Clinical trial NCT04738292
Conditions: ER-positive Breast Cancer HER2-negative Breast Cancer Metastatic Cancer
Sponsor: University of Wisconsin, Madison
Start date: 2021-10-05; Completion date: 2023-05-15
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A phase II single-arm trial of onapristone in combination with fulvestrant for women and men with ER-positive, PgR-positive or negative and HER2-negative locally advanced or metastatic breast cancer after progression on aromatase and CDK4/6 inhibitors. The study will enroll up to 39 participants.

Detailed description:

Arms: arm 1: All participants will receive onapristone 50 mg p.o. BID (twice) daily and fulvestrant (500 mg) intramuscular injection on days 1, 15 (cycle 1), then two weeks later (cycle 2, day1), then once every 28 days thereafter. A cycle is defined as 28 days.

There will be no breaks between dosing cycles.
Interventions: intervention 1: Onapristone intervention 2: Fulvestrant
Intervention descriptions: intervention 1: Onapristone is a type I antiprogestin which prevents the PgR from dimerizing and blocks ligand induced protein kinase-mediated phosphorylation of the PgR. intervention 2: Fulvestrant binds, blocks and degrades the ER, completely inhibiting ER signaling.

Protocol documents:
Prot_SAP_000.pdf: 
Short Title: The SMILE study 
1 
Version No.: 2 
Protocol No.: UW20037 
 
Version Date: 8/26/2021 
 
A Phase II Trial of OnapriStone in CoMbInation with FuLvestrant for 
Patients with ER-positive, and HER2-negative Metastatic Breast 
Cancer after Progression on Endocrine therapy and CDK 4/6 
Inhibitors 
 
 
Short Title: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sailaja Kamaraju, MD, MS (Study PI) 
 
 
Current Version Number and Date 
v2 8/26/2021 
 
 
NCT04738292 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential and may not 
be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by federal and state laws. Persons 
to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.  
 
The SMILE  
Study 


Short Title: The SMILE study 
2 
Version No.: 2 
Protocol No.: UW20037 
 
Version Date: 8/26/2021 
WON Coordinator: 
Affiliate Coordinators 
UW Carbone Cancer Center 
600 Highland Ave. 
Madison, WI 53792 
Email: affiliatecoordinators@uwcarbone.wisc.edu 
 
 
TITLE:   A Phase II Trial of OnapriStone in CoMbInation with FuLvestrant for Patients 
with ER-positive, and HER2-negative Metastatic Breast Cancer after Progression on  
Endocrine therapy and CDK 4/6 Inhibitors (The SMILE Study) 
Protocol No.: UW20037 
IRB Pro No.:  2020-0877 
Clinical trials.gov No.: NCT04738292 
FDA IND No.: 153146 
Study Chair: 
Sailaja Kamaraju, MD, MS 
Associate Professor 
Division of Hematology and Oncology 
Department of Medicine 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4600 
Email: skamaraju@mcw.edu  
 
Principal Investigator:   
Kari B. Wisinski, MD 
Associate Professor of Medicine 
Hematology/Oncology Division 
UW School of Medicine and Public Health 
UW Carbone Cancer Center 
WIMR Room 6033, 1111 Highland Ave. 
Madison, WI 53705-2275 
Telephone 608-262-2876, Fax 608-265-6905 
Email:  kbwisinski@medicine.wisc.edu 
Sub-investigator:  
Hallgeir Rui, MD, PhD 
Professor 
Department of Pathology  
Medical College of Wisconsin  
8701 W. Watertown Plank Road  
Milwaukee, WI 53226  
414-805-8454  
Email: hrui@mcw.edu    
 
Sub-investigator: 
Amy Fowler, MD, PhD 
Assistant Professor  
Department of Radiology 
University of Wisconsin-Madison 
3252 Clinical Science Center 
600 Highland Ave. 
Madison, WI 53792 
Email: AFowler@uwhealth.org 
Biostatistician: 
Sergey Tarima, PhD 
Associate Professor 
Division of Biostatistics 
Institute for Health & Society 
Medical College of Wisconsin  
8701 Watertown Plank Road 
Milwaukee, WI  53226 
414-955-5605  
Email: starima@mcw.edu  
Sub-investigator:   
Christopher R. Chitambar, MD 
Professor  
Departments of Medicine and Biophysics 
Division of Hematology and Oncology 
 
 
Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
414-805-4600 
Email: cchitambar@mcw.edu    
 


Short Title: The SMILE study 
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Version No.: 2 
Protocol No.: UW20037 
 
Version Date: 8/26/2021 
PROTOCOL SIGNATURE PAGE 
 
A Phase II Trial of OnapriStone in CoMbInation with FuLvestrant for Patients with ER-positive, 
and HER2-negative Metastatic Breast Cancer after Progression on Endocrine therapy and CDK 
4/6 inhibitors 
 
 
 
VERSION DATE:  v2 08/26/2021 
 
The signature below confirms that I have read this protocol and provides the necessary 
assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable US federal regulations and ICH guidelines. 
 
 
 
 
 
 
 
 
 
 ___________________________________ 
 _______________________  
Investigator Signature 
 
 
 
  
 Date 
 
 
___________________________________ 
Printed Investigator Name 
 
 
 ___________________________________ 
 Site Name  
 
 
 
 
 
 
 
 


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Table of Contents 
PROTOCOL SUMMARY ........................................................................................................... 8 
STUDY SCHEMA .....................................................................................................................10 
STUDY CALENDAR .................................................................................................................11 
LIST OF ABBREVIATIONS ......................................................................................................14 
1. BACKGROUND ....................................................................................................................16 
1.1 HORMONE RECEPTOR-POSITIVE HER2-NEGATIVE BREAST CANCER ...................................16 
1.2 THE PROGESTERONE RECEPTOR [PGR] .............................................................................16 
1.2.1 Role of PgR in Breast Cancer Proliferation............................................................................................. 16 
1.2.2 ESR1 Acquired Mutations Are Associated with Significant Increase in PgR Expression ..................... 17 
1.2.3 Mechanism of Action .......................................................................................................................... 18 
1.2.4 PgR Isoforms and Post-Translational Modifications .................................................................. 18 
1.2.5 PR Antisense ......................................................................................................................................... 19 
1.3 OVERVIEW OF FULVESTRANT .............................................................................................20 
1.3.1 Clinical Pharmacokinetics of Fulvestrant ...................................................................................... 20 
1.4 OVERVIEW OF ONAPRISTONE .............................................................................................21 
1.4.1 Non-clinical Experience...................................................................................................................... 21 
1.4.1.1 Onapristone Single-Agent Activity ............................................................................................................ 21 
1.4.1.2 Methylnitrosourea-Induced Mammary Tumors....................................................................................... 21 
1.4.1.3 Non-clinical PK and Metabolism of Onapristone ................................................................................... 22 
1.4.1.4 Safety, Pharmacology and Toxicology of Onapristone ........................................................................ 23 
1.4.1.5 Genotoxicity Status of Onapristone and Metabolites ........................................................................... 24 
1.4.1.6 Clinical Experience ........................................................................................................................................ 24 
1.4.1.7 Pharmacokinetics of Onapristone ............................................................................................................. 25 
1.4.2 Unmet Medical Need ................................................................................................................................. 26 
1.5 OVERVIEW OF PROGESTERONE RECEPTOR IMAGING ...........................................................27 
2 HYPOTHESIS AND OBJECTIVES ........................................................................................27 
3 STUDY DESIGN ....................................................................................................................27 
3.1 GENERAL DESCRIPTION .....................................................................................................27 
3.2 ESTIMATED TIME FOR STUDY COMPLETION .........................................................................28 
3.2.1 Primary Completion ............................................................................................................................. 28 
3.2.2 Study Completion ...................................................................................................................................... 28 
4 SUBJECT SELECTION .........................................................................................................28 
4.1 CHECKLIST. ......................................................................................................................28 
4.2 ELIGIBILITY CRITERIA- PART 1 (ENROLLMENT CRITERIA FOR THE DOSE ESCALATION 
COHORT) .....................................................................................................................28 
5. STUDY ENTRY AND WITHDRAWL .....................................................................................33 
5.1 REQUIRED PREREGISTRATION SCREENING TESTS AND PROCEDURES ..................................33 
5.2 REGISTRATION PROCESS ...................................................................................................33 
5.3 DISCONTINUATION OF STUDY TREATMENT, WITHDRAWAL, AND COMPLIANCE .......................33 
5.3.1 Consent Withdrawal ............................................................................................................................ 34 
5.3.2 Investigator-Initiated Withdrawal ..................................................................................................... 34 
5.4 LOST TO FOLLOW-UP ........................................................................................................34 
5.5 END OF STUDY DEFINITION ................................................................................................35 
5.6 STUDY DISCONTINUATION AND CLOSURE ...........................................................................35 
6 TREATMENT PLAN ..............................................................................................................35 


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6.1 INVESTIGATIONAL AGENT ADMINISTRATION ........................................................................35 
6.1.1 Fulvestrant ............................................................................................................................................. 36 
6.1.2 Onapristone ........................................................................................................................................... 36 
6.1.2 18F-FFNP ................................................................................................................................................. 36 
6.2 DOSE MODIFICATION .........................................................................................................37 
6.2.1 Dose Modification of Fulvestrant ..................................................................................................... 37 
6.2.2 Dose Modification of Onapristone ................................................................................................... 37 
6.2.2 Dose Modification of 18F-FFNP ......................................................................................................... 42 
6.3 DIETARY RESTRICTIONS ....................................................................................................42 
6.4 MONITORING SUBJECT COMPLIANCE ..................................................................................42 
6.5 FOLLOW-UP PERIOD .........................................................................................................42 
7 ADVERSE EVENTS: DEFINITIONS, COLLECTION AND REPORTING REQUIREMENTS .42 
7.1 DEFINITIONS .....................................................................................................................42 
7.1.1 Adverse Event ............................................................................................................................................ 42 
7.1.2 Serious Adverse Event (SAE) ................................................................................................................... 43 
7.1.3 Attribution of an Adverse Event ............................................................................................................... 43 
7.1.4 Expectedness of an Adverse Event ........................................................................................................... 44 
7.2 COLLECTION AND REPORTING REQUIREMENTS FOR ADVERSE EVENTS AND SERIOUS ADVERSE
 ...................................................................................................................................44 
7.2.1 Collection of Adverse Events .................................................................................................................... 44 
7.2.2 Reporting of Adverse Events and Serious Adverse Events ...................................................................... 45 
7.2.2.1 Reporting Instructions — Serious Adverse Events — Reported within 24 Hours ........................................ 45 
7.2.3 Serious Adverse Events — Reported within 10 Days ............................................................................... 45 
7.2.4 Sponsor-Investigator Responsibilities for SAE Review ........................................................................... 46 
7.2.5 Study Progress Review .............................................................................................................................. 46 
7.3 EXPEDITED REPORTING OF SERIOUS ADVERSE EVENTS ......................................................46 
7.3.1 SAE Requiring [24] Hour Reporting Occurs at UWCCC ....................................................................... 48 
7.3.2 SAE Reporting [10] Day Reporting Occurs at UWCCC .......................................................................... 48 
7.3.3 SAE Requiring [24] Hour Reporting Occurs at a WON Site .................................................................. 48 
7.3.4 SAE Requiring [10] Day Reporting Occurs at a WON site ..................................................................... 49 
7.3.5 Other Reporting Requirements ................................................................................................................. 49 
7.4 SUBJECT COMPLAINTS ......................................................................................................50 
7.5 RISK AND BENEFITS ..........................................................................................................50 
7.5.1 Fulvestrant Identified Safety Risk .................................................................................................... 50 
7.5.1.1 Risk of Bleeding ............................................................................................................................................. 50 
7.5.1.2 Increased Exposure in Patients with Hepatic Impairment ................................................................... 50 
7.5.1.3 Injection Site Reaction .................................................................................................................................. 50 
7.5.1.4 Embryo-Fetal Toxicity ................................................................................................................................... 50 
7.5.1.5 Laboratory Requirements for Postmenopausal Status ........................................................................ 51 
7.5.2 Onapristone Identified Safety Risk .................................................................................................. 51 
7.5.3 18F-FFNP PET/CT Identified Safety Risk ......................................................................................... 51 
7.5.4 Potential for Overlapping Toxicities................................................................................................ 52 
7.5.5 Potential for Onapristone-Fulvestrant Interactions .................................................................... 52 
8 PHARMACEUTICAL INFORMATION ...................................................................................52 
8.1 ONAPRISTONE ...................................................................................................................52 
8.1.1 Description ............................................................................................................................................ 52 
8.1.2 Aqueous Solubility .................................................................................................................................... 53 
8.1.3 Packaging and Labeling ..................................................................................................................... 53 
8.1.4 Storage Conditions .............................................................................................................................. 53 
8.1.5 Stability Data ......................................................................................................................................... 53 
8.1.6 Handling and Drug Accountability .................................................................................................. 53 
8.2 FULVESTRANT ...................................................................................................................53 
8.2.1 Description ............................................................................................................................................ 53 


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8.2.2 Aqueous Solubility .................................................................................................................................... 54 
8.2.3 Packaging and Labeling ........................................................................................................................... 54 
8.2.4 Storage Conditions .............................................................................................................................. 54 
8.2.5 Stability Data ......................................................................................................................................... 54 
8.2.6 Handling and Drug Accountability .................................................................................................. 54 
8.3 18F-FFNP .........................................................................................................................54 
8.3.1 18F-FFNP Description .......................................................................................................................... 54 
8.3.2 Packaging and Labeling ..................................................................................................................... 54 
8.3.3 Storage Conditions .............................................................................................................................. 55 
8.3.4 Stability Data ......................................................................................................................................... 55 
8.3.5 Handling and Drug Accountability .................................................................................................. 55 
9 STATISTICAL CONSIDERATIONS .......................................................................................55 
9.1  STUDY DESIGN .................................................................................................................55 
9.2  SAMPLE SIZE ...................................................................................................................56 
10  MEASUREMENT OF EFFECT ...........................................................................................58 
10.1  BASELINE ......................................................................................................................58 
10.2 RESPONSE EVALUATION ..................................................................................................58 
10.3 SAFETY AND TOLERABILITY ASSESSMENT ........................................................................58 
10.4  OTHER ASSESSMENTS ....................................................................................................59 
10.5  TUMOR BIOPSY AND PLASMA ANALYSES ..........................................................................59 
10.5.1  Tissue Analysis ....................................................................................................................................... 60 
10.5.2  Peripheral Blood Preparation, Storage, and Preservation ................................................................... 61 
10.5.4  Functional Imaging ............................................................................................................................... 62 
10.5.5  18F-FFNP PET/CT Imaging Analysis ................................................................................................. 63 
10.5.6  Qualitative Analysis of 18F-FFNP Uptake (Lesion-Level) .................................................................. 63 
10.5.7  Quantitative Analysis of 18F-FFNP Uptake (Lesion-Level) ................................................................ 63 
10.5.8  Definition of 18F-FFNP Blockade ........................................................................................................ 63 
11 DATA AND SAFETY MONITORING PLAN (DSMP) ...........................................................63 
11.1  OVERSIGHT AND MONITORING PLAN ................................................................................63 
11.2  MONITORING AND REPORTING GUIDELINES ......................................................................64 
11.3  UWCCC DSMC STUDY PROGRESS REVIEW....................................................................64 
11.4  UWCCC DSMC REVIEW OF AUDITING AND/OR MONITORING REPORTS ............................64 
11.5  UWCCC DSMC REVIEW OF NONCOMPLIANCE, UNANTICIPATED PROBLEM, AND OTHER IRB 
REPORTABLE EVENTS ..................................................................................................65 
11.6  UWCCC DSMC REVIEW OF SERIOUS ADVERSE EVENTS .................................................65 
12  REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT ...........................65 
12.1  ETHICAL STANDARD .......................................................................................................65 
12.2  REGULATORY COMPLIANCE ............................................................................................65 
12.3  PRESTUDY DOCUMENTATION ..........................................................................................65 
12.4  INSTITUTIONAL REVIEW BOARD .......................................................................................66 
12.5  INFORMED CONSENT PROCESS .......................................................................................67 
12.6  SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ........................68 
12.7  PROTECTION OF HUMAN SUBJECTS .................................................................................68 
12.7.1  Protection from Unnecessary Harm ...................................................................................................... 68 
12.7.2  Protection of Privacy .............................................................................................................................. 68 
12.8  INVESTIGATOR COMPLIANCE ...........................................................................................69 
13 DATA HANDLING AND RECORD KEEPING .....................................................................69 
13.1 OVERVIEW ......................................................................................................................69 


Short Title: The SMILE study 
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13.2 DATA MANAGEMENT RESPONSIBILITIES ...........................................................................69 
13.2.1 Principal Investigator ............................................................................................................................. 69 
13.2.2 Research Coordinator ............................................................................................................................. 70 
13.2.3 Research Nurse/Medical Staff ................................................................................................................ 70 
13.2.4 Biostatistician .......................................................................................................................................... 70 
13.3 HANDLING AND DOCUMENTATION OF CLINICAL SUPPLIES ..................................................70 
13.4 SOURCE DOCUMENTS ......................................................................................................70 
13.5 CASE REPORT FORMS .....................................................................................................71 
13.6 STUDY RECORD RETENTION ............................................................................................71 
13.7 INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL .............................................................72 
13.8 WON SITE OVERSIGHT ....................................................................................................72 
APPENDIX 1. PERFORMANCE STATUS CRITERIA ..............................................................73 
APPENDIX 3: SUBJECT LOST TO FOLLOW-UP LETTER .....................................................74 
REFERENCES .........................................................................................................................75 
 


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PROTOCOL SUMMARY 
 
Title 
A Phase II Trial of OnapriStone In CoMbInation with FuLvestrant for 
Patients with ER-Positive, and HER2-Negative Metastatic Breast Cancer 
after Progression on Endocrine therapy and CDK 4/6 Inhibitors 
IND Sponsor 
Sponsor-investigator 
Study Chair 
Sailaja Kamaraju, MD, MS 
Principal Investigator  
Kari Wisinski, MD 
Study Sites 
UW Carbone Cancer Center, Medical College of Wisconsin, and select 
Wisconsin Oncology Network sites. 
Clinical Trial Phase 
Phase II 
Study Disease 
ER-positive, (PgR-positive or PgR negative) and HER2-negative 
metastatic breast cancer. 
Main Eligibility 
Criteria 
Patient has advanced (locally advanced or locoregionally recurrent not 
amenable to curative therapy or metastatic ER+/PgR+/-, and HER2 
negative) breast cancer with disease progression on CDK4/6 inhibitor-
based therapy.  
Primary Objective 
Estimate the objective response rate (ORR). 
Primary Endpoint 
Best overall response of CR or PR, as per RECIST 1.1. 
Secondary Objectives 
1. To evaluate progression-free survival rate (PFS). 
2. Estimate the disease control rate (DCR). 
3. To describe time to response and duration of response. 
4. To evaluate safety and tolerability. 
Secondary Endpoints 
1. Time from date of enrollment to the date of first documented 
disease progression or death due to any cause. 
2. Best overall response of CR, PR or SD lasting for ≥ 24 weeks, as 
per RECIST 1.1. 
3. Time to response: Time from registration to first documented 
response (CR or PR). Duration of response: Time between the 
first date of documented response to progression or death due to 
breast cancer. 
4. Type, frequency and severity of adverse events and laboratory 
abnormalities according to CTCAE version 5.0. 
5. Biomarker correlatives.  
Study Design 
This is a phase II single-arm trial.  


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Study Intervention 
Description 
All patients will receive onapristone 50 mg p.o. BID daily and fulvestrant 
(500 mg) intramuscular injection on days 1, 15 (cycle 1), then two weeks 
later (cycle 2, day1), then once every 28 days thereafter. A cycle is defined 
as 28 days. 
There will be no breaks between dosing cycles.  
Number of Subjects 
A total of 39 subjects will be enrolled in the study. 
Estimated Time to 
Complete Enrollment: 
Approximately two years. 
 


 
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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
30-day post-last dose 
safety visit. 
Eligibility Confirmation 
Onapristone 50 mg BID 
Fulvestrant (500 mg) intramuscular injection will be 
administered on days 1, 15 (cycle 1), then two weeks 
later (cycle 2, day1), then once every 28 days 
thereafter. 
Treatment until progression or until discontinuation 
criteria is met. 
Follow-up. 
Outcomes assessed. 
Screening 


 
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STUDY CALENDAR 
 
Study Procedures 
Screening1 
Cycle 1 
(1 cycle = 28 days) 
(± 2 days) 
Cycle 2 and 
beyond 
 (1 cycle = 28 days) 
(± 3 days) 
Progression/ 
End of 
Treatment 
Visit 
Safety 
Visit2,3 
 
 (±14 days) 
Follow-up 
(12 months) 
Every 3 
months  
 
(±14 days) 
Study Day/Visit Day 
Day – 30 to 
Enrollment 
15 
8 
15 
1 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
AE Reporting 
Recorded from cycle 1 day 1 and every four weeks through 30 days after the last dose of 
study drug (section 7). 
 
Concomitant Medications 
Recorded from signing of the ICF through 30 days after the last dose of study drug. 
 
Physical Exam 
X 
X 
 
 
X 
X 
X 
 
Vital Signs4 
 
X 
X 
 
 
X 
X 
X 
 
Medical History 
X 
 
 
 
 
 
 
 
Prior antineoplastic therapies 
X 
 
 
 
 
 
 
 
12-lead electrocardiogram 
(ECG) 
X 
As clinically indicated. 
 
 
ECOG Performance Status 
X 
X 
 
 
X 
X 
X 
 
CBC w/ Diff and platelet count 
X 
X 
 
 
X 
X 
X 
 
Blood Chemistry including Liver 
Function tests5 
X 
X 
 
 
X 
X 
X 
 
PT/INR, PTT 
X 
 
 
 
 
 
 
 
FSH, LH, Estradiol (as indicated 
to 
monitor 
premenopausal 
women 
per 
institutional 
standards) 
X 
 
 
 
 
 
 
 
Pregnancy Test (Serum or 
Urine)6 
 
X 
X 
 
 
 
 
 
 
 
 


 
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Tumor biopsy  
 
At enrollment: Archived tissue -
samples are acceptable if the 
biopsy is no more than 18 months 
ago. Otherwise, a fresh sample is 
required 
prior 
to 
the 
study 
enrollment (see section 10.5.1) 
 
 
X 
 
 
 
 
 
 
X (Optional) 
 
 
Blood 
biomarker 
correlatives 
(required) 
 
X 
 
 
X (Cycle 3 Day 1 
only) 
X11 
X10 
 
Tumor assessment (CT/MRI)  
CT or MRI of chest, abdomen and 
pelvis 
required; 
Skin 
Photography; imaging of other 
metastatic 
sites 
if 
clinically 
indicated.9 
         X 
 
 
 
X 
Every eight weeks 
from C1D1 for the first 
12 months (every 12 
weeks after the first 12 
months). 
X 
 
 
RECIST Criteria -assessment 
        X 
 
 
 
X 
X 
 
 
18F-FFNP PET/CT (Optional)7 
 
X 
X 
 
 
 
 
 
Bone scan  
As clinically 
indicated. 
 
 
 
As clinically 
indicated. 
 
 
 
Brain CT or MRI  
As clinically 
indicated. 
 
 
 
As clinically 
indicated. 
 
 
 
Fulvestrant8   
 
 
X 
 
X 
X 
 
 
 
Onapristone 
 
Continuous dosing (see section 6.0).  
 
 
 
Drug adherence 
 
X 
 
 
X 
X 
 
 
Survival status  
 
 
 
 
 
 
 
X 
 


 
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1. All screening procedures must occur within 30 days prior to enrollment. 
2. If subject discontinues treatment early and/or progresses/relapses, the safety visit assessments can be completed prior to 
starting other therapy.   
3. The safety visit will occur 30 days (+/- 14 days) from last dose of study treatment. If a subject has disease progression/relapse 
or subject withdrawal, then they will be followed as per follow-up requirements. Subjects will be followed every three months 
(±14 days) from the end of treatment visit. An alternative follow-up with either a phone call or chart review will be acceptable. 
4. Include height and weight on screening. Weight, temperature, HR, RR, and BP or as per institutional standards at all 
timepoints.   
5. No repeat laboratory evaluation and a physical exam on day 1 are required if screening completed <7 days prior to C1D1.    
6. For women of childbearing potential. A negative pregnancy test must be obtained within seven to 10 days prior to the first 
dose of study drug(s).  
7. Subjects who chose to undergo the optional 18F-FFNP PET/CT for PR imaging will undergo a baseline scan at least 24 hours 
prior to starting treatment (no more than 7 days prior) and a follow-up scan seven to 14 days after starting treatment. 
8. Fulvestrant will be given days 1 and 15 in cycle 1. The C2D1 dose should be given two weeks after C1D15 dose. Fulvestrant 
dosing will be every 28 days beginning with C2D1.   
9. Imaging scans per section 10.1; imaging frequency (with windows) per section 10.2. Imaging at end of treatment visit not 
required if completed within the past 6 weeks. Skin photography required if skin lesions are present and amenable to 
photography.  
10. If blood for correlative studies was not collected at the end of treatment visit, it should be collected at the safety visit and 
prior to starting any new treatment.  Please refer to section 10.5.1 and 10.5.2.  
11. If a research sample was drawn at Cycle 3 Day 1 and subject stopped treatment at that time, a third sample is not required.  
 


 
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LIST OF ABBREVIATIONS 
 
 
ABCAE 
advanced breast cancer adverse event 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
CDK 
cyclin-dependent kinases 
CQ 
chloroquine 
CR 
complete response 
CRC 
clinical research coordinator 
CRF 
case report form 
CSF 
cerebral spinal fluid 
CT 
computed tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
CTL 
cytotoxic T cell 
CTO 
Clinical Trials Office 
DFS 
disease-free survival 
DLT 
dose-limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
data and safety monitoring plan 
ER 
estrogen receptor 
18F-FFNP 
18F-fluorofuranylnorprogesterone 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
HCQ 
hydroxychloroquine 
HCT 
hematocrit 
HER 2 
human epidermal growth factor receptor 2 
HGB 
hemoglobin 
IP 
investigational product 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 


 
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LMWE 
low molecule weight isoforms of cyclin E 
MCWCC 
Medical College of Wisconsin Cancer Center 
MTD 
maximum-tolerated dose 
NCI 
National Cancer Institute 
ORR 
overall response rate 
PBMC 
peripheral blood mononuclear cells 
PD 
disease progression 
PET 
positron emission tomography 
PDAC 
pancreatic ductal adenocarcinoma 
PK 
pharmacokinetics 
PR 
partial response 
PgR 
progesterone receptor 
Rb 
retinoblastoma 
RBC 
red blood cell (Count) 
ROS 
reactive oxygen species 
SAE 
serious adverse event 
SD 
stable disease 
SD 
standard deviation 
SRC 
Scientific Review Committee 
TMZ 
temozolomide 
ULN 
upper limit of normal 
UP 
unanticipated problem 
UPIRSO   
unanticipated problems involving risks to subjects or others 
WBC 
white blood cell (count) 
WON 
Wisconsin Oncology Network 
 
 
 
 
 
 
 
 
 
 
 
 


 
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1. BACKGROUND  
 
1.1 Hormone Receptor-Positive HER2-Negative Breast Cancer 
Breast cancer is the most frequent cancer among women, impacting 2.1 million women each year, 
and causing the greatest number of cancer-related deaths among women. In 2018, it is estimated 
that 627,000 women died from breast cancer — that is approximately 15% of all cancer deaths 
among women.(1) (World Health Organization Global Health Estimates, 2019).  
Estrogen-deprivation therapy is the core treatment modality in patients with hormone receptor 
positive (HR+, that is, estrogen or progesterone receptor, i.e., ER+ and/or PgR+) advanced breast 
cancer (NCCN Guidelines®).(2) Endocrine therapy options for postmenopausal women with ER+ 
advanced breast cancer (locally advanced, recurrent, or metastatic breast cancer (MBC)) include 
selective ER modulators (SERM; tamoxifen), ER antagonists (fulvestrant), selective nonsteroidal 
AIs (NSAI; anastrozole and letrozole) and steroidal AIs (exemestane). The cyclin-dependent 
kinase 4 and 6 (CDK4/6) inhibitors are rapidly transforming the care of patients with hormone 
receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2−) 
advanced breast cancer. There are currently three CDK4/6 inhibitors that have been approved by 
the U.S. Food and Drug Administration: palbociclib, ribociclib, and abemaciclib. It is generally 
recommended to use the combination of a CDK4/6 inhibitor along with an aromatase inhibitor (AI) 
for first-line treatment, pending OS data.(3-5) For patients with disease progression after front-
line endocrine therapy, a combination of fulvestrant and palbociclib demonstrated a remarkable 
improvement in progression-free survival (PFS) compared with fulvestrant plus placebo in the 
PALOMA3 trial (median 9.5 vs. 4.6 months; HR 0.46, 95% CI 0.36-0.59).  
Upon disease progression, mammalian target of rapamycin [mTOR] inhibitors plus AI based 
regimen is used as a second-line therapy, which can be somewhat toxic and difficult to tolerate.(6) 
Recent approval of alpelisib in PIK3CA-mutated hormone receptor-positive breast cancer, based 
on a phase III SOLAR trial of 572 patients, demonstrated a PFS of 11 months vs. 5.7 months in 
the alpelisib plus fulvestrant arm compared with fulvestrant alone (HR, 0.65, 95% CI 0.50–
0.85).(7) However, in this trial, the benefit was noted in patients with PI3K mutations compared to 
those without mutations. Diarrhea and hyperglycemia were the toxicities with alpelisib. In addition, 
a total of 25% discontinued therapy due to toxicities, thus, emphasizing the need for novel agents. 
One key limitation of both the everolimus and alpelisb studies is the lack of data for the role of 
these agents after prior CDK4/6 inhibitor therapy. 
Most patients progress on the above-mentioned treatments, and ultimately develop endocrine 
resistance.(8-12) While the worsening of disease is inevitable, not all patients suffer from high 
tumor burden, and those with oligometastatic disease, and low tumor burden continue to do 
well.(13) However, for patients who progress on the prior therapy with CDK inhibitors, and those 
who are ineligible to receive  PI3K, and mTOR inhibitors due to lack of PI3K mutations, or other 
comorbidities, systemic chemotherapy is the only option regardless of the disease burden, and 
thus, novel agents as proposed in this study remain as potential options for patients with 
ER+/HER2- metastatic breast cancer. 
 
1.2 The Progesterone Receptor [PgR] 
 
1.2.1 Role of PgR in Breast Cancer Proliferation 
 
Evidence that the PgR signaling pathway is also a major driver of breast cancer risk has continued 
to significantly grow during the last decade. In addition to the ER, PgR also plays a prominent role 
in breast cell proliferation leading to cancer progression.(14) In addition to ligand-activated 


 
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transcription, phosphorylation of PgR via growth factor-mediated kinases is associated with 
transcriptional hyperactivity at select phosphorylation-responsive PgR target genes that are 
important for breast cancer cell proliferation and pro-survival.(15)  
The progesterone receptor (PR) belongs to the steroid receptor family, a subset of the nuclear 
receptor family, and is the mediator of progesterone action. Expressed in the human as two major 
forms, progesterone receptor A (PRA) and progesterone receptor B (PRB), the PR is a ligand-
activated transcription factor, which plays a key role in hormonally regulated tissues, such as 
breast.(14-16) The PR is expressed in normal cells and in certain malignant tissues, mediating 
the effects of progesterone by association with a range of coregulatory proteins and binding to 
specific target sequences in progesterone-regulated gene promoters.  
Ligand activation of PR results in redistribution into discrete sub-nuclear PR foci that are 
detectable by immunofluorescence, probably representing aggregates or clusters of multiple 
transcriptionally active PR-co-regulator complexes exhibiting an activated pattern (A). In the 
absence of ligand, PR may be distributed evenly in the nucleus in a diffuse pattern (D) [Grimm 
2016]. PR foci are aberrant in cancers, being more irregular and bigger in size, suggesting that 
the co-regulator composition and number of complexes are altered. It is hypothesized that tumors 
with the A pattern (called APRpos) may benefit from onapristone treatment more than PgRpos 
patients with the D pattern. Studies have shown that APR is present in a significant number of 
postmenopausal breast and endometrial tumors.(16)  
In addition to ligand-activated transcription, phosphorylation of PR via growth factor-mediated 
kinases is associated with transcriptional hyperactivity at select phosphorylation-responsive PR 
target genes that are important for breast cancer cell proliferation and prosurvival.(15) Growth 
factor activity may reduce or supplant the need for a progestin ligand and leads to ligand-
independent activation of PR. Progesterone, but not estrogen, has emerged as a key mediator of 
both normal and neoplastic mammary gland stem cell expansion.(15) Consequently, the PR is 
considered a relevant therapeutic target for further study in breast cancer.(16-20) Activation of 
PR in breast cancer cells provides a strong rationale for the use of antiprogestins, in particular 
onapristone, that can antagonize ligand-independent and ligand-dependent PR activity for the 
treatment of breast cancer. 
1.2.2 ESR1 Acquired Mutations Are Associated with Significant Increase in PgR 
Expression 
Recent data suggest that mutations in the ESR1 gene encoding ERα play a major role in 
resistance to endocrine therapy in the clinic. The most prevalent mutations, as detected in a 
number of studies, are the Y537S and D538G mutations.(21) Specific acquired mutations from 
fulvestrant (e.g., ESR1 Y537S) are also a major driver of resistance to fulvestrant and palbociclib 
combination therapy.(22) These acquired mutations can lead to the expression of constitutively 
active ERα that can induce its downstream target genes, including PR, in the absence of 
estradiol.(22)  
Collectively, these data suggest blocking both ER and PgR signaling pathways in patients with 
advanced breast cancer is an attractive yet clinically untested hypothesis. In particular, combining 
onapristone and fulvestrant, both full antagonists of PgR and ER, respectively, is likely to lead to 
complete hormonal blockade even in patients that have acquired resistance after long-term 
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1.2.3 Mechanism of Action 
Upon ligand (e.g., progesterone) binding, the 
PR dimerizes and attracts nuclear cofactors 
to form a complex. This complex becomes 
functional 
and binds 
to specific 
DNA 
sequences 
in the 
promoters 
of 
PgR-
dependent 
genes, 
termed 
progesterone 
response elements (PRE). The DNA-PRE 
binding is an energy-requiring process and is 
associated with chromatin remodeling.(23) A 
simplified 
diagram 
of 
the 
proposed 
mechanism of transcriptional activation of the 
PR is illustrated in Figure 1. 
 
PgR has long been considered as a mere indicator of hormonal sensitivity (i.e., to antiestrogens). 
In fact, PR dramatically modulates ER action in breast cancer.(24-26) It also has been 
demonstrated that progesterone alone was a potent stimulator of proliferation in ex vivo breast 
tumor tissue samples, while estrogen was a weak stimulator.(15)  
1.2.4 PgR Isoforms and Post-Translational Modifications 
The PgR is expressed as two main forms (PRA and PRB) with different molecular weights and 
functions. In normal human tissues, expression of PRA and PRB is balanced, while in malignant 
tissues, the proportion of PRA and PRB may be profoundly altered: PgR isoform predominance, 
especially PRA predominance, is evident in a significant proportion of ductal carcinoma in situ 
(DCIS) and invasive cancers. In addition, another distinctive feature of malignancy is that there is 
marked heterogeneity of PRA: PRB expression between neighboring cells, as demonstrated in 
breast and endometrial cancers.(20, 27, 28)  
In mouse models, the knockout of PRB prevents mammary gland development(29), while the 
knockout of PRA prevents uterine development but has little effect on mammary gland 
development.(30)  
PgR 
has 
numerous 
sites 
of 
phosphorylation, which can be induced 
by ligand binding but also by kinases 
commonly active in breast cancer, such 
as MAPK, CK2, and CDK2. PgR 
phosphorylation sites are illustrated in 
Figure 2. These modifications modulate 
the PR gene activation program in a 
context-dependent and ligand-specific 
manner: for example, phosphorylated 
and desumoylated PgRs recognize 
selected antagonists (mifepristone and 
aglepristone) 
as 
potent 
receptor 
agonists relative to onapristone. Thus, the PR phosphorylation profile influences its downstream 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: Proposed model of activated PR (APR) foci in 
transcriptional activation [Arnett Mansfield 2007] 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2: Onapristone activity in MCF7 tamoxifen-resistant cell 
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effects and is likely to be key in a “high kinase” context, such as breast and other PR-positive 
cancers. Stimulation of this phosphorylation can be by MAPK, CDK, EGF or other growth factors 
or cytokines that activate MAPKs. pSer294 PRs induce HER2- and IGFR-associated gene sets 
and are required for formation of secondary mammospheres (i.e., an in vitro assay of cancer stem 
cell potential). pSer294 PR also has been implicated in regulation of PR target genes (RUNX2) 
required for mammary gland stem cell expansion. Phosphorylation of PR (Ser294) via growth 
factor-mediated kinases is associated with transcriptional hyperactivity at select phosphorylation-
responsive PR target genes that are important for breast cancer cell proliferation and 
prosurvival.(31, 32) This property is likely key, as PR seems to be constitutively phosphorylated 
and activated in a subset of patients with breast cancers through abnormal activation by aberrant 
growth factor and kinase pathways.(31, 32) The turnover of unliganded PR in cells is roughly 20 
to 22 hours, while phosphorylated PRs have a much shorter half-life, on the order of minutes to 
an hour when PR Ser294 is phosphorylated [Data on File]. Thus, when PR is phosphorylated and 
active and PR target gene products are high, such as the mRNA transcripts induced by PRs, the 
PR protein is often undetectable by standard Western or IHC-based protocols. This observation 
has key implications from both PD and diagnostic standpoints. Onapristone treatment does not 
permit Ser294 phosphorylation, even in the presence of progesterone. This contrasts with other 
antiprogestins.(15, 33, 34) Knutson et. al. concluded that “antiprogestins that block PR SER294 
phosphorylation should be included ‘up-front’ as part of routine endocrine therapies for women 
undergoing long term management of ER+ luminal breast cancer.”(15)  
In the literature, the assumption has been that in tumor tissues the PgR had no function in the 
absence of progesterone, and that ligand was required for PgR activation. We postulate, and 
stipulate that in addition to ligand-dependent activation of PgR, in a subset of breast cancer 
patients, PgR can also be activated in a ligand-independent manner or in the presence of low 
levels of endogenous ligand via phosphorylation by abnormal growth factor or kinase-type 
pathways. In the malignant cells, this phosphorylation of the PgR results in either a constitutively 
activated PgR or PgR activated by low levels of ligand; and the PgR ligand may not necessarily 
be nascent progesterone.  
This working hypothesis does not apply to normal stromal cells, which continue to require 
physiologic levels of PR ligand to activate the PR-associated gene set in a ligand-dependent 
manner.(31, 32)  
 
1.2.5 PR Antisense 
Several animal models have shown that antiprogestins were able to inhibit tumor growth as single 
agents in progestin-induced, 7, 12-dimethylbenz (α) anthracene (DMBA)-induced, or estrogen-
induced and even in progestin-induced but progestin-growth independent tumors. It seems that 
the direct antagonism of PgR is critical for growth inhibition, as shown recently with the use of 
PgR antisense oligodeoxynucleotides. In one study, BALB/c mice with SC 25 mm2 mammary 
carcinomas expressing ERα and PR were injected intraperitoneally with PgR antisense oligos 
every 24 or 12 hours for five to 10 days, or continuous mifepristone SC once every 24 hours or 
once as an SC implant. Control mice received vehicle or scrambled oligonucleotide to PgRs. 
Tumor growth was inhibited by PgR antisense oligos, onapristone and mifepristone, and the 
authors concluded that this provided further evidence for a critical and hierarchical role for the 
PgR pathway in mammary carcinomas.(35, 36)  


 
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1.3 Overview of Fulvestrant 
Fulvestrant is the first-in-class unique ER downregulator with no known agonist effects.(37) 
Fulvestrant binds, blocks and, unlike tamoxifen or other SERMs, degrades the ER, completely 
inhibiting ER signaling. As a result, there is less chance of the ER being activated by alternative 
pathways that are believed to cause resistance (e.g., growth factor-mediated mechanisms) 
.Fulvestrant is approved for the treatment of HR+ metastatic breast cancer in postmenopausal 
women with disease progression following antiestrogen therapy. Premenopausal women who 
receive ovarian suppression with GnRH analogues (leuprolide, goserelin) also can be treated with 
fulvestrant for metastatic HR+ metastatic breast cancer.(2) However, in postmenopausal women 
without symptomatic visceral disease after recurrence or progression on an AI, current clinical 
practice and treatment guidelines also include fulvestrant as a single agent.(2)  
In postmenopausal patients who experienced progression after prior endocrine therapy (either AI 
or tamoxifen), fulvestrant 500 mg emerged as the optimal dose based on the results of the 
CONFIRM study, which showed that the higher dose (500 mg monthly) significantly prolonged 
PFS compared to the 250 mg dose (mPFS 6.5 vs. 5.5 months; HR= 0.80; p = 0.006).(38)  
The most common clinically significant adverse reactions occurring in ≥5% of patients receiving 
fulvestrant 500 mg were: injection site reactions, nausea, bone pain, arthralgia, headache, back 
pain, fatigue, pain in extremity, hot flashes, vomiting, anorexia, asthenia, musculoskeletal pain, 
cough, dyspnea, and constipation. Pooled safety analysis (SmPC) identified aspartate 
aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase increases in 
approximately 15% of the treatment population with grade 3 increases seen in 1–2%. There was 
no difference in rates of AST, ALT, and AP elevations between groups treated with 250 mg and 
500 mg doses.(39)  
 
1.3.1 Clinical Pharmacokinetics of Fulvestrant 
The recommended dose (intramuscular injection) is 500 mg at intervals of one month, with an 
additional 500 mg dose given two weeks after the initial dose. Fulvestrant is slowly absorbed, 
reaching maximum plasma concentrations after about five days. Steady state is achieved within 
the first month of dosing. At steady state there is more than a twofold difference between mean 
Cmax and Cmin. After intramuscular administration, the exposure is approximately dose 
proportional in the dose range of 50 to 500 mg.(39) Fulvestrant is subject to extensive and rapid 
distribution. Fulvestrant is eliminated mainly by metabolism. The major route of excretion is via 
the feces with less than 1% being excreted in the urine. Fulvestrant has a high clearance, 
suggesting that it is a drug with a high extraction ratio. The terminal half-life after intramuscular 
administration is governed by the absorption rate and was estimated to be 40 to 50 days. An in 
vitro inhibition study showed no relevant inhibition of CYP1A2, 2C9, 2C19, 2D6 or 3A4 by 
fulvestrant. The lack of inhibition of CYP3A4 was confirmed in an in vivo interaction study with 
midazolam. Studies using human liver preparations and recombinant human enzymes indicate 
that CYP3A4 is the only P450 isoenzyme involved in the oxidation of fulvestrant; however, non-
P450 routes appear to be more predominant in vivo as interaction studies with rifampicin 
(CYP3A4 inducer) and ketoconazole (CYP3A4 inhibitor) demonstrated no effect on fulvestrant 
pharmacokinetics. The relative contribution of P-450 and non-P-450 routes in vivo is 
unknown.(39) The potential for interaction with fulvestrant therefore appears to be low. Increased 
exposure to fulvestrant was observed in patients with moderate hepatic impairment (Child-Pugh 
class B); therefore, a dose of 250 mg is recommended in these cases. Fulvestrant has not been 
administered to patients with severe hepatic impairment.(39)  


 
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1.4 Overview of Onapristone 
Onapristone is a type I antiprogestin which prevents the PgR from dimerizing and blocks ligand-
induced protein kinase-mediated phosphorylation of the PgR.(15, 34) Nondimerized PR does not 
bind to DNA.(20) This aspect is key to the activity of onapristone, as dimerization is necessary for 
binding with PREs in PR-dependent genes and subsequently with coactivators to induce 
transcription. In addition, onapristone blocks coactivator binding to gPR and stabilizes 
corepressor binding. Without functional PgR dimers and PRE binding, no PgR-dependent gene 
transcription can occur. Studies have been conducted to examine the ability of PgR to recruit a 
chromatin-remodeling complex to the promoter when bound to different classes of antagonists 
and the influence of this interaction on PgR dynamics and function in vivo.(27) contrast to 
mifepristone, onapristone reverses the assembly of DNA-bound PgR complexes induced by 
progestins.(23)  
 
1.4.1 Non-clinical Experience 
 
1.4.1.1 Onapristone Single-Agent Activity 
Onapristone was compared with anastrozole and androstenedione in an MTT proliferation assay 
in the MCF7 tamoxifen-resistant cell line. The study showed that onapristone reduced the 
proliferative index of the cancer cells by approximately 50% vs control or either of the other 
hormonal agents (Figure 2) [Personal communication S Fuqua]. 
Onapristone also is active in T47D cell lines stimulated by either progesterone or estradiol in 
steroid-free serum, but not in other PgR-positive cell lines. Onapristone also blocks estradiol-
stimulated growth of soft agar colony formation of tamoxifen-sensitive (MCF7L) and tamoxifen-
resistant (MCF7 1GX) cells (Figure 3).(24) In their preliminary results, Lange et al. (2019, in press) 
found that the commercially available PR antibodies may fail to recognize phosphorylated PR, 
and many of these tumors will be reported as PR-, when they are actually phosphor-PR positive, 
where onapristone is highly active. Therefore, it is suggested that onapristone is active in both 
PgR+ and PgR negative tumors (2019, in press).   
 
1.4.1.2 Methylnitrosourea-Induced Mammary Tumors 
In a study of rats bearing methylnitrosourea (NMU)-induced mammary tumors, tumor-bearing 
animals were treated with onapristone or megestrol acetate alone or in combination with 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3: Onapristone blocks estradiol-stimulated growth 


 
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tamoxifen for four weeks. Monotherapy with either onapristone or tamoxifen caused partial 
remission of tumors in 30% of animals. When both antihormones were administered 
concomitantly, 80% partial and 20% complete remission were achieved, while oophorectomy 
induced 22% partial and 67% complete remission (see Table 1).(40)  
Table 1: Remission rates of NMU-induced mammary tumors in rats treated with onapristone, 
tamoxifen or a combination of both antihormones 
 
 
Complete Remission 
(%) 
Partial Remission 
(%) 
Control 
0 
0 
Ovariectomy 
67 
22 
Onapristone (3 mg/kga) 
0 
30 
Tamoxifen (5 mg/kga) 
0 
30 
Onapristone + tamoxifena 
20 
80 
a Daily SC treatment over four weeks, NMU = methylnitrosourea 
 
With respect to tumor growth, the combination of onapristone and tamoxifen was as effective as 
ovariectomy (Figure 3).(40)  
Therefore, it is reasonable to hypothesize that the antitumor effect of tamoxifen may be 
enhanced by the combination with onapristone.(40, 41)  
 
1.4.1.3 Non-clinical PK and Metabolism of Onapristone 
The PK of onapristone has been characterized in male and female SD rats and female 
cynomolgus monkeys, the species used in the nonclinical safety evaluation of onapristone. 
Following oral dosing, onapristone showed a rapid absorption in both nonclinical species, and a 
moderate clearance. The systemic plasma exposure of onapristone increased in an 
approximately linear manner between 10 and 90 mg/kg/day in female monkeys, after 28 days of 
administration. In monkeys, the mean ratio of the prominent metabolite N-desmethyl-onapristone 
(M1)/onapristone AUC0-t ranged from 0.31 to 0.74 in the 10 to 90 mg/kg/day dose range. Overall, 
there was no notable sex difference in onapristone or M1 plasma exposure in rats. Renal 
clearance was a minor pathway of elimination for onapristone in chimeric mice. Incubation of 
sandwich-cultured human hepatocytes with onapristone did not reveal any significant excretion in 
bile canaliculi, suggesting that biliary excretion is not expected to be an important pathway of 
elimination in human.  
Onapristone was highly protein bound in human female plasma with an unbound fraction of 0.56 
± 0.03%. Jang [1997] previously reported that onapristone does not bind to α-1-acid glycoprotein. 
Twelve metabolites of onapristone were identified in rat, monkey and/or human liver microsomes. 
In humans, nine metabolites were observed with N-demethylation, mono-oxidation, and 
dehydrogenation as prominent metabolic pathways. None of the metabolites were unique to 
humans, thus, rat and monkey were appropriate toxicology test species. The chemical structures 
of M1 and M2 (di-N-demethyl onapristone) were confirmed using a reference standard. M1 
formation kinetics was shown to be similar in female and male HLM.  
Recombinant CYP phenotyping experiments suggested that M1 formation is predominantly 
mediated by CYP3A4 and CYP3A5, with minor contribution from CYP2C9. CYP3A4 and CYP3A5 
were also the major isoforms responsible for the demethylation of M1 to M2. Similarly, using CYP-


 
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specific chemical inhibitors in HLM suggested that M1 and M2 formation was predominantly 
mediated by CYP3A, and to a lesser extent by CYP2C8 and CYP2C9. 
Onapristone did not reversibly inhibit CYP1A2 and CYP2D6. However, onapristone inhibited 
CYP2C8, CYP2C9 and CYP3A4, with IC50 values in the range of 4.3 to 30 µM. Onapristone was 
a time-dependent inhibitor of CYP3A4. In a pilot study, CYP1A2, CYP2B6, CYP2C and CYP3A 
induction was observed using hepatocytes from a human female donor. 
In agreement with the high permeability and lack of efflux of onapristone in Caco-2 cells, 
onapristone was not a substrate of the efflux transporters MRP2, P-gp, breast cancer resistance 
protein (BCRP) or the bile-salt export pump (BSEP) in human hepatocytes. In addition, 
onapristone was not a substrate of the sinusoidal uptake transporter MRP3. Onapristone was not 
an inhibitor of MRP2 or BSEP. Similarly, M1 did not inhibit BSEP in human hepatocytes. 
1.4.1.4 Safety, Pharmacology, and Toxicology of Onapristone 
Safety pharmacology studies were conducted to identify the potential adverse effects of 
onapristone on several physiological systems. Central nervous system (CNS) was evaluated 
using Functional Observational Battery (FOB) and respiratory was evaluated using whole-body 
plethysmography assessment. CNS and respiratory safety pharmacology endpoints were 
integrated into a good laboratory practice (GLP) compliant four weeks repeat dose rat toxicology 
study. Cardiovascular safety pharmacology endpoints were evaluated in a GLP-compliant 
cynomolgus monkey study and HEK293 cells transfected with hERG. 
Table 2 Summary of Safety Pharmacology Studies 
Organ 
systems 
evaluated 
Species / 
Strain 
Method 
of 
admin. 
Doses 
(mg/kg) 
Gender  
and N 
per 
group 
Noteworthy findings 
VPT1140 
GLP 
compliant 
CNS  
 
Crl:CD(S
D) rats 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oral 
0 (vehicle), 
10, 30 and 
90 mg/kg/da
y (twice a 
day dosing at 
0, 5, 15 and 
45 mg/kg, 12 
hours apart) 
for 4 weeks 
followed by a 
2-week 
treatment 
free period. 
Female 
4 rats 
per 
group 
No effect in the neurobehavioral 
parameters as measured in an 
FOB. 
A small increase in piloerection 
resulted in a statistically 
significant difference between 
the vehicle and mid (30 
mg/kg/d) and high 
(90 mg/kg/day) dose. 
No effects observed in 10 
mg/kg/day dose, except for a 
trend for increases in tremors, 
Increase in bizarre behavior 
was observed in some animals 
treated with 30 and 90 mg/kg;  
there was a trend for increases 
in tremors in all test doses; no 
statistically significant effect 
was reached in any of the 
doses evaluated.  


 
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Organ 
systems 
evaluated 
Species / 
Strain 
Method 
of 
admin. 
Doses 
(mg/kg) 
Gender  
and N 
per 
group 
Noteworthy findings 
Respiratory 
 
 
 
 
Onapristone did not alter 
respiratory parameters 
measured in the whole-body 
plethysmography assessment 
at 10, 30, 90 mg/kg/day daily 
dosing. 
VPT1326 
GLP 
compliant 
 
Cardiovasc
ular: Arterial 
blood 
pressure, 
Lead II 
Electrocardi
ography 
(ECG) 
 
Monkey/ 
Cynomol
gus 
 
Oral 
0, 10, 30 and 
90 mg/kg  
(1 day) 
Males 
4/group 
10 and 30 mg/kg: no effects 
90 mg/kg: transient decrease in 
heart rate of 38 bpm at 4 hours 
after treatment only; QT and 
QTcV increase up to 37 
(average 29 msec) and 30 
msec (average 25 msec) 
respectively from 2 to 10 hours 
after treatment. 
No changes on arterial blood 
pressure, QRS complex, PgR 
and QA intervals. 
VPT1318 
GLP 
compliant 
 
Cardiac 
electro- 
physiology 
in vitro 
test 
(hERG 
assay) 
NA 
Phase A: 30 
µM 
Phase B: 1,3 
and 10 µM 
Groups 
of 3 
cells/ 
concent
ration  
Effect level of 10µM 
(4.5 µg/mL) in the hERG test 
was observed; indicated the 
potential to prolong QT 
No effects were present at a 
concentration of 3µM 
(1.35 µg/mL) 
 
1.4.1.5 Genotoxicity Status of Onapristone and Metabolites 
The Ames test and in vitro chromosome aberration assays were negative, indicating a lack of 
genotoxicity and mutagenicity. Earlier mouse micronucleus testing was also reported to be 
negative. 
1.4.1.6 Clinical Experience  
 
Onapristone (ONA) is a type I antiprogestin which prevents the PRA and PRB monomers from 
dimerizing, inhibits ligand-induced phosphorylation and prevents association of the PR with its 
coactivators, thus, preventing PR-mediated DNA transcription.(42) In contrast to other 
antiprogestins, ONA does not allow the PR complex to bind to DNA, minimally modulates PR-
mediated genes, and inhibits ligand-induced PR phosphorylation.(33, 34) clinical anticancer 
activity of ONA has been previously documented in patients with hormone therapy-naïve(43) or 
tamoxifen-resistant(19) breast cancer (BC).  
 


 
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Onapristone in endocrine sensitive malignancies 
 
More recently, an open-label, multicenter, randomized, parallel-group, phase I study (target n = 
60; NCT02052128) included female patients >18 years with PR+ tumors. Fifty-two patients were 
randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg 
BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint 
was to identify the recommended phase II dose. Secondary endpoints included safety, clinical 
benefit and pharmacokinetics. Tumor diagnosis included: endometrial carcinoma 12; breast 
cancer 20; ovarian cancer 13; other 7. Median age was 64 (36–84). No dose-limiting toxicity was 
observed with reported liver function test elevation related only to liver metastases. The RP2D 
was 50 mg ER BID. Median therapy duration was eight weeks (range 2–44), and nine patients 
had clinical benefit lasting at least 24 weeks, including two patients with APRpos endometrial 
carcinoma. 
 
In terms of safety, no dose-limiting toxicity (DLT) was observed. Only transient elevations in LFTs 
occurred, mostly in patients with liver metastases and abnormal LFTs at baseline. Fifty-one 
patients discontinued ONA treatment for disease progression, and one for an AE (bilirubin G3 
elevation, eventually deemed progression of disease in the liver). Refer to section 8.2 for 
additional safety information. 
 
Clinical benefit rate (partial response and stable disease lasting for at least 24 weeks) was 
observed in 17% of all patients including one partial response in a patient with ovarian cancer 
who had three prior therapies and three breast cancer patients with stable disease lasting for 
more than 24 weeks. These three breast cancer patients received seven, seven, and three 
therapies, respectively, prior to receiving onapristone and two of these patients had liver 
metastases. 
 
The authors concluded that clinical benefit with excellent tolerance was seen in heavily pretreated 
patients with endometrial, ovarian and breast cancer.(16)  
 
1.4.1.7 Pharmacokinetics of Onapristone 
 
In the phase I trial(16), plasma concentrations of ONA, mono-demethylated ONA (M1) and other 
metabolites in plasma and urine were analyzed with a validated ultra-performance liquid 
chromatography with tandem mass spectrometry detection (UPLC-MS/MS) assay. Results 
showed that ONA AUC and Cmax were dose-proportional across dose levels, with high 
correlation coefficients (R2 values are 0.76 and 0.97, respectively, see Figures 5 and 6). Average 
Tmax was 3.01 hours (2.71–3.2) vs 1.84 hours for ER versus IR formulations, respectively, and 
concentrations of drug were sustained longer with a 60% (±20) relative bioavailability for ER vs 
IR formulation. Steady state for the ER formulation was attained before day 8, and the mean ONA 
minimum concentrations at steady state were up to five times those obtained at day 1; day 8 
through levels were similar to day 1 for IR. There was no evidence of ONA accumulation at day 
57. The observed mean t1/2 for the ER formulation was approximately 18.01 hours (range, 13.9 
to 37), consistent with steady state achievement before day 8. ONA plasma concentration versus 
time curves suggest biphasic elimination.  


 
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1.4.2 Unmet Medical Need 
1. The current standard of care treatment for stage IV, HR+/HER2- recurrent/metastatic breast 
cancer (MBC) includes treatment with one of the cyclin dependent kinase (CDK) 4/6 inhibitors 
(palbociclib, ribocilcib, abemaciclib) in combination with one of the anti-estrogens as first-line 
therapy.(3-5) For patients with disease progression after front-line endocrine therapy, the 
fulvestrant plus palbociclib combination demonstrated a remarkable improvement in 
progression-free survival (PFS) compared with fulvestrant plus placebo in the PALOMA3 trial 
(median 9.5 vs. 4.6 months; HR 0.46, 95% CI 0.36-0.59).(3, 44, 45)  
2. Upon disease progression, PI3 kinase /mTOR inhibitors are used in combination with 
endocrine therapy as the second-line regimen for disease progression.(6) Recently, alpelisib, 
a PI3Kinase inhibitor,  was approved in combination with fulvestrant for PI3Kinase-mutated 
tumors, based on the SOLAR-1 trial data. This trial also reported a small cohort of patients 
who achieved a 15% RR with prior exposure to CDK4/6 inhibitor therapy.(7) Hyperglycemia, 
and diarrhea were main side effects of alpelisib, and 25% of the study patients discontinued 
alpelisib due to adverse effects.(7) Despite the promising data, both everolimus and alpelisib 
have concerning side effects, and are somewhat toxic and difficult to tolerate due to pulmonary 
toxicity, and hyperglycemia (4). While there are no approved treatments for anti-PgR-based 
regimens beyond progression on CDK4/6 inhibitors, it is anticipated that treatment with 
antiprogesterone agents, such as onapristone, may overcome the drug resistance due to the 
ESR mutations that develop over the time.(12)  
3. Regardless, most patients progress on these agents, and ultimately develop endocrine 
resistance. While the worsening of disease is inevitable, not all patients suffer from high tumor 
burden, and those with oligometastatic disease, and low tumor burden continue to do well.(13) 
However, for patients who progress on the prior therapy with CDK inhibitors, PI3K, and mTOR 
inhibitors, systemic chemotherapy is the only option regardless of the disease burden, thus, 
emphasizing the critical need for novel treatments. Exploring later lines of therapy, previous 
trials utilizing single-agent tamoxifen reported a 10% ORR.(46) Everolimus plus exemestane 
in the second-line setting led to an ORR of 9.5% in the combination arm, compared to 
exemestane alone (0.4%)(6)  In patients who had three prior lines of therapy, single-agent 
abemaciclib provided 20% response rates, median PFS six months (Monarch 1).(47) 
Therefore, based on these trials’ data, the proposed study with a combination of onapristone 
plus fulvestrant may be considered promising for further study if an ORR of 20% is identified 
in patients with prior treatment with CDK4/6 inhibitors-based regimens. 
 
  
 
Figure 5: Onapristone AUC0-last versus first dose level 
 
Figure 6: Onapristone Cmax versus first dose level 


 
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1.5 Overview of Progesterone Receptor Imaging 
 
Tumoral expression of PgR can be visualized and quantified through the use of a radiolabeled 
progestin, 
18F-fluorofuranylnorprogesterone 
(18F-FFNP), 
and 
positron 
emission 
tomography/computed tomography (PET/CT) imaging (48-53). A “first-in-human” study involving 
20 patients with invasive breast cancer has been published using FFNP-PET/CT imaging.(54) 
There were no adverse events, changes in vital signs, laboratory values or electrocardiograms, 
or clinically detectable pharmacologic effects. Dosimetry evaluation determined that the effective 
dose equivalent of 18F-FFNP is comparable to other clinically utilized PET imaging agents. 18F-
FFNP uptake was greater in PR+ cancers compared to PR- cancers. Thus, 18F-FFNP PET 
appears to be a feasible method of imaging PgR in breast cancer patients.(48-54)  
 
 
2 HYPOTHESIS AND OBJECTIVES  
Table 3 Objectives and Endpoints 
Objective 
Endpoint 
Primary 
Estimate the objective response rate 
(ORR).  
Best overall response of CR or PR, as per 
RECIST 1.1. 
Secondary 
To evaluate progression-free survival 
rate (PFS).  
Time from date of enrollment to the date of first 
documented disease  
progression or death due to any cause. 
Estimate the disease control rate (DCR).  
Best overall response of CR, PR or SD lasting for 
≥ 24 weeks, as per RECIST 1.1. 
To describe time to response and 
duration of response.  
Time to response: Time from enrollment to first 
documented response (CR or PR).  
 
Duration of response: Time between the first date  
of documented response to progression or death 
due to breast cancer. 
To evaluate the safety and tolerability.  
Type, frequency and severity of adverse events 
and laboratory abnormalities according to CTCAE 
version 5.0. 
 
3 STUDY DESIGN 
 
3.1 General Description 
 
A phase II single-arm trial of onapristone in combination with fulvestrant for women and men with 
ER-positive, PgR-positive or negative and HER2-negative locally advanced or metastatic breast 
cancer after progression on aromatase and CDK4/6 inhibitors. The study will enroll up to 39 
patients. 


 
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3.2 Estimated Time for Study Completion 
 
3.2.1 Primary Completion 
The study will reach primary completion in approximately 36 months from the time the study opens 
to accrual. 
 
3.2.2 Study Completion 
 
The study will reach study completion 48 months from the time the study opens to accrual. 
  
4 SUBJECT SELECTION 
4.1 Checklist. Use the below checklist to confirm a subject’s eligibility. For each subject, this 
checklist must be completed and maintained in the subject’s chart.  
4.2 Eligibility Criteria 
 
No waivers of protocol eligibility will be granted. When clinical factors relating to an eligibility item 
are 
unclear 
or 
questionable, 
the 
study 
PI 
or 
study 
chair 
(Kari 
Wisinski 
kbwisinski@medicine.wisc.edu or Sailaja Kamaraju, skamaraju@mcw.edu) can only provide 
guidance or clarification on eligibility.  
 
Enrolling investigator to initial next to each eligibility criteria. 
 
Inclusion Criteria 
 
Each subject must meet all the following inclusion criteria to be enrolled in the study: 
1. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care with the understanding that consent may be withdrawn by 
the subject at any time without prejudice to future medical care. 
 
2. Men and women with advanced ER+, (PgR positive or negative), and HER2 negative 
breast cancer. Advanced is defined as locally advanced or locoregionally recurrent or 
metastatic and not amenable to curative therapy.  
 
3. Below-mentioned prior lines of therapy are allowed in the adjuvant and or metastatic 
HR+/HER2- setting.  
 
• 
Patients must have had prior endocrine therapy either in the adjuvant or metastatic 
setting (SERM (tamoxifen, raloxifene, toremifene) or any of the aromatase inhibitors 
(anastrozole, letrozole, exemestane), or oral SERD on a clinical trial, either in the 
adjuvant or metastatic setting (but not prior exposure to fulvestrant)  
• 
Patients must have received prior therapy with oral CDK4/6 inhibitors in the metastatic 
setting. 
• 
Other standard therapies in the metastatic setting (such as mTOR inhibitors) are allowed 


 
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• 
Patients who previously received any one of the standard adjuvant chemotherapy 
regimens in a curative setting are eligible for this study. 
• 
One line of prior chemotherapy in the metastatic setting is allowed (i.e. any single agent 
or doublet cytotoxic chemotherapy, not limited to xeloda).   
 
4. Histologically and/or cytologically confirmed diagnosis of ER+, PgR+/- and HER2- breast 
cancer by local laboratory at diagnosis of metastatic disease. Hormone receptor positivity is 
defined as ER and PgR positivity in at least 1% cells by immunohistochemistry (IHC). HER2-
negative breast cancer is defined as a negative in situ hybridization test or an IHC status of 
0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is 
required. 
 
5. Measurable disease, i.e., at least one measurable lesion, as per RECIST 1.1 criteria. A 
palpable, and measurable breast mass is acceptable. 
 
6. ECOG Performance status ≤ 2. 
ECOG PS: ________  
Date: ___________ 
 
7.  Adequate organ function: 
 AST, ALT ≤ 2.5 times institutional upper limit.  
 
AST: _____________ 
ULN: _____________ 
Date: _____________ 
 
ALT: _____________ 
ULN: _____________ 
Date: _____________ 
 
 Total bilirubin ≤ 1.5 × ULN, except for subjects with Gilbert’s syndrome who may be 
included if their total bilirubin is ≤ 3.0 × ULN and direct bilirubin ≤ 1.5 × ULN. 
 
T. Bili: _____________ 
ULN: _____________ 
Date: _____________ 
 
If subject has Gilbert’s syndrome:  
 
D. Bili: _____________ 
ULN: _____________ 
Date: _____________ 
 
 ALP ≤ 2.5 times institutional upper limit with exception that ALP of < 5 x ULN is 
acceptable in patients with elevated with ALP due to bone metastases (in the absence 
of liver metastases).  
 
ALP: _____________ 
ULN: _____________ 
Date: _____________ 
 
 
 Serum creatinine <1.5 × ULN. 
 
Creatinine: ____________  ULN: ______________ 
Date: ____________ 
 
 
 Absolute neutrophil count (ANC) ≥1000/µL. 
 
ANC: _____________ 
Date: _____________ 
 
 
 


 
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 Patients with lymphopenia are eligible at the discretion of the treating provider. 
 
 Hemoglobin (Hb) ≥ 8g/dL.       
Hemoglobin: _________ 
Date: _____________ 
 
 Platelet count ≥ 100,000/µL.  
 
Platelets: _________ 
Date: _____________ 
 
8. Female subjects must meet one of the following:  
 Postmenopausal for at least one year before enrollment,  
OR  
 Surgically sterile (i.e., undergone bilateral oophorectomy),  
            OR 
 Premenopausal is defined as someone who has had menses at any time in the          
preceding 12 months. Premenopausal women who are eligible for this trial will require a 
GnRH analogue and treating physician may choose to monitor the ovarian function with 
laboratory tests (FSH/LH/Estradiol) to ensure a complete menopausal status with 
cessation of menses. 
       
9. Women of childbearing potential must have a negative pregnancy test within seven days 
of registration. Subjects must have a negative pregnancy test seven to 10 days prior to 
starting study treatment.     
 
Date of negative pregnancy test: ___________ 
 
10. An FFPE tumor biopsy block or up to 20 superplus frost slides with unstained histological 
sections at 4 micrometer thickness are required at the time of study entry. Archived tumor 
tissue acceptable (metastatic disease from non-bone and non-brain sites preferred, but 
primary breast or lymph node tissue is permitted) if obtained in the 18 months prior to 
study registration, otherwise a fresh biopsy will be required if deemed safe by the treating 
physician (minimal risk to patient) (see section 10.5.1). Confirmation of adequate and 
available tissue sample is to be determined by the site’s pathologist. Tumor samples do 
not need to be shipped for eligibility purposes. Tumor samples do not need to be shipped 
until subject is confirmed eligible and is registered for treatment.  
 
11. Ability to take oral medications (without crushing). Please refer to section 6.1.2 for 
directions on taking the study drug (onaprisone).  
 
12. To participate in the optional 18F-FFNP PET/CT imaging, the subject must have ER 
positive, HER2 negative, AND PgR positive disease and at least one extra hepatic lesion 
measuring at least 10 mm in size. 
 
 
 
 
 


 
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Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
 
1. Prior treatment with an anti-progesterone agent. 
 
2. Prior treatment with fulvestrant in the metastatic setting. 
 
3. Prior treatment with CDK4/6 inhibitors in the neoadjuvant/adjuvant setting. 
 
4. History of malignancy other than breast cancer within three years prior to registration 
except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ.  
  
5. History or presence of clinically active, and symptomatic CNS metastasis: If the patient 
fulfills the following criteria, they will be eligible for the trial:  
 
 Completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 
days prior to the start of study treatment and CNS tumor is clinically stable at the time 
of screening and patient is not receiving steroids and/or enzyme inducing anti-epileptic 
medications for brain metastases. 
 
6. Subjects with any of the following conditions:   
 Clinically significant illness or systemic disease as determined by the treating 
physicians.  
 Active hepatitis or uncontrolled infection or any other clinically significant cirrhosis or 
other disease that, in the opinion of the investigator would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. Testing for infectious 
hepatitis is not required for the study. Treating provider may choose additional testing 
if indicated clinically. 
 
7. Patients who have had systemic chemotherapy, or targeted therapy, within two weeks 
prior to starting study treatment or those who have not recovered from acute effects of 
any prior therapy to baseline or Grade ≤1. Grade 2 or higher exceptions include 
alopecia, up to grade 2 neuropathy or other grade 2 AEs or lab values not constituting a 
safety risk in the opinion of the treating physician. NCI CTCAE v5.0 will be used   
 
8. Co-administration with any prescriptions during the four weeks prior to first  
onapristone dosing and concerns for possible drug interactions should be discussed 
with the pharmacist. Please review Table 6 for additional details. 
 
9. Patients who are pregnant or breast feeding. 
 
10.  History of acute coronary syndromes (including myocardial infarction, unstable 
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or 
symptomatic pericarditis within 6 months prior to registration. 
 
11. Symptomatic congestive heart failure (New York Heart Association III-IV). 


 
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12. Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g. bifasicucular block, Mobitz type II and 
third-degree AV block). 
 
13. Any episode of atrial fibrillation in the prior 12 months. 
 
14. QT interval >480 msec. 
 
15. Long QT syndrome or family history of idiopathic sudden death or congenital long QT 
syndrome. 
 
16. Concomitant use of medication(s) with a known risk to prolong the QT interval and/or 
known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 
7 days prior to starting study drug) or replaced by safe alternative medication. 
 
17. Systolic blood pressure (SBP) > 160 mmHG or <90 mmHg at screening. 
 
“I have reviewed all inclusion and exclusion criteria and confirm the subject is eligible.” 
 
 
_______________________________________         
 
_______________ 
(CRC Signature)                                                         
                 (Date) 
 
 
____________________________________         
 
_______________ 
(Investigator/Enrolling Physician Signature)                                          (Date 
 


 
 
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5. STUDY ENTRY AND WITHDRAWL 
 
5.1 Required Preregistration Screening Tests and Procedures 
 
The study-specific assessments are detailed in this section and outlined in the Study Calendar of 
Events. Screening assessments must be performed within 30 days prior to registration. Any 
results falling outside of the reference ranges may be repeated at the investigator’s discretion. 
Visit procedures that were performed as standard of care prior to consent (without the specific 
intent to make the subject eligible for the trial), may count toward screening tests and eligibility if 
they are within the screening window.  
 
A written, signed informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A signed ICF copy will be given to the subject and a copy will be filed 
in the medical record. The original will be kept on file with the study records.  
All WON sites under the purview of their local IRBs follow recruitment and consent processes 
approved by the local IRB of record. WON sites for which UW HS-IRB is serving as the IRB of 
record, will follow recruitment and consent process approved by UW HS-IRB. Documentation of 
both the informed consent process and that the process occurred prior to a subject’s entry into a 
WON study is recorded in the subject’s source documents.  
All subjects who agree to participate and provide written informed consent and HIPAA 
authorization will be registered in OnCore®, the UWCCC and WON Cancer Center Clinical Trial 
Management System. The system is password protected and meets HIPAA requirements. 
 
5.2 Registration Process 
 
Patients must not start protocol treatment prior to registration. 
 
Research personnel at WON sites who enter data into OnCore® must have completed human 
subjects training and Health Insurance Portability and Accountability Act (HIPAA) training. 
 
At the time of registration, the following will be required and verified by (UWCCC):  
 
o Subject eligibility  
o Signed informed consent form  
o Signed HIPAA authorization form  
 
Refer to the Study Operations Manual for additional details regarding registration and eligibility 
verification. 
 
5.3 Discontinuation of Study Treatment, Withdrawal, and Compliance 
 
Discontinuation from the study treatment does not mean discontinuation from the study. Subject 
will be considered in follow-up, study procedures should still be completed as indicated by the 
study protocol, and AEs/SAEs will continue to be reported according to this protocol. 
 


 
 
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In the absence of treatment delays due to adverse events, study treatment/intervention may 
continue until:  
 
• 
Disease progression.  
• 
General or specific changes in the subject’s condition renders the subject unacceptable 
for further treatment in the investigator’s judgment.  
• 
Intercurrent illness that prevents further treatment administration.  
• 
Subject decides to withdraw from the study.  
• 
The subject has significant noncompliance with the protocol (see below).   
• 
Unacceptable adverse event(s) and/or dose level reduction beyond requirements as 
detailed in this protocol.  
• 
Study stopping rules are met. 
 
Subjects who sign the informed consent form, enroll, and receive the study intervention, but 
subsequently withdraw, or are withdrawn or discontinued from the study will not be replaced.  
 
5.3.1 Consent Withdrawal 
 
A subject may decide to withdraw from the study at any time by informing the study principal 
investigator or the site study team.  
 
If a subject intends on withdrawing consent, staff should confirm which of the following options 
the subject chooses and document the discussion: 
 
• 
Full consent withdrawal with no study follow-up. 
• 
Selective consent withdrawal from interventional portion of the study but agrees to 
continued follow-up of associated clinical outcome information.      
    
5.3.2 Investigator-Initiated Withdrawal 
 
The investigator will withdraw a subject whenever continued participation is no longer in the 
subject’s best interests. Reasons for withdrawing a subject include, but are not limited to, disease 
progression, the occurrence of an adverse event or a concurrent illness, a subject’s request to 
end participation, a subject’s noncompliance or simply significant uncertainty on the part of the 
investigator that continued participation is prudent. The reason for study withdrawal and the date 
the subject was removed from the study must be documented. 
 
Subjects withdrawn from study treatment will be asked to return for a 30-day follow-up visit, and 
future appointments are at the discretion of the treating provider, but not required beyond 
30 days per the study guidelines.  
 
Withdrawal Documentation Procedure:  The reason for study withdrawal and the date the 
subject was removed from the study must be documented in the case report form. 
 
5.4 Lost to Follow-Up 
 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit and/or is unable to be reached for follow-up: 
 


 
 
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The investigator or designee must make every effort to regain contact and/or reschedule 
a missed visit with the subject. 
• 
A subject is deemed lost to follow-up if his/her status cannot be obtained after all of the 
following occurs at two consecutive scheduled protocol calendar time points: 
o Three telephone calls (at least one day apart) from the study team are 
unanswered,  
AND  
o A letter to the subject’s last known mailing address goes unanswered,  
AND 
o These contact attempts must be documented in the subject’s medical record or 
study file.  
• 
Update OnCore® (follow-up tab and eCRF) when a subject is officially considered lost to 
follow-up. 
• 
If a subject is considered lost to follow-up, but subsequently contacts the study team, the 
subject should be considered in follow-up again. 
 
5.5 End of Study Definition 
 
A subject is considered to have completed the study if he or she completes all phases of the 
study, including the last visit or the last scheduled procedure shown in the calendar of events or 
is discontinued. 
 
5.6 Study Discontinuation and Closure 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause (as determined by the study PI, DSMC, sponsor, and/or IRB). Written 
notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to study participants, investigator, funding agency, the 
Investigational New Drug (IND) sponsor and regulatory authorities. If the study is prematurely 
terminated or suspended, the principal investigator (PI) will promptly inform the Institutional 
Review Board (IRB), and the sponsor and will provide the reason(s) for the termination or 
suspension. Study participants will be contacted, as applicable, and be informed of changes.  
 
6 TREATMENT PLAN 
 
6.1 Investigational Agent Administration 
 
All patients will receive onapristone 50 mg by mouth twice (BID) daily and fulvestrant (500 mg) 
intramuscular injection on cycle1 days 1 and 15, then, 500 mg once monthly until progression 
beginning with cycle 2 day 1. There will be no breaks between dosing cycles. A complete cycle 
of treatment is defined as 28 days. All dosages prescribed and dispensed to the subject and all 
dose changes during the study must be recorded on the CRF. 
 
Treatment or visit delays for public holidays or weather conditions do not constitute a protocol 
violation. 
 
 
 
 


 
 
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6.1.1 Fulvestrant 
 
Fulvestrant dose of 500 mg (or two injections of 250 mg each) will be used. For information on 
fulvestrant and management of related AEs refer to the Faslodex® prescribing information. 
Fulvestrant will be procured locally according to local practice and regulation. Fulvestrant (500 
mg) intramuscular injection will be administered on days 1, 15 (cycle 1), then two weeks later 
(cycle 2, day1), then once every 28 days thereafter. 
 
6.1.2 Onapristone 
 
The dose of onapristone will be 50 mg twice daily (BID). Context Therapeutics or its designee will 
provide onapristone as coated tablets of 20 mg and 10 mg strength to allow for dose modification 
for management of adverse events in bottles of 60 tablets each. The storage conditions for the 
onapristone will be described on the medication label. Medication labels will comply with the legal 
requirements in the United States. 
  
The investigator should instruct the subject to take the study drugs as per protocol and drug 
accountability must be performed on a regular basis. Subjects will be instructed to return unused 
study drugs and empty containers to the site at the end of each cycle. Subjects will be given a pill 
diary to track onapristone dosing and will be instructed to return the diary at their next clinic visit 
along with all pill bottles (including empty bottles). Site personnel will review the diary with each 
subject to evaluate adherence to the dosing schedule.  
 
All dosages prescribed and dispensed to the subject and all dose changes during the study must 
be recorded on the CRF. The following general guidelines should be followed for onapristone 
administration: 
 
Subjects should be instructed to take onapristone twice daily every 12 hours, and the dosing is 
independent of food intake. For any missed doses, subjects are allowed a 4 hour window, and 
any dose missed by more than 4 hours should not be taken (at least 8 hours between doses). For 
example, if the first dose is taken at 6 am, the evening dose will be at 6 pm. If the morning dose 
is missed, they can take onapristone up until 10 am and skipped doses aren’t allowed after 10 
am. If the subject ends up taking the morning dose at 10 am (instead of 6 am), the subject can 
take the evening dose at 6 pm as originally planned, and get back to the regular schedule starting 
the next day.  
 
Onapristone should be taken with a glass of water. Subjects should swallow the tablet as a whole 
and not chew or crush them. If vomiting occurs during the course of treatment, no redosing of the 
subject is allowed before the next scheduled dose. The occurrence and frequency of any vomiting 
during a treatment cycle must be noted in the adverse events section of the CRF. 
 
6.1.3 18F-FFNP  
 
18F-FFNP is an investigational radiopharmaceutical used with PET/CT for visualizing PR-rich 
target tissues and quantifying available PR-binding sites. It is given in a tracer dose amount for 
imaging purposes. The compound is not a therapeutic agent. 
 
If funding is secured and workflows are in place, the optional PET/CT scans will be performed at 
UWCCC and may also be performed at other WON sites participating in the Wisconsin Oncology 
Network of Imaging eXcellence (WONIX).  
 


 
 
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The optional PET/CT will be completed at least 24 hours prior to C1D1 (no more than 7 days 
prior) and repeated 7 to 14 days after C1D1. Prior to arrival, the subject should be well-hydrated 
and does not need to be fasting. 
 
Upon arrival, the subject’s height, weight, and vital signs (blood pressure, heart rate, respiratory 
rate, and temperature) should be recorded. The subject will have an intravenous line placed (e.g., 
20 g, antecubital vein), typically in the arm opposite to the side of primary breast cancer or side 
of prior axillary lymph node surgery. 
 
The dose of the investigational imaging agent, 18F-FFNP, is approximately 7 mCi (259 MBq), IV 
slow infusion over approximately two minutes followed by saline flush. The injection site will be 
inspected by the technologist to assess for any possible infiltration.   
 
Vital signs (blood pressure, heart and respiratory rate, and temperature) will be taken after 
injection. The subject will wait approximately 60 minutes to allow for biodistribution and tumor 
uptake of the radiopharmaceutical prior to imaging. The subject should void immediately prior 
(five to 10 minutes) to image acquisition. Vital signs (blood pressure, heart and respiratory rate, 
and temperature) will be taken after the imaging acquisition is complete. Subjects will be 
contacted by site personnel to evaluate for adverse events occurring in the 24 hours following the 
PET/CT scan. This can be done via a telephone call at least 24 hours, but not more than 72 hours 
after the completion of the PET/CT scan. 
 
Supportive Care 
 
During the study period, blood transfusions, bone-modifying agents for bone metastases, 
radiation, and other supportive care measures (i.e., growth factor support, physical therapy, 
lymphedema therapy, acupuncture) are allowed for symptom control.  
Patients are allowed to continue the study treatment during radiation if agreeable to the treating 
provider. New symptoms, such as pain, are not considered disease progression, and patients are 
allowed to be on the study treatment unless/until there is a clear disease progression on imaging.  
 
6.2 Dose Modification 
 
6.2.1 Dose Modification of Fulvestrant  
 
During the study period, dose modifications of fulvestrant are allowed as decided by the treating 
physician.  
 
6.2.2 Dose Modification of Onapristone 
 
In the preliminary studies, there were no grade 4 adverse effects (AEs) reported with a single 
dose of onapristone (10 mg immediate release (IR)) in healthy female volunteers. The treatment 
doses of onapristone (10–50 mg extended release BID or 00 mg /day) in patients with prostate 
cancer, breast, ovarian and endometrial cancers also demonstrated no grade 4 toxicities. The 
majority of the adverse toxicities were related to asthenia (16%), GGT increase (15%), nausea 
(14%), increased AST (12%), and increased ALT (11%).Two subjects discontinued onapristone 
due to AEs, and one patients discontinued due to unrelated AEs (cytopenias) due to marrow 
involvement of the disease secondary to bone metastases. One patient had 25% dose reduction 
due to liver toxicity, and ultimately discontinued onapristone due to diseases progression and LFT 
abnormalities. One death was reported within 30 days of discontinuation of onapristone due to 


 
 
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respiratory distress related to progressive lung metastases. Based on this available data under 
the Context Therapeutics development program, no major adverse effects are anticipated from 
onapristone, and the table below provides additional guidelines for dose modifications.  
 
Management of severe or intolerable adverse reactions at least possibly, probably or definitely 
related to onapristone requires dose reduction, temporary interruption, and/or discontinuation of 
onapristone therapy. A maximum of two dose reductions will be allowed, at which point the patient 
will be allowed to continue treatment at that reduced dose for the following cycles. Any adverse 
events even after the dose reductions will indicate treatment discontinuation with onapristone. 
Dose reduction should be based on the worst preceding toxicity. Please refer to Tables 4, and 5 
for guidance. 
 
Table 4 Dose Reduction Steps for Onapristone 
 
 
Dose level 
Dose and schedule 
Number of tablets and strength 
Starting dose 
50 mg BID continuously 
2 × 20 mg tablet and 1 × 10 mg tablet 
Dose level 1 
40 mg BID continuously 
2 × 20 mg tablet 
Dose level 2 
30 mg BID continuously 
1 × 20 mg tablet and 1 × 10 mg tablet 
 
Recommendations for dose reduction or interruption of onapristone in the management of 
adverse reactions are summarized in Table 5. Clinical judgment of the treating physician, 
including confirmation of lab values (by means of retesting as deemed necessary), should guide 
the management plan of each subject based on individual benefit/risk assessment.  
Once the onapristone dose has been reduced, no re-escalation will occur, even upon resolution 
of the AE. If a subject requires a dose delay of onapristone for > 28 days from the intended day 
then the subject must be discontinued from onapristone but may continue fulvestrant. 
 
Table 5 Criteria for Dose Modification of Onapristone Treatment 
 
Adverse event 
Dose of Onapristone 
Hematological* 
Neutropenia (ANC)  
Grade 1 (< LLN - 1.5 × 109/L) 
Maintain dose level. 
Grade 2 (< 1.5–1.0 × 109/L) 
Maintain dose level.  
Grade 3 (< 1.0–0.5 × 109/L) 
 
First occurrence  
Dose interruption until ANC ≥ 1.0 × 109/L ; when 
improved, resume and reduce by one dose level.   
Second occurrence 
Dose interruption until ANC ≥ 1.0 × 109/L ; when 
improved, resume and reduce by one dose level.    
Third occurrence 
Discontinue onapristone and continue fulvestrant at the 
discretion of treating physician. 
Grade 4 (< 0.5 × 109/L) 
Discontinue onapristone and continue fulvestrant at the 
discretion of treating physician. 


 
 
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Adverse event 
Dose of Onapristone 
Febrile neutropenia: ANC < 1.0 × 
109/L, with a single temperature of 
≥ 38.3 °C or a sustained 
temperature of ≥ 38 °C for more 
than one hour. 
First or second episode: Dose interruption until resolved 
until ANC ≥ 1.0 × 109/L ; when improved and afebrile, 
resume and reduce by one dose level. 
 
Third episode of febrile neutropenia: Discontinue 
onapristone and continue fulvestrant at the discretion of 
treating physician. 
 
Thrombocytopenia (PLT)  
Grade 1 (<LLN - 75 × 109/L) 
Maintain dose level. 
Grade 2 (<75–50 × 109/L) 
Maintain dose level. 
Grade 3 (<50–25 × 109/L) 
 
 
First  occurrence 
Dose interruption until platelets count is ≥75,000, then 
resume and reduce by one dose level.   
Second  occurrence 
Dose interruption until the platelet count is ≥75,000, 
then resume and reduce by one dose level.   
Third  Occurrence 
Discontinue onapristone and continue fulvestrant at the 
discretion of treating physician. 
Grade 4 (< 25 × 109/L) 
Discontinue onapristone and continue fulvestrant at the 
discretion of treating physician. 
Laboratory 
Serum creatinine 
Grade 1 (<1.5 × ULN) 
Maintain dose level. 
Grade 2 (>1.5–3 × ULN) 
Hold, evaluate for other causes. If the workup is 
negative, and creatinine resolved to <1.5XULN within 
14 days, resume and consider maintaining the dose 
level but may reduce by one dose level. 
Grade 3 (>3.0–6.0 x ULN) 
Hold, evaluate for other causes. If related to 
onapristone, then permanent discontinuation of 
treatment. If not related, and the creatinine level 
improves to <1.5XULN within 14 days, then resume at 
same dose level. If renal dysfunction is related to 
onapristone and or >14 days required for recovery, then 
discontinue onapristone and continue fulvestrant at the 
discretion of the treating physician. 
Grade 4 (>6.0 x ULN) 
Hold, evaluate for other causes. If related to 
onapristone, then permanent discontinuation of 
treatment. If not related, and the creatinine level 
improves to <1.5XULN within 14 days, then resume at 
same dose level. If renal dysfunction is related to 
onapristone and or >14 days required for recovery, then 
discontinue onapristone and continue fulvestrant at the 
discretion of the treating physician. 
 
Total bilirubin** 
Grade 1 (> ULN - 1.5 × ULN) 
Maintain dose level. 


 
 
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Adverse event 
Dose of Onapristone 
Grade 2 (> 1.5–3.0 × ULN) 
Dose interruption. Evaluate for other causes, and 
repeat LFT every week until resolved to ≤ 1.5 x ULN.  
− 
If resolved in ≤14 days, maintain dose level.  
− 
If resolved in >14 days, then resume and reduce by 
one dose level.   
Grade 3 (> 3.0–10.0 × ULN) ** 
Dose interruption. Evaluate for other causes, and 
repeat LFT every 72 hours until resolved to ≤ 1.5 × 
ULN.  
− 
If resolved in ≤14 days, then resume and reduce by 
two dose levels 
− 
If resolved in >14 days, discontinue onapristone and 
continue fulvestrant at the discretion of treating 
physician. 
Grade 4 (> 10.0 × ULN) ** 
Discontinue onapristone and continue fulvestrant at the 
discretion of treating physician. 
Liver function tests (ALT or AST) 
Grade 1 (> ULN – 3.0 × ULN) 
Maintain dose level. 
Grade 2 (>3.0–5.0 × ULN) 
 Dose interrupt, and evaluate for other causes, and     
repeat LFT every week until resolved to ≤ 3.0 x ULN.  
If resolved in ≤14 days, maintain dose level.  
If resolved in >14 days, then resume and reduce by 
one dose level   
 
Grade 3 (> 5.0–20.0 × ULN) 
Dose interruption. Repeat LFT every 72 hours until 
resolved to < or equal to grade 1 value.  
− 
If resolved in ≤14 days, then resume and reduce by 
one dose level.  
− 
If resolved in >14 days, may resume with reducing 
two dose levels and monitoring of LFTs twice a 
week for the first week and then weekly for four 
weeks (then return to study calendar).  
Grade 4 (> 20.0 × ULN) 
Discontinue onapristone and continue fulvestrant at the 
discretion of treating physician. 
Hy’s Law Criteria 
 
Grade ≥ 2 bilirubin in 
conjunction with grade ≥2 
transaminase and without 
elevation of alkaline 
phosphatase) 
Discontinue onapristone and continue fulvestrant at the 
discretion of treating physician. 
Other non-hematological toxicity*** 
Grade 1 
Maintain current dose. 
Grade 2 
Continue unless intolerable despite optimal medical 
management, then dose interruption. Monitor toxicity 
until resolved to grade 1 or tolerable grade 2. If grade 2 
event was tolerable to subject, the study treatment 
could continue under the supervision of the treating 
provider. 


 
 
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Adverse event 
Dose of Onapristone 
− 
If resolved in ≤14 days, maintain dose level.  
− 
If resolved in >14 days, then resume and reduce by 
one dose level. 
Grade 3 
 
Dose interruption. Monitor toxicity until resolved to 
grade 1 or better.  
First Occurrence 
− 
If resolved in ≤14 days, maintain dose level.  
− 
If resolved in >14 days, then resume and reduce by 
one dose level. 
Second Occurrence 
Dose interruption. Monitor toxicity until resolved to 
grade 1 or better.  
− 
If resolved in ≤14 days, maintain dose level.   
− 
If resolved in >14 days, discontinue onapristone and 
continue fulvestrant at the discretion of treating 
physician. 
Third Occurrence 
- Discontinue onapristone and continue fulvestrant at 
the discretion of treating physician. 
Grade 4 
Discontinue onapristone and continue fulvestrant at the 
discretion of treating physician. 
*No dose modifications planned for other hematologic parameters (i.e., lymphocytes).  
**For patients with Gilbert Syndrome, these dose modifications apply to changes in direct bilirubin 
only. 
***Dose modifications for nausea, vomiting, diarrhea or electrolyte abnormalities only required if 
toxicity lasts longer than 48 hours despite maximal medical therapy. Treating providers may 
choose to evaluate subjects with pertinent labs for further evaluation (for fatigue, only if toxicity 
lasts longer than seven days despite maximal medical therapy). 
 
Potential for Drug-Drug Interaction 
In vitro, onapristone is a reversible as well as a time-dependent inhibitor of CYP3A4 and 
showed potential for CYP3A4 induction. Therefore, until more data are available, patients 
should be advised to avoid those agents which are sensitive substrates or strong inducers or 
inhibitors of CYP3A4 (see Table 6). 
Inhibitors of CYP3A4: Coadministration with strong inhibitors of CYP3A4 should be avoided. 
Coadministration with moderate CYP3A4 inhibitors should be used in caution. Seville orange,  
star fruit, grapefruit and their juices affect P450. Concomitant use should be avoided.  
Inducers of CYP3A4: Avoid the use of strong CYP3A4 inducers. If patients require 
coadministration of strong CYP3A4 inducers (i.e., phenytoin, carbamazepine, rifampin, 
rifabutin, phenobarbital, St. John’s wort), treating providers and the designated pharmacists are 
required to monitor patients’ labs given that there are no clinical data to guide dose adjustment 
for onapristone in patients receiving strong CYP3A4 inducers or inhibitors.  
 
 


 
 
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Table 6: Clinically relevant drug interactions: inducers and inhibitors of isoenzyme CYP3A. 
Treating providers may choose to use the reference link below for drug interactions. 
Inducers 
Barbiturates, carbamazepine, enzalutamide, glucocorticoids, modafinil, oxcarbazepine, phenobarbital, 
phenytoin, pioglitazone, rifabutin, rifampin, St. John’s wort, troglitazone, efavirenz, nevirapine. 
Strong inhibitors 
Clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin. 
Moderate inhibitors 
Aprepitant, diltiazem, erythromycin, fluconazole, grapefruit juice, verapamil. 
Indiana 
University 
School 
of 
Medicine’s 
Drug 
Interaction 
Table 
(https://drug-
ineteractions.medicine.iu.edu/Main-Table.aspx (accessed on March 1, 2019) 
 
6.2.3 Dose Modification of 18F-FFNP 
No dose modification of 18F-FFNP is planned in this study. 
6.3 Dietary Restrictions 
 
None. 
 
6.4 Monitoring Subject Compliance  
 
Study drug will be administered or dispensed only to eligible subjects under the supervision of the 
investigator or identified sub-investigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing. Comprehensive instructions will be provided to the 
subject in order to ensure compliance with dosing procedures. The subject will be requested to 
maintain a medication diary of each dose of medication. The medication diary and all study drug 
containers will be returned to clinic staff at the end of each cycle. 
 
6.5 Follow-Up Period 
 
Subjects will be followed for one year after removal from the study treatment or until death, 
whichever occurs first. 
 
 
7 ADVERSE EVENTS: DEFINITIONS, COLLECTION AND REPORTING 
REQUIREMENTS 
 
7.1 Definitions 
 
7.1.1 Adverse Event 
 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. (International Conference on Harmonization [ICH], E2A, E6). 
 


 
 
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This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0, located on the CTEP web site: 
 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination or other diagnostic procedures. 
 
7.1.2 Serious Adverse Event (SAE)  
 
Serious Adverse Event (SAE) means any untoward medical occurrence that results in any of the 
following outcomes: 
• 
Death. Results in death. 
• 
Life threatening. Is life threatening (refers to an AE in which the patient was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
• 
Hospitalization. Requires inpatient hospitalization or prolongation of an existing 
hospitalization (see clarification in the paragraph below on planned hospitalizations). 
• 
Disability/incapacity. Results in persistent or significant disability or incapacity. 
(Disability is defined as a substantial disruption of a person’s ability to conduct normal life 
functions). 
• 
Pregnancy 
• 
Medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent one of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse; any organism, 
virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or nonpathogenic, is considered an infectious agent. 
7.1.3 Attribution of an Adverse Event 
Attribution is an assessment of the relationship between the AE and the medical intervention. 
 
Relationship Assessment:  In-Depth Definitions 
For all collected AEs, the clinician who examines and evaluates the subject will determine the 
adverse event’s causality based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below: 
Definitely Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (de-


 
 
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challenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory re-challenge procedure if necessary.  
Probably Related: There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs 
within a reasonable time sequence to administration of the drug, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (de-challenge). Re-challenge information is not required to fulfill this definition.  
Possibly Related: There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, the 
influence of other factors may have contributed to the event (e.g., the subject’s clinical condition, 
other concomitant events). Although an adverse drug event may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be upgraded to 
“probably related” or “definitely related”, as appropriate. 
Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event did 
not occur within a reasonable time after administration of the trial medication) and in which other 
drugs or chemicals or underlying disease provides plausible explanations (e.g., the subject’s 
clinical condition, other concomitant treatments).  
Unrelated: The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician.  
 
7.1.4 Expectedness of an Adverse Event 
 
Study investigator or treating physician will be responsible for determining whether an AE is 
expected or unexpected as indicated in the protocol, informed consent form and/or drug 
information brochure. An AE will be considered unexpected if the nature, severity, or frequency 
of the event is NOT consistent with the risk information previously described for the study 
intervention. 
 
7.2 Collection and Reporting Requirements for Adverse Events and Serious Adverse 
Events 
 
 
7.2.1 Collection of Adverse Events 
 
All (or specify if only certain grade AE needed) adverse events (including SAEs) must be recorded 
in OnCore® and an adverse event log. All AEs required to be collected must be graded according 
to the CTCAE v5. When possible, signs and symptoms indicating a common underlying pathology 
should be noted as one comprehensive event. Investigator’s or treating physician’s assessment 
of AE attributions must also be documented.  
 
AEs will be collected from the time the subject signs the consent form through 30 days following 
last dose of study drug(s). AEs will be tracked and followed until resolution, subject withdraws 
consent, or is lost to follow-up (including subjects who discontinue early). All adverse events 
collected per the protocol will be followed with appropriate medical management until they are 
resolved, if they are related to the study treatment, or until the investigator deems the event to be 
chronic.  


 
 
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Please see Table 7 to identify the adverse events that need to be reported.  
 
 
7.2.2 Reporting of Adverse Events and Serious Adverse Events 
 
All serious adverse events (SAEs) that occur after the subject has signed the consent form 
through 30 days following last dose of study drug(s) will be reported. All SAEs will be followed 
until satisfactory resolution, or until the investigator deems the event to be chronic. 
 
All serious adverse events (SAEs) must also be documented in OnCore®. 
 
7.2.2.1 Reporting Instructions — Serious Adverse Events — Reported within 24 Hours 
 
Serious adverse events requiring reporting within 24 hours (as described in the protocol) must 
also be reported to the Data and Safety Monitoring Committee (DSMC) chair via an email to 
saenotify@uwcarbone.wisc.edu within one business day. The OnCore® SAE Details Report must 
be submitted along with other report materials as appropriate (NCI AERs form or FDA Medwatch 
Form no. 3500 and/or any other documentation available at that time of initial reporting). The 
DSMC chair will review the information and determine if immediate action is required.  
Within 10 working days, all available subsequent SAE documentation must be submitted 
electronically along with a 24-hour follow-up SAE Details Report and a completed UWCCC SAE 
Routing Form to saenotify@uwcarbone.wisc.edu. All information is entered and tracked in the 
UWCCC database. 
The principal investigator notifies all investigators involved with the study at the UWCCC, the IRB, 
the sponsor, and the funding agency and provides documentation of these notifications to the 
DSMC. If the SAE occurs on a clinical trial in which the UW PI serves as the sponsor investigator, 
the PI reviews the event to determine whether the SAE requires reporting to the FDA and other 
participating investigators. For a multiple institutional clinical trial, the PI is responsible for 
ensuring that SAEs are reported to the sponsor as well as to all participating investigators. See 
Section 7.3 for detailed instructions on SAE reporting. 
7.2.3 Serious Adverse Events — Reported within 10 Days 
Serious adverse events requiring reporting within 10 days (as described in the protocol) must also 
be reported to the Data and Safety Monitoring Committee (DSMC) chair via an email to 
saenotify@uwcarbone.wisc.edu. The OnCore® SAE Details Report must be submitted along with 
other report materials as appropriate (NCI AERs form or FDA Medwatch Form no. 3500 and/or 
any other documentation available at the time of initial reporting). The DSMC chair will review the 
information and determine if further action is required. All information is entered and tracked in 
the UWCCC database.  
The Principal Investigator notifies all investigators involved with the study at the UWCCC, the IRB, 
the sponsor, and the funding agency and provides documentation of these notifications to the 
DSMC.  
If the SAE occurs on a clinical trial in which the UW PI serves as the sponsor-investigator, the PI 
reviews the event to determine whether the SAE requires reporting to the FDA and other 
participating investigators.  
For a multiple institutional clinical trial, the PI is responsible for ensuring SAEs are reported to the 
sponsor as well as to all participating investigators.  


 
 
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7.2.4 Sponsor-Investigator Responsibilities for SAE Review 
In the event the UWCCC principal investigator is acting as the sponsor-investigator (i.e., the PI 
holds the IND), the PI assumes responsibilities of the study sponsor in accordance with FDA 21 
CFR 312.32. In this capacity, the UWCCC PI reviews all reports of serious adverse events 
occurring on the study at UWCCC and participating external sites and makes a determination of 
1) suspectedness (i.e., whether there is a reasonable possibility that the drug caused the AE); 
and 2) unexpectedness (the event is not listed in the investigator’s brochure or is not listed at 
the specificity or severity that has been observed) in the context of this study. SAEs with 
suspected causality to study drug and deemed unexpected are reported as IND Safety Reports 
by the UWCCC PI to the FDA, all participating investigators on the study, and the external global 
sponsor (if applicable) within 15 calendar days. All fatal or life-threatening SAEs that are 
unexpected and have suspected causality to the study drug will be reported by the UWCCC PI to 
the FDA, all participating investigators on the study, and the external global sponsor (if applicable) 
within seven calendar days. 
7.2.5 Study Progress Review 
Protocol summary reports (PSR) are required to be submitted to the DSMC in the time frame 
determined by the risk level of the study (when known or per the WON guidelines (i.e., semi-
annually)). The PSR provides a cumulative report of SAEs, as well as instances of 
noncompliance, protocol deviations, and unanticipated problems, toxicities and responses that 
have occurred on the protocol in the time frame specified. PSRs for those protocols scheduled 
for review are reviewed at each DSMC meeting. 
Protocol summary reports enable DSMC committee members to assess whether significant 
benefits or risks are occurring that would warrant study suspension or closure. This information 
is evaluated by the DSMC in conjunction with other reports of quality assurance activities (e.g., 
reports from internal audits, quality assurance reviews) occurring since the prior review of the 
protocol by the DSMC. Additionally, the DSMC requires the study team to submit external DSMB 
or DSMC reports, external monitoring findings for industry-sponsored studies, and any other 
pertinent study-related information. 
In the event that there is significant risk warranting study suspension or closure, the DSMC will 
notify the PI of the DSMC findings and ensure the appropriate action is taken for the protocol 
(e.g., suspension or closure). The DSMC ensures that the PI reports any temporary or permanent 
suspension of a clinical trial to the sponsor (e.g., NCI program director, industry sponsor medical 
monitor, cooperative group study chair) and other appropriate agencies. DSMC findings and 
requirements for follow-up action are submitted to the CRC. 
7.3 Expedited Reporting of Serious Adverse Events 
Depending on the nature, severity, and attribution of the serious adverse event, an SAE report 
will be phoned in, submitted in writing, or both according to the table below. All serious adverse 
events must also be reported to the UWCCC Data and Safety Monitoring Committee Chair. All 
serious adverse events must also be reported to the UW IRB (if applicable), and any 
sponsor/funding agency not already included in the list. 
Determine the reporting timeline for the SAE in question by using the following table. Then refer 
to sections 7.3.3 AMD 7.3.5 below if the SAE occurred at the UWCCC or sections 7.3.4 and 
7.3.5 if the SAE occurred at 1 South Park, Johnson Creek, or a WON Site. 
 


 
 
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Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1,2 
 
TABLE 7:- FDA Reporting Requirements for Serious Adverse Events (21 CRF Part 312) 
NOTE: Investigators MUST immediately report to the UWCCC and any other parties outlined in the 
protocol ANY serious adverse events, whether or not they are considered related to the investigational 
agent(s)/intervention (21 CFR 312.64). 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death. 
2) A life-threatening adverse event. 
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IMEs) that may not result in death, be life-threatening, or require 
hospitalization, may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
UWCCC within the time frames detailed in the table below: 
Hospitalization 
Grade 1 and Grade 2 Time Frames 
Grade 3-5 
Time Frames 
Resulting in 
hospitalization  ≥ 
24 hrs 
10 Calendar Days 
24 Hour; 5 Calendar Days 
Not resulting in 
Hospitalization ≥ 
24 hrs 
Not required 
Expedited AE reporting timelines are defined as: 
• 
24-Hour; Five Calendar Days – The AE must initially be reported within 24 hours of learning 
of the AE, followed by a complete expedited report within five calendar days of the initial 24-
hour report. 
• 
10 Calendar Days – A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
 
Expedited 24-hour notification followed by complete report within five calendar days for: 
• 
All grade 3, 4, and 5 AEs. 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization. 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-
lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. 
Footnote “1” above applies after this reporting period. 


 
 
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7.3.1 SAE Requiring [24] Hour Reporting Occurs at UWCCC 
Report to the UWCCC:  
Reference the SAE SOP (Standard Operating Procedure) and the SAE Reporting Workflow 
for DOTs on the UWCCC website (https://kb.wisc.edu/uwccc/internal/41020) for specific 
instructions on how and what to report to the UWCCC for [24] hour initial and follow-up reports. 
A follow-up report is required to be submitted within 10 days of the initial [24] hour 
report.  
For this protocol, the following UWCCC entities are required to be notified:  
a) saenotify@uwcarbone.wisc.edu  
b) Sailaja Kamaraju, MD, MS: skamaraju@mcw.edu  
c) Kari Wisinski, MD: kbwisinski@medicine.wisc.edu 
d) Tamara Koehn: tmkoehn@medicine.wisc.edu  
e) Any other appropriate parties listed on the SAE Routing Form   
 
Report to the IRB:  
Consult the UW Health Sciences IRB’s website for reporting guidelines. 
 
7.3.2 SAE Reporting [10] Day Reporting Occurs at UWCCC: 
Report to the UWCCC:  
Reference the SAE SOP (Standard Operating Procedure) and the SAE Reporting Workflow 
for DOTs on the UWCCC website (https://kb.wisc.edu/uwccc/internal/41020) for specific 
instructions on how and what to report to the UWCCC for [10] day reports. 
For this protocol, the following UWCCC entities are required to be notified:  
a) saenotify@uwcarbone.wisc.edu  
b) Sailaja Kamaraju, MD, MS: skamaraju@mcw.edu 
c) Kari Wisinski, MD: kbwisinski@medicine.wisc.edu 
d) Tamara Koehn: tmkoehn@medicine.wisc.edu 
e) Any other appropriate parties listed on the SAE Routing Form   
 
Report to the IRB:  
Consult the UW Health Sciences IRBs website for reporting guidelines. 
 
7.3.3 SAE Requiring [24] Hour Reporting Occurs at a WON Site: 
Report to the UWCCC:  
Reference the SAE SOP and the SAE Reporting Workflow for other Affiliates on the UWCCC 
website (https://kb.wisc.edu/uwccc/internal/41020) for specific instructions on how and what to 
report to the UWCCC for [24] hour initial and follow-up reports. A follow-up report is required 
to be submitted within 10 days of the initial [24] hour report. 


 
 
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Send the OnCore® SAE details report and any supporting, applicable documentation to: 
saenotify@uwcarbone.wisc.edu 
NOTE: After a WON site has submitted the [24] hour SAE follow-up report, the report is triaged 
initially to the UW principal investigator or study chair, the DOT program manager, the affiliate 
coordinator, and the DSMC chair for review.  
The principal investigator or study chair is then responsible for ensuring the SAE is reported to 
the FDA, the global sponsor (if applicable), the UW IRB, and any other entity requiring notification, 
in accordance each entity’s reporting requirements. 
 
Report to the IRB:  
WON sites should follow the reporting requirements of their IRB of record for SAE submission. 
The UW PI/study chair is responsible for the submission of the SAE to the UW Health Sciences 
IRBs for any sites for which the UW serves as the IRB of record. 
 
7.3.4 SAE Requiring [10] Day Reporting Occurs at a WON site:  
Report to the UWCCC: 
Reference the SAE SOP and the SAE Reporting Workflow for other Affiliates on the UWCCC 
website (https://kb.wisc.edu/uwccc/internal/41020) for specific instructions on how and what to 
report to the UWCCC for [10] day reports.  
Send the OnCore® SAE details report and any supporting, applicable documentation to: 
saenotify@uwcarbone.wisc.edu 
NOTE: After a WON site has submitted the [24] hour SAE follow-up report, the report is triaged 
initially to the UW principal investigator or study chair, the DOT program manager, the affiliate 
coordinator, and the DSMC chair for review.  
The principal investigator or study chair is then responsible for ensuring the SAE is reported to 
the FDA, the global sponsor (if applicable), the UW IRB, and any other entity requiring notification, 
and in accordance each entities’ reporting requirements. 
Report to the IRB: 
The UW PI/study chair is responsible for the submission of the SAE to the UW Health Sciences 
IRBs. WON sites should follow their local IRB reporting guidelines for SAE submission. 
 
7.3.5 Other Reporting Requirements 
Reporting to the FDA  
Serious adverse events occurring on studies on which a UW PI is acting as sponsor/investigator 
must be reported to the FDA within the appropriate time frame. Mandatory and voluntary reporting 
guidelines and instructions are outlined on the FDA website: 
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm  
 
 
 


 
 
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7.4 Subject Complaints 
 
If a complaint is received by anyone on the study staff, it will be discussed with the study staff and 
will be addressed on a case-by-case basis. The PI will be notified of any complaints. Complaints 
will be reported to the IRB if indicated.  
 
If the subject has questions about his or her rights as a study subject, wants to report any 
problems or complaints, obtain information about the study or offer input, the subject can contact 
the research subject advocate/patient relations contact at the enrolling institution. The contact 
information will be provided to subjects in the consent form.    
 
A product complaint is a verbal, written or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality or stability of a drug product. Individuals who identify 
a potential product complaint situation should immediately contact the drug manufacturer and 
report the event. Whenever possible, the associated product should be maintained in accordance 
with the label instructions pending further guidance from a drug manufacturer representative. 
Product complaints in and of themselves are not reportable events. If a product complaint results 
in an SAE, an SAE form should be completed. 
 
7.5 Risk and Benefits 
 
7.5.1 Fulvestrant Identified Safety Risk 
The most common adverse reactions observed in patients receiving fulvestrant are: injection site 
pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremities, hot flashes, 
vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea and constipation (fulvestrant 
U.S. prescribing information). Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of 
patients. 
7.5.1.1 Risk of Bleeding 
Because fulvestrant is administered intramuscularly, it should be used with caution in patients 
with bleeding diatheses, thrombocytopenia, or anticoagulant use. 
7.5.1.2 Increased Exposure in Patients with Hepatic Impairment 
Fulvestrant exposure was increased in patients with moderate hepatic impairment, therefore, a 
dose of 250 mg is recommended in this group of patients. Fulvestrant was not evaluated in 
patients with severe hepatic impairment, dose modifications are allowed as mentioned in the 
section 6.2. 
7.5.1.3 Injection Site Reaction 
Injection site-related events, including sciatica, neuralgia, neuropathic pain, and peripheral 
neuropathy, have been reported with fulvestrant injection. Caution should be taken while 
administering fulvestrant per the institutional standards. 
7.5.1.4 Embryo-Fetal Toxicity 
Fulvestrant can cause fetal harm when administered to pregnant women. Women who are not 
post-menopausal or surgically sterile must be treated with a GnRH agonist to be eligible to 
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after stopping the drugs. Male breast cancer patients participating in the trial must not donate 
sperm or get their partners pregnant during treatment or within 6 months after their last dose. 
Subjects who have sexual intercourse which may result in pregnancy will be required to use 
contraception during study participation and for 6 months after their last dose.  
7.5.1.5 Laboratory Requirements for Postmenopausal Status 
Due to structural similarity of fulvestrant and estradiol, fulvestrant can interfere with estradiol 
measurement by immunoassay, resulting in falsely elevated estradiol levels. Therefore, for 
premenopausal women, the treating providers will determine the menopausal status by either 
repeating the laboratory tests such as estradiol, FSH, and LH as clinically indicated, and correlate 
with clinical parameters. 
7.5.2 Onapristone Identified Safety Risk 
In the phase I trial [Cottu 2018], seven patients (13%) experienced transient dose interruptions 
for AEs (one each: nausea, ALT increase, gastroenteritis, GGT increased, thoracic pain, 
postprocedural cellulitis, LDH increase, abdominal pain and atrial fibrillation). 
 
Thirty patients (58%) experienced at least one grade 3 or grade 4 adverse event. In 10 patients 
(19%), the following adverse events were considered related to ONA: increased GGT (13%), 
increased AST and ALP (6% each), increased bilirubin (4%), and increased ALT and LFTs, 
asthenia and pulmonary embolism (2% each). All except two of these AEs were associated with 
progressive disease: one G3 GGT elevation at week 12 in a responding patient, lasting one month 
with associated transient G1 AST and bilirubin increase, with no clinical symptoms; and the other 
a G3 GGT elevation at week 3, lasting three weeks, in a patient with liver metastases and baseline 
G1 GGT elevation. Both elevations decreased spontaneously with no action taken. None of the 
G3 AST, ALT or bilirubin elevations were considered to be dose limiting by the independent data 
review committee due to the presence of concurrent progressive disease in the liver. 
7.5.3 18F-FFNP PET/CT Identified Safety Risk 
To date, no significant adverse events have been reported as a result of the intravenous 
administration of 18F-FFNP for PET imaging applications [54].  
 
As with any IV administered agent, 18F-FFNP could cause an allergic reaction that could 
potentially pose a threat to life (anaphylaxis). This has not been observed in reported human 
exposure to date. Reasonable precautions should be taken, consistent with normal radiologic and 
clinical facility practice. The patient should be monitored until the PET procedure is completed, 
and trained personnel and emergency equipment should be available per facility standards. 
 
For purposes of informed consent regarding reasonably foreseeable risks to subjects in trials 
utilizing 18F-FFNP, the following potential adverse events are considered: 
 
• 
Injection-related risks that may include infection, or accidental extravasation of the dose 
that may lead to discomfort, localized pain, or infection (rare occurrence).  
• 
Risks related to allergic reaction/anaphylaxis that may be life-threatening (extremely rare 
occurrence). 
 
As with all PET imaging agents, 18F-FFNP is a radiopharmaceutical that decays with positron 
emission. As such, it poses an intrinsic radiation exposure risk. The radiation effective dose 
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mSv/MBq (54). Thus, for an administered dose of 7 mCi (259 MBq), the whole-body effective 
dose equivalent is approximately 5 mSv. The dose-limiting organ is the gall bladder, with an 
average absorbed dose of 0.113 mGy/MBq. The average absorbed dose to the breasts is 0.010 
mGy/MBq and the whole-body dose is 0.015 mGy/MBq. The organ and total body doses 
associated with 18F-FFNP PET imaging are comparable to or lower than those associated with 
other widely used clinical nuclear medicine procedures and are well below the maximum 
suggested individual study and annual total body dose of 30 and 50 mGy, respectively, suggested 
for investigational radiopharmaceuticals by the FDA. 
 
The CT component of the PET/CT scan are used for both attenuation correction of the PET signal 
and for anatomic localization and not as a diagnostic CT exam. The estimated effective dose 
equivalent for the CT component is 5 mSv. Thus, for one 18F-FFNP PET/CT scan, the whole-body 
effective dose equivalent is approximately 10 mSv. 
7.5.4 Potential for Overlapping Toxicities 
Based on the fulvestrant prescribing information and current compound- and class-related risks 
identified for onapristone, the following overlapping toxicities might occur:   
• 
Nausea, vomiting, diarrhea   
• 
Fatigue/asthenia.  
For further details on clinical safety, please refer to the latest version of [Onapristone 
Investigator’s Brochure] and the U.S. prescribing information for fulvestrant. 
Since there have been no significant adverse events reported as a result of the intravenous (IV) 
administration of 18F-FFNP for PET imaging applications, the potential for overlapping toxicities 
between 18F-FFNP and the study treatment is considered minimal. 
7.5.5 Potential for Onapristone-Fulvestrant Interactions 
The potential for a drug-drug interaction between fulvestrant and coadministered drugs is 
considered low. There are no known drug interactions with fulvestrant. In vitro studies showed no 
relevant inhibition of the major CYP enzymes, including CYP1A2, 2C9, 2C19, 2D6 or 3A4 by 
fulvestrant. The lack of inhibition of CYP3A4 was confirmed in an in vivo interaction study with 
midazolam. In addition, interaction studies with rifampicin (strong CYP3A4 inducer) and 
ketoconazole (strong CYP3A4 inhibitor) demonstrated no effect on fulvestrant pharmacokinetics. 
Therefore, a DDI involving fulvestrant and onapristone are unlikely to occur [Faslodex® 
Prescribing Information].  
8 PHARMACEUTICAL INFORMATION 
8.1 Onapristone 
 
8.1.1 Description 
Onapristone is a yellow to green solid with a melting point of 155 °C. Onapristone is a weak base 
with a pKa of 5.15 (± 0.15). The logP is 4.03 and the logD is 3.97. Onapristone can crystallize into 
different polymorphic/solvated forms. During polymorph screening studies, five crystalline forms 
of onapristone were identified (Forms A, B, C, D and E). The chemical name of onapristone is 
11β-(4-dimethylaminophenyl)-17α-hydroxy-17β-(A3-hydroxypropyl)-13α-methylgona-4, 9-dien-3-
one; [also known as ZK-299; ZK-98299]. 


 
 
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Full details are available in the investigator’s brochure. 
 
8.1.2 Aqueous Solubility 
The solubility of onapristone has been determined across the physiological pH range. 
Onapristone is slightly too very slightly soluble in aqueous buffer solutions at acidic pH up to pH 
5.0 (pH 1.2, 2.0, 3.0 and 5.0). There is a decrease in solubility at pH values 6.0 – 8.0. 
8.1.3 Packaging and Labeling 
A 50 mg dose will consist of one 10 mg and two 20 mg onapristone XR tablets. The tablet 
strengths are differentiated by size and weight of round uncoated tablets (200 and 400 mg tablet 
weights). 60 tablets are packaged in a labeled HDPE bottle with child-resistant cap.   
8.1.4 Storage Conditions 
The tablets are stored under ambient conditions, at 15 to 30° C.  
8.1.5 Stability Data 
 
The drug substance and XR tablets are being tested for stability per the International Conference 
on Harmonization (ICH) guidelines. 
 
8.1.6 Handling and Drug Accountability 
 
The investigator is fully responsible for the investigational products at the trial site per institutional 
guidelines. Dispensing of investigational products will be delegated to site staff. The person 
responsible for dispensing the investigational products will be responsible for maintaining 
adequate control of the investigational products and for documenting all transaction with them. 
The investigator, or a responsible party designated by the investigator, will maintain a careful 
record of the inventory and disposition of all agents. Each participating site investigator, or 
authorized designee, is responsible for maintaining careful record of inventory and disposition of 
all investigational agents received at the site. Use of the NCI Drug Accountability Record Form is 
recommended, but sites may use their own accountability logs per institutional standards. Sites 
must ensure accountability records capture the same information as the NCI Drug Accountability 
Record Form and in addition, capture the preparation time. Any used or partially used vials may 
be destroyed on site per the institutional standard of practice. Expired vials remaining at the end 
of the study may be destroyed onsite per institutional standards. 
8.2 Fulvestrant 
 
8.2.1 Description 
Fulvestrant is an estrogen receptor antagonist indicated for the treatment of hormone receptor 
(HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast 
cancer in postmenopausal women not previously treated with endocrine therapy, HR-positive 
advanced breast cancer in postmenopausal women with disease progression following endocrine 
therapy, HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal 
women in combination with ribociclib, as initial endocrine-based therapy or following disease 
progression on endocrine therapy and HR-positive, HER2-negative advanced or metastatic 
breast cancer in combination with palbociclib or abemaciclib in women with disease progression 
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Full details of dose modifications are available in the package insert.  
 
8.2.2 Aqueous Solubility 
As per package insert. 
 
8.2.3 Packaging and Labeling 
Fulvestrant is commercially available. 
 
8.2.4 Storage Conditions 
As per package insert. 
 
8.2.5 Stability Data 
As per package insert. 
 
8.2.6 Handling and Drug Accountability 
 
As per institutional guidelines.  
8.3 18F-FFNP  
 
8.3.1 18F-FFNP Description 
The chemical name of 18F-FFNP is 21-[18F] fluoro-16α,17α–[(R)-1’-α-furylmethylidene) dioxyl]-19-
norpregn-4-ene-3,20-dione. 
18F-FFNP is a radiolabeled progestin analog that binds to 
progesterone receptor with high affinity and selectivity (7-9). In primary and metastatic breast 
cancer, uptake of 18F-FFNP measured by PET/CT imaging has been shown to correlate with PR 
expression in biopsy material assayed by immunohistochemistry. 18F-FFNP is primarily cleared 
from the body via hepatobiliary elimination.(50-54) 
 
8.3.2 Packaging and Labeling 
18F-FFNP is not currently commercially available. cGMP-grade 18F-FFNP will be manufactured on 
site in the UW-Madison Radiopharmaceutical Production Facility. This facility has been qualified 
and approved for production by the NCI Cancer Imaging Program and ECOG-ACRIN for clinical 
trials using other investigational radiopharmaceuticals, such as 18F-fluoroestradiol and 18F-
fluorothymidine. Specific manufacturing processes will follow our approved Drug Master File for 
18F-FFNP. The investigational pharmacist or qualified nuclear medicine technologist will be the 
responsible party designated by the investigator.  
18F-FFNP is synthesized with high specific activity so the quantity of progestogenic material 
injected with the radiopharmaceutical is < 7 μg (<16.3 nmol). The final 18F-FFNP product solution 
contains 90% (v: v) USP 0.9% sodium chloride injection and 10% (v:v) USP ethanol alcohol 
injection. Up to 10 mL of 18F-FFNP may be administered for a single PET scan. 


 
 
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The injected dose of 18F-FFNP will be approximately 7 mCi (259 MBq) with a specific activity 
greater than 200 Ci/mmol.    
18F-FFNP is the only active ingredient. There is no evidence that nonradioactive and radioactive 
FFNP molecules display different biochemical behavior. 
 
8.3.3 Storage Conditions 
In accordance with regulations, the radiopharmaceutical facility conducts several quality control 
tests on the 18F-FFNP product prior to release for human administration. Once delivered, doses 
will be stored in the appropriate storage area in the nuclear medicine facility until they are 
administered to the subject.  
The drug solution is stored at room temperature in a gray butyl septum sealed, sterile, pyrogen-
free glass vial. 
 
8.3.4 Stability Data  
 
The expiration time of 18F-FFNP is six hours. 
 
8.3.5 Handling and Drug Accountability 
 
The investigator is fully responsible for the investigational products at the trial site. Dispensing of 
investigational products will be delegated to site staff. The investigational pharmacist or qualified 
nuclear medicine technologist will be the responsible party designated by the investigator. The 
person responsible for dispensing the investigational products will be responsible for 
maintaining adequate control of the investigational products and for documenting all transaction 
with them. 
 
9 STATISTICAL CONSIDERATIONS 
 
9.1 Study Design 
This is a single-arm phase II clinical trial to determine the efficacy and monitoring the safety of 
treatment with fulvestrant plus onapristone with ER-positive, (PgR-positive or PgR negative), 
HER2-negative locally advanced or metastatic breast cancer, which progressed on or after 
treatment with an endocrine therapy and a CDK4/6 inhibitor.  
Tumor response to treatment will be based on RECIST 1.1 criteria using local radiological 
assessments. Subjects will be treated until disease progression, unacceptable toxicity, or 
discontinuation from the study treatment for any other reason. A total of 39 patients will be 
enrolled.  
 
 


 
 
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9.2 Sample Size 
The sample size calculation for the fulvestrant and onapristone combination arm are made using 
Simon Two-Stage design (Simon 1989). Using a 5% non-inferiority margin, the ORR rate of 7% 
or lower will be considered unacceptable as the third-line treatment. The following Simon’s design 
controls type 1 error at 5% (recommending the combination for phase III if the true ORR = 7%) 
and type 2 error at 20% (NOT recommending the combination for phase III if the true ORR = 
20%).  
A total of 39 patients will be enrolled, and the study will be conducted in two stages.  
Stage I – 21 Subjects  
If ≤1 response was observed, then the combination of fulvestrant and onapristone will be not 
considered an active treatment in this group of patients, and the trial will be terminated.  
If ≥2 responses were observed, then 18 additional subjects will be enrolled.  
Stage II – 18 Additional Subjects  
If ≤5 of 39 responses were observed, then the combination of fulvestrant and onapristone will be 
not considered an active treatment in this group of subjects, and the study will be terminated.  
If ≥6 of 39 responses were observed, then the activity of fulvestrant and onapristone will be 
considered sufficient to launch a phase III clinical trial.  
This design yields a one-sided type I error rate of 5% if the ORR is 7%, and power of 80% when 
the true response rate of the combination is 20%.  
Safety monitoring: To prevent exposing more than one-third of enrolled subjects to high levels of 
adverse events or severe adverse events leading to discontinuation of the combination, the 
following sequential procedure will be used. If the number of such discontinuation events is higher 
than three of the first 11 subjects, 4/21, 5/30, and 7/39 [sequential stopping boundaries for (1) 
33% rate of discontinuation at a <5% chance of not stopping the study early and (2) 10% rate of 
discontinuation at a <10% chance of stopping the study early], the principal investigator and study 
chair will meet to discuss early termination of the study. 
Point and 95% interval estimate of ORR will be evaluated accounting for possibility of early futility 
stopping as describe in Koyama T et al. 2008.(55) 
PSF will be described with Kaplan-Meier (KM) Curve and its pointwise asymptotic 95% confidence 
bounds. Median PFS if reached will be extracted from this KM estimator. Parametric forms (such 
Weibull) of survival probability will be fitted to the collected data.  
DCR will be estimated with relative frequency and exact two-sided 95% binomial confidence 
interval. Time from registration to first documented response (CR or PR) will be evaluated with a 
cumulative incidence where death will be as a competing risk to response.  


 
 
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Duration of response will be assessed for a subgroup of subjects with observed response. The 
date of response will be denoted as time zero and time to progression or death will be evaluated 
with KM curve and 95% CI. Median time to response will be extracted from this KM curve.  
The impact of possibility of early stopping due to futility will be evaluated under plausible 
parametric models using Monte-Carlo simulations with 10,000 repetitions under each plausible 
scenario.  
Type, frequency and severity of adverse events will be summarized with descriptive frequency 
tables.  
 
Figure 7 Minimax Simon Two-Stage Design Enrolling 39 Subjects 
 
 
 
 
 
 
 
 
 
 
Secondary analyses: Regression analysis will be completed using Cox proportional regression 
model for PFS and logistic regression model for ORR. Due to a relatively small number of patients 
in the study, we will investigate the impact of categorical variable if the number of events 
(responses for ORR and progression or death for PFS) is greater than five per category. The 
impact of the following predictors will be explored: age, race, ER status, PgR status, prior therapy 
(type of therapy AI or SERMs such as tamoxifen alone or CDK4/6+endocrine therapy combo), 
number of metastatic sites, measurable disease, and biomarkers. Single-predictor models will be 
used. The possibility of multiple Cox and logistic regressions will be considered as well, but due 
to a small number of patients we are not expecting to fit multiple regressions. 
All planned data analyses will be completed with SAS 9.4. Monte-Carlo simulation studies will be 
completed in R v3.5.1. 
 
 
 
≥2 responses 
Initiate Phase III clinical trial 
≥6/39 responses 
Stop 
≤5/39 
responses            
Stage -1 
Accrue 21 
subjects  
≤1 responses 
Stop 
 18 subjects 


 
 
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10  MEASUREMENT OF EFFECT 
10.1  Baseline 
Imaging assessments will be performed at screening/baseline within 30 days prior to enrollment. 
Any imaging assessments already completed during the regular workup of the patient within 30 
days prior to enrollment, including before signing the main study ICF, may be considered as the 
baseline images for this study.  
The following assessments are required at screening/baseline:  
• 
Chest, abdomen and pelvis CT or magnetic resonance imaging (MRI).  
• 
CT or MRI of other metastatic sites, if clinically indicated. PET scan is an acceptable 
modality of imaging, as decided by the treating provider. 
• 
Whole-body bone scan per institutional standard of care. Localized bone CT, MRI or X-
ray should be performed for any lesions identified on the whole-body bone scan that are 
not visible on the chest, abdomen and pelvis CT or MRI. 
• 
Brain CT or MRI, if clinically indicated. 
• 
If skin lesions are present at screening, and amenable to photography, color photography 
should be acquired using a digital camera in clear focus, including a scale/ruler, in such a 
way that the size of the lesion(s) can be determined from the photograph. 
• 
Measurements of breast mass on imaging are permitted as measurable disease. 
• 
Routine blood tests prior to and during the study are listed in Table 8. 
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion, unless the lesion has clearly progressed since the 
radiotherapy. Chest X-rays and ultrasound should not be used to measure tumor lesions. 
10.2 Response Evaluation 
Imaging assessments for response evaluation will be performed every eight weeks (±7 days) 
during the first 12 months and every 12 weeks (±14 days) thereafter. Additional imaging 
assessments may be performed at any time as clinically indicated. This schedule should be 
followed until radiological progression is documented, irrespective of compliance to treatment, or 
until the subject enters follow-up. 
Each lesion that is measured at baseline must be measured by the same method and the same 
local radiologist throughout the study.  
10.3 Safety and Tolerability Assessment 
Safety assessment will include routine safety monitoring of adverse events and serious adverse 
events; laboratory testing measurement of vital signs, performance status, physical examination 
and ECG will be performed at baseline and at each visit thereafter. Laboratory assessments will 
be performed in the local laboratory. 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 
5.0 will be used for all grading. The following safety assessments will be performed along the 
study: 
• 
Lab parameters: Hematology, biochemistry, coagulation, urinalysis, thyroid  
• 
Adverse events. 
• 
Concomitant medications. 
• 
ECG. 
• 
Medical history, vital signs, performance status, and physical exam.  


 
 
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Table 8 
Clinical laboratory parameters collection plan 
Test 
Items 
Hematology 
Hematocrit, hemoglobin, MCH, MCHC, MCV, platelets, red blood 
cells, white blood cells, RBC morphology, differential (basophils, 
eosinophils, lymphocytes, monocytes, neutrophils) 
Chemistry  
Calcium, potassium, sodium, glucose, alkaline phosphatase, ALT 
(SGPT), AST (SGOT), total bilirubin, total protein, albumin, 
creatinine, chloride, bicarbonate. Direct bilirubin must be performed 
ONLY if total bilirubin is elevated. 
Coagulation at 
baseline 
International 
normalized 
ratio 
(INR), 
and 
activated 
partial 
thromboplastin time (aPTT) or partial thromboplastin time (PTT). 
Urine or serum 
pregnancy test 
At baseline.  
All laboratory analysis will be performed locally. 
 
10.4  Other Assessments  
Cardiac Assessments 
A standard 12-lead ECG will be performed at screening. The interpretation of the ECG must be 
made by a qualified physician and documented in the ECG section of the CRF. Clinically 
significant abnormalities present when the patient signed informed consent should be reported 
on the medical history CRF page. New or worsened clinically significant findings occurring after 
informed consent must be recorded on the adverse events CRF page. Additional cardiac imaging 
during treatment is to be performed as clinically indicated.  
 
10.5  Tumor Biopsy and Plasma Analyses 
A summary of biomarker assessments and biomarker sample collection plan is in Tables 9, 10 
and 11. All assessments will be performed by a central designated laboratory.  
There are no plans to share the results with subjects. The correlative studies are not expected to 
provide adequate information to guide any future treatment decisions. 
All FFPE tumor blocks, unstained histological slides, and research blood samples need to be 
shipped to: 
 
Attn: Mary Rau  
Dr. Hallgeir Rui’s lab 
9200 W. Wisconsin Ave. 
Wisconsin Diagnostic Laboratories Building 
Room L50 MCW Tissue Bank 
Milwaukee, WI 53226  
 
Sample Processing: Upon receipt of the samples, MCW’s lab manager, Mary Rau, will 
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biomarker analysis by Dr. Hallgeir Rui (MCW) and Natera Inc. (Mary Rau, Tissue Bank 
Manager, Medical College of Wisconsin, Department of Pathology, mrau@mcw.edu, 
Office Phone: 414-805-9569, Lab Phone:  414-805-8829, Fax:  414-805-8825, MCW 
Tissue Bank Website: www.mcw.edu/tissuebank) 
If adequate tissue is not available for all the evaluations of study biomarkers, additional biopsies 
may be requested. However, if a subject chooses to decline additional biopsies, he or she would 
still be eligible for study enrollment. Any remaining tissue of the tumor samples will be preserved 
as coded specimens in the MCW Tissue Bank provided the subject has provided consent for the 
tissue banking. Subjects who decline to participate in tissue banking will remain eligible for the 
proposed study. FFPE blocks are stored long-term in metal Sakura block cabinets under 
ambient temperature. Room temperature is recorded and monitored daily. Samples are logged 
and tracked in the MCW Tissue Bank’s tissue tracking software, OnCore®. 
 
10.5.1  Tissue Analysis 
An FFPE tumor biopsy block or up to 20 superplus frost slides, with unstained histological 
sections at 5 micrometer thickness are required at the time of study entry. A single H&E slide is 
also requested.  
 
If the archival tissue has not been obtained in the 18 months prior to study registration, analysis 
of a more recent biopsy will be required for study entry if deemed safe (minimal risk to patient) 
by the treating physician. ER/PR/HER2 testing will be performed at the facilities/clinics where 
the patients are routinely seen, and the biopsy was performed. The remaining block will be sent 
(for sectioning or 20 precut sections) to Mary Rau at the above-mentioned address. 
 
1. Tissue analysis for IHC, protein expression and other makers (performed by Dr. 
Hallgeir Rui, MD, PhD): Protein expression will be quantified on slides, using optimized 
immunohistochemistry [IHC] protocols for planned study biomarkers. Ki-67 assessment 
on pre- and post-treatment specimens would include assessment by manual counting of 
stained tumor cells by our pathologists, as well as quantitative IHC.  
 
2. The degree of PgR expression levels will be determined using standard 
immunohistochemistry methodology on all tissue and reported as percent tumor cells with 
PgR staining. In cases where no PgR results are available, one to three 4-micrometer 
histological sections on superplus frost slides will be used for IHC testing. This testing 
will be performed at the Medical College of Wisconsin CLIA-approved clinical pathology 
laboratory using the Dako progesterone receptor antibody. Upon receipt of the slide in 
the clinical laboratory, results will be reported within 72 hours. The relationship between 
tumor response and degree of PgR expression, and/or PgR signaling, will be examined.  
 
3. Additional exploratory biomarkers will be evaluated on FFPE tissue, including 
phosphorylated PgR and PgR target gene expression. If ≥ 1% phosphorylated Ser294 
PgR (pPgR) tumor staining is seen on ≥ 1 slide the tumor will be considered to be 
pPgR+. Nuclear localization of pPgR will also be evaluated. PgR target gene analysis 
will be completed using the NanoString nCounter oncology panel system. NanoString 
analysis will require 25 ng of FFPE tissue. Tables 9, 10 and 11 include a complete list of 
tissue and blood-based genomic alterations of the breast tumor samples, and their 
preparation for this study.   
 
4. Tissue analysis for ctDNA testing (performed by Natera): Tumor samples will be 


 
 
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processed and shipped to Natera for ctDNA testing as noted above. 
 
 
 
 
Table 9 
 
 
Biomarker Correlatives 
Tissue Biopsy 
Liquid Biopsy (Plasma) 
Collection 
Pre-treatment core 
biopsy (archival or new 
FFPE biopsy) and post-
treatment core biopsy 
(FFPE; if available) 
Three time points: pre,  during 
(C3D1) and post-treatment (or at 
next follow-up visit) 
Immunohistochemistry (IHC) 
ER, PgR, HER2, Ki67, 
CD24, CD44, LDH1, 
KLF4, CK 5/6, Phospho-
Ser294-PgR 
 
Mutational Analysis of the 
tumor tissue (performed by 
Natera) 
 
A personalized assay is 
designed based on the 
unique mutation 
signature of each 
patient’s tumor 
A personalized assay is designed 
based on the unique mutation 
signature of each patient’s tumor 
and correlated with peripheral 
blood. This will allow to accurately 
monitor for the presence or 
absence of the disease over time.  
 
 
10.5.2  Peripheral Blood Preparation, Storage, and Preservation 
The proposed study aims to evaluate genomic alterations and or others (from a routine blood 
draw) for research purposes to be performed for this cohort of subjects with ER+/HER2- breast 
cancer. The blood samples will be prospectively collected at various time points and 
retrospectively evaluated (i.e., pretreatment, , Cycle 3 Day 1 and post-treatment on the study) (if 
post-treatment blood draw is not collected for any given reason, the treating provider may 
choose to do a blood sample collection at the follow-up visit).  
The blood sample collection will be per Natera (Signatera TM) guidelines for possible blood 
marker analysis for research purposes. Peripheral blood received fresh in the MCW Tissue 
Bank from consented participants. Sample collection kits (provided by Natera) will be used for 
blood collection.   
Blood samples for Germline testing: Two 10 mL Streck tubes of blood  will be collected pre-
treatment, at Cycle 3 Day 1 and at the end of treatment  for germline testing.  The tube should 
be inverted a couple times after collection and shipped to MCW (see operations manual for 
further instructions). 
 
Matched Normal Blood – in the form of frozen buffy-coat or frozen whole blood in a purple top 
EDTA (>1ml frozen whole blood, >200ul buffy coat). A 6 mL EDTA tube will be collected pre-
treatment.  The tube should be inverted a couple times after collection and shipped to MCW 
(see operations manual for further instructions). 
  


 
 
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10.5.3  Functional Imaging 
 
18F-FFNP PET/CT Imaging Protocol 
For this study, PR functional imaging using 18F-FFNP PET/CT will be performed for up to 12 
subjects. Quantitative molecular imaging with 18F-FFNP PET/CT before and seven to 14 days 
after starting therapy may be useful to confirm optimal dosing of onapristone to block PR binding 
to 18F-FFNP in patients with extrahepatic metastases. Incomplete receptor blockade, indicating 
suboptimal dosing, may be associated with earlier disease progression. The change in tumor 18F-
FFNP uptake after starting therapy will be evaluated as an estimate of PR binding availability. 
Tumor 18F-FFNP uptake parameters (SUVmax, SUVmean, SUVpeak, tumor-to-normal tissue uptake 
ratio, functional tumor volume, and total lesion uptake) will be measured before and after starting 
therapy. 
 
PET/CT scanners at UW-Madison are qualified by the American College of Radiology (ACR) 
Imaging Core Laboratory and have been approved for use in current ECOG/ACRIN trials. The 
scanner routinely will be assessed for quantitative integrity and stability by being tested using 
various imaging protocols on a standard phantom. For SUV measurement, this includes a 
comparison against a dose calibrator to ensure accuracy. A daily QC check will be performed at 
the beginning of the day, including PET/CT scanner and dose calibrator, in accordance with the 
manufacturer recommendations. If any of the QC results are outside of the manufacturer’s 
guidelines, the study will be rescheduled, and the problem rectified before scanning any subjects. 
18F-FFNP PET/CTs not completed within the protocol-specified windows due to QC results will 
not be considered a protocol deviation. 
 
A PET Imaging Protocol Manual specific to this clinical trial will be prepared for the research study 
coordinators and nuclear medicine technologists at UW-Madison. Subjects do not need to be 
fasting for 18F-FFNP PET/CT imaging, but will be encouraged to be well hydrated. The subject’s 
weight will be measured the day of imaging. 18F-FFNP will be synthesized according to cGMP 
requirements and processed for QA/QC by the UW Radiopharmaceutical Production Facility. For 
each research imaging session, subjects will receive 18F-FFNP, approximately 7 mCi (259 MBq), 
IV slow infusion over approximately two minutes followed by saline flush, once administered in 
the PET imaging suite.  
 
After approximately 60 minutes of uptake time, the subject will be positioned supine in the PET/CT 
scanner (Discovery 710 or Discovery MI at UW-Madison) for a standard body PET/CT scan from 
skull vertex to mid-thigh (typically five to seven fields of view depending on scanner specifications 
and the subject’s height) covering all known sites of metastatic disease and will include normal 
organs with expected 18F-FFNP uptake (pituitary gland and uterus). This scan will usually take 
approximately 20 to 30 minutes, depending upon the scanner used. Subjects will be asked to void 
prior to and soon after the exam to further minimize radiation dose to the urinary bladder. All 
sequential PET/CT imaging sessions will be performed on the same scanner to minimize 
variability. An iterative ordered-subsets expectation maximization algorithm will be used for PET 
image reconstruction. The PET data will be corrected for attenuation and scatter and co-registered 
with the CT images.  
 


 
 
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All adverse events occurring within a 24-hour period post-18F-FFNP infusion will be recorded 
from the subject within one to three days post-18F-FFNP infusion. Events to be specifically 
monitored during the infusion include localized discomfort at the IV injection site, pain, respiratory 
difficulties, flushing, dizziness, pruritus/rash, and any other symptoms that could be secondary to 
an anaphylactic reaction. The subject will be instructed to report any symptoms or sensory 
changes noted. 
10.5.4  18F-FFNP PET/CT Imaging Analysis 
 
18F-FFNP PET/CT images will be reviewed for general quality, including quality of the PET 
images, quality of CT images, the adequacy of PET/CT alignment, and the presence of any 
significant attenuation artifact. Lesions of interest will be visually identified by 18F-FFNP uptake 
and confirmed on at least one other conventional imaging modality, which may include the CT 
portion of the same PET/CT examination. Each site of disease will be analyzed for (1) qualitative 
and (2) quantitative 18F-FFNP uptake. For subjects with innumerable lesions, an arbitrary 
maximum of five lesions will be recorded. 
 
10.5.5  Qualitative Analysis of 18F-FFNP Uptake (Lesion-Level) 
 
18F-FFNP uptake will be evaluated qualitatively with the following scale: no uptake (tumor < 
background), minimal uptake (tumor = background), mild (tumor slightly > background), moderate 
uptake (tumor >> background), and intense uptake (tumor >>> background). Tumor uptake will 
be defined as increased (moderate or intense uptake) or absent (no uptake, minimal or mild 
uptake) for up to five target lesions. 
 
10.5.6  Quantitative Analysis of 18F-FFNP Uptake (Lesion-Level) 
 
Up to five target lesions with increased 18F-FFNP uptake, as defined by the qualitative analysis, 
will be further evaluated. Regions of interest (ROI) will be manually drawn to include the tumor 
and 18F-FFNP uptake will be quantified using standardized uptake value (SUV) measurements 
including SUVmax, SUVmean, SUVpeak, tumor-to-normal (T/N) tissue ratio, and tumor-to-blood 
pool ratios. 
 
10.5.7  Definition of 18F-FFNP Blockade 
 
The same five target lesions will be analyzed for quantitative 18F-FFNP uptake on the second 
18F-FFNP PET/CT examination as on the initial scan. If the SUVmax for all five lesions have 
decreased by > 75% or all five lesions have SUVmax < 1.5 on the second scan, then these 
subjects will be prospectively defined as having complete 18F-FFNP blockade. If the SUVmax for 
any of the five lesions has not decreased by > 75% or if any new lesions arise with SUVmax ≥1.5, 
then these subjects will be defined as having incomplete 18F-FFNP blockade. Changes in 
radiotracer uptake in normal organs with expected 18F-FFNP uptake (pituitary gland and uterus) 
will also be measured as an internal reference.  
 
11 DATA AND SAFETY MONITORING PLAN (DSMP) 
 
11.1  Oversight and Monitoring Plan 
 


 
 
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The UWCCC Data and Safety Monitoring Committee (DSMC) regularly reviews and monitors 
clinical research at the UWCCC and WON. A summary of DSMC activities are as follows: 
 
• 
Reviews clinical trials conducted at the UWCCC for subject safety, protocol compliance, 
and data integrity. 
• 
Reviews serious adverse events (SAEs) requiring expedited reporting, as defined in the 
protocol, for clinical trials conducted at the UWCCC, and studies conducted at external 
sites for which the UWCCC DSMC acts as an oversight body. 
• 
Reviews reports generated through the UWCCC Data and Safety Monitoring System 
(DSMS) elements (e.g., internal audits, quality assurance reviews, compliance reviews, 
response reviews, and protocol summary reports). 
• 
Notifies 
the 
UWCCC 
protocol 
principal 
investigator 
of 
DSMC 
decisions, 
recommendations, and, if applicable, any requirements for corrective and/or preventive 
actions related to data or safety issues. 
• 
Works in conjunction with the UW Health Sciences IRB in the review of relevant safety 
information, as well as non-compliance and unanticipated problems reported to the IRB. 
• 
Ensures that notification of SAEs requiring expedited reporting is provided to external sites 
participating in multi-site clinical trials coordinated by WON. 
 
11.2  Monitoring and Reporting Guidelines 
UWCCC quality assurance and monitoring activities are determined by study type, study 
sponsorship, and risk level of the protocol as determined by the UWCCC Protocol Review and 
Monitoring Committee (PRMC). 
 
Protocols subject to intermediate monitoring generally include UW institutional phase I/II and 
phase II Trials. These protocols undergo review of subject safety at regularly scheduled DOT 
meetings where the results of each subject’s treatment are discussed, and the discussion is 
documented in the DOT meeting minutes. The discussion includes the number of subjects 
enrolled, significant toxicities, dose adjustments, and responses observed. Protocol summary 
reports are submitted on a semi-annual basis by the study team for review by the DSMC. 
 
11.3  UWCCC DSMC Study Progress Review 
The review of protocol summary reports (PSRs) enables the UWCCC DSMC to assess whether 
the study should continue, continue with modifications, be suspended, or be closed. Following 
their review, the UWCCC DSMC will notify the PI of their recommendation and the authority for 
continuing, modifying, suspending, or closing the protocol is the responsibility of the applicable 
sponsor-investigator, PI, IRB, FDA, or other regulatory authority associated with the protocol. 
 
Based on the risk level of this study, as determined by the UWCCC PRMC, PSRs must be 
submitted to the UWCCC DSMC by the UWCCC site study team on a twice-yearly basis. 
 
The UWCCC Affiliate Office is responsible for coordinating with WON sites to ensure the data 
used to populate the PSRs are entered into the UWCCC OnCore® in a timely manner. This data 
includes, but are not limited to accrual information, SAEs, response to treatment, IRB reportable 
events (e.g., non-compliance, unanticipated problems). 
 
11.4  UWCCC DSMC Review of Auditing and/or Monitoring Reports 


 
 
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Reports created through the auditing and/or monitoring activities at all participating sites are 
submitted in real time to the UWCCC DSMC by the UWCCC staff performing these activities. 
Summary data and/or query reports are submitted in lieu of detailed reports. Following the review 
of these reports, the UWCCC DSMC may issue a request for additional corrective and/or 
preventive action(s), protocol suspension, or for-cause audit(s). 
 
11.5  UWCCC DSMC Review of Noncompliance, Unanticipated Problem, and other IRB 
Reportable Events 
 
Participating sites are to follow the reporting guidelines of their IRB of record. The UWCCC 
Affiliate Office will assist sites with study wide event data that are required to be reported. If WON 
sites utilize the UW IRBs as their IRB of record, submissions are to be coordinated with the 
UWCCC Affiliate Office.  
 
IRB reportable events are to be submitted to the UWCCC DSMC via an email to 
DSMC@uwcarbone.wisc.edu at the same time they are submitted to the IRB of record. 
 
11.6 UWCCC DSMC Review of Serious Adverse Events 
 
The UWCCC DSMC chair, or designee, reviews all SAEs occurring on the study in real time, 
regardless of site, to determine if immediate action is required. 
 
12 REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT 
 
12.1  Ethical Standard 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable 
regulatory requirements. 
12.2  Regulatory Compliance 
This study will be conducted in compliance with: 
 
The protocol 
 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and §312 
(Investigational New Drug Application; and 45 CFR 46 Subparts A (Common Rule), B 
(Pregnant Women, Human Fetuses and Neonates), C (Prisoners), and D (Children), 
GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply 
with the regulations in 21 CFR §56 and applicable regulatory requirements. 
12.3  Prestudy Documentation 
Prior to implementing this protocol, the protocol, the informed consent form, HIPAA authorization 
and any other information pertaining to participants must be approved by the UW Health Sciences 
IRB. Prior to implementing this protocol at the participating sites, approval for the UW Health 
Sciences IRB-approved protocol must be obtained from the participating site’s IRB.  


 
 
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The following documents must be provided to UWCCC before the participating site can be 
initiated and begin enrolling participants:  
 
 
Participating site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization.  
 
Participating site IRB approved consent form.  
 
Participating site IRB membership list.  
 
Participating site IRB’s Federal Wide Assurance number and OHRP registration number. 
 
Curriculum vitae and medical license for each investigator and consenting professional.  
 
Documentation of Human Subject Research Certification training for investigators and key 
staff members at the participating site. 
 
Participating site laboratory certifications and normals.  
 
Upon receipt of the required documents, UWCCC will formally contact the site and grant 
permission to proceed with enrollment. 
 
12.4  Institutional Review Board 
The protocol, the proposed informed consent form and all forms of participant information related 
to the study (e.g., advertisements used to recruit participants) will be reviewed and approved by 
the UW Health Sciences IRB (or designated central IRB). Prior to obtaining UWCCC approval, 
the protocol must be approved by the UWCCC Protocol Review and Monitoring Committee. The 
initial protocol and all protocol amendments must be approved by the IRB prior to implementation.  
After the UW Health Sciences Institutional Review Board (HS-IRB) (or designated central IRB) 
grants initial approval for a WON study, the affiliate coordinator provides the WON sites with the 
approved documents. Sites use the IRB-approved consent document for UWCCC as a template. 
WON sites may make minor changes to the consent form to reflect their institutional standards. 
No substantial changes, including changes to the risk language, are allowed (sites can always 
clarify existing risk information or add risk language if they wish to do so).  
Each WON site must receive local IRB approval of both the UW IRB (or designated central IRB) 
approved protocol and informed consent/HIPAA documents (with minor revisions allowed). The 
local IRB approval notice and informed consent documents are forwarded to the affiliate 
coordinator at the address listed below. Once all of UWCCC administrative requirements are 
completed and local IRB approval is verified, the affiliate coordinator issues an activation notice 
for the site. Study activities can begin at the local site only once this activation notice is issued.  
Any site under the UW HS-IRB’s (or designated central IRB) purview must receive UW HS-IRB 
approval for its participation prior to study activation at the site. UWCCC-Johnson Creek uses the 
same UW HS-IRB (or designated central IRB) approval process and consent form as UW. Of 
note, member sites of the Wisconsin IRB Consortium (WIC), may be approved for participation 
through IRB deferral agreements made possible by the WIC mechanism. Both UWCC-Johnson 
Creek and WIC institutions must also be issued activation notices prior to enrolling subjects.  
The affiliate coordinator is responsible for continued oversight of regulatory documentation for 
each WON site. The affiliate coordinator distributes all additional UW HS-IRB (or designated 
central IRB) approved amendments and consents to participating WON sites. The affiliate 
coordinator uses OnCore® and additional spreadsheets to track local IRB approvals of all 
amendments and consents for participating WON sites. All local IRB approvals and informed 
consent documents should be forwarded to the affiliate coordinators at the UWCCC by email 
(affiliatecoordinators@uwcarbone.wisc.edu) or regular mail:  


 
 
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Affiliate Coordinators  
University of Wisconsin Carbone Cancer Center  
600 Highland Avenue, CSC, K4/6  
Madison, WI 53792-6164  
 
 
 
12.5 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and their families. 
Consent forms describing in detail the study interventions/products, study procedures, and risks 
are given to the subject and written documentation of informed consent is required prior to starting 
intervention/administering study product. 
Potential subjects will be told, and a statement will be included that this study is designed to 
determine both safety and effectiveness. The consent forms will include the approved UW Health 
Sciences IRB template language. 
Consent forms will be IRB-approved, and the subject will be asked to read and review the 
document. Upon reviewing the document, the investigator will explain the research study to the 
subject and answer any questions that may arise. In accordance with 46 CR 46.111, the subject 
will sign and date the informed consent document prior to any procedures being done specifically 
for the study.  
The subjects will have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The subjects may withdraw consent at any time throughout the 
course of the trial.  
A copy of the informed consent document will be given to the subjects for their records. The rights 
and welfare of the subjects will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. If there are 
changes to the consent form, all revisions will be reviewed with study subject at the next 
appropriate opportunity. Subjects that require reconsenting will be defined in the IRB-approved 
amendment submission. The process for obtaining informed consent will again be performed. 
Study subjects will not be reconsented for continuing reviews. Sites should follow their IRB’s 
policy for subjects who demonstrate limited English proficiency or limited literacy.  
After the subject’s visit in which the consent is signed, it is documented in the clinic chart that 
the consent has been signed and that all questions have been answered to the subject’s 
satisfaction after adequate time for review of the consent. It is also documented that a copy of 
the consent is given to the subject. The original consent is kept with the subject’s study file, and 
a copy of the consent is sent for inclusion in the legal medical record. 
All WON sites under the purview of their local IRBs follow recruitment and consent processes 
approved by the local IRB of record. 
Documentation of both the informed consent process and that the process occurred prior to a 
subject’s entry into a WON study is recorded in the subject’s source documents. The original 
consent form, signed and dated by the subject and by the person consenting the subject, must 
be maintained in the investigator’s study files at each site. All current FDA, NCI, state, federal 
and Institutional regulations concerning informed consent will be followed. 
 


 
 
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12.6  Subject Confidentiality and Access to Source Documents/Data 
Subject confidentiality is strictly held in trust by the principal investigator and all research staff. 
This confidentiality includes the clinical information relating to participating subjects, as well as 
any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study, or the data will be released to any unauthorized 
third party without prior written approval of the principal investigator/study chair  
The conditions for maintaining confidentiality of the subjects’ records are required for the life of 
the data. Identifiable subject information will be maintained at the enrolling site. All source 
documentation will be maintained within the subject’s research chart which will be accessible only 
to authorized study personnel. Subject research charts will be stored in a locked research office 
at each enrolling site. 
Study data will be collected via the UWCCC Oncore® database. Each enrolling site is responsible 
for entering data into study specific eCRFs. Subject data used for analysis will be coded.  
Databases in which the study subject information is stored and accessed are password protected, 
allowing for limited access by authorized personnel only. Data/PHI kept in the electronic case 
report forms contain the study identifiers, subject initials, date of birth and date of service.  
Personal identifiers, such as name and medical record number, will be removed from 
accompanying laboratory reports and test results. Any data/PHI that are not stored for the 
purposes of the study are shredded in the Clinical Trials Office. 
After all study queries and analyses are completed, the data/PHI will not be destroyed but will be 
archived in a secure long-term storage site in order to keep an accurate record of screened and 
enrolled subjects for the sponsor and potential audit purposes only specific for this study. 
Data/PHI would not be destroyed until permission is granted by the sponsor to destroy the 
records.  
The principal investigator/study chair will allow access to all source data and documents for the 
purposes of monitoring, audits, IRB review, and regulatory inspections.  
The study monitors or other authorized representatives of the principal investigator/study chair 
may inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the subjects 
in this study. Each clinical study site will permit access to such records. 
 
12.7  Protection of Human Subjects 
12.7.1  Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. This 
is accomplished through the IRB mechanism and the informed consent process. The IRB reviews 
all proposed studies involving human experimentation and ensures that the subject’s rights and 
welfare are protected and that the potential benefits and/or the importance of the knowledge to 
be gained outweigh the risks to the individual. The IRB also reviews the informed consent 
document associated with each study in order to ensure that the consent document accurately 
and clearly communicates the nature of the research to be done and its associated risks and 
benefits. 
12.7.2  Protection of Privacy 
 


 
 
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As noted, subjects will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, they will 
be invited to sign informed consent documents. The original signed document will become part of 
the subject’s medical records, and each subject will receive a copy of the signed documents.  
12.8  Investigator Compliance 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority(ies).  
Onsite Audits 
WON sites will be audited in accordance with the WON auditing and monitoring plan. 
Regulatory authorities, the IRB and/or sponsor may request access to all source documents, data 
capture records and other study documentation for on-site audit or inspection. Direct access to 
these documents must be guaranteed by the investigator, who must provide support at all times 
for these activities. 
 
13 DATA HANDLING AND RECORD KEEPING 
 
13.1 Overview 
 
Every effort is made to uphold the integrity of the project, the research, the institution, and the 
researchers involved. Data collection guidelines and methodologies are carefully developed 
before the research begins. Investigators focus on the following to ensure data integrity:  well-
trained data collectors/recorders to ensure consistency and quality, well-designed data collection 
protocols and ongoing monitoring. In this way, study rigor and validity are maintained. Data are 
protected from physical damage as well as from tampering, loss or theft. This project’s data 
management is a multidisciplinary activity that includes investigators, research coordinators and 
nurses, data mangers, support personnel, biostatisticians and database programmers. Quality 
control will be applied to each stage of data handling to ensure that all data are reliable and have 
been processed correctly.  
13.2 Data Management Responsibilities 
13.2.1 Principal Investigator 
 
The principal investigator oversees the management of subject records/case report forms and 
ensures that a) complete and accurate data will be obtained and provided to the sponsor; b) 
subject records are maintained to include history, prescribed medication and investigational 
product(s), measurements, exams, evaluations and adverse events; c) corrections are applied 
to clinical research data according to principles of good research practice (i.e., single-line 
delete, date and initial). He or she will ensure that there is correlation between the case report 
forms and the source documents. The principal investigator will have additional oversight 
responsibilities as applies to subjects enrolled through Wisconsin Oncology Network affiliate 
sites: 
• 
Verify that weekly summaries are obtained and verified. 
• 
Review all SAEs submitted by WON sites. 


 
 
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• 
Verify remote or on-site auditing occurs at participating WON sites.  
13.2.2 Research Coordinator  
A research coordinator creates, collects and organizes clinical trial documentation. He or she 
ensures that source documentation and data abstraction and entry are being done at protocol-
specified time points. 
 
13.2.3 Research Nurse/Medical Staff 
The research nurse and medical staff documents protocol-required care or assessment of the 
subject’s outcomes, adverse events and compliance to study procedures. 
 
13.2.4 Biostatistician 
The biostatistician may assist in CRF development (content and design), dataset specifications 
(annotation of CRFs and record layout) and validation. 
 
13.3 Handling and Documentation of Clinical Supplies 
The principal investigator will maintain complete records showing the receipt, dispensation, return, 
or other disposition of all investigational drugs. The date, quantity and batch or code number of 
the drug, and the identification of subjects to whom study drug has been dispensed by subject 
number and initials will be included. The sponsor-investigator will maintain written records of any 
disposition of the study drug. 
The principal investigator shall not make the investigational drug available to any individuals other 
than to qualified study patients. Furthermore, the principal investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 
 
13.4 Source Documents 
Source documents for clinical information (e.g., patient history, diagnosis, clinical and diagnostic 
test reports) are maintained in the patient’s clinical file. Source documents for the correlative 
studies are maintained in the laboratory conducting the study.  
All source documents will be written following ALCOA standards:  
Table 12 
ALCOA Attribute 
Definition 
Attributable 
Clear who has documented the data. 
Legible 
Readable and signatures identifiable. 
Contemporaneous 
Documented in the correct time frame along with the flow of 
events. If a clinical observation cannot be entered when made, 
chronology should be recorded. Acceptable amount of delay 
should be defined and justified. 
Original  
Original, if not original should be exact copy; the first record made 
by the appropriate person. The investigator should have the 
original source document. 
Accurate 
Accurate, consistent and real representation of facts. 
Enduring 
Long-lasting and durable. 


 
 
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Table 12 
ALCOA Attribute 
Definition 
Available and 
accessible 
Easily available for review by treating physicians and during 
audits/inspections. The documents should be retrievable in 
reasonable time. 
Complete 
Complete until that point in time. 
Consistent 
Demonstrate the required attributes consistently. 
Credible 
Based on real and reliable facts. 
Corroborated 
Data should be backed up by evidence. 
13.5 Case Report Forms 
  
The principal investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study-
specific case report forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis. All study data will be entered into OnCore® via standardized CRFs, 
in accordance with the study calendar, using single data entry with a secure access account. The 
clinical research coordinator will complete the CRFs as soon as possible upon completion of the 
study visit; the investigator will review and approve the completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the subject’s medical records maintained by  each 
site’s personnel. All source documentation should be kept in separate research folders for each 
subject. 
In accordance with federal regulations, the investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  
All source documentation and data will be available for review/monitoring by the UWCCC DSMC 
and regulatory agencies. 
 
13.6 Study Record Retention 
 
The principal investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity and use by subjects, as well as written records of the disposition of the 
drug when the study ends.  
The principal investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. Case 
histories include the case report forms and supporting data including, for example, signed and 
dated consent forms and medical records including, for example, progress notes of the physician, 
the individual's hospital chart(s), and the nurses' notes. The case history for each individual shall 
document that informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
sponsor-investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 


 
 
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In accordance with FDA regulations, the investigator shall retain records for a period of two years 
following the date a marketing application is approved for the drug for the indication for which it is 
being investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until two years after the investigation is discontinued and FDA is notified. 
 
13.7 Institutional Review Board (IRB) Approval 
The protocol, informed consent form, HIPAA authorization and any other applicable documents 
must be approved by the UW HS-IRB prior to activating the protocol at UW. Once UW has IRB 
approval, the UWCCC Affiliate Office is responsible for disseminating the IRB-approved 
documents to the WON sites and collecting the required regulatory documents for activation as 
outlined in the Study Operations Manual.   
 
The UW PI is responsible for informing the IRB of any amendment to the protocol in accordance 
with local requirements. The protocol must be reapproved by the IRB, as local regulations require. 
 
The Affiliate Office is responsible for continued oversight of regulatory documentation for each 
WON site. The affiliate coordinator distributes all additional HS-IRB approved amendments to 
WON sites and is responsible for tracking local IRB approvals as outlined in the Study Operations 
Manual. 
 
13.8 WON Site Oversight  
The UWCCC Affiliate Office serves as the coordinating center for WON. Coordinating center 
responsibilities are shared between the affiliate coordinator and UWCCC Breast/Melanoma DOT. 
A detailed description of coordinating center responsibilities, as well as other WON processes 
and procedures, is provided in the WON Manual available on the UWCCC website.  
Regular communication between the UWCCC Affiliate Office and WON sites ensures that all 
participating parties are notified of protocol changes, informed consent document revisions, action 
letters, study status changes, reportable events/serious adverse events (as necessary), and any 
other applicable information. This communication is accomplished through regular email updates 
and conference calls. 
 
 


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


 
 
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APPENDIX 2: SUBJECT LOST TO FOLLOW-UP LETTER 
 
 
 
 
 
Date: ___________________________________ 
 
 
 
Dear ___________________________________, 
 
 
 
 
 
 
The research study team has been unable to contact you regarding the clinical trial (A Phase II 
Trial of Onapristone in Combination with Fulvestrant for women with ER-positive, PR-positive and 
HER2-negative Metastatic Breast Cancer after Progression on Aromatase and CDK 4/6 
Inhibitors) you participated in. 
 
 
 
We would like to discuss how you are doing and if we may continue contacting you. 
 
 
 
 
 
Please contact us at 
_____________________________________________________________ 
 
 
 
 
 
Sincerely, 
 
 
 
 
 
___________________________________ 
 
 
 
 
 


 
 
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REFERENCES 
 
 
1. 
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer 
statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 
185 countries. CA Cancer J Clin. 2018;68(6):394-424. 
2. 
 [Available from: https://www.nccn.org/professionals/physician_gls/default.aspx. 
3. 
Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus 
palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-
negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): 
final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 
2016;17(4):425-39. 
4. 
Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. Palbociclib and Letrozole 
in Advanced Breast Cancer. N Engl J Med. 2016;375(20):1925-36. 
5. 
Rugo HS, Rumble RB, Macrae E, Barton DL, Connolly HK, Dickler MN, et al. Endocrine 
Therapy for Hormone Receptor-Positive Metastatic Breast Cancer: American Society of Clinical 
Oncology Guideline. J Clin Oncol. 2016;34(25):3069-103. 
6. 
Baselga J, Campone M, Piccart M, Burris HA, 3rd, Rugo HS, Sahmoud T, et al. 
Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J 
Med. 2012;366(6):520-9. 
7. 
Andre F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for 
PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 
2019;380(20):1929-40. 
8. 
Chandarlapaty S, Chen D, He W, Sung P, Samoila A, You D, et al. Prevalence of ESR1 
Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis 
of the BOLERO-2 Clinical Trial. JAMA Oncol. 2016;2(10):1310-5. 
9. 
Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, et al. Double-blind, 
randomized placebo controlled trial of fulvestrant compared with exemestane after prior 
nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-
positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008;26(10):1664-70. 
10. 
Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S, et al. Pictilisib for 
oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer 
(FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 
2016;17(6):811-21. 
11. 
Nardone A, De Angelis C, Trivedi MV, Osborne CK, Schiff R. The changing role of ER in 
endocrine resistance. Breast. 2015;24 Suppl 2:S60-6. 
12. 
Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, et al. Fulvestrant 
versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: 
a prospective combined analysis of two multicenter trials. Cancer. 2003;98(2):229-38. 
13. 
Di Lascio S, Pagani O. Oligometastatic breast cancer: a shift from palliative to potentially 
curative treatment? Breast Care (Basel). 2014;9(1):7-14. 
14. 
Hilton HN, Graham JD, Clarke CL. Minireview: Progesterone Regulation of Proliferation 
in the Normal Human Breast and in Breast Cancer: A Tale of Two Scenarios? Mol Endocrinol. 
2015;29(9):1230-42. 
15. 
Knutson TP, Truong TH, Ma S, Brady NJ, Sullivan ME, Raj G, et al. Posttranslationally 
modified progesterone receptors direct ligand-specific expression of breast cancer stem cell-
associated gene programs. J Hematol Oncol. 2017;10(1):89. 
16. 
Cottu PH, Bonneterre J, Varga A, Campone M, Leary A, Floquet A, et al. Phase I study 
of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or 
metastatic progesterone receptor-expressing cancers. PLoS One. 2018;13(10):e0204973. 


 
 
Short Title: The SMILE study 
76 
Version No.: 2 
Protocol No.: UW20037 
 
Version Date: 8/26/2021 
17. 
Faivre EJ, Lange CA. Progesterone receptors upregulate Wnt-1 to induce epidermal 
growth factor receptor transactivation and c-Src-dependent sustained activation of Erk1/2 
mitogen-activated protein kinase in breast cancer cells. Mol Cell Biol. 2007;27(2):466-80. 
18. 
Hagan CR, Regan TM, Dressing GE, Lange CA. ck2-dependent phosphorylation of 
progesterone receptors (PR) on Ser81 regulates PR-B isoform-specific target gene expression 
in breast cancer cells. Mol Cell Biol. 2011;31(12):2439-52. 
19. 
Jonat W, Bachelot T, Ruhstaller T, Kuss I, Reimann U, Robertson JF. Randomized 
phase II study of lonaprisan as second-line therapy for progesterone receptor-positive breast 
cancer. Ann Oncol. 2013;24(10):2543-8. 
20. 
Scarpin KM, Graham JD, Mote PA, Clarke CL. Progesterone action in human tissues: 
regulation by progesterone receptor (PR) isoform expression, nuclear positioning and 
coregulator expression. Nucl Recept Signal. 2009;7:e009. 
21. 
Kuang Y, Siddiqui B, Hu J, Pun M, Cornwell M, Buchwalter G, et al. Unraveling the 
clinicopathological features driving the emergence of ESR1 mutations in metastatic breast 
cancer. NPJ Breast Cancer. 2018;4:22. 
22. 
O'Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K, et al. The Genetic 
Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in 
the PALOMA-3 Trial. Cancer Discov. 2018;8(11):1390-403. 
23. 
Rayasam GV, Elbi C, Walker DA, Wolford R, Fletcher TM, Edwards DP, et al. Ligand-
specific dynamics of the progesterone receptor in living cells and during chromatin remodeling 
in vitro. Mol Cell Biol. 2005;25(6):2406-18. 
24. 
Daniel AR, Gaviglio AL, Knutson TP, Ostrander JH, D'Assoro AB, Ravindranathan P, et 
al. Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via 
scaffolding PELP1- and estrogen receptor-containing transcription complexes. Oncogene. 
2015;34(4):506-15. 
25. 
Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, Tarulli GA, et al. 
Progesterone receptor modulates ERalpha action in breast cancer. Nature. 
2015;523(7560):313-7. 
26. 
Singhal H, Greene ME, Tarulli G, Zarnke AL, Bourgo RJ, Laine M, et al. Genomic 
agonism and phenotypic antagonism between estrogen and progesterone receptors in breast 
cancer. Sci Adv. 2016;2(6):e1501924. 
27. 
Arnett-Mansfield RL, DeFazio A, Mote PA, Clarke CL. Subnuclear distribution of 
progesterone receptors A and B in normal and malignant endometrium. J Clin Endocrinol 
Metab. 2004;89(3):1429-42. 
28. 
Sasaki M, Tanaka Y, Perinchery G, Dharia A, Kotcherguina I, Fujimoto S, et al. 
Methylation and inactivation of estrogen, progesterone, and androgen receptors in prostate 
cancer. J Natl Cancer Inst. 2002;94(5):384-90. 
29. 
Mulac-Jericevic B, Lydon JP, DeMayo FJ, Conneely OM. Defective mammary gland 
morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci U S A. 
2003;100(17):9744-9. 
30. 
Acharya KD, Finkelstein SD, Bless EP, Nettles SA, Mulac-Jericevic B, Conneely OM, et 
al. Estradiol Preferentially Induces Progestin Receptor-A (PR-A) Over PR-B in Cells Expressing 
Nuclear Receptor Coactivators in the Female Mouse Hypothalamus. eNeuro. 2015;2(4). 
31. 
Lange CA, Yee D. Progesterone and breast cancer. Womens Health (Lond). 
2008;4(2):151-62. 
32. 
Pierson-Mullany LK, Lange CA. Phosphorylation of progesterone receptor serine 400 
mediates ligand-independent transcriptional activity in response to activation of cyclin-
dependent protein kinase 2. Mol Cell Biol. 2004;24(24):10542-57. 
33. 
Afhuppe W, Sommer A, Muller J, Schwede W, Fuhrmann U, Moller C. Global gene 
expression profiling of progesterone receptor modulators in T47D cells provides a new 
classification system. J Steroid Biochem Mol Biol. 2009;113(1-2):105-15. 


 
 
Short Title: The SMILE study 
77 
Version No.: 2 
Protocol No.: UW20037 
 
Version Date: 8/26/2021 
34. 
Beck CA, Zhang Y, Weigel NL, Edwards DP. Two types of anti-progestins have distinct 
effects on site-specific phosphorylation of human progesterone receptor. J Biol Chem. 
1996;271(2):1209-17. 
35. 
Lamb CA, Helguero LA, Giulianelli S, Soldati R, Vanzulli SI, Molinolo A, et al. Antisense 
oligonucleotides targeting the progesterone receptor inhibit hormone-independent breast cancer 
growth in mice. Breast Cancer Res. 2005;7(6):R1111-21. 
36. 
Montecchia MF, Lamb C, Molinolo AA, Luthy IA, Pazos P, Charreau E, et al. 
Progesterone receptor involvement in independent tumor growth in MPA-induced murine 
mammary adenocarcinomas. J Steroid Biochem Mol Biol. 1999;68(1-2):11-21. 
37. 
Addo S, Yates RA, Laight A. A phase I trial to assess the pharmacology of the new 
oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal 
volunteers. Br J Cancer. 2002;87(12):1354-9. 
38. 
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, et al. 
Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in 
postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 
2010;28(30):4594-600. 
39. 
Faslodex® Prescribing Information [Available from: https://www.faslodex.com/how-
faslodex-fulvestrant-works.html. 
40. 
Nishino T, Ishibashi K, Hirtreiter C, Nishino Y. Potentiation of the antitumor effect of 
tamoxifen by combination with the antiprogestin onapristone. J Steroid Biochem Mol Biol. 
2009;116(3-5):187-90. 
41. 
El Etreby MF, Liang Y. Effect of antiprogestins and tamoxifen on growth inhibition of 
MCF-7 human breast cancer cells in nude mice. Breast Cancer Res Treat. 1998;49(2):109-17. 
42. 
Klein-Hitpass L, Cato AC, Henderson D, Ryffel GU. Two types of antiprogestins 
identified by their differential action in transcriptionally active extracts from T47D cells. Nucleic 
Acids Res. 1991;19(6):1227-34. 
43. 
Robertson JF, Willsher PC, Winterbottom L, Blamey RW, Thorpe S. Onapristone, a 
progesterone receptor antagonist, as first-line therapy in primary breast cancer. Eur J Cancer. 
1999;35(2):214-8. 
44. 
Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, et al. Palbociclib in Hormone-
Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015;373(3):209-19. 
45. 
Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, et al. Overall Survival 
with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2018;379(20):1926-
36. 
46. 
Thurlimann B, Robertson JF, Nabholtz JM, Buzdar A, Bonneterre J, Arimidex Study G. 
Efficacy of tamoxifen following anastrozole ('Arimidex') compared with anastrozole following 
tamoxifen as first-line treatment for advanced breast cancer in postmenopausal women. Eur J 
Cancer. 2003;39(16):2310-7. 
47. 
Dickler MN, Tolaney SM, Rugo HS, Cortes J, Dieras V, Patt D, et al. MONARCH 1, A 
Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with 
Refractory HR(+)/HER2(-) Metastatic Breast Cancer. Clin Cancer Res. 2017;23(17):5218-24. 
48. 
Fowler AM, Chan SR, Sharp TL, Fettig NM, Zhou D, Dence CS, et al. Small-animal PET 
of steroid hormone receptors predicts tumor response to endocrine therapy using a preclinical 
model of breast cancer. Journal of nuclear medicine : official publication, Society of Nuclear 
Medicine. 2012;53(7):1119-26. 
49. 
Chan SR, Fowler AM, Allen JA, Zhou D, Dence CS, Sharp TL, et al. Longitudinal 
noninvasive imaging of progesterone receptor as a predictive biomarker of tumor 
responsiveness to estrogen deprivation therapy. Clin Cancer Res. 2015;21(5):1063-70. 
50. 
Vijaykumar D, Mao W, Kirschbaum KS, Katzenellenbogen JA. An efficient route for the 
preparation of a 21-fluoro progestin-16 alpha,17 alpha-dioxolane, a high-affinity ligand for PET 
imaging of the progesterone receptor. The Journal of organic chemistry. 2002;67(14):4904-10. 


 
 
Short Title: The SMILE study 
78 
Version No.: 2 
Protocol No.: UW20037 
 
Version Date: 8/26/2021 
51. 
Lee JH, Zhou HB, Dence CS, Carlson KE, Welch MJ, Katzenellenbogen JA. 
Development of [F-18]fluorine-substituted Tanaproget as a progesterone receptor imaging 
agent for positron emission tomography. Bioconjug Chem. 2010;21(6):1096-104. 
52. 
Buckman BO, Bonasera TA, Kirschbaum KS, Welch MJ, Katzenellenbogen JA. Fluorine-
18-labeled progestin 16 alpha, 17 alpha-dioxolanes: development of high-affinity ligands for the 
progesterone receptor with high in vivo target site selectivity. Journal of medicinal chemistry. 
1995;38(2):328-37. 
53. 
Zhou D, Lin M, Yasui N, Al-Qahtani MH, Dence CS, Schwarz S, et al. Optimization of the 
preparation of fluorine-18-labeled steroid receptor ligands 16alpha-[18F]fluoroestradiol (FES), 
[18F]fluoro furanyl norprogesterone (FFNP), and 16beta-[18F]fluoro-5alpha-dihydrotestosterone 
(FDHT) as radiopharmaceuticals. Journal of labelled compounds & radiopharmaceuticals. 
2014;57(5):371-7. 
54. 
Dehdashti F, Laforest R, Gao F, Aft RL, Dence CS, Zhou D, et al. Assessment of 
progesterone receptors in breast carcinoma by PET with 21-18F-fluoro-16alpha,17alpha-[(R)-
(1'-alpha-furylmethylidene)dioxy]-19-norpregn- 4-ene-3,20-dione. J Nucl Med. 2012;53(3):363-
70. 
55. 
Koyama T, Chen H. Proper inference from Simon's two-stage designs. Stat Med. 
2008;27(16):3145-54.