradiol administration is critical so that the effect of estradiol will be 
captured within the imaging session.  The first dose of estradiol can be administered as 
soon as immediately following the baseline 18F-FFNP-PET/CT imaging session with the 
post estradiol 18F-FFNP -PET/CT imaging session being scheduled for the following day.  
No more than a maximum of 4 weeks should occur between the baseline and the post 
estradiol challenge 18F-FFNP -PET/CT imaging sessions.  A subject specific calendar 
will be given to each participant that includes dates and times for estradiol administration 
and follow up 18F-FFNP-PET/CT imaging session.  Whenever possible, blood will be 
obtained for measurement of the serum estradiol level, using a high-sensitivity 
radioimmunoassay (Herting MM. BJ. Cereb Cortex. 2012 Sep;22(9):1979-92) before 
injection of 18F-FFNP at the baseline and after estradiol challenge before the 2nd 18F-
FFNP injection to document that it increased appropriately.   
 


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5.4 
Risks Related to Estradiol Challenge Test.  
Side effects from taking a total 6 mg of estradiol over a 24 hour period are expected to be 
minimal.  Subjects may experience nausea from a dose this small.  When estradiol is 
administered in much higher doses as therapy and given daily over a longer period of 
time the following side effects have been reported:  nausea and or vomiting; bone pain, 
breast tenderness and/or enlargement; vaginal bleeding, tiredness, changes in skin color; 
insomnia (difficulty falling or staying asleep); yeast infections, increase or decrease in 
vaginal secretions, and headaches 
  
6.0 
IMAGING PARAMETERS AND ANALYSIS 
All research imaging studies will be performed using the CTI/Siemens Biograph 40 
PET/CT scanner.  The Biograph 40 is a 4-ring PET scanner made up of a multi-LSO-
detector ring system with 3D acquisition and reconstruction and 109 image planes with 
an extended 21.6 cm axial field of view, enabling the detection of 78% more photons 
(compared with a conventional-field-of-view scanner).  The scanner features high 
resolution (less than 5mm in transaxial and axial dimensions) with Pico 3D ultra-fast 
electronic for decreased dead-time and high signal-to-noise ratio.   
 
All patients will undergo routine clinical staging as dictated by the treating medical 
oncologist or surgeon.  The results of the PET studies will not be provided to the patient 
or the treating oncologist unless the CT images demonstrate an unsuspected, potentially 
life-threatening abnormality that warrants further investigation and/or urgent therapy 
(e.g., a mass impinging on the spinal cord seen on the CT images). 
 
If performed for research purposes, the results of the 18F-FDG-PET/CT scan will be fully 
interpreted and reported to the medical record following the same procedures as if done 
as a standard of care examination.   
 
6.1 Drug Preparation 
6.1.1 
18F-FFNP 
18F-FFNP  will be prepared using an adaptation of a published procedure 
(Buckman BO J Med Chem. 1995;38(2):328-37; Kym PR J Med Chem. 
1993;36(9):1111-9 ; Vijaykumar D J Org Chem. 2002;67(14):4904-10) . The 
diastereomerically pure 21-mesylate, endo-9a precursor was reacted with non–
resin-treated [18F]-fluoride, Kryptofix222 (Aldrich), and potassium carbonate in 
acetonitrile at 85C for 5 min. The reaction mixture was prepurified by passing 
through a silica light SepPak (Waters), followed by reversed-phase high-
performance liquid chromatography purification. 18F-FFNP was extracted from 
the high-performance liquid chromatography mobile phase using solid-phase 
extraction and was reconstituted in 10% ethanol in saline. Starting from 11.1 GBq 
(300 mCi) of 18Ffluoride and using 0.4 mg of potassium carbonate and prompt 
work-up to avoid the decomposition of the acid- and base-labile 18F-FFNP, we 


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produced 0.74–1.11 GBq (20–30 mCi) of 18F-FFNP at the end of synthesis (90 
min). The final formulation of 18F-FFNP is stabilized in ethanol or saline. Non–
resin-treated 18F-fluoride was used to achieve high specific activity. The specific 
activity was measured by high-performance liquid chromatography to be 185– 
740 GBq (5,000–20,000 mCi)/µmol, and the effective specific activity was 
measured by receptor binding assay to be up to 740 GBq (20,000 mCi)/µmol. 
6.1.2 
18F-FDG 
FDG  will be prepared and distributed under the Washington University 
Cyclotron Facility’s ANDA for FDG.   
 
6.2 
18F-FDG-PET/CT Imaging Parameters  
If performed for research purposes, subjects will undergo standard oncologic 18F-FDG-
PET/CT imaging that includes the base of the skull to upper thighs (or extended to 
include metastatic disease in the lower legs, or possible brain metastasis, if applicable) 
imaging.   
Subjects will be asked to fast for a minimum of 4 hours with only plain water to drink 
during the fasting period.  On the day of the scheduled scan a small IV catheter will be 
placed in an upper extremity arm vein (preferably contralateral to the patient’s breast 
cancer) to allow for injection of FDG.  Prior to injection a small sample of blood (less 
than 1 teaspoon) will be obtained for glucose measurement.  Injection of FDG will 
proceed if blood glucose, if 200 mg/dL or less or with approval of the PI or nuclear 
medicine co-investigator (authorized user), if blood glucose is greater than 200 mg/dL. 
FDG dose will be based upon weight according to the standard nuclear medicine imaging 
protocol with the average dose injected 15 mCi.  Imaging will occur 50-70 minutes post 
FDG injection.  Subjects should be asked to rest and remain quiet, comfortable, and 
warm during the uptake phase.  To avoid brown fat uptake the use of warm blankets is 
encouraged.  IV or oral hydration (up to 500 ml unless subject has known fluid 
restrictions) is also encouraged during the uptake period.   
Immediately prior to imaging, subjects will be asked to empty the bladder in the 
restroom.  The subject will be placed supine on the imaging table with arms resting above 
the head or secured comfortably by the side of the body.  A spiral CT scan for attenuation 
correction will be obtained from the skull through the upper thighs.  The CT will consist 
of a 10-20 second topogram for determining correct anatomical positioning followed by a 
spiral CT at a maximum of 50 mAS.  Care dose will be calculated for each scan and the 
care dose imaging parameters will be used if less than the maximum 50 mAs is 
calculated.  CT imaging will be acquired with a standard 120 kVp.  Average spiral CT 
scan time is 15-30 seconds.  Scans are acquired using a 5 mm slice thickness.  


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Immediately after the attenuation CT scan and approximately 30 minutes after injection 
of FFNP, emission imaging will be obtained (2-5 minutes per bed position adjusted as 
needed based on subject height, weight, and injected dose). 
 
6.3 
18F-FFNP-PET/CT Imaging Parameters 
 
18F-FFNP-PET body imaging will includes the base of the skull to upper thighs (or 
extended to include metastatic disease in the lower legs, or possible brain metastasis as 
applicable) imaging.  Site of scan can also be modified based on information obtained 
from FDG-PET/CT imaging.   
 
There are no eating or drinking restrictions for 18F-FFNP-PET imaging.  On the day of 
the scheduled scan a small IV catheter will be placed in an upper extremity arm vein 
(preferably contralateral to the patient’s breast cancer) to allow for injection of 18F-FFNP.  
NOTE: FFNP is sticky and injection through port-a cath or extended amounts of IV 
tubing should be avoided whenever possible.  Baseline vital signs consisting of blood 
pressure, heart rate, breathing rate and temperature will be obtained prior to the injection 
of 18F-FFNP.  A maximum dose 10 mCi (dose range 7-10 mCi) of 18F-FFNP will be 
injected into the established IV line.  The dose will be followed with a normal saline 
flush of 10-30 ml.  Subjects will be asked to rest comfortably in the injection room for 
approximately 30-40 minutes while 18F-FFNP circulates in the body (warm blankets and 
oral hydration is encouraged).  Approximately 10-30 minutes after injection and during 
this resting period vital signs will be taken to assess for any post injection changes.   
 
Immediately prior to imaging, subjects will be asked to empty the bladder in the 
restroom.  The subject will be placed supine on the imaging table with arms resting above 
the head or secured comfortably by the side of the body.  A spiral CT scan for attenuation 
correction will be obtained from the skull through the upper thighs.  The CT will consist 
of a 10-20 second topogram for determining correct anatomical positioning followed by a 
spiral CT at a maximum of 50 mAS.  Care dose will be calculated for each scan and the 
care dose imaging parameters will be used if less than the maximum 50 mAs is 
calculated.  CT imaging will be acquired with a standard 120 kVp.  Aveage spiral CT 
scan time is 15-30 seconds.  Scans are acquired using a 5 mm slice thickness.  
Immediately after the attenuation CT scan and approximately 30 minutes after injection 
of FFNP, emission imaging will be obtained (2-5 minutes per bed position adjusted as 
needed based on subject height, weight, and injected dose). The 18F-FFNP dose and the 
scans parameters will be kept as close as possible for both 18F-FFNP-PET/CT scans in 
each patient. 
 
At the end of the imaging session, subjects will be encouraged to void and post imaging 
vital signs will be assessed prior to discharge.   
 


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6.4 Vital Sign Assessments 
All vital signs will be recorded on the case report form. Vital signs may be obtained with 
the subject in the supine or upright position. Care will be taken to obtain subsequent 
recordings with the subject in the same position (supine or upright). Although allergic or 
other immediate adverse reactions are not anticipated, subjects will be monitored for at 
least 30 min post injection in an area where emergency equipment is available. Vital 
signs will be obtained pre-injection, within 30 min post injection, and at the completion 
of each imaging session. Vital signs will include the following: heart rate, systolic blood 
pressure, diastolic blood pressure, respiratory rate, and body temperature. Changes in 
vital sign assessment will be determined separately at each imaging session and 
considered noteworthy if they fall outside of normal range and / or the subject is 
symptomatic: Subjects whose baseline ranges start outside of normal range will be 
assessed if they are symptomatic and / or meet criteria for assessment due to change in 
readings as noted in table below   The following changes from baseline will be 
considered noteworthy:   
 
 
Observation  
Normal Range  
Change for Assessment 
Heart rate  
50 – 110 beats/min 
 > 30 beats per minute  
Systolic Blood Pressure 
80-140 mm Hg 
> 30 mm Hg 
Diastolic Blood Pressure 
60-90 mm Hg  
> 20 mm Hg  
Heart rate: 
 
 
> 30 beats per minute 
 
Systolic blood pressure 
> 30 mm Hg 
 
Diastolic blood pressure 
> 20 mm Hg 
Noteworthy changes will be documented on the Case Report Forms (CRF). The Principal 
Investigator will indicate on the CRF whether or not the changes in vital signs are 
clinically significant. If clinically significant, the principal investigator will assess the 
causality of the change to the injection of 18F-FFNP or PET/CT imaging. Clinically 
significant changes in vital signs will be followed as needed until they return to baseline 
or normal levels, or until follow-up is no longer warranted. If a clinically significant 
change of a vital sign is noted, it will be reported on the adverse event log.  
 
6.5 Image Analysis 
 
The emission images will be corrected for measured attenuation using CT data according 
to the provide scanner manufacturer software package.  FDG-PET/CT images will be 
evaluated and reported according to standard of care imaging procedures. 
 
FFNP-PET/CT images will be evaluated by one observer qualitatively.  PET images also 
will be evaluated semiquantitatively with the knowledge of the location of the lesion(s) 
by the use of the standardized uptake value (SUV) and tumor-to-normal tissue (T/N) 


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ratio.  The SUV is widely used for assessment of regional tracer accumulation in 
oncological studies, is technically simple to perform, and makes imaging easier for the 
patient because longer dynamic imaging is not required.  SUV is a decay-corrected 
measurement of activity per volume of tissue (nCi/mL) divided by the average activity 
per unit mass in the entire body.  The absolute change and the percent change in uptake 
of 18F-FFNP will be assessed semiquantitatively and correlated with the clinical and 
radiologic results and subsequently with the results of the clinical follow-up evaluation. 
In patients with multiple lesions, the uptake up to 5 most intense lesions seen on PET 
images will be determined and the overall average values for all of the known lesions 
also will be recorded. The changes in SUV and T/N between the baseline and post 
estradiol challenge FFNP-PET/CT images will be compared in responders and 
nonresponders. Volumes of interest (VOIs) will be drawn around the entire lesion with 
the knowledge of the location of the tumor. SUVmax will be determined within the VOI. 
In addition, a similar volume of interest will be drawn in a comparable normal tissue 
region. The T/N ratio will be calculated by dividing the SUVmax of the tumor by the 
average SUV of normal comparable tissue. The absolute change and the percent change 
in uptake of 18F-FFNP will be assessed semi-quantitatively and correlated with the 
clinical and radiologic results and subsequently with the results of the clinical follow-up 
evaluation. In patients with multiple lesions, the uptake of up to 5 lesions, selected as the 
most intense lesions seen on PET, will be determined and the overall average values for 
all of the known lesions also will be recorded. In addition, in patients with multiple 
lesions, SUVmax and T/N ratio will be measured for all known measurable lesions to 
assess within-patient heterogeneity in 18F-FFNP uptake. Considering the optimum cutoff 
value for 18F-FFNP uptake that distinguishes responders from nonresponders, lesions will 
be classified as 18F-FFNP+ for lesions with 18F-FFNP uptake at or greater than the cutoff 
value and 18F-FFNP– for lesions with 18F-FFNP uptake below the cutoff value. The 
changes in SUV and T/N after treatment will be compared in responders and 
nonresponders. The results of the PET studies will not be provided to the patient or the 
treating oncologist (see above). Clinical follow-up will provide information on tumor 
response, which will then be correlated with the sequential PET results to determine if 
these are predictive of ultimate response to estrogen therapy.  
 
6.6 Toxicities Related to 18F-FDG &-18F-FFNP PET/CT Imaging 
 
Likely: 
• Mild discomfort from the placement of the IV in the patient’s arm. 
 
Less Likely: 
• Discomfort from lying still on the imaging table. 
• There is a slight risk of bruising at sites of vein puncture. 
 
Rare: 
• There is a remote risk of infection and an even smaller risk of blood clot at the 
site of the IV placement 
• There is a rare possibility of an allergic-type or other adverse reaction to 
radioactively labeled drugs. While none have been reported to date with the 


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radioactive materials 18-F-FFNP or 18F-FDG, such a reaction could be serious 
and may result in death. 
 
• RADIATION EXPOSURE FROM PET/CT IMAGING: the amount of radiation 
exposure the patient will receive from one injection (15mCi) of 18F-FDG and 
the CT scan for attenuation correction is equivalent to a uniform whole body 
exposure of approximately 1.51 rem.  The amount of radiation exposure from  
18F-FFNP injection and the CT scan for attenuation correction is equivalent to a 
uniform whole body exposure of approximately 1.39 rem.  Patients will be 
scanned on 2 separate occasions with FFNP plus one FDG scan resulting in a 
total exposure of 4.28 rem.   
 
 
6.7 
Toxicities Related to Estradiol Challenge  
Because of the low dose and single administration toxicities from the estradiol challenge 
are not expted.  The following side effects have been reported by patients taking estradiol 
as treatment for breast cancer over an extended period of time: 
 
Likely/Common 
• upset stomach 
• nausea 
• vomiting 
• changes in appetite 
• generalized feeling of weakness or fatigue 
• fever 
• headache 
 
Less Likely/Less Common 
• weight gain 
• fluid retention 
• insomnia (unable to sleep) or drowsiness 
• vaginal discharge 
• spotting to darkening of the skin 
• breast discomfort or enlargement 
 
Rare 
• uterine fibroids 
• stroke 
• blood clots 
• allergic reaction and symptoms such as-unexplained rash, itching, hives, and 
swelling, irregular heartbeat, difficulty breathing and shortness of breath.  
• There is a rare possibility that the administration of estrace will cause symptoms 
of clinical flare.  Clinical flare can occur with any hormone used in the 
treatment of breast cancer.  Physicians recognize that women who experience a 


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clinical flare are likely to benefit from hormone therapy.  Clinical flare is a 
temporary worsening of the symptoms associated with your breast cancer such 
as increased bone and joint pain.  
6.8 
Evaluation of Tumor Response 
 
The patients will be followed by their treating oncologist every 3 months per 
standard of care scheduling and not dictated by protocol (or earlier in case of a 
suspicion of early progression) until disease progression. Clinical benefit (compete 
response + partial response + stable disease) will be determined ≥ 6 months after 
initiation of therapy. Response will be evaluated according to RECIST 1.1 
(Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in 
solid tumors:  Revised RECIST guideline (version 1.1).  Eur J Cancer 2009; 
45:228-47). This evaluation will be based on the composite results of imaging 
studies (CT, MRI, bone scintigraphy, FDG-PET, etc.), serum tumor markers and 
evaluation of symptoms as deemed appropriate by the treating physician at the 6-
month visit or at the time that there is evidence of clinical progression of disease, if 
before six months. Clinical response using RECIST version 1.1 by an oncologist 
will be defined as: 
 
6.7.1 
Complete Response: 
Disappearance of all target lesions: Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to <10 mm. 
 
6.7.2 
Partial Response (PR): 
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions 
taking as reference the baseline sum LD.  
 
6.7.3 
Progression (PD): 
At least a 20% increase in the sum of the LD of target lesions taking as references 
the smallest sum LD recorded since the treatment started or the appearance of one 
or more new lesions. 
 
6.7.4 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD taking as references the smallest sum LD since the treatment started. Patients 
having a documented response with no reconfirmation of the response will be listed 
with stable disease. 
 
6.7.5 
Osseous disease only or osseous-dominant disease:  
For patients with osseous metastasis only, a complete response was deﬁned as 
disappearance of all objective and clinical disease, including complete 
normalization of radiological studies and tumor markers. A partial response was 
deﬁned as a decrease in pain with evidence of recalciﬁcation of known osseous 
lesions on radiography. Disease progression was deﬁned as worsening of disease on 
nuclear medicine scan or radiographs or worsening of pain and decline in 


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performance status. Any response that did not meet the criteria for complete 
response, partial response, or progression was deﬁned as stable disease. 
 
6.9 
FOLLOW UP PROCEDURES 
Follow up will consist of 2 parts.  To assess for adverse events, approximately 24 ± 6 
hours following injection, a follow-up telephone call will be made to the patient, or if the 
patient chooses another family member who will be able to assess for adverse events.  In 
the event the patient is scheduled to be at the hospital for other testing or appointments, 
the assessment can also be made in person 
Clinical follow-up via chart review will occur to document clinical progression of disease 
or change in therapy.  Follow up chart review to assess for overall treatment response will 
also be conducted.  A chart review will be conducted periodically until recurrence, 
progression or change in treatment.  Data collected from the chart will include office 
notes from treating physicians, laboratory test results used to determine overall response 
and radiology reports and images.  Response will be determined by the treating 
physician(s)  
 


Version 02/01/2019 
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7.0 
STUDY CALENDAR   
 
Screening 
Baseline 
Estradiol 
Challenge3 
Post 
Estradiol  
Follow-
Up 
Informed Consent 
X 
 
 
 
 
Standard of Care chart 
review/Data 
collection1  
X 
 
 
 
X 
Serum Estradiol level 
blood draw  
 
X 
X 
X 
 
18F-FFNP -PET/CT 
Imaging2 
 
X 
X 
X 
 
18F-FDG-PET/CT 
Imaging4 
X 
 
 
 
 
1. 
Chart review/ data collection consists of obtaining source documents for eligibility check at screening and 
records pertaining to eligibility and treatment response as specified in section 6.6 at follow-up time point(s) 
2. 
FFNP-PET/CT imaging  one 2 separate occasions as described in section 6.0-6.2 of protocol  and follow up 
for adverse events as described in section 6.7 
3. 
Estradiol challenge 18F-FFNP-PET/CT imaging can be completed as soon as the following day as described 
in section 5.3.  A maximum of 4 weeks is allowed between the baseline and estradiol challenge scans  
4. 
If performed, FDG-PET/CT imaging must be done on day separate from FFNP-PET/CT.  Preference is for 
FDG to be scanned prior to FFNP but alternative scheduling options may be necessary 
 
7.1 Data Submission Schedule 
Case report forms with appropriate source documentation will be completed 
according to the schedule listed in this section. 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Eligibility Form  
Prior to baseline imaging session  
PET Imaging Form  
At time of each imaging session  
PET Image Analysis 
Approximately 24 weeks after estradiol 
FFNP-PET/CT challenge scan 
 
8.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
Subjects will be monitored for adverse events during the actual imaging period. Since FDG-
PET/CT imaging is provided per standard of care no adverse event assessments will be recorded.  
For FFNP-PET/CT imagings, subjects will be contacted by phone or in person approximately 


Version 02/01/2019 
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24± 6 hours after the injection of 18FFNP to assess for adverse events as related to 18F-FFNP 
injection, or PET/CT imaging.  Any adverse events that occur within 24 hours of administration 
of 18F-FFNP or within 24 hours of the first dose of estradiol which are graded related or possibly 
related to participation in the research will be reported according to the guidelines below: 
 
8.1 Adverse Events (AEs) 
Definition: any unfavorable medical occurrence in a human subject who receives 18F-
FFNP-PET/CT and / or estradiol as part of the estradiol challenge for research purposes 
only, including any abnormal sign, symptom, or disease. The event does not necessarily 
have to be causally related to injection of 18FFNP or PET/CT imaging to qualify as an 
adverse event, just temporally related.   
 
Grading: The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all 
toxicity reporting. A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
website.  
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human 
Services’ Office for Human Research Protections (OHRP). A copy of this guidance can 
be found on OHRP’s website: (http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm). 
 
8.2 Unanticipated Problems 
 
Definition:  
• Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
  
• Related or possibly related to participation in the research (in this guidance document, 
possibly related means there is a reasonable possibility that the incident, experience, 
or outcome may have been caused by the procedures involved in the research); and  
 
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  
 
8.3 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human subjects research or failure to follow the determinations of the IRB. 
Noncompliance may occur due to lack of knowledge or due to deliberate choice to ignore 
regulations, institutional policies, or determinations of the IRB. 
 


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8.4 Serious Noncompliance 
Definition: noncompliance that materially increases risks that result in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants. 
 
8.5 Protocol Exceptions 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control.  
 
Exceptions apply only to a single participant or a singular situation. Research imaging 
protocols which involve the injection of radioactive tracers can produce unique situations 
not common to standard treatment protocols.  In the event a situation occurs which 
requires deviation from this protocol- for example less than expected tracer production, 
problems with the scanner, patient unable to tolerate the imaging protocol as described,- 
the principal investigator will have final authority over whether or not a study is 
completed. Any protocol deviations will be documented on the PET imaging data form. 
Deviations such as less than expected tracer production can be accounted for during data 
analysis and will not necessarily result in cancellation of the scan  
 
Except as described above, pre-approval of protocol exceptions must be obtained prior to 
the event. 
 
8.6 Reporting to the Human Research Protection Office (HRPO) and the Quality 
Assurance and Safety Monitoring Committee (QASMC) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct 
of the study.  
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB.  
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study.  
 
These events must be reported to the IRB within 10 working days of the occurrence of 
the event or notification to the PI of the event. The death of a research participant that 
qualifies as a reportable event should be reported within 1 working day of the occurrence 
of the event or notification to the PI of the event. 
 
 


Version 02/01/2019 
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8.7 Timeframe for Reporting Required Events 
 
Deaths 
Any reportable death while on study or within 
30 days of study 
Immediately, within 24 hours, to PI 
and the IRB 
Any reportable death while off study 
Immediately, within 24 hours, to PI 
and the IRB 
Adverse Events/Unanticipated Problems 
Any reportable adverse events as described in 
Sections 8.1 and 8.2 (other than death) 
Immediately, within 24 hours to PI 
and within 10 working days to the IRB 
All adverse events regardless of grade and 
attribution should be submitted cumulatively 
Include in DSM report 
Noncompliance and Serious Noncompliance 
All noncompliance and serious noncompliance 
as described in Sections 8.3 and 8.4 
Immediately, within 24 hours, to PI 
and within 10 working days to the IRB 
 
9.0 
DATA AND SAFETY MONITORING PLAN 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, 
the Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the 
Washington University Quality Assurance and Safety Monitoring Committee (QASMC) semi-
annually beginning six months after accrual has opened (if at least five patients have been 
enrolled) or one year after accrual has opened (if fewer than five patients have been enrolled at 
the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of 
study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol 
exceptions, error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date and 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who 
have met the early stopping rules 


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• Summary of toxicities 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC 
according to institutional guidelines. 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
Study Objectives and Endpoints 
The primary endpoints of the study are the change in 18F-FFNP uptake following one-
day of estradiol measured as the SUV, T/M and tumor-to-normal tissue ratio (T/N), and 
the response to ET among cancer patients (responders vs. non-responders). The 
secondary endpoint of the study is the immunohistochemical (IHC) determination of 
PgR status (PgR+ vs. PgR–) in ER+ breast carcinoma.  
Study Design: This is a pilot study aiming to evaluate if response to ET of breast cancer 
can be predicated by the changes in tumor uptake of 18F-FFNP after a one-day estradiol 
challenge test. The sampling method is non-random. The change of 18F-FFNP uptake 
after estradiol will be correlated with responsiveness to ET. Additionally, an optimal 
threshold of the change in 18F-FFNP uptake will be developed to differentiate therapy 
responding and non-responding patients. Also, the change in 18F-FFNP uptake after 
estradiol challenge will be compared with the IHC determination of PgR status with 
respect to the prediction of ET responsiveness.  
Accrual:  The rate of accrual for the study is expected to be about 1 - 2 patients per 
month.  It is expected that the accrual period of the study will be completed in 30 
months with total 50 patients enrolled.  
Power Analysis: It is estimated that the response rate to ET in the recruited patients will 
range from 20-50%. Using a 2-sided independent t-test with 80% power at a 0.05 
significance level, a sample of 10 responders vs. 40 non-responders (i.e., 20% response 
rate)  will allow us to detect a minimum of 101% SD between-group difference, where 
SD represents a pooled standard deviation of the 18F-FFNP uptake changes among both 
therapy responding and non-responding patients; and a sample of 25 responders vs. 25 
non-responders (i.e., 50% response rate) will allow us to detect a minimum of 80.9% SD 
between-group difference.  
Data Analysis: Demographic and clinical characteristics of all the enrolled patients will 
be summarized using descriptive statistics. The changes in 18F-FFNP uptake after 
estradiol challenge will be compared between responders and non-responders via 


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Wilcoxon rank sum test. A receiver operating characteristic (ROC) curve will be plotted 
to identify an optimal threshold of 18F-FFNP uptake change to determine a criterion for 
the future prediction of therapy responsiveness. The positive and negative predictive 
values (PPV and NPV) will be calculated for response to ET using both the 18F-FFNP 
uptake-based criterion and IHC determination of PgR receptor status. Multivariate 
logistic analyses of therapy response will be used to examine prediction power among 
the changes in 18F-FFNP uptake and PgR receptor status 
 
 


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Buckman BO, Bonasera TA, Kischbaum KS, Welch MJ, Katzenellenbogen JA, Fluorine-18-
labeled progestin 16 alpha, 17 alpha-dioxolanes:  development of high-affinity lignads for the 
progesterone receptor with high in vivo target site selectivity.  J Med Chem. 1995;38(2):328-37;  
Kym PR, Carlson KE, Katzenellenbogen JA, Progestin 16 alpha, 17 alpha-dioxolane ketals as 
molecular probes for progesterone receptor: synthesis, binding affinity, and photochemical 
evaluation.  J Med Chem. 1993;36(9):1111-9  
Vijaykumar D, Mao W, Kirschbaum KS, Katzenellenbogen JA, An efficient route for the 
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ICF_001.pdf: 
 
FOR IRB USE ONLY 
IRB ID #: 201411005 
APPROVAL DATE: 02/19/19 
RELEASED DATE: 02/21/19 
EXPIRATION DATE: 02/18/20 
 
Version 07/12/2016 
INFORMED CONSENT DOCUMENT 
 
Project Title: 
ASSESSMENT OF FUNCTIONAL STATUS OF ESTROGEN RECEPTORS IN 
BREAST CANCER BY POSITRON EMISSION TOMOGRAPHY 
 
Principal Investigator: 
Farrokh Dehdashti 
 
Research Team Contact: 
Dr. Farrokh Dehdashti 314-362-1474 
 
This consent form describes the research study and helps you decide if you want to participate.  It 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights and responsibilities as a research participant. By signing this 
form you are agreeing to participate in this study. 
• You should read and understand the information in this document including the procedures, 
risks and potential benefits. 
• If you have any questions about anything in this form, you should ask the research team for 
more information before you agree to participate.   
• You may also wish to talk to your family or friends about your participation in this study. 
• Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study.  
 
WHAT IS THE PURPOSE OF THIS STUDY? 
 
This is a research study. We invite you to participate in this research study because you have been 
diagnosed with new, advanced, metastatic or recurrent breast cancer and your doctor is planning to treat 
you with endocrine therapy (ET).  Your tumor has been tested for series of factors including estrogen 
receptor (ER), progesterone receptor (PR) and a protein called human epidermal growth factor (HER2).  
Patients whose tumors are hormone receptor positive (ER+ & / or PR+) can be treated with ET which is 
less toxic and has less side effects compared to chemotherapy treatments.  Based on your test results 
your doctor has recommended that ET is the best treatment option for you.   
 
One problem with the current way breast cancers are diagnosed and treatment decisions are made is that 
we must rely on biopsies or small samples of tissue that are taken from the tumor to tell us what types of 
cancer cells are present. A tumor may not be uniform in the type of cells present so the biopsy sample 
may not accurately represent the actual function of the cells within the tumor. Additionally, just because 
a tumor was classified as, for example, ER+ at initial diagnosis recurrent or metastatic tumors may not 
have the same characteristics.   
 
The purpose of this research study is to see if a radioactive tracer called ([18F]fluoro-16α,17α-[(R)-1’-α-
furylmethylidene)dioxy]-19-norpregn-4-ene-3,20 dione) (also referred to as 18F-FFNP) with positron 
emission tomography (PET) scanning can provide more information about your response to ET.  The 
PET scanner is actually a combination PET scanner and a computed tomography (CT) or computed 
axial tomography (CAT) scanner.  It is often called a PET/CT scan.  18F-FFNP is a radioactive form of 
the hormone progesterone.  18F-FFNP is considered investigational, which means that it has not been 
approved by the U.S. Food and Drug Administration.   
 


 
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Endocrine therapy works by blocking or lowering the amount of estrogen hormone in your body.  18F-
FFNP-PET/CT scanning is a way to determine the amount of working hormone receptors throughout 
your body.   
 
WHAT WILL HAPPEN DURING THIS STUDY? 
 
18F-FDG PET/CT Imaging:  If you have not recently undergo imaging which can be used to determine 
the site(s) of metabolically active cancer cells in your body you will be asked to undergo a 18F-FDG 
PET/CT scan.   FDG is a radioactive form of sugar and an FDG-PET/CT scan identifies cancer cells in 
the body based upon the amount of sugar they use.  For the FDG PET/CT scan you will be asked not to 
eat anything for at least 4 hours before the scan.  On the day of the scan a small IV will be placed in a 
vein of your arm.  The IV will be used to collect a small sample of blood (less than 1 teaspoon) and will 
be used to test your blood sugar or glucose level.  If your glucose level is within test limits you will 
receive the FDG medication into your IV line.  The FDG will be allowed to  circulate in your body for 
about 60 minutes.  During this time you might be asked to drink water or you may be given IV solution 
(saline) through your IV line to ensure you are well hydrated.  After the FDG has circulated you will be 
asked to empty your bladder in the restroom before being placed on the scanning table for pictures.  The 
scan will take 20-30 minute and your total visit time will be 2 ½ - 3 hours.  If you have recently had this 
test or similar type of scan performed it may not be necessary to repeat the FDG-PET/CT scan for study 
purposes.   
 
18F-FFNP PET/CT Scanning:  For this research project your will be asked to undergo two 18F-FFNP-
PET/CT scans before you begin treatment with ET.  The first scan will be a baseline scan which will 
identify the sites of cancer which are hormone positive.  The second scan will be performed after a 1-
day estradiol challenge test.  Both 18F-FFNP-PET/CT scans will be performed in the same way.  On the 
day of the scan there are no restrictions.  You may eat and drink like normal and take all your normal 
medications.  A small IV will be placed in a vein of your arm.  The IV will be used to collect a small 
sample of blood as described below and for the injection of the 18F-FFNP study medication.  After you 
receive 18F-FFNP you will be asked to rest comfortably for approximately 30-40 minutes while it 
circulates in your body.    
 
After the FFNP has circulated you will be asked to empty your bladder in the restroom for the scan.  
You will be positioned on the imaging table with your arms resting above your head or secured to your 
side for the scan.  It will take about 20-60 minutes to complete your scan.  The amount of time depends 
on several factors including your height and weight, how much 18F-FFNP you received and where your 
tumor(s) is located in your body.   The total amount of you will need to be at the PET facility for the 
scan is approximately 3 -3 ½ hours.   
 
Vital Sign Assessment:  Your vital signs (blood pressure, heart rate, breathing rate and temperature) 
will be recorded before you receive the injection of 18F-FFNP, within 30 minutes after the injection and 
after the scan is complete.   
 
Follow up Phone Call:  The day after your 18F-FFNP-PET/CT scan you will be contacted by the study 
coordinator for a quick follow up conversation.  The purpose of this is to review with you how you are 
feeling and to see if you had any problems related to the injection of 18F-FFNP, or the scan.  On the day 
of the 2nd scan you will be questioned to see if you had any problems related to the estrogen medication 


 
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given to you as part of the estradiol challenge test.    
 
Blood Samples for Laboratory Testing: A small sample of blood (less than 2 teaspoons) will be taken 
from your IV line after it has been placed and before you receive your injection of 18F-FFNP on each of 
the scanning days.  This blood sample will be tested at a later date and time using a very sensitive test to 
measure the amount of estrogen in your blood stream.  The results of these tests will be compared with 
your scan and also with your overall response to treatment.   
 
Estradiol Challenge Test:  Within 2 weeks of your baseline scan you will be scheduled to return to the 
PET facility for your 2nd 18F-FFNP-PET/CT scan.  This scan will be scheduled to be close to your 
estradiol challenge test.  For the estradiol challenge test you will be given a total of 6 mg of the 
medication estrogen. The estradiol medication will be provided to you from the study and given to you 
by a coordinator or physician working with the study.  The 6 mg will be in the form of three 2 mg tablets 
which you will take orally (by mouth).  You will be asked to take one 2 mg tablet three times spaced 
approximately 8 hours apart.  Approximately 8-48 hours after you take your last tablet of estrogen you 
will be scheduled to return to the PET facility for your 2nd scan.    The purpose of the estradiol challenge 
test is to identify how metabolically active the hormone receptors within the cancer are.  We believe a 
change in the tumor uptake following a 1-day estradiol challenge will be predictive of those women who 
are going to respond best to ET. The 2 tables below are SAMPLE study calendars of how this could be 
scheduled: 
 
Tuesday: 
 Baseline FFNP-PET/CT Scan 
Appointment @ 11:30  
Wednesday start estradiol challenge 
Take one 2mg tablet @ 2pm 
Take one 2mg tablet @ 10 pm 
Thursday: 
Take one 2mg tablet @ 6AM 
FFNP-PET/CT scan @ 2PM  
OR 
Friday: 
 Baseline FFNP-
PET/CT Scan 
  
Saturday  start 
estradiol challenge 
Take one 2mg tablet 
@ 10 PM 
 
Sunday: Continue estradiol challenge 
Take one 2 mg tablet @ 6AM 
Take one 2 mg tablet @ 2 PM   
 Tuesday:  
FFNP-PET/CT scan 
@ 2PM  
 
If you need to have an FDG-PET/CT scan for study purposes it must be done on a day different from 
FFNP PET/CT scans.  It can be done either before or after the first FFNP PET/CT scan but must be done 
before the estradiol medication is given.   
 
Standard Endocrine Therapy Treatment:  After your second 18F-FFNP PET/CT scan you will begin 
your treatment with endocrine therapy as prescribed by your doctor.  Endocrine therapy is standard of 
care.  You are not required to receive any special type of endocrine therapy as part of this research 
project.  What you receive, how you are instructed to take your medication, and how often you follow 
up with your doctor will be determined by your doctor who treats you for breast cancer.  The study will 
follow your medical records to see how well you respond to treatment.  The study will follow your 
medical records until you are no longer receiving endocrine therapy. The information collected from 
your chart will include any test results that were ordered to determine your response to therapy: scanning 
such as CT, or bone scan, magnetic resonance imaging (MRI), ultrasound or mammography, and 
laboratory or pathology test results.  The study will also look at any notes such as history and physical 
exam, treatment notes, or treatment team correspondence related to your treatment and response to 


 
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treatment.   
 
Your FDG PET/CT scan if done for study purposes will be reviewed by a radiologist and the results and 
images will be made part of your medical record so that the doctor(s) who treatment you may have this 
additional information.  The results of your FFNP-PET/CT scans are not meant to be used to determine 
or change the treatment you will be receiving.  The FFNP-PET/CT scan will be reviewed by the study 
doctor and discussed with the doctor who referred you to the study.  The FFNP-PET/CT scan results will 
not be part of your medical record and the images will be used for research purposes only.   
 
Will you save my samples or research data to use in future research studies?  
 
As part of this study, we are obtaining PET/CT images from you. We would like to use this PET/CT 
images for studies going on right now as well as studies that are conducted in the future.  These studies 
may provide additional information that will be helpful in understanding breast cancer, or other diseases 
or conditions, including research to develop investigational tests, treatments, drugs or devices that are 
not yet approved by the U.S. Food and Drug Administration.  It is unlikely that what we learn from these 
studies will have a direct benefit to you.  There are no plans to provide financial compensation to you 
should this occur.  By allowing us to use your PET/CT images you give up any property rights you may 
have in the PET/CT images. 
   
If you change your mind and do not want us to store and use your PET/CT images for future research 
you should contact the research team member identified at the top of this document.  The PET/CT 
images will no longer be used for research purposes. However, if some research with your PET/CT 
images has already been completed, the information from that research may still be used. Also, if the 
PET/CT images have been shared with other researchers it might not be possible to withdraw the 
PET/CT images to the extent it has been shared. 
 
HOW MANY PEOPLE WILL PARTICIPATE? 
 
Approximately 50 people will take part in this study conducted by investigators at Washington 
University. 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
If you agree to take part in this study, your active involvement will last for up to 6 days.  
• If you receive an FDG-PET/CT scan about 2 ½ - 3 hours of your time will be needed 
• Each 18F-FFNP-PET/CT will require about 3 – 3 ½ hours of your time (2 scans) 
• Each follow up phone call will require 5 minutes or less of your time (2 phone calls) 
• Estradiol challenge – this does not require a visit to the hospital but you will be required to take 
the estrogen medication as directed over the course of a 24 hour period.  Depending on the 
timing this may require you to wake up earlier than you normally do or to set an alarm clock to 
take the medication at the times prescribed.   
 
 
 


 
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WHAT ARE THE RISKS OF THIS STUDY? 
 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study.  
 
Some risks described in this consent document, if severe, may cause death.  
 
18 F-FDG Injection:   
 
Likely/Common:  pain or discomfort at the injection site.   
• Rare:  There is a rare possibility of an allergic-type or other adverse reaction to 
radioactively labeled drugs. While none have been reported to date with the radioactive 
material FDG, such a reaction could be serious and may result in death. 
 
18F-FFNP- Injection:  The amount of progesterone in the radioactive tracer 18F-FFNP is very small and 
is no side effects from the progesterone itself are expected.  The following side effects have been noted 
when progesterone is given at much greater doses than is used in this study:  
 
Likely/Common  
Mild 
• pain at the injection site 
• upset stomach 
• changes in appetite 
• generalized feeling of weakness or fatigue 
• fever 
• headache   
Less Likely/Less Common 
Serious   
• weight gain 
• fluid retention 
• insomnia (unable to sleep) or drowsiness 
• breast discomfort or enlargement 
Rare 
Life Threatening   
• allergic reaction and symptoms such as-unexplained rash, itching, hives, and swelling, 
irregular heartbeat, difficulty breathing and shortness of breath.   
 
Estradiol Challenge Test: The following side effects have been reported by patients taking 
estradiol as treatment for breast cancer.  The dose of estradiol you will receive for the challenge 
test is much smaller than the treatment dose. 
 
Likely/Common 
Mild 
• upset stomach 
• nausea 


 
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• vomiting 
• changes in appetite 
• generalized feeling of weakness or fatigue 
• fever 
• headache 
 
Less Likely/Less Common 
Serious 
• weight gain 
• fluid retention 
• insomnia (unable to sleep) or drowsiness 
• vaginal discharge 
• spotting to darkening of the skin 
• breast discomfort or enlargement 
Rare 
Life Threatening   
• uterine fibroids 
• stroke 
• blood clots 
• allergic reaction and symptoms such as-unexplained rash, itching, hives, and swelling, 
irregular heartbeat, difficulty breathing and shortness of breath.  
• There is a rare possibility that the administration of estrace will cause symptoms of 
clinical flare.  Clinical flare can occur with any hormone used in the treatment of breast 
cancer.  Physicians recognize that women who experience a clinical flare are likely to 
benefit from hormone therapy.  Clinical flare is a temporary worsening of the symptoms 
associated with your breast cancer such as increased bone and joint pain.  
  
While it is rare, clinical flare is most often seen during the first weeks of treatment with estradiol 
and other forms of hormonal therapy.  The small dose of estradiol you are given for only a single 
day is not expected to cause a noticeable flare reaction.  The small dose is meant to cause 
changes at the cellular level that can be detected on the PET/CT imaging.   
   
PET/CT Imaging: 
 
 
Mild / Likely:    Discomfort from lying still on the imaging table  
Rare: Malfunction of worn or implanted electronic medical devices. 
 
If you have electronic medical devices implanted such as a pacemaker or a drug pump, please make sure 
you tell your study doctors and research staff.  The CT scan may cause a malfunction of electronic 
medical devices. 
 
Radiation Exposure:  This study will expose you to radiation from the injection of the PET study 
medication 18F-FDG and the investigational radioactive drug, 18F-FFNP, and from CT scanning used as 
part of each PET/CT scan.  The amount of radiation from one FDG PET/CT scan when averaged over 
your entire body, is 30% of the amount a person who works with radiation is allowed to have in one 


 
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year.  The amount of exposure from is 18F-FFNP-PET/CT scan is equivalent to approxately 28% of the 
amount a person who works with radiation is allowed to receive in on year.   The maximum amount you 
will receive is from 1 FDG and 2 FFNP-PET/CT scans which is approximately 86% of the allowable 
annual dose for a radiation worker.  The risk from the radiation exposure in this study is too small to be 
measured. It is not a big risk when compared with other risks you take every day.  If you want to know 
more about radiation exposure, please see the “Radiation Fact sheet” at http://hrpo.wustl.edu or ask the 
study staff for a copy. 
 
IV Placement and Blood Drawing: 
 
Likely/Common 
Mild 
• discomfort from placement of the IV in your arm or hand or from the needle used to draw 
blood  
Less Likely/Less Common 
Serious 
• There is a slight risk of bruising 
• Some people feel dizzy or faint when an IV is placed or blood is drawn from them 
Rare 
Life Threatening 
• There is a rare risk of infection at the site of IV placement or blood drawing. 
 
Vital Signs:  You may feel discomfort from the squeezing of the blood pressure cuff around your arm.   
 
Participation in future research studies:  Treatments in this study may disqualify you for other 
research studies. 
 
Breach of Confidentiality 
One risk of participating in this study is that confidential information about you may be accidentally 
disclosed.  We will use our best efforts to keep the information about you secure.  Please see the section 
in this consent form titled “How will you keep my information confidential?” for more information. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
 
You will not benefit from being in this study. 
 
However, we hope that, in the future, other people might benefit from this study because being able to 
accurately determine who will and will not benefit from endocrine therapy as primary treatment for 
breast cancer can prevent unnecessary treatments and treatment related side effects.   
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
 
You may have additional costs for being in this research study. 
• You will be asked to visit the hospital for two separate visits. If you are making the trip to 
the hospital only for the research visits you will have travel related expenses. 


 
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You and/or your medical/hospital insurance provider will remain responsible for your regular medical 
care expenses. 
 
WILL I BE PAID FOR PARTICIPATING? 
 
You will be paid for being in this research study. You will need to provide your social security number 
(SSN) in order for us to pay you. You may choose to participate without being paid if you do not wish to 
provide your social security number (SSN) for this purpose.  You may also need to provide your address 
because payment will be made in the form of a check mailed to you.  It can take up to 4-6 weeks for 
processing and delivery of the check to the address you provide.   If your social security number is 
obtained for payment purposes only, it will not be retained for research purposes.    
 
You will receive $100 for each 18F-FFNP-PET/CT imaging session.  If you also need to have a FDG-
PET/CT scan you will receive an additional $100.  If you complete both FFNP imaging session on study 
you will receive a total of $200.  If you receive 1 FDG-PET/CT scan and 2 FDG-PET/CT scans you will 
receive a total of $300.  If you do not complete both FFNP PET/CT scans, you will be paid for the scan 
you complete. If you receive any one of the injection(s) but are not able to complete the scan you will be 
paid $25. You will also be provided coverage for parking expenses. Overnight hotel stay(s) may be 
available if needed as well. 
 
WHO IS FUNDING THIS STUDY? 
 
The National Institutes of Health is funding this research study.  This means that Washington University 
is receiving payments from the National Institutes of Health to support the activities that are required to 
conduct the study.  No one on the research team will receive a direct payment or increase in salary from 
the National Institutes of Health for conducting this study. 
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
 
Washington University investigators and staff will try to reduce, control, and treat any complications 
from this research. If you feel you are injured because of the study, please contact Dr. Farrokh Dehdashti 
at 314-362-1474 and/or the Human Research Protection Office at 1-(800)-438-0445.  
 
Decisions about whether payment for medical treatment for injuries relating to your participation in 
research will be made by Washington University.  If you need to seek medical care for a research-related 
injury, please notify the investigator as soon as possible.  
 
HOW WILL YOU KEEP MY INFORMATION CONFIDENTIAL? 
 
We will keep your participation in this research study confidential to the extent permitted by law.   
However, it is possible that other people such as those indicated below may become aware of your 
participation in this study and may inspect and copy records pertaining to this research.  Some of these 
records could contain information that personally identifies you.  
• Government representatives, (including the Office for Human Research Protections) to complete 
federal or state responsibilities 


 
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• The U.S. Food and Drug Administration 
• The National Institutes of Health 
• Your primary care physician if a medical condition that needs urgent attention is discovered 
• Hospital or University representatives, to complete Hospital or University responsibilities 
• Information about your participation in this study may be documented in your health care records 
and be available to your health care providers who are not part of the research team. 
• The last four digits of your social security number may be used in hospital or University systems 
to track billing information for research procedures  
• Washington University’s Institutional Review Board (a committee that oversees the conduct of 
research involving human participants) and the Human Research Protection Office. The 
Institutional Review Board has reviewed and approved this study.  
The Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital 
is supported by funding from the National Cancer Institute (NCI). To meet NCI requirements, your 
protected health information relating to your participation in this study (including your social security 
number) will be stored in a secure database at the Siteman Cancer Center.  This database and also your 
health care records may be reviewed by Siteman Cancer Center personnel.  All information will be 
securely and confidentially maintained.  
 
To help protect your confidentiality, we will store all paper documents behind two locks. All electronic 
data will be password protected and stored on a password protected computer. Your blood samples will 
be temporarily stored in a locked freezer behind two locks.  Blood samples will be processed in groups 
or batches. Once processed, they will be destroyed as biological waste and not kept for any future 
testing.   If we write a report or article about this study or share the study data set with others, we will do 
so in such a way that you cannot be directly identified. 
 
This consent form or similar documentation that you are participating in a research study may be 
included in your health care record.  Anyone with access to your health care record, including your 
health insurance company may be able to see that you are participating in a research study. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
To further protect your privacy, this research is covered by a Certificate of Confidentiality from the 
federal government. This means that the researchers can refuse to disclose information that may identify 
you in any legal or court proceeding or to anyone who is not connected with the research except if:  
• there is a law that requires disclosure, such as to report child abuse and neglect, or harm to self or 
others;  
• 
you give permission to disclose your information, including as described in this consent form; or 
• it is used for other scientific research allowed by federal law. 
You have the right to share your information or involvement in this study with anyone at any time. You 
may also give the research team permission to disclose your information to a third party or any other 
person not connected with the research.  
 
 


 
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Are there additional protections for my health information? 
 
Protected Health Information (PHI) is health information that identifies you. PHI is protected by federal 
law under HIPAA (the Health Insurance Portability and Accountability Act). To take part in this 
research, you must give the research team permission to use and disclose (share) your PHI for the study 
as explained in this consent form.  The research team will follow state and federal laws and may share 
your health information with the agencies and people listed under the previous section titled, “How will 
you keep my information confidential?”. 
 
Once your health information is shared with someone outside of the research team, it may no longer be 
protected by HIPAA.   
 
The research team will only use and share your information as talked about in this form or as permitted 
or required by law.  When possible, the research team will make sure information cannot be linked to 
you (de-identified).  Once information is de-identified, it may be used and shared for other purposes not 
discussed in this consent form. If you have questions or concerns about your privacy and the use of your 
PHI, please contact the University’s Privacy Officer at 866-747-4975.  
 
Although you will not be allowed to see the study information, you may be given access to your health 
care records by contacting your health care provider.  
 
If you decide not to sign this form, it will not affect 
• your treatment or the care given by your health provider. 
• your insurance payment or enrollment in any health plans.   
• any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
• You authorize the use of your PHI for this research 
• This authorization does not expire. 
• You may later change your mind and not let the research team use or share your information 
(you may revoke your authorization).  
• To revoke your authorization, complete the withdrawal letter, found in the Participant section 
of the Human Research Protection Office website at 
https://hrpo.wustl.edu/participants/withdrawing-from-a-study/ or you may request that the 
Investigator send you a copy of the letter.    
 
 
 
o If you revoke your authorization: 
▪ The research team may only use and share information already collected for 
the study. 
▪ Your information may still be used and shared as necessary to maintain the 
integrity of the research, for example, to account for a participant’s 
withdrawal from the research study or for safety reasons.  
▪ You will not be allowed to continue to participate in the study. 
 


 
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IS BEING IN THIS STUDY VOLUNTARY? 
 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time.  Any data that was collected as 
part of your participation in the study will remain as part of the study records and cannot be removed. 
 
If you decide not to be in this study, or if you stop participating at any time, you won’t be penalized or 
lose any benefits for which you otherwise qualify. 
 
What if I decide to withdraw from the study? 
 
You may withdraw by telling the study team you are no longer interested in participating in the study or 
you may send in a withdrawal letter. A sample withdrawal letter can be found at 
https://hrpo.wustl.edu/participants/withdrawing-from-a-study/ under Withdrawing from a Research 
Study. 
 
Will I receive new information about the study while participating? 
 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
 
Can someone else end my participation in this study? 
 
Under certain circumstances, the researchers might decide to end your participation in this research 
study earlier than planned.  This might happen for no reason or because staying in the study would be 
harmful, you need treatment that is not allowed while on the study, you fail to follow instructions, you 
develop a major side effect, or the study is canceled.  
 
WHAT IF I HAVE QUESTIONS? 
 
We encourage you to ask questions.  If you have any questions about the research study itself, please 
contact: Dr. Farrokh Dehdashti at 314-362-1474. If you experience a research-related injury, please 
contact: Dr. Farrokh Dehdashti at 314-362-1474.   
If you have questions, concerns, or complaints about your rights as a research participant, please contact 
the Human Research Protection Office, 660 South Euclid Avenue, Campus Box 8089, St. Louis, MO  
63110, 1-(800)-438-0445, or email hrpo@wustl.edu.   General information about being a research 
participant can be found on the Human Research Protection Office web site, http://hrpo.wustl.edu.  To 
offer input about your experiences as a research participant or to speak to someone other than the 
research staff, call the Human Research Protection Office at the number above. 


 
FOR IRB USE ONLY 
IRB ID #: 201411005 
APPROVAL DATE: 02/19/19 
RELEASED DATE: 02/21/19 
EXPIRATION DATE: 02/18/20 
 
Version 02/01/2019 
 
Page 12 of 12 
 
 
This consent form is not a contract. It is a written explanation of what will happen during the study if 
you decide to participate. You are not waiving any legal rights by agreeing to participate in this study.  
As a participant you have rights and responsibilities as described in this document and including: 
• To be given enough time before signing below to weigh the risks and potential benefits and 
decide if you want to participate without any pressure from the research team or others. 
• To understand all of the information included in the document, have your questions answered, 
and receive an explanation of anything you do not understand. 
• To follow the procedures described in this document and the instructions of the research team to 
the best of your ability unless you choose to stop your participation in the research study. 
• To give the research team accurate and complete information. 
• To tell the research team promptly about any problems you have related to your participation, or 
if you are unable to continue and wish to stop participating in the research study. 
 
Your signature indicates that this research study has been explained to you, that your questions have 
been answered, and that you agree to take part in this study.  You will receive a signed and dated copy 
of this form. 
 
 
Do not sign this form if today’s date is after EXPIRATION DATE: 02/18/20. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Participant) 
 
 
 
 
(Date) 
 
 
____________________________________________ 
(Participant's name – printed) 
 
 
 
Statement of Person Who Obtained Consent 
 
The information in this document has been discussed with the participant or, where appropriate, with the 
participant’s legally authorized representative.  The participant has indicated that they understand the 
risks, benefits, and procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date) 
 
 
___________________________________________ 
(Name of Person who Obtained Consent - printed)