Clinical trial NCT03300557
Conditions: Atypical Hyperplasia Endometrial Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia Endometrial Carcinoma FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2017-11-15; Completion date: 2025-08-14
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot phase IIa trial studies how well exemestane works in treating patients with complex atypical hyperplasia of the endometrium/endometrial intraepithelial neoplasia or low grade endometrial cancer. Exemestane may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine if there is a decrease in proliferation index, measured by Ki-67 expression, in complex atypical hyperplasia (CAH)/endometrial intraepithelial neoplasia (EIN) or low grade (grade 1 and grade 2) endometrial cancer cells from baseline to post-exemestane treatment.

SECONDARY OBJECTIVES:

I. Circulating serum estradiol and progesterone. II. Pathological response (regression of CAH/EIN or low grade \[grade 1 and grade 2\] endometrial carcinoma).

III. Tissue biomarkers. IV. Deoxyribonucleic acid (DNA) mutational analysis through next generation sequencing and methylation status of endometrial tumor.

V. Protein markers via tampon recovery before and after treatment. VI. DNA markers via tampon recovery. VII. Safety and adverse effects of treatment. VIII. Comparison of Ki-67 expression changes between study subjects and a historical cohort.

IX. Evaluation of the levels of exemestane in the plasma samples pre and post treatment.

OUTLINE:

Patients receive exemestane orally (PO) once daily (QD) over 21-42 days in the absence of disease progression or unaccepted toxicity. Patients undergo standard of care surgery between days 22-43.

After completion of study treatment, patients with unresolved adverse events on day of surgery are followed up periodically.

Arms: arm 1: Patients receive exemestane PO QD over 21-42 days in the absence of disease progression or unaccepted toxicity. Patients undergo standard of care surgery between days 22-43.
Interventions: intervention 1: Exemestane intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacokinetic Study intervention 4: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies intervention 4: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
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 COVER PAGE 
 
 
 
 
 
DCP Protocol #: 
UWI2016-08-01 
 
Local Protocol #: CPRC #2016LS183 / UW17010 / UAB 1788 / 28UCS2019 
 
Pilot Study of Daily Exemestane in Women with Complex Atypical Hyperplasia of the 
Endometrium / Endometrial Intraepithelial Neoplasia or Low Grade Endometrial Cancer 
 
 
 
Consortium Name: 
 
 
University of Wisconsin Chemoprevention Consortium 
Name of Consortium Principal 
Howard H Bailey, MD 
Investigator:  
 
 
University of Wisconsin Carbone Cancer Center 
 
 
 
 
 
600 Highland Ave.  
 
 
 
 
 
CSC K4/654 
 
 
 
 
 
Madison, WI 53792-6164 
Telephone: (608)263-8624 
Fax: (608)299-3765 
E-mail: hhb@medicine.wisc.edu  
 
Organization Name: 
 
 
Masonic Cancer Center, University of Minnesota 
Protocol Principal Investigator: 
Britt Erickson, MD 
 
 
 
 
 
Gynecologic Oncology 
 
 
 
 
 
OB/GYN & Women's Health 
 
 
 
 
420 Delaware St. SE   MMX 395 
 
 
 
 
Minneapolis, MN 55455 
 
 
 
 
 
Telephone: 612-626-6283 
 
 
 
 
 
Fax: 612-626-0665 
 
 
 
 
 
Email: bkeric@umn.edu  
 
Organization:  
 
 
University of Wisconsin 
Investigator:  
 
 
Lisa Barroilhet, MD 
 
 
 
 
 
Gynecologic Oncology 
 
 
 
 
 
600 Highland Ave 
 
 
 
 
 
H4/638 Clinical Science Center 
 
 
 
 
 
Telephone: 608-265-2319 
 
 
 
 
 
Fax: N/A 
 
 
 
 
 
E-mail: barroilhet@wisc.edu   
 
Organization:   
 
 
University of Alabama at Birmingham 
Investigator:  
 
 
Rebecca Arend, MD 
 
 
 
 
 
Gynecologic Oncology 
 
 
 
 
 
619 19th Street South 
176F Rm 10250 
Birmingham, Alabama 35249  
 
 
 
 
 
Telephone: 205-934-4986 
 
 
 
 
 
Fax: 205-975-6174 
 
 
 
 
 
E-mail: rarend@uabmc.edu  
 


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Organization:   
 
 
E.O. Ospedali Galliera 
Investigator:  
 
 
Andrea De Censi, MD 
 
 
 
 
 
Division of Medical Oncology 
 
 
 
 
 
16128 Genova, Italy 
 
 
 
 
 
Telephone: +39 010 5634501 
 
 
 
 
 
Fax: +39 010 57481090 
 
 
 
 
 
E-mail: andrea.decensi@galliera.it 
 
DCP Scientific  Monitor: 
        Goli Samimi, Ph.D., M.P.H. 
        Scientific Monitor 
        Breast and Gynecologic Cancer Research Group  
        Division of Cancer Prevention, NCI, NIH  
        9609 Medical Center Drive, Rm 5E-336, MSC9783 
        Bethesda, MD 20892 (For FedEx, use Rockville, MD  20850) 
        Telephone: (240) 276-6582  
        Fax: (240) 276-7828 
        Email: goli.samimi@nih.gov  
 
DCP Medical Monitor:                     Eva Szabo, MD 
Chief, Lung & Upper Aerodigestive Cancer Research Group  
NCI/Division of Cancer Prevention 
9609 Medical Center Drive, Room 5E-102, MSC 9781 
Bethesda, MD  20892-9781 (For FedEx, use Rockville, MD 20850)  
Phone: (240) 276-7011 
FAX: (240) 276-7848 
email: szaboe@mail.nih.gov 
 
Organization:  
 
 
University of Wisconsin - Madison 
Statistician: 
 
 
 
Richard Chappell, PhD 
 
 
 
 
 
610 Walnut St, WARF 207E  
 
 
 
 
 
Madison, WI 53726   
 
 
 
 
 
Telephone: 608-263-5572 or 608-229-6541 
 
 
 
 
 
No fax number 
 
 
 
 
 
chappell@biostat.wisc.edu 
 
IND Sponsor: 
NCI/Division of Cancer Prevention  
 
IND#  
 
 
Agent(s)/Supplier: 
Exemestane/NCI, Division of Cancer Prevention / Galliera hospital 
Pharmacy 
NCI Contract # 
HHSN261201200033I 
 
Protocol Version Date:  
November 08, 2021 
 
Protocol Revision or   
Amendment #  
Version 10.0 
 


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SCHEMA 
 
Pilot Study of Daily Exemestane in Women with Complex Atypical Hyperplasia of the 
Endometrium / Endometrial Intraepithelial Neoplasia or Low Grade Endometrial Cancer 
 
Up to 40 post-menopausal women age 45 years and older with diagnosis of complex atypical endometrial 
hyperplasia/ endometrial intraepithelial neoplasia (CAH/EIN) or low grade (grade 1 or grade 2) 
endometrial carcinoma who are candidates for hysterectomy.  
↓ 
Pre-screening and Eligibility determination 
For Site in Italy:  
1. Prescreening visit: 
-  Before the diagnostic hysteroscopy,  
participants will sign a biopsy consent 
-  During the exam, gynecologist will perform the 
double pass biopsy (one pass for diagnosis and 
one for research). 
2. Screening/pre-baseline visit (day 0):  
-  If CAH/EIH or low grade endometrial cancer 
confirmed, participants will sign the main study 
consent  
-  Perform lab tests for eligibility requirement 
assessment.  
-  Tampon will be placed by a study nurse.  
-  Send eligibility documents to Consortium Lead 
Organization (CLO) for eligibility 
confirmation. 
3. Baseline visit (day 1):  
-  During clinic visit the tampon will be collected 
-  Study drug dispensed.  
-  Establish date of surgery 
For Sites in USA:  
1. Prior to baseline (pre-surgical) clinic visit  
- Pre-Screening by record review/introductory 
telephone contact 
- If interested, mail screening consent packet 
and 2 tampons 
- Phone call reminder the day before baseline 
(pre-surgical) clinic visit to place tampon 
before visit 
2. Baseline (pre-surgical) clinic visit (minimum 
of 22 days prior to planned surgery) 
- Obtain written consent 
- Perform baseline tests and procedures 
(including tampon removal and biopsy) 
- Establish date of surgery 
3. Confirm eligibility  
-  Send via courier exemestane with start date 
instructions and pill diary 
-  Also, send a tampon kit (2 tampons + 
instructions); tampon to be inserted 8-12 hours 
before surgery 
↓ 
Day 0 telephone contact (US sites only) 
Phone call reminder to start taking exemestane and reminder to note the time taken in the pill diary 
↓ 
Day 1 of exemestane (US sites only) 
Participant begins once a day exemestane dosing on day 1, allowing between 21 and 42 days of dosing 
prior to surgery 
↓ 
Day 15 (±2), of exemestane  
Study coordinator or designee contacts participant via telephone to assess adverse effects/toxicity 
↓ 
Day before Surgery  
For Site in Italy:  
Participant visits the center for symptoms assessment 
and concomitant medications review.  
Tampon will be placed by a study nurse. 
Remind to bring pill diary and medication bottle next 
day. 
For Sites in USA:  
Study coordinator contacts participant via telephone 
to remind her to insert the tampon 8-12 hours before 
surgery and to bring exemestane bottle and pill diary 
with her to the hospital 


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↓ 
Final study visit - Day of surgery 
Obtain research blood tests  
Reconcile exemestane dosing 
Remove research tampon intraoperatively 
Procure surgical pathology tissue 
↓ 
Follow up contact on or before first post-surgical follow-up (only if adverse events were ongoing at the 
time of surgery) 
Study coordinator contacts participant regarding any ongoing exemestane attributed toxicity 
 
The following research specimens  will be collected for each enrolled patient:  
1. Tissue from research biopsy and surgical specimen will be obtained for each enrolled participant  
2. Samples from tampon collection pre and post treatment 
3. Blood samples pre and post treatment – for estradiol, progesterone and pharmacokinetic levels in 
plasma 
Additional archived tissue will be obtained from 30 historic matched controls 
Study Endpoints: 
Primary: Change in tumor proliferation (measured by change in Ki-67 expression) pre and post 
exemestane treatment  
 
Secondary: 
1. Changes in circulating serum estradiol and progesterone pre and post exemestane treatment  
2. Pathological response to exemestane – (regression of CAH/EIN or low grade endometrial carcinoma) 
3. Tissue biomarkers 
a. Apoptosis (cleaved caspase 3) 
b. Proliferation (cyclin D1) 
c. Insulin pathway (pAKT, IGF-1R) 
d. Endocrine regulation (ER/PR/AR)  
4. DNA mutational analysis through Next Generations Sequencing and methylation status of 
endometrial tumor  
5. Protein and DNA markers via tampon recovery pre and post exemestane treatment 
6. Comparison of Ki-67 expression between participants samples and historically matched samples 
7. Evaluation of plasma levels of exemestane pre and post treatment 
 


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TABLE OF CONTENTS 
 
COVER PAGE.............................................................................................................................................. 1 
SCHEMA ...................................................................................................................................................... 3 
1. 
OBJECTIVES ..................................................................................................................................... 7 
1.1 
Primary Objective ........................................................................................................................................ 7 
1.2 
Secondary Objectives .................................................................................................................................. 7 
2. 
BACKGROUND................................................................................................................................. 8 
2.1 
CAH/EIN and Low Grade Endometrial Cancer ........................................................................................ 10 
2.2 
Exemestane ................................................................................................................................................ 10 
2.3 
Rationale for CAH/EIN and Low Grade Endometrial carcinoma Prevention with Exemestane ............... 11 
3. 
SUMMARY OF STUDY PLAN ...................................................................................................... 11 
4. 
PARTICIPANT SELECTION .......................................................................................................... 13 
4.1 
Inclusion Criteria ....................................................................................................................................... 14 
4.2 
Exclusion Criteria ...................................................................................................................................... 15 
4.3 
Inclusion of Women and Minorities .......................................................................................................... 15 
4.4 
Recruitment and Retention Plan ................................................................................................................ 16 
5. 
AGENT ADMINISTRATION .......................................................................................................... 16 
5.1 
Dose Regimen and Dose Group ................................................................................................................. 16 
5.2 
Exemestane Administration ....................................................................................................................... 16 
5.3 
Run-in Procedures ..................................................................................................................................... 17 
5.4 
Contraindications ....................................................................................................................................... 17 
5.5 
Concomitant Medications .......................................................................................................................... 17 
5.6 
Dose Modification ..................................................................................................................................... 17 
5.7 
Adherence/Compliance .............................................................................................................................. 17 
6. 
PHARMACEUTICAL INFORMATION ......................................................................................... 17 
6.1 
Exemestane (IND 
 NCI, DCP) ...................................................................................................... 17 
6.2 
Reported Adverse Events and Potential Risks ........................................................................................... 18 
6.3  
Availability ................................................................................................................................................ 18 
6.4 
Agent Distribution ..................................................................................................................................... 18 
6.5  
Agent Accountability ................................................................................................................................. 19 
6.6 
Packaging and Labeling ............................................................................................................................. 19 
6.7 
Storage ....................................................................................................................................................... 19 
6.8 
Registration/Randomization ...................................................................................................................... 19 
6.9 
Blinding and Unblinding Methods ............................................................................................................. 20 
6.10 Agent Destruction/Disposal ....................................................................................................................... 20 
7. 
CLINICAL EVALUATIONS AND PROCEDURES ...................................................................... 21 
7.1 
Schedule of Events .................................................................................................................................... 21 
7.2 
Pre-Screening and Initial Patient Contact .................................................................................................. 22 
7.3 
Baseline (pre-surgical) clinic Visit ............................................................................................................ 23 
7.4 
Day 15 Phone Contact ............................................................................................................................... 25 
7.5 
One Day (-2 days) Prior to Surgery ........................................................................................................... 25 
7.6 
Final Study Visit – Day of Surgery............................................................................................................ 25 
7.7 
Follow-up Contact ..................................................................................................................................... 26 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION............................................... 26 
8.1 
Primary Endpoint ....................................................................................................................................... 26 
8.2 
Secondary Endpoints ................................................................................................................................. 26 
8.3 
Off-Agent Criteria ..................................................................................................................................... 32 
8.4 
Off-Study Criteria ...................................................................................................................................... 32 
8.5 
Study Termination ..................................................................................................................................... 32 
9. 
CORRELATIVE/SPECIAL STUDIES ............................................................................................ 32 
10. 
SPECIMEN MANAGEMENT ......................................................................................................... 32 
10.1 Laboratories ............................................................................................................................................... 32 


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10.2 Collection and Handling Procedures ......................................................................................................... 34 
10.3 Shipping Instructions ................................................................................................................................. 35 
10.4 Tissue Banking .......................................................................................................................................... 36 
11. 
REPORTING ADVERSE EVENTS ................................................................................................. 36 
11.1 Adverse Events .......................................................................................................................................... 36 
11.2 Serious Adverse Events ............................................................................................................................. 37 
11.3  Suspected Unexpected Serious Adverse Reaction ..................................................................................... 39 
12. 
STUDY MONITORING ................................................................................................................... 39 
12.1 Data Management ...................................................................................................................................... 39 
12.2 Case Report Forms .................................................................................................................................... 39 
12.3 Source Documents ..................................................................................................................................... 39 
12.4 Data and Safety Monitoring Plan ............................................................................................................... 39 
12.5 Sponsor or FDA Monitoring ...................................................................................................................... 40 
12.6 Record Retention ....................................................................................................................................... 40 
12.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) ......... 40 
13. 
STATISTICAL CONSIDERATIONS .............................................................................................. 40 
13.1 Study Design/Description .......................................................................................................................... 40 
13.2 Randomization/Stratification ..................................................................................................................... 40 
13.3 Accrual and Feasibility .............................................................................................................................. 41 
13.4 Primary Objective, Endpoint(s), Analysis Plan ......................................................................................... 41 
13.5 Secondary Objectives, Endpoints, Analysis Plans ..................................................................................... 41 
13.6 Reporting and Exclusions .......................................................................................................................... 42 
13.7 Evaluation of Toxicity ............................................................................................................................... 43 
13.8 Evaluation of Response ............................................................................................................................. 43 
13.9 Interim Analysis......................................................................................................................................... 43 
13.10 Ancillary Studies ....................................................................................................................................... 43 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................ 43 
14.1 Form FDA 1572 ......................................................................................................................................... 43 
14.2 Other Required Documents ....................................................................................................................... 43 
14.3 Institutional Review Board Approval ........................................................................................................ 44 
14.4 Informed Consent ...................................................................................................................................... 44 
14.5 Submission of Regulatory Documents ....................................................................................................... 44 
14.6 Other .......................................................................................................................................................... 45 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE ...................................................................... 45 
REFERENCES ........................................................................................................................................... 46 
APPENDIX A ............................................................................................................................................. 50 
APPENDIX B ............................................................................................................................................. 51 
APPENDIX C ............................................................................................................................................. 53 
APPENDIX D ............................................................................................................................................. 56 
APPENDIX E ............................................................................................................................................. 57 


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1. 
OBJECTIVES 
 
1.1 
Primary Objective 
The primary objective is to determine if there is a decrease in proliferation index, measured by Ki-
67 expression, in complex atypical hyperplasia (CAH)/ endometrial intraepithelial neoplasia (EIN) 
or low grade (grade 1 and grade 2) endometrial cancer cells from baseline to post-exemestane 
treatment.  
 
1.2 
Secondary Objectives 
1. 
Circulating serum estradiol and progesterone:   
Measure pre- and post-treatment circulating serum estradiol and progesterone levels to determine 
the effect of a daily dose of 25 mg of exemestane for 21-42 days.  
2. 
Pathological response (regression of CAH/EIN or low grade (grade 1 and grade 2) 
endometrial carcinoma):  
Examine pathologic changes in CAH/EIN or low grade (grade 1 and grade 2) endometrial 
carcinoma from pre-treatment biopsies to final (post-treatment) pathology. 
3. 
Tissue biomarkers:  
 Using immunohistochemistry, examine differences in the expression of biomarkers from baseline 
to post-treatment for the following cellular pathways:      
a) Apoptosis (cleaved caspase 3) 
b) Proliferation (cyclin D1) 
c) Insulin pathway (pAKT, IGF-1R) 
d)  Endocrine regulation (ER/PR/AR)  
4. 
DNA mutational analysis through Next Generation Sequencing and methylation status of 
endometrial tumor: 
Analyze DNA from CAN/EIN or low grade (grade 1 and grade 2) endometrial carcinoma for 
specific genetic mutations, microsatellite instability and methylation status in order to correlate 
exemestane response to mutational status. 
5. 
Protein markers via tampon recovery before and after treatment:  
Perform pre- and post-treatment proteomic analysis of vaginal proteins from tampon recovery to 
identify biomarkers that may predict response to exemestane treatment. 
6. 
DNA markers via tampon recovery:  
Analyze vaginal DNA from tampon recovery to determine if tumor DNA can be detected vaginally. 
If tumor DNA can be detected vaginally, this could represent an innovative, non-invasive method 
for detecting endometrial cancer or predicting treatment response. 
7. 
Safety and adverse effects of treatment:  
Evaluate safety and adverse effects of the treatment by CTCAE 4.0 toxicity scale. 
8. 
Comparison of Ki-67 expression changes between study subjects and a historical cohort.  
Participants will be matched with a historical nonrandomized control group. The control group will 
provide a reference for how Ki-67 may change based on differences in specimen collection 
(endometrial biopsies versus surgical specimen) and time between biopsy and surgery, independent 
of exemestane exposure. 
9. 
 Evaluation of the levels of exemestane in the plasma samples pre and post treatment.  
Comparison of pharmacokinetic (PK) levels of plasma exemestane pre-and post-treatment.  
 
 
 
 


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2. 
BACKGROUND 
 
Rationale/Hypothesis: Endometrial cancer is the most common gynecologic malignancy in the U.S. with 
over 60,000 new cases predicted in 20161. It is increasing in frequency, most likely as a consequence of 
increasing rates of obesity. The standard of care remains hysterectomy, which, given the comorbidities of 
this patient population (diabetes mellitus, obesity, cardiovascular disease), is associate with significant 
perioperative morbidity and cost2. Like breast cancer, endometrial cancer is a hormonally sensitive disease. 
Specifically, it is estrogen responsive and in a percentage of women, can be treated with progesterone 
therapy. However, progesterone therapy is not always effective and therefore is only recommended as 
primary therapy in women who are not surgical candidates or in women who desire fertility preservation. 
In a large systematic review of progestin therapy in fertility preservation, durable response to therapy was 
noted in only 53% of women, suggesting a need for improved therapies 3.Therefore, we are in need of a 
non-surgical, low side effect treatment for endometrial carcinoma and its precursors. Moreover, given its 
increase in frequency, a chemopreventive strategy would be helpful in reducing the burden of disease.   
Exemestane, an aromatase inhibitor (AI), is used for the primary chemoprevention of breast cancer in high-
risk populations, as well as in the upfront and adjuvant treatment of women with advanced and local disease, 
respectively. 4 It has also been used off label for the treatment of advanced endometrial carcinoma and 
leiomyosarcoma as well as in the adjuvant treatment of high risk endocrine responsive premenopausal 
breast cancer in combination with LHRH agonists.5,6 Given its anti-estrogen effects, it holds promise as a 
potential therapeutic or chemopreventive intervention for women with (or at high-risk of developing) 
endometrial cancer. In the present pilot study, we hypothesize that short-term exposure (21-42 days) of 
patients with low grade endometrial carcinoma and CAH/EIN to exemestane will result in significant 
reduction in tumor proliferation, as measured by a decrease in Ki-67 expression.  
Excess estrogen, progesterone and endometrial carcinoma: Obesity is proposed to contribute to 
endometrial cancer through multiple mechanisms, of which excess exposure to estrogen relative to 
progesterone and metabolic disturbances, such as diabetes and metabolic syndrome, play critical roles 
among postmenopausal women. Data suggests that endometrial cancers develop over many years from 
progressively more severe endometrial proliferation. Accordingly, there are multiple potential approaches 
that may reduce the incidence of endometrial cancer including endocrine chemoprevention, agents that 
correct metabolic disturbances, and weight reduction. Notably, the 1994 WHO classification of simple and 
complex hyperplasia with or without atypia has been since replaced by the newer 3-tier system of: 1- benign 
(benign endometrial hyperplasia) 2- premalignant (endometrial intraepithelial neoplasia) and 3- malignant 
(adenocarcinoma).7,8 For this proposal, endometrial intraepithelial neoplasia (EIN) will be synonymous 
with complex atypical hyperplasia (CAH) and endometrial hyperplasia (EH).  
Traditionally endometrial endometrioid adenocarcinoma has been described in a 3-tier system: grade 1, 
grade 2, and grade 3. With an improved molecular understanding these tumors, the 3 tier system can be 
separated into low-grade and high-grade endometrial cancer.56, 57  Low-grade tumors (grade 1 and grade 2) 
are usually early stage, have a better prognosis and are associated with estrogen exposure. High grade 
tumors (grade 3 as well as uterine serous and clear cell tumors) are aggressive tumors with higher rates of 
metastases, poor prognosis and are often unrelated to estrogen exposure.58, 59    
Excess estrogen exposure is strongly linked to the development of low-grade endometrial cancer and its 
precursors. Ten years of excess estrogen has been shown to increase risk 10 fold 9, and prospective data 
demonstrate that increased serum estrogen levels double the risk when comparing the highest to the lowest 
serum level groups10. Consistent with these findings, obesity, reproductive, and menstrual factors linked to 
endometrial cancer risk are proposed to be mediated through increased levels of estrogen. Recent data from 
a health maintenance organization suggest that breast cancer survivors who have received aromatase 
inhibitors, which lower circulating estrogen levels, are associated with reduced risk for endometrial cancer 


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compared to women who received  tamoxifen 11.  
Endometrial cancer precursors, particularly if less severe than endometrial intraepithelial neoplasia, 
frequently do not progress to endometrial cancer, suggesting that risk of endometrial cancer may be highly 
modifiable. In support of this, administering exogenous progesterone is highly effective in treating 
endometrial cancer precursors and useful in reversing low grade endometrial cancer. For example, oral 
medroxyprogesterone (MPA) (Provera) is approved to "reduce the incidence of endometrial hyperplasia" 
in the presence of estrogen replacement therapy, an approach validated by the Women's Health Initiative 
study. Oral progestins such as MPA and norethindrone (NET) (Aygestin) have also been successfully used 
to treat endometrial hyperplasia in the absence of estrogen replacement therapy 12. Additionally, an 
intrauterine form of progestin, levonorgestrel (LNG) (Mirena) has demonstrated some efficacy in 
endometrial hyperplasia treatment.13,14 While numerous trials have demonstrated that progestins are a good 
option for treatment of endometrial hyperplasia, resistance to progestin has been reported in 12 to 53% of 
treated women. The development of resistance is associated with various factors including patient 
characteristics, such as age, co-morbidities, and molecular characteristics 15. Further, use of exogenous 
progesterone after menopause may be undesirable because it increases breast cancer risk, whereas use of 
AIs lowers risk of both endometrial and breast cancer. Given that obesity is a major risk factor for both 
endometrial and breast cancer, the use of AIs to reduce circulating estrogen levels among women at elevated 
risk of endometrial cancer may be a promising approach for reducing risk of both cancers.  
Exemestane (6-methylenandrosta-1,4-diene-3,17-dione) is a type I, 3rd generation, steroidal aromatase 
inhibitor, which means it directly competes with androgens for the enzyme active site, causing irreversible 
inactivation of the aromatase enzyme. This is in contrast to type II non-steroidal AIs (such as letrozole and 
anastrozole), which prevent androgens from reversibly binding the enzyme through the heme moiety of the 
enzyme. 17,18 After binding to aromatase, exemestane is converted into intermediate active metabolites, 
which covalently bind to the enzyme causing degradation and inactivation, also known as “suicide 
inhibition”19.  The primary active metabolite of exemestane is 17B-hydroexemestane (17-BHE), which has 
been shown to have a high affinity for androgen receptors.  It has been suggested that variability in clinical 
response to treatment with exemestane could be due to differences in P450 enzymes between patients. 20  
Exemestane is absorbed orally, with maximum plasma concentrations reached within 2 hours. Multiple 
trials have found that, although doses up to 800mg daily were tolerated, the most favorable effects were 
observed at the 25mg daily dosing. 21,22 Greater than 98% reduction of estrogen synthesis has been 
demonstrated in vivo at this dose 23. A single dose can reduce levels of estrogens up to 95% for 2-3 days. 24 
Exemestane is distributed extensively in peripheral tissues and it has a mean terminal elimination half-life 
of 24 hours. 18   
Exemestane has been studied extensively in the neoadjuvant, adjuvant, chemopreventive, and metastatic 
setting of ER+ breast cancer. It has been studied alone as well as in combination with or compared to non-
steroidal 3rd generation AIs (anastrozole) as well as tamoxifen. In the neoadjuvant setting, Fontein et al 
enrolled 102 women with ER+ untreated breast cancer. In this phase II trial, women received exemestane 
for 6 months prior to surgery. 68% of women had a clinical response to treatment and rates of breast 
conservation surgery increased by nearly 10% suggesting a true anti-tumor effect of exemestane. 25 In the 
chemoprevention setting, the randomized, placebo-controlled, double blind Mammary Protocol  3 (MAP.3) 
trial of 4,560 women at high risk for developing breast cancers, 11 invasive breast cancers where detected 
in those women receiving exemestane compared to 32 invasive cancers detected in those receiving placebo 
(0.19% vs 0.55%; HR 0.35; 95% CI 0.18 - 0.70; p= 0.002) 26. Studies are currently underway in stage 0-II 
breast cancer patients to determine whether less than a daily dose of exemestane results in non-inferior 
reduction in estrogen levels compared with daily dosing to assess whether adverse events can be reduced 
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Since estrogen levels are associated with the progression of hyperplasia to cancer, estrogen reduction by 
aromatase inhibition is a viable treatment option for women with hyperplasia. In the case series of 5 infertile 
premenopausal women presenting with endometrial hyperplasia with or without atypia, Li et al has 
observed no hyperplasia after 3 months of treatment with letrozole. 27 Barker et al reported retrospective 
outcomes of 16 of the postmenopausal women with EH or endometrial carcinoma who were not surgical 
candidates, treated with either anastrozole or letrozole.28 After three years of treatment, the eight patients 
with endometrial hyperplasia and the four patients with localized endometrial cancer experienced mean 
reduction in endometrial thickness of 82% and 67%, respectively, but 4 patients with metastatic endometrial 
carcinoma patients experienced no change in endometrial thickness.  Burnett et al, were able to effectively 
restore well differentiated endometrium in two women with grade 1 endometrial cancer using MPA and 
anastrozole (one patient was treated for 3 months and the other for 6 months) in order to maintain fertility29. 
In a more recent non-randomized prospective study, Smith et al reported that five of 12 (41%) patients with 
grade 1 or 2 endometrial carcinoma demonstrated a significant decrease in the cellular proliferation marker, 
Ki-67 following daily letrozole treatment for 3 weeks prior to surgery. No study has yet to evaluate if 
exemestane could cause regression of endometrial pre-cancer or cancer.  
The strong link between estrogen levels and endometrial carcinoma, and the role of aromatase inhibitors in 
reducing circulating estrogen levels suggests that aromatase inhibitors should be used as a treatment for 
women with endometrial hyperplasia or low grade endometrial cancer. This drug could also be employed 
as a chemopreventive agent in women at high risk for developing endometrial cancer. Furthermore, 
treatment with aromatase inhibitors provides a strong added value potentially decreasing risk of breast 
cancer in this high-risk (obese) population.  
2.1 
CAH/EIN and Low Grade Endometrial Cancer 
A pilot study is proposed to address, whether a daily dose of 25mg of exemestane is effective in decreasing 
the proliferation marker Ki-67 in CAH/EIN and low grade (grade 1 and grade 2) endometrial cancer. The 
data generated from this pilot study, including pathologic response, hormone levels, genomics, proteomics 
and immunohistochemical biomarkers, will help guide potential future studies to determine optimal 
exemestane dosage scheduling as well as combination therapies for CAH/EIN and low grade endometrial 
cancer.  
2.2 
Exemestane 
Exemestane is an aromatase inhibitor initially approved by the FDA in 1999 for the treatment of advanced 
breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.  On 
October 5, 2005, it was approved by the FDA for the adjuvant treatment of postmenopausal women with 
estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are 
switched to exemestane for completion of a total of five consecutive years of adjuvant hormonal therapy.  
Standard approved dosing is 25 mg by month per day continuously. 
 
Adverse Reactions: Early breast cancer: Adverse events occurring in ≥10% of patients in any treatment 
group (exemestane vs. tamoxifen) were hot flashes (21.2% vs. 19.9%), fatigue (16.1% vs. 14.7%), arthralgia 
(14.6% vs. 8.6%), headache (13.1% vs. 10.8%), insomnia (12.4% vs. 8.9%), and increased sweating (11.8% 
vs. 10.4%). Discontinuation rates due to AEs were similar between exemestane and tamoxifen (6.3% vs. 
5.1%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) 
were exemestane 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: exemestane 0.4%, tamoxifen 0.3%. 
 
Advanced breast cancer: Most common adverse events were mild to moderate and included hot flashes 
(13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased 
appetite (3% vs. 6%) for exemestane and megestrol acetate, respectively. 
 


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2.3 
Rationale for CAH/EIN and Low Grade Endometrial carcinoma Prevention with 
Exemestane 
The majority of circulating estrogen comes from the pre-menopausal ovary. However, many other extra-
ovarian tissues use the enzyme aromatase to convert androgens into estrogens thereby increasing local and 
circulating estradiol levels. Adipose tissue has high aromatase levels, and thus has been found to contribute 
significantly to the level of circulating estrogen.  
 
As our understanding of the aromatase enzyme pathway has increased, so has our ability to develop novel 
AIs with potentially lower side effect profiles. Aromatase is a cytochrome p450 enzyme, which is 
responsible for the conversion of androgens (specifically testosterone and androstenedione) into estrogens 
(specifically estradiol and progesterone, respectively)16. Blocking the aromatase enzyme therefore lowers 
circulating estrogen levels, which may have an anti-proliferative effect on the endometrium. 
 
Increasing evidence suggests that tobacco and alcohol use are risk factors in the development of 
intraepithelial neoplasia and cancer. In addition, tobacco and alcohol use may adversely affect agent 
intervention, for example by altering the safety profile or metabolism of a drug. Standardized assessments 
of tobacco and alcohol use during clinical trials will aid in understanding the potential relationship between 
the use of these products and clinical endpoints or cancer prevention biomarkers. Therefore, NCI, DCP is 
including assessment of tobacco and alcohol use at baseline (pre-surgical) clinic visit and Surgery, to 
determine the potential impact of tobacco and alcohol use on 1) treatment toxicity and symptom burden, 
and 2) the efficacy of treatment intervention. 
 
3. 
SUMMARY OF STUDY PLAN 
 
Study Plan:  This is a multi-center, phase IIA, single-arm ‘window of opportunity’ pilot study of 25 mg 
per day of exemestane for 21 to 42 days in patients undergoing hysterectomy for CAH/ EIN or low grade  
endometrial cancer (grade 1 or grade 2). Tissue from participant’s research endometrial biopsy will be used 
for pre-surgical biomarker analysis.  The tissue obtained from surgical excision will be used for post-
treatment biomarker analysis.     
 
Study recruitment will occur in gynecology oncology clinics at participating institutions. A lead 
gynecologic oncology surgeon has been identified at each site. Up to 40 patients will be accrued for this 
pilot study. An age, disease and body mass index (BMI) matched historical comparator cohort will also be 
identified in order to compare changes in the primary outcome, Ki-67 expression between biopsy and 
surgical specimen in an untreated cohort.  
 
For the U.S. based sites, prior to the baseline (pre-surgical) clinic visit, a pre-screening telephone contact 
will be completed to determine interest and basic eligibility for the study. If the participant gives verbal 
consent, study materials will be mailed to them. Materials will include a full study consent form to read 
through prior to their visit as well as 2 tampons (one to be inserted prior to the baseline (pre-surgical) clinic 
visit and other one as back up) and instructions for inserting the tampon (appendix D). 
 
At the baseline (pre-surgical) clinic visit, participants will meet the study team to discuss and sign the 
informed consent form. The study team (including the research coordinator and the treating gynecologic 
oncologist) will review their medical history, conduct physical examination and review of concomitant 
medications.  Participants will also have baseline laboratory tests.  These tests include Complete Blood 
Count (CBC) with differential and platelets, Comprehensive Metabolic Panel (CMP), Estradiol, 
Progesterone and Follicle Stimulating Hormone (FSH) in all women 45-55 years old and in women 56-59 
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blood will be drawn for exemestane pharmacokinetics. This research blood sample for exemestane 
pharmacokinetics will be destroyed if the participant does not qualify for the study.  
 
Because this is a window of opportunity study, the study period will be limited to the time between the 
initial pre-surgical visit and definitive surgery (hysterectomy). In order to reduce number of visits for the 
study participants and to start treatment in a timely fashion, all eligibility tests will be performed at the 
baseline (pre-surgical) clinic visit. Being able to acquire an adequate endometrial biopsy specimen is an 
important part of eligibility given that the primary endpoint of this study compares Ki-67 expression 
between pre and post treatment tissue. Therefore, an endometrial biopsy for research purposes will be 
performed at the baseline (pre-surgical) clinic visit during the standard pelvic exam. Laboratory tests will 
also be performed at the baseline (pre-surgical) clinic visit, either before or after the physical exam and 
endometrial biopsy. The vaginal tampon, which was inserted by participant prior to the baseline (pre-
surgical) clinic visit, will be removed during the pelvic exam. If the participant is subsequently deemed 
ineligible (either due to inadequate biopsy tissue, laboratory values or physical exam results), the 
endometrial biopsy samples of the participant will be destroyed and her tampon will be destroyed.  
 
Although attempts will be made to contact all participants prior to their baseline (pre-surgical) visit, the 
study can also be presented at their baseline (pre-surgical) visit. If interested, the participants will sign the 
consent form and then undergo study procedures (research biopsy, lab tests, etc)  on the day of their baseline 
(pre-surgical) visit. In this case, participants will not have a tampon sample collection as part of their  
baseline (pre-surgical) visit.  This will not be considered a protocol deviation. If participants are willing to 
return for an additional visit, they will be permitted to return for a biopsy and tampon collection within 1-
2 weeks of signing consent form.  
 
For E.O. Ospedalli Galliera (EOG) site only, participants will be approached to participate prior to their 
actual diagnosis of CAH/EIN/low grade endometrial cancer. Standard of care in this region includes a visit 
with a gynecologic oncologist and subsequent hysteroscopy with biopsies when patients have 
postmenopausal bleeding and a high suspicion for pre-invasive or invasive disease. Therefore, the research 
team will meet the potential participants for a prescreening visit before the diagnostic hysteroscopy. Patients 
will sign a pre-screening consent on this day before the procedure. During the examination, the surgeon 
will perform one diagnostic biopsy and one research only biopsy. If CAH/EIN/low grade EC is confirmed 
then participants will sign the main study consent. If the patient does not meet the CAH/EIN/low grade EC 
diagnosis the research tissue samples will be destroyed. On the day before the baseline (pre-surgical) clinic 
visit the team will obtain written consent for study participation. A tampon will be placed by a study nurse.  
Lab tests for eligibility will be collected. Eligibility documents will be submitted to CLO for verification. 
On the day of the pre-surgical clinic visit, the study nurse will remove the tampon and place in cold PBS. 
The study drug will be dispensed to the participant at this visit after receiving the eligibility confirmation 
from CLO. If the lab test results are not within study required parameters, the patient will be deemed 
ineligible and the tampon will be removed and discarded during this clinic visit.  
 
Participants who meet eligibility requirements will begin oral exemestane daily for at least 21 days (no 
longer than 42 days) with a dose of 25 mg/day by mouth (PO) until the day prior to surgery.  
 
The day the participant begins taking exemestane is considered Day 1 of the study.  The study team will 
make telephone contacts to the participants on  
• 
Day 0/1 as a reminder to start exemestane 
• 
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• 
One day prior to surgery to assess for adverse events and other symptoms and review medications. 
In addition, the participants will be reminded to insert a tampon 8-12 hours before surgery. 
Participants will be encouraged to contact the investigator or study coordinator with any new symptoms or 
concerns at any time during the trial.   
 
Participants will place a tampon 8-12 hours before surgery. For US based sites, a tampon kit will be mailed 
to the participants. The study agent will be mailed along with an additional tampon kit. The kit will include 
2 tampons (one to be inserted prior to surgery and one as back up) and instructions to insert the tampon 
(appendix D).  
 
For EOG site only, the participants will come back to the clinic the day before surgery and have the second 
tampon placed by a study nurse.     
 
Surgery must occur between Days 22-43 of the study.  On the day of surgery, participants will undergo a 
physical exam, laboratory tests (Complete Blood Count (CBC) with differential and platelets, 
Comprehensive Metabolic Panel (CMP), estradiol and progesterone), and an additional blood draw for 
plasma levels of exemestane. In addition, adverse events and concomitant medications will be reviewed. 
At the time of surgery, the self-inserted tampon will be removed by the surgeon. 
 
Following surgery, and after completion of necessary standard of care surgical pathology, an additional 
section of the tumor (up to 1x1x1 cm) will be collected, cut in half and snap frozen as per institutional 
policy and stored for genetic analysis. If there is not a visible lesion, a random 1x1x1 cm area from the 
endometrium will be selected.  This can be smaller if the pathology team needs to review more of the 
endometrium.  The amount and location of the sample is at the investigators clinical discretion. In addition, 
ten unstained 5µm formalin fixed paraffin embedded (FFPE) slides will be obtained from the primary tumor 
surgical specimen for IHC biomarker analysis.   
 
For EOG site only, follow-up at the standard of care post-operative visit will be performed in order to 
collect long-term safety information of the study treatment, whether or not the participant has any ongoing 
adverse events at the surgery visit. 
 
If any reported adverse events attributed to the study agent are ongoing on the day of surgery, the participant 
will be contacted by the study team on or before the post-operative visit to perform safety assessments for 
ongoing adverse events or symptoms. 
 
The study participants will be matched with a historical nonrandomized control group based on age (± 5 
years), disease type and BMI (>20-24, 25-30, > 30).  Historical samples (no more than 5 years old) will be 
identified through pathologic databases that exist at all participating sites. Medical records will be reviewed 
to ensure correct matching. The pre-surgical and post-surgical tissue samples, within 42 days of each other, 
will be obtained from each historical subject.  All subjects will be de-identified. IHC analysis of Ki-67 
expression will be performed on the pre-surgical and post-surgical samples.  
 
4. 
PARTICIPANT SELECTION 
In the U.S. based sites, whenever feasible, potential participants will be pre-screened for the study and 
contacted by the study team prior to their planned baseline (pre-surgical) clinic visit.  The advantage of this 
is to introduce the study concept to the potential participant and allow her to place a tampon for specimen 
collection prior to her baseline (pre-surgical) clinic visit. If the participant gives verbal consent over the 
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contain an informed consent form for her review and 2 commercially available tampons (one to be inserted 
in her vagina 8-12 hours before her baseline (pre-surgical) clinic visit and one for back up) along with 
instructions on how to insert a tampon (Appendix D). The tampon will be removed during the baseline (pre-
surgical) clinic visit by the physician at the time of the pelvic exam. If the participant is eligible and agrees 
to take part in the study, the tampon will be processed and the resultant protein and DNA will serve as a 
pre-treatment sample.  If the participant is either not eligible or refuses to sign the study consent, the tampon 
will be discarded. If a subject was unable to place a tampon prior to their baseline (pre-surgical) clinic visit, 
she will still be eligible for participation in this study.  
For EOG site only, the patient will be approached for study participation when they first present with 
postmenopausal bleeding.  
 
4.1 
Inclusion Criteria 
Eligible participants must meet the following requirements:   
4.1.1 
Females with a histologically proven CAH/ EIN or low grade (grade 1 or grade 2) endometrial 
carcinoma (EC) for which surgery is planned. The pathologic report from the referring facility will 
be used to determine pathologic eligibility. This report must be within 45 days of their baseline 
(pre-surgical) clinic visit.   
 
4.1.2 
No prior treatment for CAH/EIN/EC 
 
4.1.3 
Age ≥45 years 
 
4.1.4 
Post-menopausal confirmed with one the following criteria:  
• 
≥ 60 years of age 
• 
age 56 to 59 years of age with ≥ 2 years of amenorrhea  
• 
age 56 to 59 years of age with < 2 years of amenorrhea and FSH within institutional post-
menopausal range.  
• 
age 45 to 55 years of age with FSH within institutional post-menopausal range.  
 
The Ki-67 expression changes based on menopausal status and specifically varies based on what 
phase of the menstrual cycle the sample is collected. Therefore, in order to eliminate this source of 
variability, only postmenopausal women will be included in this trial. In addition, exemestane is 
currently approved for use in post-menopausal women only.  
 
4.1.5 
ECOG performance status ≤1 (appendix A) 
 
4.1.6 
Participants must have normal organ and marrow function as defined below: 
• 
Hemoglobin ≥ 9 g/dL 
• 
Serum creatinine ≤ 1.5× upper limit of normal or calculated creatinine clearance ≥ 60 
mL/min using Cockcroft-Gault equation for patients with creatinine levels > 1.5× 
Institutional ULN  
• 
Total bilirubin ≤ 1.5× ULN OR direct bilirubin ≤ 1× ULN,  
• 
AST and ALT ≤ 2.5× ULN 
• 
Hematologic function: WBC  3000/mcl;  
• 
platelets  100,000/mcl.  
4.1.7 
Able and willing to take oral medications.  
 


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4.1.8 
Ability to understand and the willingness to sign a written informed consent document. 
 
4.1.9    BMI > 20 
 
4.2 
Exclusion Criteria 
 
Criteria for Exclusion:  Participants will be excluded from the study for the following reasons:  
4.2.1 
Participants who had curatively treated invasive malignancies for which all treatments ended within 
1 year prior to the study (with the exception of basal cell or squamous cell carcinoma of the skin), 
 
4.2.2 
Not a surgical candidate or surgery is not scheduled within 43 days from starting the study drug.  
 
4.2.3 
Receiving any other investigational agents. 
 
 
4.2.4 
Any gastrointestinal condition causing malabsorption or obstruction (e.g. celiac sprue, gastric 
bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome). 
 
4.2.5 
Has been on any hormonal treatment (including progestin-containing IUD) for CAH/EIN or low 
grade (grade 1 or grade 2) endometrial carcinoma in last 3 months. 
 
4.2.6 
Use hormone replacement therapy (including systemic or topical estrogen, progesterone, or 
testosterone based medication) or/and phytoestrogen supplements (i.e. black cohosh) or has been 
on progestin (including progestin containing IUD), tamoxifen or aromatase inhibitor within the 
prior 3 months. 
 
4.2.7 
Concomitant use of strong CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, 
phenobarbital or St. John’s wort as these may significantly reduce the availability of exemestane.  
 
4.2.8 
Known hypersensitivity to exemestane or its excipients. 
 
4.2.9 
Known intercurrent illness or psychiatric illness/social situations that will limit compliance with 
study requirements. 
 
4.2.10 Evidence or high suspicion of metastatic disease at enrollment. 
 
 
4.2.11 Women with severe bone density issues/osteoporosis (defined as any medical treatment for 
osteoporosis, and/or a T-score of -2.5 or lower, and/or history of fracture of the hip or spine).  
 
4.2.12  Unwilling or unable to undergo research biopsy during the baseline (pre-surgical) clinic visit, or 
inadequate research biopsy obtained during the baseline (pre-surgical) clinic visit (determined by 
the gynecologic oncologist at the time of the subject’s pelvic exam). 
 
4.3 
Inclusion of Women and Minorities 
Study entry is open to post-menopausal women regardless of race or ethnic background.  While there will 
be every effort to seek out and include minority women, the patient population is expected to be similar to 
that of the general population of newly diagnosed CAH/EIN and low grade(grade 1 or grade 2) endometrial 
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Women of childbearing potential are not eligible for the study. Refer to section 4.1.4.   
 
4.4 
Recruitment and Retention Plan 
University of Minnesota (UMN): The University of Minnesota Gynecologic Oncology team sees 
approximately 100 new low grade (grade 1 and grade 2) endometrial cancers or CAH/EIN patients yearly. 
Approximately 30 patients will be screened for the current trial. 
University of Wisconsin (UWI):  The University of Wisconsin estimates that based on historical low grade 
endometrial cancer patients or CAH/EIN patients that are seen each year in clinic, they will see 
approximately 10 eligible patients each month for this study.  Approximately 30 patients will be screened 
for the current trial. 
University of Alabama (UAB):  The University of Alabama at Birmingham anticipates seeing 
approximately 100 new low grade endometrial cancers or CAH/EIN patients yearly based on historical 
numbers. Approximately 30 patients will be screened for the current trial. 
E. O. Ospedali Galliera (EOG):  E. O. Ospedali Galliera anticipates seeing approximately 100 new low 
grade endometrial cancers or CAH/EIN patients yearly based on historical numbers. Approximately 30 
patients will be screened for the current trial. 
 
Each site will review the gynecologic oncologists’ clinic patient list to identify potential participants.  
Through a review of the medical record, the study team will determine if a patient is eligible and contact 
them for interest in the study. Review of medical records prior to consenting to the research study is very 
minimum risk of harm to the potential study participants and involves no study related procedures for which 
written consent is normally required outside of the research context. 
A study specific flyer can be provided to the contacted patients as a means to give them a brief 
understanding of the study. 
 
The principal investigator at each of the sites are gynecologic oncologist and will have a team of other 
gynecologic oncologists helping to identify participants for the study. Each site will have a lead study 
coordinator trained on the study related procedures to carry out the tasks for the study. Sites will be 
encouraged to have back up coordinators to help the lead coordinator.  
  
5. 
AGENT ADMINISTRATION 
Exemestane will be self-administered on an outpatient basis. Reported AEs and potential risks are described 
in Section 6.2.  
 
5.1 
Dose Regimen and Dose Group 
Exemestane 25 mg per day is taken by mouth once a day (participant self-administers) for at least 21 days 
but not to exceed 42 days prior to surgery. The last dose is taken on the day before surgery. 
 
5.2 
Exemestane Administration 
Exemestane will be dispensed by an investigational pharmacist or appropriate study staff at the participating 
organization (PO) and then self-administered by the participant at home. Depending on when the surgery 
is scheduled, the participant will be given 1 or 2 bottles of the study agent. Each bottle contains 30 tablets 
of exemestane. After confirmation of eligibility, the agent will be mailed to the participants via courier. 
 
Exemestane is a 25 mg tablet to be taken by mouth following a meal once daily at approximately the same 
time each day.  If the dose is missed by more than 8 hours, the patient will skip that dose and take the next 
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The patient will be provided with a daily pill diary to record the time of administration, side effects, and 
any missed doses.  The patient will be instructed to bring the pill diary and study drug bottles (including 
any empties) on the day of surgery. 
 
5.3 
Run-in Procedures  
Not applicable 
 
 
5.4 
Contraindications 
Exemestane tablets are contraindicated in patients with a known hypersensitivity to the drug or to any of 
the excipients. Refer to package insert for an accurate list. 
 
5.5 
Concomitant Medications 
All medications (prescription and over-the-counter), vitamin and mineral supplements, and/or herbs taken 
by the participant will be documented on the concomitant medication CRF until the time of surgery and 
will include start and stop date, dose and route of administration, and indication. Medications taken for a 
procedure should also be included.  Medications given prior to surgery or in the hospital as part of the 
standard surgical protocol will not be documented as concomitant medications.  However, any medications 
given to treat an adverse or unexpected event following surgery will be documented. 
 
Exemestane is extensively metabolized by CYP3A4, but co-administration of ketoconazole, a potent 
inhibitor of CYP3A4, has no significant effect on exemestane pharmacokinetics. Significant 
pharmacokinetic interactions mediated by inhibition of CYP isoenzymes therefore appear unlikely, and are 
acceptable to be taken while on study. Co-medications that induce CYP3A4 (e.g., rifampicin, phenytoin, 
carbamazepine, phenobarbital, or St. John’s wort) may significantly decrease exposure to exemestane.  
Therefore, participants on CYP3A4 inducers will not be enrolled in the study and participants should not 
take CYP3A4 inducers while on study. 
 
5.6 
Dose Modification 
Dose modification is not applicable for this study. However if a participant is unable to tolerate exemestane, 
it will be discontinued. Any grade 3 or greater adverse event (based on CTCAE v4.0), grade 2 heart failure, 
grade 2 rash (paputopustular, acneiform, maculo-papular, etc.) covering 10-30% of the body surface area 
(BSA) and grade 2 thromboembolic event (DVT requiring medical intervention) that is at least possibly 
related to exemestane will result in permanent discontinuation. 
 
5.7 
Adherence/Compliance 
Participants will be considered compliant for secondary “per protocol” statistical analysis if they have taken 
 80% of their exemestane doses based on a tablet count and review of the participant completed pill diary. 
 
6. 
PHARMACEUTICAL INFORMATION 
6.1 
Exemestane (IND #
 NCI, DCP)   
Exemestane  is a steroidal, suicide inhibitor of aromatase, the principal enzyme that converts androgens to 
estrogens. Exemestane is approved in the US for adjuvant treatment of postmenopausal women with 
estrogen receptor-positive early breast cancer (EBC) after receiving 2−3 years of prior tamoxifen therapy 
and for treatment of advanced breast cancer in postmenopausal women whose disease has progressed 
following tamoxifen therapy. Though not officially approved for cancer prevention, exemestane 
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year risk score >1.66%; prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal 
carcinoma in situ with mastectomy) resulted in a 65% relative risk reduction of invasive breast cancer 
compared with placebo treatment after three years of follow-up in the MAP.3 trial50. NCI, DCP is 
continuing to evaluate exemestane for estrogen-dependent cancer prevention such as CAH/EIN.  
 
Exemestane (25 mg) is provided as an oral tablet for once daily administration after a meal and is packaged 
as 30 tablets per bottle. The compound is a white to slightly yellow powder that is practically insoluble in 
water but freely soluble in organic solvents (methanol, N,N-dimethylformamide). Each tablet contains 25 
mg exemestane; inactive ingredients may vary based on commercial source of generic materials, but may 
include mannitol, copovidone, crospovidone, silicified microcrystalline cellulose, sodium starch glycolate, 
magnesium stearate, titanium dioxide, polyethylene glycol 400 or 8000, and hypromellose, polysorbate 80, 
polydextrose, triacetin, and povidone K30. 
 
Exemestane (Aromasin, Pfizer) for E.O. Galliera will be purchased by the Hospital Pharmacy as an oral 
tablet for once daily administration after a meal and will be packaged as 30 tablets per bottle specifically 
labeled for the trial. Each tablet contains 25 mg exemestane; inactive ingredients may vary based on 
commercial source of generic materials, but may include silica colloidal hydrated, crospovidone, 
hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, sodium starch glycolate, 
polysorbate; coating: hypromellose, polyvinylalcohol, simeticone, macrogol, sucrose, magnesium 
carbonate light, titanium dioxide, methyl parahydroxybenzoate, cetyl esters wax, talc and carnauba wax. 
 
6.2 
Reported Adverse Events and Potential Risks 
According to the exemestane US prescribing information, treatment-emergent adverse events (TEAEs) 
more commonly reported by EBC patients treated with exemestane compared with placebo were (in order 
of frequency): hot flashes (33%), alopecia (15%), hypertension (15%), depression (10%), diarrhea (10%), 
dermatitis (8%), headache (7%), and myalgia (6%). TEAEs similarly or less commonly reported by EBC 
patients treated with exemestane compared with placebo were (in order of frequency): arthralgia (29%), 
increased sweating (18%), insomnia (14%), nausea (12%), fatigue (11%), abdominal pain (11%), dizziness 
(10%), edema (6%), and anxiety (4%). Elevations of alkaline phosphatase (14–15%), bilirubin (5–7%), and 
creatinine (6%) were more commonly seen in patients receiving exemestane than tamoxifen or placebo. 
Though rare, cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were 
elevated in EBC patients treated with exemestane (1.6%) compared with tamoxifen (0.6%) 51. 
 
6.3  
Availability 
Exemestane will be supplied by NCI, DCP. E.O. Ospedali Galliera will obtain exemestane through the 
hospital pharmacy which will purchase it from the Pfizer local vendor.  
 
6.4 
Agent Distribution 
Exemestane will only be released by NCI, DCP (hospital pharmacy, vendor for Galliera) after 
documentation of CIRB approval of the DCP-approved protocol and consent is provided to DCP and the 
collection of all essential documents is complete (see DCP website for description of essential documents). 
These essential documents should be submitted to the CLO for processing.  When a site has submitted all 
of the required documents, the DCP’s regulatory contractor will issue drug shipment authorization for that 
site. No study agent will be shipped to a site until the drug shipment authorization has been issued and a 
study initiation visit or teleconference has been completed.  
The request for study agent to be shipped to each site will be generated by the CLO using the DCP clinical 
drug request form (NIH-986) (US only).  At the time of study initiation, the CLO will request complete 
shipping contact information for the site’s investigational pharmacy. If the site does not have an 
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agent accountability at the site will be requested. DCP guidelines require that the agent be shipped directly 
to the institution or site where the agent will be administered. DCP does not permit the transfer of agents 
between institutions (unless prior approval from DCP is obtained). The CLO will submit study agent 
requests to:  
 
John Cookinham 
MRIGlobal DCP Repository 
1222 Ozark Street 
North Kansas City, MO 64116 
Phone: (816) 360-3805 
FAX: (816) 753-5359 
Emergency Telephone: (816) 360-3800 
 
Exemestane will be purchased by the Hospital Pharmacy of E.O. Ospedali Galliera from Pfizer, local 
vendor. Pfizer is the only authorized dealer for Liguria region. The tablet will be packaged and labeled 
specifically for the trial. 
 
Carla Elda Angela Fraguglia 
Director of Hospital Pharmacy 
E.O. Ospedali Galliera 
Corso Mentana, 10  
16128 - Genova 
 
6.5  
Agent Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of all agents received from DCP or vendor using the NCI Drug Accountability 
Record Form (DARF). The investigator is required to maintain adequate records of receipt, dispensing and 
final disposition of study agent. Include on receipt record from whom the agent was received and to whom 
study agent was shipped, date, quantity and batch or lot number. On dispensing record, note quantities and 
dates study agent was dispensed to and returned by each participant. POs can use the computerized 
inventory system if available on site and provide the updated copy of computerized DARF upon request by 
CLO monitors.  
 
6.6 
Packaging and Labeling 
Exemestane will be packaged by NCI, DCP. E.O. Ospedali Galliera will obtain packaged medication from 
local vendors. The costs of drug purchasing are covered by the study specific budget. 
 
6.7 
Storage 
Study drug will be stored in a secure location at controlled room temperature, 25°C (77ºF) with excursions 
permitted between 15°–30°C (59°–86°F). 
 
6.8 
Registration/Randomization 
CLO will be informed about the expected date and time of the scheduled baseline (pre-surgical) clinic visit 
as soon as it has been scheduled. This will happen after the verbal telephone consent is obtained to dispense 
the tampon kit to the potential participant.  
Once a participant has signed a study informed consent form and has satisfied all eligibility criteria: 
• 
Fax (608-299-3765) or email (prevention@uwcarbone.wisc.edu) the participant’s eligibility checklist 
signed by Investigator and copy of the signed consent form to CLO.  


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CLO will verify eligibility documents are complete and then give confirmation to dispense the study 
medication. The following documents should be sent: 
• 
Informed consent form                    
• 
Eligibility questionnaire 
• 
Clinical safety/eligibility lab report 
• 
Pre-study diagnostic biopsy report 
• 
Medical/surgical history worksheet 
• 
Concomitant medication log 
• 
Physical exam  
• 
PID will be assigned sequentially to all participants who sign consent at the PO and will designate the 
recruitment site, the study and the participant. 
• 
As soon as a subject has been determined to be eligible, the CLO will email a confirmation of accrual 
to the study coordinator at the participating institution. If a confirmation is not received within two 
hours, the coordinator should contact the CLO to confirm that eligibility documents were received.  
• 
For EOG site, the confirmation is due within 24 hours because of the different time zone. 
  
6.9 
Blinding and Unblinding Methods 
This is not a blinded study. 
 
6.10 
Agent Destruction/Disposal 
At the completion of investigation, all unused study agent will be returned to NCI, DCP Repository 
according to the DCP “Guidelines for AGENT RETURNS” and using the DCP form “Return Drug List”.  
 
 




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5. Comprehensive metabolic panel consists of albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), blood urea nitrogen (BUN), calcium, creatinine, glucose, electrolytes (CO2, Cl, 
Na, K), total bilirubin, and total protein 
6. Research samples for estradiol and progesterone are ordered and processed through each institution’s clinical 
laboratory with CBC and CMP  
7. Research blood draws–plasma PK of exemestane will be drawn using the study kit sent to sites.  
8. Serum FSH test for all women that are 45-55 years old and for women that are 56-59 years old and < 2 years of 
amenorrhea.  
9. EOG site will determine eligibility using the pathology report obtained after the biopsy. 
10. Exemestane will be mailed once eligibility is determined at or following baseline (pre-surgical) clinic visit. 
11. Telephone reminder to start study drug can be done on Day 1 or Day 0. This is to make sure the participant starts 
taking the study agent at the planned date. 
12. Appendix E – administer the baseline version of tobacco and alcohol assessments at baseline visit, administer the 
follow-up version of tobacco and alcohol assessments at surgery visit. 
 
7.2 
Pre-Screening and Initial Patient Contact  
The study coordinator or designee will prescreen upcoming clinic visits for women aged 45 years or older 
with newly diagnosed CAH/EIN or low grade (grade 1 or grade 2) endometrial cancer (EC) by reviewing 
the outside hospital referral pathology report. The report is available in the electronic medical record as part 
of the referral process to a gynecologic oncologist.  
 
Telephone contact will be made, introducing the concept of the protocol using the telephone consent form 
(Appendix B). If the patient expresses interest, verbal consent to participation in the tampon collection will 
be obtained and, a kit will be mailed. The kit will include 2 commercially available plastic applicator vaginal 
tampons and instructions (Appendix D) along with the informed consent form for review. She will be 
instructed to place the tampon in her vagina for 8–12 hours before coming to the baseline (pre-surgical) 
clinic visit.  If the patient has trouble inserting the first tampon she can use the second tampon in the kit. If 
her visit is in the afternoon, she will be instructed to place the tampon the morning of her visit. Informed 
consent form will be signed in person before any study related procedures are conducted at the baseline 
(pre-surgical) clinic visit. The tampon will be removed by the gynecologic oncologist during the standard 
pelvic exam.  
 
The tampon will be processed at each institution and sent to the University of Minnesota for protein and 
DNA extraction and analysis per section 10.2. If a subject was unable to place a tampon prior to their 
baseline (pre-surgical) clinic visit, they will still be eligible for participation in this study trial. Every effort 
should be made to collect the tampon; however, if this is not feasible, the patient is still eligible for 
participation and a protocol deviation will not be filed.   
 
For E.O. Ospedalli Galliera site only, participants will be approached to participate prior to their actual 
diagnosis of CAH/EIN/low grade endometrial cancer. Standard of care in this region includes a visit with 
a gynecologic oncologist and subsequent hysteroscopy with biopsies when patients have postmenopausal 
bleeding and a high suspicion for pre-invasive or invasive disease. Therefore, the research team will meet 
the potential participants for a prescreening visit before the diagnostic hysteroscopy. Patients will sign a 
pre-screening consent on this day before the procedure. During the examination, the surgeon will perform 
one diagnostic biopsy and one research only biopsy. If CAH/EIN/low grade EC is confirmed then 
participants will sign the main study consent. If the patient does not meet the CAH/EIN/low grade EC 
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On the day before the baseline (pre-surgical) clinic visit the team will obtain written consent for study 
participation. A tampon will be placed by a study nurse.  Lab tests for eligibility will be collected. Eligibility 
documents will be submitted to CLO for verification by email. 
 
7.3 
Baseline (pre-surgical) clinic Visit 
 
A written informed consent form will be signed before any study related procedures (specifically blood 
draws and biopsy) are conducted at the baseline (pre-surgical) clinic visit.  
The following procedures will be performed to determine eligibility (within 30 days of starting 
exemestane):  
• 
Review of diagnostic pathology report, medical history, concomitant medications, and baseline 
symptoms 
• 
Physical exam with vitals including height, weight, and BMI as well as ECOG performance score.  
• 
Endometrial biopsy will be performed to ensure an adequate amount of tissue for IHC and genetic 
analysis. If a biopsy is not feasible, or if insufficient tissue is obtained (noted by the physician at the 
time of biopsy), the subject will not be eligible for this trial, as comparative IHC is the primary outcome 
for the study.  
o This biopsy is done for research purposes only.  
o Endometrial biopsies will be performed in the gynecologic oncology clinic by the gynecologic 
oncologist. This is a common outpatient procedure, which is performed during the pelvic/speculum 
exam (part of the standard pre-surgical physical exam). With the speculum in place, the physician 
will pass an endometrial pipelle through the cervix and then sample endometrial cells through 
standard biopsy techniques. This procedure is similar to a Pap smear in terms of sample acquisition 
except instead of scraping cells from the cervix, a straw-sized pipelle is passed through the cervix 
and cells are aspirated from the endometrium.  
o No additional sedation or monitoring is required for this procedure.  
o Two biopsy “passes” with the endometrial pipelle will be performed. The first specimen will be 
formalin-fixed, paraffin embedded (FFPE), and sent to the University of Minnesota for IHC analysis 
and central pathologic review . The second specimen will be placed directly into a stabilizing agent 
(AllProtect) for genetic analysis.  
o This sample will be destroyed if the participant does not meet eligibility criteria 
Note that the subjects will consent to the study prior to their physical examination. It is important to 
minimize discomfort to the study subjects and therefore we plan to perform the research-related endometrial 
biopsy at the same time as the standard pre-operative pelvic/speculum exam. This is done to avoid the 
discomfort of having multiple pelvic exams and to reduce the number of visits for the study participant.  
For participants who would like to delay their decision regarding participating until after discussion with 
the physician, written consent can be signed on the day of baseline (pre-surgical) clinic visit and the 
participant can come back to the clinic to get the research biopsy and have the tampon collected. 
Being able to acquire an adequate endometrial biopsy specimen is an important part of eligibility given that 
the primary endpoint of this study compares Ki-67 expression between pre- and post-treatment tissue. If 
the participant is subsequently deemed ineligible based on the laboratory values, the endometrial biopsy 
samples will be destroyed. We anticipate this will happen infrequently, as biopsies will only be performed 
in women who have been found otherwise eligible up until this point.  
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Baseline laboratory tests for eligibility will include CBC with a Differential, a complete metabolic 
profile (CMP) and a serum FSH level in all women 45-55 years old and in women 56-59 years old if 
they report less than 2 years of amenorrhea to confirm the post-menopausal status to confirm post-
menopausal status. 
o 
For EOG site only this can be performed 1 day prior to the pre-surgical clinic visit after 
the participant is consented. 
• 
Baseline research blood sample to measure plasma pharmacokinetics of exemestane. If participant does 
not meet eligibility criteria this sample will be destroyed. Additionally, estradiol, and progesterone 
levels will be measured for the clinical laboratory.   
o 
For EOG site only this can be performed 1 day prior to the pre-surgical clinic visit after 
the participant is consented. 
• 
Demographic information such as age and race/ethnicity.  
• 
Appendix E: baseline tobacco and alcohol assessment questionnaires will be administered. 
o For EOG site only this can be performed 1 day prior to the pre-surgical clinic visit after 
the participant is consented.  
• 
The vaginal tampon will be removed during the pelvic examination. 
o For EOG site only, the study nurse will remove the tampon and place in cold PBS.  
o If the lab test results are not within study required parameters, the tampon will be removed 
and discarded during the baseline (pre-surgical) clinic visit. 
Patients meeting criteria set forth in the protocol will pass the screening phase of the trial. Eligibility will 
be confirmed at the Contract Lead Organization (CLO).  E.O. Ospedali Galliera, can submit the documents 
for confirmation of eligibility day before the baseline (pre-surgical) clinic visit to account for the difference 
in time zones and timely verification of eligibility.  
 
Once a surgery date is scheduled, patients will begin daily oral exemestane for at least 21 days (but not 
longer than 42 days) prior to surgery. Exemestane and pill diary will be mailed to the subject so that they 
can begin taking this medication at home. The day the patient begins taking study drug is considered Day 
1 of the study.  
 
E.O. Ospedali Galliera can dispense the study drug to the participant at this visit after receiving the 
eligibility confirmation from CLO.  
 
Once enrolled, subjects will also be given an additional tampon to be placed by the subject 8-12 hours 
before surgery. They will be supplied with 2 tampons (one to place 8-12 hours before surgery and one extra 
in case they are unable to place it correctly the first time) along with the instructions (Appendix D).   
Participants will be compensated $150.00 for additional time and effort associated with being in the study 
including the endometrial biopsy as well as tampon collection. Since the regulations in Italy do not permit 
for research participants to be compensated with money, no compensation will be provided to the 
participants enrolled at E.O. Ospedali Galliera. 
 
On the day of the pre-surgical clinic visit, the study nurse will remove the tampon and place in cold PBS. 
The study drug will be dispensed to the participant at this visit as well. If the lab test results are not within 
study required parameters, the patient will be deemed ineligible and the tampon will be removed and 
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7.4 
Day 15 Phone Contact  
Participants will be contacted by telephone at Day 15 (±2) of exemestane treatment by the study coordinator 
or designated study team member. The purpose of this contact is to query for exemestane-associated side 
effects/adverse events, review of the pill diary to confirm compliance, review any new or changes to 
medications and answer any questions the participant may have. It will be reiterated that the participant 
should continue exemestane daily with the last dose the day before surgery. In addition, the participant will 
be reminded to place the tampon (provided to her at the baseline (pre-surgical) clinic visit) 8-12 hours 
before the surgery. 
 
7.5 
One Day (-2 days) Prior to Surgery 
The study coordinator or designee will again contact the participant and remind her to insert the tampon in 
her vagina 8-12 hours before the surgery and to bring her exemestane bottle(s) with any leftover tablets and 
the pill diary with her on the day of surgery. If her surgery is in the afternoon, she will be instructed to place 
the tampon the morning of her visit.  Also, a review of exemestane associated side effects/adverse events, 
review of the pill diary to confirm compliance and review any new or changes to medications. 
For EOG site only, the participant would return to clinic for this visit. The research nurse will place the 
tampon for surgery visit.  
 
7.6 
Final Study Visit – Day of Surgery 
The surgical procedure will be standard of care and not altered based on participation. 
 
The following research procedures will occur prior to surgery: 
• 
Physical exam with vitals including height, weight and body mass index 
• 
Medical/ surgical history review and update 
• 
Review of concomitant medications and adverse events.  
• 
Laboratory tests will include CBC with a differential, CMP, estradiol and progesterone. 
• 
Appendix E: follow-up tobacco and alcohol assessment questionnaires will be administered. 
• 
The vaginal tampon, which was placed by the participant 8-12 hours before surgery will be removed 
in the operating room by the surgeon prior to the surgical procedure. Attempt should be made to 
obtain tampon specimen at day of surgery visit even if baseline sample was not obtained.  
• 
Research blood sample to obtain plasma pharmacokinetics of exemestane 
 
At the time of surgery, once the patient is under anesthesia the vaginal tampon will be removed and 
processed in the same way as the pre-treatment tampon. The tampon will be processed at each institution 
and the resultant cells and washings will be frozen and shipped on dry ice to the University of Minnesota 
for DNA and protein extraction per section 10.2. 
 
The surgical pathologic specimen (the uterus) will be processed as is the usual standard at each institution. 
A portion of the FFPE tumor block will be collected and batch shipped to UMN at the end of the study to 
be cut into 10 unstained 5µm slides. If the FFPE block cannot be sent due to limited amount of tumor, then 
10 unstained 5µm slides will be cut and the slides will be shipped to UMN. An additional section of the 
tumor, up to 1x1x1cm, will be collected after removal of the uterus or from the pathology lab, cut in half 
and snap frozen as per institutional policy for genetic and protein analysis. If there is not a visible lesion, 
select a random 1x1x1 cm from the endometrium, or smaller if the pathology team needs to review more 
of the endometrium.  This is done at the investigators clinical discretion.  This tumor section will also be 
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unstained slides will be sent to the University of Minnesota (UMN) for proteomics, DNA analysis, 
histologic review, and IHC.  
 
The study coordinator or designee will collect the exemestane supply and completed drug log. 
 
7.7 
Follow-up Contact 
The final study visit will coincide with the day of surgery unless there are any unresolved AEs (with a 
possible, probable or definite attribution to the study agent) on the day of surgery. The unresolved AEs will 
be assessed via telephone call during the postoperative period, before or on the day of the 1st post-surgical 
follow-up visit. AEs that occurred after surgery will not be recorded. 
 
For EOG site only, follow-up at the standard of care post-operative visit will be performed in order to 
collect long-term safety information of the study treatment, whether or not the participant has any ongoing 
adverse events at the surgery visit. 
 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 
8.1 
Primary Endpoint 
Estrogen stimulates the proliferation of endometrial cells; we hypothesize that blocking the enzyme 
aromatase will lead to less estrogen available to stimulate the growth of pre-cancer and cancerous 
endometrial cells. Thus, exemestane treatment should lead to decreased levels of Ki-67, an important 
marker of cellular proliferation.  
Unlike in breast cancer, proliferation indices in endometrial cancer are not well study and a threshold that 
predicts ongoing response to Aromatase Inhibitor therapy does not yet exist. Choosing a threshold at which 
to power this study would be arbitrary. Our goal is to help begin to establish these important biomarkers in 
endometrial cancer. Therefore, the primary endpoint of the study is the absolute change in proliferation 
index (Ki-67) expression in CAH/EIN or low grade (grade 1 and grade 2) endometrial cancer cells from 
baseline to post-exposure.  We will evaluate the change from baseline to post-exposure in absolute change 
in percent Ki-67 using one-sample Student’s t-test or Wilcoxon signed-rank test, as appropriate. 
Immunohistochemistry will be performed at the UMN Histology and IHC Laboratory and then read by Dr. 
Mahmoud Khalifa. 
 
Tissue collected from the research biopsy and surgical specimen will be fixed in 10% neutral buffered 
formalin and processed into paraffin blocks. Antigen retrieval is performed on slides using a 6.0 pH buffer 
in a steamer, followed by a cool down period. Slides are rinsed in water followed by immersion in 1x Tris-
buffered saline/0.1% Tween-20 (TBST).  Subsequent steps are automated using an IHC staining platform 
(Nemesis, Biocare).  Endogenous peroxidase activity is quenched by slide immersion in 3% hydrogen 
peroxide solution followed by TBST rinse.  A serum-free blocking solution is placed on sections.  Blocking 
solution is removed and slides are incubated in primary antibody diluted in 10% blocking solution/90% 
TBST followed by TBST rinse. A two step polymer detection (Novalink, Leica) is used according to 
manufacturer’s instruction. Following the detection, the slide is rinsed with TBST and diaminobenezie is 
applied followed by TBST rinse. Slides are then counterstained with CAT Hematoxylin (Biocare) rinsed, 
dehydrated and coverslipped.   
 
8.2 
Secondary Endpoints 
 
8.2.1 Circulating serum estradiol and progesterone:   
Evaluate pre and post treatment circulating serum estradiol and progesterone levels to determine the effect 


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of a daily dose of 25 mg of exemestane for 21-42 days.  
 
8.2.2 Pathological response (regression of CAH/EIN and low grade (grade 1 and grade 2)endometrial 
carcinoma):  
Examine pathologic changes in CAH/EIN or carcinoma from pre-treatment biopsies to final pathology. 
Ultimately, the goal of any pharmacologic intervention will be regression of CAH/EIN and low grade 
endometrial carcinoma to a normal endometrium. Given that the average time for regression for 
progesterone therapy is approximately 6 months3, we do not anticipate that 3 weeks of exemestane therapy 
will result in high levels of tumor regression. However, we do anticipate that there may be some change in 
histology. All preoperative biopsy specimens and postoperative surgical specimens will undergo H&E 
staining. Central pathology review will be performed by Dr. Mahmoud Khalifa at the University of 
Minnesota. Review will be in accordance with the updated pathologic criteria32.  
 
8.2.3 Tissue biomarkers:  
Examine biomarker differences in pre and post treatment samples with regards to expression (measured by 
immunohistochemistry) of markers of these cellular functions or pathways.   
a) Apoptosis (cleaved caspase 3) 
b) Proliferation (cyclin D1) 
c) Insulin pathway (pAKT, IGF-1R) 
d)  Endocrine regulation (ER/PR/AR)  
 
Estradiol induces the production of IGF-1 and the expression of IGF-1 receptor (IGF-1R) is higher in the 
endometrium of patients with CAH/EIN and endometrial cancer compared to normal endometrium30 
31Thus, our hypothesis is that by using exemestane to reduce the levels of systemic estradiol, this will lead 
to lower levels of IGF-1 and reduced IGF-1R expression. Activation of IGF-1R by IGF1 leads to 
phosphorylation of AKT through the PI3K/AKT pathway, which in turn causes accumulation of nuclear 
cyclin D1, leading to increased mitosis and cellular proliferation in addition to having a potent anti-
apoptotic effect. Therefore, reducing IGF-1R activation by decreasing estradiol will lead to decreased 
pAKT, cell cycle arrest, and increased apoptosis. We hypothesize that exemestane will not only show a 
decrease in cellular proliferation as evidenced by a decrease in Ki-67, but a decrease in the cell cycle 
regulatory protein, cyclin D1, and lead to an increase in cleaved caspase 3, which is a marker of apoptosis.  
We also hypothesize that due to exemestane’s inhibition of androgen binding sites and subsequent effects 
on hormone levels, there may be a change in hormone receptors (estrogen, progesterone and androgen 
receptors), as measure by IHC. The following biomarkers, all of which are commercially available, will be 
assessed: Cyclin D1, cleaved caspase 3, pAKT, IGF-1R, ER-alpha, PR, AR. Staining technique will be as 
above.  
8.2.4 DNA mutational analysis through Next Generation Sequencing and methylation status of 
endometrial tumor and vaginal DNA: 
Analyze DNA from the CAH/EIN or low grade endometrial carcinoma for specific genetic mutations, 
microsatellite instability and hypermethylation in order to correlate exemestane response to mutational 
status. Additionally, vaginal DNA (recovered from tampon collection) will be analyzed for presence of 
tumor mutations or hypermethylation. 
 
8.2.4.1 Tumor genetics:  As evident by the recent TCGA analysis of >350 endometrial carcinomas, 
endometrioid tumors have frequent mutations in a variety of genes including PTEN, CTNNB1, PIK3CA, 
KRAS, and POLE33. Furthermore, the TCGA categorized endometrial carcinoma into 4 prognostically 
significant groups characterized by; 1) POLE hotspot mutations and endometrioid morphology; 2) 
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stable (MSS) tumors with mutated PTEN and endometrioid morphology; and 4) MSS tumors with mutated 
TP53, high somatic copy number alteration burden and predominantly serous or mixed morphology. We 
hypothesize that response to exemestane may correlate with tumor genetics and these described subtypes. 
We therefore seek to determine the mutational status of all tumors with DNA panel testing to see if this 
correlates with treatment response.  In this context, tumor response will be defined as any decrease in 
absolute Ki-67 expression by ≥ 5%. 
Pre and post treatment specimens will be sent to the MDL for DNA extraction from AllProtect or fresh 
frozen tissue. Mutation testing will be performed via Next Generation sequencing using a CLIA-validated 
62 gene solid tumor panel. This panel includes clinically actionable genes identified from high quality 
somatic mutation databases including the Dienstmann52, DOCM53, MD Anderson Personalized Cancer 
Therapy, and My Cancer Genome databases. All cases from the TCGA dataset demonstrated at least one 
mutated gene from this 62-gene panel and the critical genes needed for subtype assessment (POLE, PTEN, 
TP53) are covered within it. DNA will be extracted using the QIAamp DNeasy Tissue kit (Qiagen. Inc).  
DNA will be quantified using Qubit reagents (ThermoFisher) and target specific enrichment will be 
performed using the Fluidigm Access Array microfluidics PCR system. Sample specific barcodes are 
appended in a second step PCR reaction, pooled, and sequenced on a MiSeq instrument (Illumina). Raw 
sequencing data is analyzed through a validated custom bioinformatics pipeline54. Average coverage is 
>2000X, and limit of detection sensitivity is 5% variant allele fraction (VAF) for single nucleotide variants 
(SNV) and 1% VAF for indels.  
Microsatellite instability will be assessed using the NCI recommended 5 marker panel55. DNA from tumor 
and matched normal tissue (if available) will be PCR amplified (GeneAmp® PCR Reagent Kit Applied 
Biosystems) with fluorescently labeled primers for the 5 variable maker regions and separated by capillary 
electrophoresis (Applied Biosystems 3100 Genetic Analyzer).  Cases will be categorized as MSI-high if 3 
or more markers are shifted, MSI-low if 1 or 2 markers are shifted, and MSS if zero markers are shifted. 
 
8.2.4.2 DNA Recovery from Tampon Experiments: Given that the endometrium communicates with the 
vagina through the endocervix, we speculate that we could identify protein and DNA that descend through 
the endocervix and into the vagina through tampon collection, based on a recently published manuscript on 
DNA recovery from vaginal tampons for the detection of ovarian cancer34. This ovarian cancer detection 
study focused primary on identifying tumor specific somatic DNA through deep sequencing of vaginal 
DNA. In this present study, we propose a similar method of DNA collection for cancer detection through 
tampon recovery.  
Tampons will be collected in the clinic or operating room and will be placed into a 50 mL conical 
polypropylene tube with a screw-top lid into which 30 mL of cold, sterile phosphate buffer saline (PBS) 
will be added.  The tampon can soak in the cold PBS solution for up to 12 hours before agitation. The tube 
will be mounted on a platform rocker for 30 minutes at 4°C for gentle agitation.  The tampon will be 
carefully removed from the conical tube and inserted into a 35cc syringe.  The plunger of the syringe will 
be slowly depressed to completely compress the tampon, thereby releasing cells and any of the remaining 
PBS solution from the tampon. The tampon will then be discarded.  The PBS solution that was in the initial 
conical tube with the tampon should be combined with the PBS solution that was compressed out of the 
tampon to yield approximately 30 mL.  This 30 mL cell suspension will be equally divided into two 50 mL 
conical polypropylene tubes and centrifuged for 10 minutes to pellet the cells. The 14 mL of supernatant 
from both of the conical tubes will be gently removed by pipet and combined into one conical polypropylene 
tube. The cell pellets will be re-suspended in the remaining 1 mL of PBS using a disposable glass pipet and 
transferred to 1.5 mL Eppendorf tubes each and spun for 10 minutes at 3000xg.  After separating the cell 
pellets the remaining 1 mL of supernatant from both tubes will be combined with the supernatant in the 50 
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The cell pellets that remain at the bottom of the two 1.5 mL Eppendorf tube will be frozen and shipped to 
the University of Minnesota on dry ice.  
 
DNA will be extracted from the cell pellet using a modified protocol and reagents from the QIAamp DNA 
mini kit (Qiagen) as previously described by Erickson et al34. DNA concentration will be quantified using 
Qubit reagents (ThermoFisher). Extracted DNA will be used to identify genomic alterations observed in 
tumor DNA. We will modify the 62-gene solid tumor NGS assay (or a subset of genes enriched for 
mutations in the study population) for this purpose to incorporate unique identifiers (UIDs) as described by 
Kinde et al.55. Our laboratory has extensive experience using amplicon based enrichment on the 
microfluidics platform for enrichment of targets using NGS. Using a combination of both microfluidic PCR 
and UIDs, we anticipate capability to detect somatic alterations at least as low as 0.01% in the tampon DNA 
which will be compared to matched sequencing of the concurrent endometrial biopsy specimen.  
 
8.2.4.3 DNA Methylation  
To better define the sensitivity of vaginal DNA methylation in the detection of endometrial cancer, an 
additional experiment whereby vaginal DNA extracted through tampon collection will be evaluated for 
hypermethylation. DNA from the corresponding endometrial tumor (low grade endometrial carcinoma or 
CAH/EIN) will be separately analyzed and the tumor DNA-vaginal DNA pairs will be analyzed for 
concordance of methylation across 850,000 CpG sites. Vaginal DNA will be extracted per methods already 
described for the genomics portion of this study from the cell pellets. The same DNA extracted from the 
cell pellet will be used for NGS. A bisulfite conversion step will be performed as part of the standard 
Illumina Methylation array protocol, which requires 250 ng minimum DNA input. Vaginal and tumor DNA 
methylation studies will be performed using the EPIC methylation chip (Illumina Inc.), which evaluates 
methylation in 850,000 CpG sites that include both promoter and enhancer elements using 500 ng of DNA. 
 
The proposed experimental design will accomplish several novel goals. First, this design will establish the 
global methylation pattern of each patient’s endometrial carcinoma/EIN which can be statistically 
compared to the primary study endpoint (Ki-67 response to exemestane treatment) in the context of 
potentially clinically relevant methylation groups established by the TCGA. Second, the design will allow 
to rigorously test the sensitivity/limit of detection for specific methylation pattern discrimination in the 
tampon DNA for underlying carcinoma. Finally, the design will allow for a robust comparison of clinical 
utility between ultra-sensitive DNA sequencing, methylation analysis, and proteomics to determine which 
platform is most sensitive for detection of disease. 
 
8.2.5 Protein markers via tampon recovery before and after treatment:  
 
We propose a proteomic analysis of vaginal specimens and endometrial biopsies as an exploratory 
experiment to determine if response to exemestane correlates with a change in vaginal and endometrial 
proteins.  Proteins identified in this experiment could potentially serve as surrogate biomarkers for 
exemestane response. We also anticipate discovering a different protein profile in the tampon collected 
proteins and tissue biopsies of women with CAH/EIN vs. low grade endometrial cancer.  
Dr. Skubitz has successfully performed proteomic studies using the Olink platform on serum protein from 
healthy women and women with ovarian cancer.  The methodology that Dr. Skubitz optimized in her 
preliminary studies will be applied to this study.  The concentration of protein in each sample will be 
determined by using the bicinchoninic acid (BCA) assay. If necessary due to low protein yields in the 
tampon washings, they will be passed through an Amicon filter (3 kD cut-off) in order to concentrate the 
proteins.  In preliminary studies, the total amount of protein in each 1 mL of tampon washing sample ranged 
from 65 to 500 ug (i.e. enough for multiple proteomic analyses). We also plan to extract protein from the 


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cell pellet that is saved from the tampon washing (described in 8.2.6.1) and from tumor biopsies (pre- and 
post-treatment with exemestane).   
For the proteomic pilot studies, we will analyze samples from the first 10 patients that will be sent directly 
to the University of Minnesota.  In particular, we will be analyzing 4 samples from each patient: (i) the PBS 
tampon washing pre-treatment, (ii) the cell pellet from the tampon washing pre-treatment, (iii) the PBS 
tampon washing post-treatment with exemestane, and (iv) the cell pellet from the tampon washing post-
treatment with exemestane.  
The rationale for using the PBS rinse of the tampon as well as the cell pellet from the tampon is four-fold.   
 
1. The PBS rinse from the tampon is a rich source of protein that contains proteins that are secreted from 
the uterus (and endometrium), cervix, and vagina by the patient over the time period that the tampon 
was placed in her vagina.  These proteins will be absorbed by the tampon (along with blood proteins 
and cells that are shed).  In our previous studies, we found a sufficient amount of protein in the PBS 
rinse to perform protein based assays. . 
2. The number of cells that are present in the cell pellet from the tampon may not be sufficient for us to 
perform the genomic studies and the proteomic studies.   If the genomic study would take priority, then 
we would not have a sufficient amount of protein to conduct proteomics.  Thus, we do not want to limit 
the proteomic portion of this study to just the cell pellet. 
3. The proteins that are present in the PBS rinse may not be the same as those that are in the cell 
pellet.  Thus, if were to limit this study to the identification of proteins present only in the cell pellet, 
we may miss proteins that could serve as candidate biomarkers for early stage endometrial cancer. 
4. The proteomic results that we obtain from the PBS rinse will play a significant role in future 
applications for the detection of early stage endometrial cancer.  In particular, we anticipate that women 
in the near future will be able to perform an at home self-administered vaginal swab, and then send the 
swab into a lab for proteomic detection of biomarkers for specific gynecological diseases.  The PBS 
rinse is the closest we have come to this test becoming a reality. 
 
We anticipate that the samples will contain varying amounts of blood, so we will use commercially 
available platforms that were specifically designed to be used with serum or plasma samples.  There are 
currently two major companies that have products that would be amenable to the identification of protein 
biomarkers in serum samples: Olink and SomaLogic.  Olink technology was initially designed to quantify 
the levels of proteins in sera and/or plasma using Proximity Extension Assays.  (See their website at 
https://www.olink.com/)  Thus, the Olink platform is well suited to handle the endometrial samples, which 
contain high amounts of blood proteins.  The unique technology behind the Olink® Target 96 panels 
enables high-throughput, multiplex immunoassays that measure 92 proteins across 96 samples 
simultaneously using only one microliter of serum, or plasma.  The Olink panels have also been used on 
other type of biological samples.  We have searched their lists of more than 1500 proteins that they can 
measure in their 13 commercially available “Target 96” panels.  We found >100 proteins that fall into the 
category of “proliferation” (which is the focus of this project) on five of their panels.  Since each panel 
measures 92 proteins, this will result in generating data for the levels of 92 x 5 = 460 proteins.  This is far 
better than we could expect from MS experiments that are contaminated with blood proteins.  
 
We propose to: 1-Determine the feasibility of using the Olink panels by running one panel (Immuno-
Oncology) to analyze the tampon washing samples, since we are not certain of the dilution of protein that 
will yield optimal results.  We will extract protein from the 20 tampon washing cell pellets and use 
various dilutions of the tampon washing cell pellet lysates and supernatants.  We will place aliquots of the 
diluted samples into a 96-well microtiter plate from the 40 tampon washing samples (10 pre-treatment 
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pellets).  We will provide these samples to the University of Minnesota Genomics Center, whose staff 
will run the samples as a fee-for-service.  - send Olink ~50 ug of protein from the 40 tampon washing 
samples (10 pre-surgery supernatant, 10 post-surgery supernatant, 10 pre-surgery cell pellets, and 10 post-
surgery cell pellets). 2- Once optimal dilutions have been determined, we will be able to test the other 4 
Olink panels that are relevant to this study as a fee-for-service.  
 
SomaLogic technology was also initially designed to quantify the levels of proteins in sera and/or plasma.  
However, SomaLogic uses technology based on aptamers to quantify protein levels in many types of 
samples (See their website at https://somalogic.com/).  Their technology allows for the quantification of 
7000 proteins simultaneously from 75 ul of protein at 0.2 ug/ul.   
 
We propose to: 1- Send SomaLogic ~10 ug of protein from the 40 tampon washing samples (10 pre-
treatment supernatants, 10 post-treatment supernatants, 10 pre-treatment cell pellets, and 10 post-
treatment cell pellets). 2-  As a fee-for-service, have SomaLogic run the 40 samples on their SomaScan 
platform. 
 
Once we have the data back from Olink and SomaLogic, we will be able to analyze the data to identify 
proteins that are differentially expressed between the tampon supernatants and cell pellet lysates, the pre- 
and post-treatment samples from the same patient, as well as those proteins that are differentially 
expressed between the women whose tumors respond to Exemestane treatment and those whose tumors 
do not respond. 
 
Since the Olink and SomaLogic platforms are not compatible with denatured proteins, it will not be possible 
to use either platform to analyze the protein extracts from the biopsies (which were extracted in AllPrep 
reagent for recovery of DNA and protein) or tumor tissues. The tissue sample extracts can be used for other 
protein experiments, such as validation of the proteins identified in the tampon washing samples by Western 
immunoblotting. 
Option 3 of this project is to analyze a subset of the samples from the remaining 30 patients by proteomic 
techniques in a similar manner to those outlined above for Patients #1-10.  In particular, based on the results 
that we obtain from the Proteomic Pilot study using 10 patients and 40 samples, we will be able to limit our 
next set of experiments to the one sample type (tampon washing or tampon cell pellet) that provided the 
best results, instead of analyzing all of the remaining 120 samples (i.e. 30 remaining patients x 4 samples 
each).  For example, we would omit a sample type(s) that did not yield sufficient protein after removal of 
the highly abundant proteins.  Or we may omit the sample type(s) that did not show any significant 
differences in proteins identified or quantified between the pre-treatment and the post-treatment.   We may 
also decide to limit the samples to cases where the women responded to treatment.  Thus, we will limit 
Option #3 to the analysis of an additional 30 samples.  Thus, the cost of performing the experiments in 
Option #3 would cost the same as the experiments outlined in the Proteomic Pilot study. The data from 
these experiments will allow us to make comparisons between the sample sets and validate our results. 
 
8.2.6 Safety and adverse effects of treatment:  
Evaluate safety and adverse effects of the treatment by CTCAE 4.0 toxicity scale. 
 
8.2.7 Comparison of Ki-67 expression changes between subjects and a historical cohort 
The reason a historic cohort will be studied is to provide the context in which to assess the effects of 
exemestane in reducing Ki-67 from baseline to post-exposure to exemestane. Specifically, there may be a 
change in Ki-67 expression from pretreatment biopsy to final surgical specimen in the historical control 
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acquisition (biopsy versus surgical specimen) may have an impact on Ki-67 expression. 
 
The study participants will be matched with a historical nonrandomized control group based on age (+/- 5 
years), disease type and BMI (>20-24, 25-30, > 30). This  control group will provide a reference for how 
Ki-67 may change based on time (specifically time between biopsy and surgery which has to be within 42 
days)  or differences in specimen collection (endometrial biopsies versus surgical specimen), independent 
of exemestane exposure. 
 
8.2.8 Evaluation of the levels of exemestane in the plasma samples pre and post treatment  
Comparison of pharmacokinetic (PK) levels of plasma exemestane pre-and post treatment will analyzed at 
Cancer Pharmacology Laboratory (CP Laboratory) at University of Wisconsin Carbone Cancer Center 
(UWCCC). The plasma samples collected during the baseline (pre-surgical) clinic visit and before surgery 
will be processed as mentioned in section 10.2.4 at each participating center and batch shipped to CP 
Laboratory for analysis.  
 
8.3 
Off-Agent Criteria  
Participants may stop taking exemestane for the following reasons: completed the protocol-prescribed 
intervention, AE or serious adverse event (SAE), noncompliance, contraindicated medications, medical 
contraindication or surgery is not performed within 21 to 42 days of the first dose of exemestane. Any 
participant discontinuing exemestane prior to 1 day before surgery will be instructed to bring the 
exemestane bottles and the completed pill diary to her next appointment. A final study visit will occur at 
the participant’s first post-surgical visit. 
 
8.4 
Off-Study Criteria 
Participants may go ‘off-study’ for the following reasons: surgery and the final study visit has occurred, 
AE/SAE, lost to follow-up, non-compliance, contraindicated medication, medical contraindication, 
withdrawal of consent, death, determination of ineligibility (including screen failure).  
 
8.5 
Study Termination 
NCI, DCP as the study sponsor has the right to discontinue the study at any time.  
 
9. 
CORRELATIVE/SPECIAL STUDIES 
Not Applicable 
 
10. 
SPECIMEN MANAGEMENT  
 
10.1 
Laboratories 
See lab manual for more detailed instructions. 
 
10.1.1 Tissue samples 
Endometrial biopsy tissue sample at baseline (pre-surgical) clinic visit 
• 
First pass will immediately go into formalin and within 24 hours a Formalin Fixed Paraffin 
Embedded (FFPE) block will be made. Blocks will be shipped on frozen ice packs to prevent 
melting of the FFPE block.  
• 
Second pass will be placed in a stabilizing agent (AllProtect) and stored at 4°C and then shipped 
on frozen ice packs. 
 
Hysterectomy Tumor tissue sample at surgery  


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• 
Section snap-frozen and stored at -70/-80°C. Remove up to 1x1x1 cm of tumor and cut in half. If 
there is not a visible lesion, select a random 1x1x1 cm area from the endometrium. This can section 
can be smaller if the pathology team needs to review more of the endometrium.  The amount and 
location of removal of specimen is at the investigators clinical discretion.   This should be snap 
frozen and shipped on dry ice.  
• 
A portion of the formalin fixed paraffin embedded block, which was collected as standard of care 
per institutional pathology guidelines, will be sent to the University of Minnesota and cut into 10 
unstained 5µm slides. If the FFPE block cannot be sent due to limited amount of tumor, then 10 
unstained 5µm slides will be cut and the slides will be shipped to UMN. Blocks will be shipped on 
ice to prevent melting of the paraffin. 
 
Historical matched controls from repository:  
• 
Identify a list of potential matched controls from the repository for each site that will satisfy the 
matching criteria mentioned in section 3 of the protocol.  
• 
For each matched control, two samples will be collected, first from the pre-surgical biopsy remnant 
tissue and the second from the surgical tissue. This tissue can be sent as a block or cut into 10 
unstained 5µm slides.  
• 
All blocks or slides will be shipped at the end of study.  
• 
If slides are sent, they should NOT be cut until the time of shipment.   
 
Tissue analysis will be performed at the University of Minnesota (UMN) as detailed below.  Specimens 
from the University of Wisconsin and University of Alabama will shipped by an overnight carrier to the 
Biorepository laboratory at the University of Minnesota: 
 
Biorepository & Laboratory Services 
Attn: Tyler Colgan 
420 Delaware St SE  
C338 Mayo Memorial Building  
MMC 76 
Minneapolis, MN 55455-0341 
 
There the samples will be logged in and then transferred to the appropriate laboratory within the University 
of Minnesota. Please contact the lab prior to shipping/mailing, to inform the lab that a specimen is on the 
way: Tyler Colgan: colga007@umn.edu  
 
10.1.2 Blood 
Clinical labs (CBC with differential, Comprehensive Metabolic Panel, FSH, estradiol, and progesterone 
level) will be sent to the clinical laboratories at each institution for processing. 
 
Plasma for exemestane concentration will be shipped to: 
 
 
CP Laboratory 
 
 
University of Wisconsin Hospital and Clinics 
 
 
Room K4/559 
 
 
600 Highland Ave.  
 
 
Madison, WI 53792-5669 
 
 
 
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The day before baseline (pre-surgical) clinic visit and surgery, the participant will be provided tampons 
for insertion. The tampon will be removed during the baseline (pre-surgical) clinic visit by the physician 
at the time of the pelvic exam and during surgery.  
 
10.2 
Collection and Handling Procedures 
The UWCCC CP Laboratory  will prepare sample kits for each subject enrolled on the study, which will 
include tampons, endometrial pipelles and two 6mL green top tubes for collecting the pharmacokinetic 
samples. 
 
10.2.1 Vaginal Tampon (baseline (pre-surgical) clinic visit and day of surgery) - Tampons will be 
collected in the clinic or operating room and immediately will be placed into a 50 mL conical polypropylene 
tube with a screw-top lid into which 30 mL of cold, sterile phosphate buffer saline (PBS) will be added.  
The tampon can soak in the cold PBS solution for up to 12 hours before agitation. The tube will mounted 
on a platform rocker for 30 minutes at 4°C for gentle agitation. The tampon will be carefully removed from 
the conical tube and inserted into a 35cc syringe.  The plunger of the syringe will be slowly depressed to 
completely compress the tampon, thereby releasing cells and any of the remaining PBS solution from the 
tampon. The tampon will then be discarded.  The PBS solution that was in the initial conical tube with the 
tampon should be combined with the PBS solution that was compressed out of the tampon to yield 
approximately 30 mL.  This 30 mL cell suspension will then be equally divided into two 50 mL conical 
polypropylene tubes and centrifuged for 10 minutes to pellet the cells.   Remove 14 mL of supernatant from 
both of the conical tubes by gently pipetting and combine into one 50 mL conical polypropylene tube. The 
cell pellets will be re-suspended in the remaining 1 mL of PBS using a disposable glass pipet and transferred 
to 1.5 mL Eppendorf tubes each and spun for 10 minutes at 3000xg.  After separating the cell pellets the 
remaining 1 mL of supernatant from both tubes will be combined with the supernatant in the 50 mL conical 
polypropylene tube. The supernatant and two cell pellets that remain at the bottom of the two 1.5 mL 
Eppendorf tubes will be stored at -70/ -80°C until it is sent to the UMN for analysis after the surgical tampon 
is collected at the below mentioned address. 
 
Biorepository & Laboratory Services 
Attn: Tyler Colgan 
420 Delaware St SE  
C338 Mayo Memorial Building  
MMC 76 
Minneapolis, MN 55455-0341 
 
10.2.2 Tumor biopsy specimens (baseline (pre-surgical) clinic visit) - At the baseline (pre-surgical) clinic 
visit, participants will undergo an endometrial biopsy in clinic to ensure adequate tissue for IHC and genetic 
analysis as well as to confirm pathology. All biopsy samples will be sent to the UMN for proteomics, DNA 
analysis, central pathology review, and IHC. This biopsy will be done for research purposes only and is 
routinely performed during a pelvic/speculum exam in gynecologic oncology clinics without additional 
anesthesia, sedation or monitoring. Two biopsy “passes” with an endometrial pipelle will be performed. 
The first will be formalin-fixed, paraffin embedded (FFPE), and sent to UMN for central pathology review 
and IHC analysis. The first pass will be made go into formalin and within 24 hours a Formalin Fixed 
Paraffin Embedded (FFPE) block will be made. Blocks will be shipped on ice to UMN for central pathology 
review and IHC analysis. The second pass will be placed in a stabilizing agent (AllProtect) stored at 4 °C 
and then shipped on frozen ice packs.  
    
10.2.3 Surgical Samples - The surgical pathologic specimen (the uterus) will be processed as is the usual 
standard at each institution. A portion of the FFPE tumor block will be collected and batch shipped to UMN 


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to be cut into 10 unstained 5µm slides. If the FFPE block cannot be sent due to limited amount of tumor, 
then 10 unstained 5µm slides will be cut and the slides will be shipped to UMN. Blocks and slides will be 
shipped on frozen ice packs to prevent melting of the paraffin. An additional section of the tumor (up to 
1x1x1 cm) will be collected, cut in half and snap frozen to -70/-80°C  for genetic sequencing.  If there is 
not a visible lesion, select a random 1x1x1 cm area from the endometrium.  This section can be smaller if 
the pathology team needs to review more of the endometrium.  The amount and location of the sample is at 
the investigators clinical discretion. This tumor section will also be batch shipped to UMN on dry ice. 
 
10.2.4 Research Blood Samples - At each pharmacokinetic time point (baseline and Day 22-43 (Day of 
surgery - drawn before the surgery), blood will be drawn to fill one 6mL heparinized tube.  The tubes will 
be centrifuged for 10 minutes at 4C to separate plasma.  The plasma will be divided into 2 cryovial 
tubes.  The 2 cryovial tubes will be labeled with the labels provided in the kit.  The participants’ number, 
initials, and date of processing will be added to the labels.  The cryovial tubes will be frozen at -70/-80°C, 
and save for transport to the UWCCC CP Laboratory.   
 
10.3 
Shipping Instructions 
All samples will be shipped in compliance with the International Air Transport Association (IATA) 
Dangerous Goods Regulations. Kits with pre-printed Fed-Ex billing labels will be provided to each 
participating institution. For E.O. Osepdali Galliera, the supply required for the study will be obtained 
locally and not provided by CP lab. The samples will be shipped in batches of 4 participants.  
 
10.3.1 Methods for shipping tissue 
Tissue Samples are shipped (Monday-Thursday) for next day delivery to the Biorepository lab at the 
University of Minnesota. Tissue samples will not be shipped the day before major university holidays.  
 
10.3.2.  Methods for shipping the plasma pharmacokinetics samples: 
Once the patient has completed the study, ship the carton containing the pharmacokinetic samples for one 
patient to the address below. If multiple patients are completing the study, samples from multiple patients 
can be combined in one shipment. Please note this address is for the pharmacokinetic samples ONLY. 
Tissue samples should be sent to the address above at UMN.  
 
CP Laboratory   
University of Wisconsin Hospital and Clinics 
Room K4/559  
600 Highland Ave 
Madison, WI 53792-5669 
 
Call the CP Laboratory to inform them of a shipment (608) 263-5369 or email the CP Laboratory  mailing 
list 3plab@lists.medicine.wisc.edu  
 
Use the express courier service indicated by the shipping label contained in the kit. Closely follow all 
special shipping instructions outlined in the kit instruction packet.  
 
Ship the PK samples only on Monday, Tuesday or Wednesday to ensure safe arrival during the week. Do 
not ship the day before a holiday.  
 
Fill the styrofoam cooler with dry ice and put all of the blood samples into the cooler. Place the cooler into 
the shipping box in which you received the kit. 
 


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10.4 
Tissue Banking 
Biologic specimens collected during the conduct of each clinical trial that are not used during the course of 
the study will be considered deliverables under the contract and thus the property of the NCI. At study 
completion, NCI reserves the option to either retain or relinquish ownership of the unused biologic 
specimens. If NCI retains ownership of specimens, the contractor shall collect, verify and transfer the 
requested biologic specimens from the site to a NCI-specified repository or laboratory at NCI’s expense.  
 
11. 
REPORTING ADVERSE EVENTS  
DEFINITION: AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign), 
symptom, or disease temporally associated with participation in a study, whether or not related to that 
participation. This includes all deaths that occur while a participant is on a study. 
 
Please note that all abnormal clinical laboratory values that are determined to be of clinical significance 
based on a physician’s assessment are to be reported as AEs. Those labs determined to be of no clinical 
significance or of unknown clinical significance (per the physician’s assessment) should not be reported as 
AEs. Any lab value of unknown clinical significance should continue to be investigated/followed-up further 
for a final determination, if possible. 
 
A list of AEs that have occurred or might occur can be found in §6.2 Reported Adverse Events and Potential 
Risks, as well as the Investigator Brochure or package insert.  
 
11.1 
Adverse Events 
11.1.1 Reportable AEs 
All AEs that occur after the informed consent is signed and baseline assessments are completed (including 
run-in) must be recorded on the AE CRF (paper and/or electronic) whether or not related to study agent and 
stop at the beginning of surgery. EOG site must also record on the AE CRF all the AEs that occur after the 
pre-screening informed consent is signed and screening assessments are completed. 
All SAEs, including all hospitalizations, during the study period will be reported as per DCP SAE reporting 
procedures, with the following exception;  
i. Hospitalization for planned surgery will not be reported. However, if this hospitalization event lasts 
longer than the usual period at the institution (as determined by the Site Principal Investigator or 
Sponsor), it will be reportable as an SAE. Adverse events (AEs) relevant to the prolongation of this 
hospitalization will also be collected and reported on AE CRFs.  
 
11.1.2 AE Data Elements: 
The following data elements are required for AE reporting. 
• 
AE verbatim term 
• 
NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) AE term 
(MedDRA lowest level term) 
• 
CTCAE (MedDRA) System Organ Class (SOC) 
• 
Event onset date and event ended date 
• 
Treatment assignment code (TAC) at time of AE onset 
• 
Severity grade 
• 
Attribution to study agent (relatedness) 
• 
Whether or not the event was reported as a SAE 
• 
Whether or not the subject dropped due to the event 
• 
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11.1.3  Severity of AEs 
 
11.1.3.1 
Identify the AE using the CTCAE version 4.0. The CTCAE provides descriptive 
terminology (MedDRA lowest level term) and a grading scale for each AE listed. A copy of the CTCAE 
can be found at http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
 
AEs will be assessed according to the grade associated with the CTCAE term. AEs that do not have a 
corresponding CTCAE term will be assessed according to the general guidelines for grading used in the 
CTCAE v4.0. as stated below.  
 
CTCAE v4.0 general severity guidelines:  
 
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL)*. 
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL**. 
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Fatal 
Death related to AE. 
   
ADL 
 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
11.1.4 Assessment of relationship of AE to treatment 
 
 
The possibility that the AE is related to study agent will be classified as one of the following: not related, 
unlikely, possible, probable, and definite. 
  
11.1.5 Follow-up of AEs 
 
All AEs, including lab abnormalities that in the opinion of the investigator are clinically significant, will be 
followed according to good medical practices and documented as such.  
 
11.2 
Serious Adverse Events  
 
11.2.1 DEFINITION: Regulations at 21 CFR §312.32 (revised April 1, 2014) defines an SAE as any 
untoward medical occurrence that at any dose has one or more of the following outcomes: 
 
• 
Death 
• 
A life-threatening AE 
• 
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A persistent or significant incapacity or substantial disruption of the ability to perform normal life 
functions 
• 
A congenital anomaly or birth defect 
• 
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization should also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require intervention to 
prevent one of the other outcomes. 
 
11.2.2 Reporting SAEs to DCP 
 
11.2.2.1 
The Lead Organization and all Participating Organizations will report SAEs on the DCP SAE 
Report Form found at http://prevention.cancer.gov/clinical-trials/clinical-trials-management/protocol-
information-office/pio-instructions-and-tools/2012-consortia. 
 
11.2.2.2 
Contact the DCP Medical Monitor by phone or email (email preferable) within 24 hours of 
knowledge of the event.  
 
Eva Szabo, MD 
Chief, Lung & Upper Aerodigestive Cancer Research Group  
NCI/Division of Cancer Prevention 
9609 Medical Center Drive, Room 5E-102, MSC 9781 
Bethesda, MD  20892-9781 (For FedEx, use Rockville, MD 20850)  
Phone: (240) 276-7011 
FAX: (240) 276-7848 
email: szaboe@mail.nih.gov 
 
Include the following information when calling the Medical Monitor: 
• 
Date and time of the SAE 
• 
Date and time of the SAE report 
• 
Name of reporter 
• 
Call back phone number 
• 
Affiliation/Institution conducting the study 
• 
DCP protocol number 
• 
Title of protocol 
• 
Description of the SAE, including attribution to drug 
 
11.2.2.3 
The Lead Organization and all Participating Organizations will email written SAE reports 
to DCP’s Regulatory Contractor CCS Associates, Inc. (CCSA; phone: 650-691-4400) at 
safety@ccsainc.com as well as DCP medical monitor simultaneously within 48 hours of learning of the 
event using the fillable PDF SAE Report Form.    
  
11.2.2.4 
The DCP Medical Monitor and CCSA regulatory and safety staff will determine which 
SAEs require FDA submission as IND safety reports. 
 
11.2.2.5 
The Lead Organization and all Participating Organizations will comply with applicable 
regulatory requirements related to reporting SAEs to the IRB/IEC.  
 
11.2.3 Follow-up of SAE 


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Site staff should send follow-up reports as requested when additional information is available. Additional 
information should be entered on the DCP SAE Report Form in the appropriate format. Follow-up 
information should be sent to DCP as soon as available. Any SAE will be followed-up until resolution as 
per the GCP practice.   
 
11.3  Suspected Unexpected Serious Adverse Reaction 
 
An adverse event or suspected adverse reaction is considered by the sponsor and/or study investigator as 
being unexpected, serious and as having a reasonable possibility of a causal relationship with the study 
drug. At EOG site, in case of SUSAR (Suspected Unexpected Serious Adverse Reaction) the 
Pharmacovigilance Unit performs the regulatory notification to EudraVigilance and to the local EC in order 
to comply with the current European regulatory requirements. 
 
 
12. 
STUDY MONITORING 
 
12.1 
Data Management 
All of the procedures outlined in the University of Wisconsin Chemoprevention Consortium standardized 
Data Management Plan (approved 09/23/2019) will be followed in this protocol. Please refer to this 
document for additional details on data management procedures.  The University of Wisconsin Carbone 
Cancer Center’s OnCore database will be the database of record for the protocol and subject to NCI and 
FDA audit. OnCore is a web-based clinical trials database.  Data entry will be performed by the CLO where 
staff is trained in OnCore and applicable regulatory requirements such as 21 CFR: Part 11. Data from the 
OnCore database will be transferred to Federal Security Compliant formats for transmission to DCP 
according to pre-established DCP standards and procedures.  
 
12.2 
Case Report Forms 
In lieu of a CRF set, a System Variable Attribute Report (SVAR) will be used to document all questions 
and data elements to be collected in the database for this protocol. The NCI/DCP approved SVAR will be 
used to create the electronic data entry pages in the OnCore database.  Amendments to the SVAR will be 
submitted to the DCP Protocol Information Office for review and approval.  Data will be extracted from 
source documents submitted by the PO.  
 
12.3 
Source Documents 
To standardize the collection of study data, the CLO will provide the PO’s with protocol specific Visit 
Guides and Source Document Worksheets to ensure that all required data elements are captured.  These 
documents will be used to supplement data collected on primary clinical source documents.  All data 
reported must be documented either on a separate source document found in the participant’s medical record 
or on the Visit Guides and Source Document Worksheets.  All source documents must be signed by the 
study team member that collected or elicited the information in the source documents.  Source documents 
will be submitted to the CLO (either by fax, or e-mail) for entry into the OnCore database within 10 business 
days of each study contact.  Primary clinical source documents will be de-identified and relabeled with the 
participant’s PID number prior to submission.  Documents containing participant personally identifiable 
information that has not been completely obscured cannot be accepted and will be returned to the site.  
 
12.4 
Data and Safety Monitoring Plan 
All of the procedures outlined in the University of Wisconsin Chemoprevention Consortium standardized 
Data and Safety Monitoring Plan (approved 03/20/2018) as well as the Master Data and Safety Monitoring 


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Plan will be followed in this protocol.  The UW Chemoprevention Consortia Data and Safety Monitoring 
Committee meet every 6-12 months to review all data from ongoing consortium studies. 
 
12.5 
Sponsor or FDA Monitoring 
The NCI, DCP (or their designee), pharmaceutical collaborator (or their designee), or FDA may 
monitor/audit various aspects of the study. These monitors will be given access to facilities, databases, 
supplies and records to review and verify data pertinent to the study. 
 
12.6 
Record Retention 
Clinical records for all participants, including CRFs, all source documentation (containing evidence to study 
eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as IRB 
records and other regulatory documentation will be retained by the Investigator in a secure storage facility 
in compliance with Health Insurance Portability and Accountability Act (HIPAA), Office of Human 
Research Protections (OHRP), Food and Drug Administration (FDA) regulations and guidance, and 
NCI/DCP requirements, unless the standard at the site is more stringent. The records for all studies 
performed under an IND will be maintained, at a minimum, for two years after the approval of a New Drug 
Application (NDA). For NCI/DCP, records will be retained for at least three years after the completion of 
the research. NCI will be notified prior to the planned destruction of any materials. The records should be 
accessible for inspection and copying by authorized persons of the Food and Drug Administration. If the 
study is done outside of the United States, applicable regulatory requirements for the specific country 
participating in the study also apply. 
 
12.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
Not Applicable 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Description 
This is a multi-center, phase IIA, single-arm ‘window of opportunity’ pilot study of 25 mg per day 
exemestane for 21 to 42 days in patients undergoing planned surgery for CAH/EIN or low grade 
endometrial cancer, with an age, disease and BMI-matched comparator cohort, obtained from each 
institution’s biobank,   
We plan to enroll up to 40 patients over 12-18 months at an accrual rate of 2-3 patients per month. Although 
all subjects will have CAH/EIN or low grade endometrial cancer based on their referral biopsy, we 
anticipate that some subjects will not have CAH/EIN or low grade endometrial cancer on central pathology 
review, thus making them ineligible for final analysis43. Additionally, tissue samples may not be adequate 
for measuring Ki-67 expression.  We therefore anticipate that approximately 25% of subjects will not be 
eligible for final analysis. This will result in 30 evaluable patients, the effective sample size for the study. 
13.2 
Randomization/Stratification  
In the absence of randomized placebo controls, we will obtain age, disease and BMI matched comparator 
cohort from each institution’s biobank. The historical samples from each matched control will need to be 
obtained within 42 days of each other in order to be consistent with the study participants. This matching 
will be one-to-one.  A comparison of Ki-67 expression between subjects on this study and historic controls 
is not a primary goal of the study. The primary outcome is the overall change in Ki-67 expression between 
pre and post-treatment of each subject. The reason a historic cohort will be studied is to provide the context 
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exemestane. Specifically, there may be a change in Ki-67 expression from pretreatment biopsy to final 
surgical specimen in the historical control cohort suggesting that time alone (between biopsy and surgery) 
or potentially differences in tissues acquisition (biopsy versus surgical specimen) may have an impact on 
Ki-67 expression.  
13.3 
Accrual and Feasibility 
Each participating organization sees over 100 new patients annually with diagnosis of CAH/EIN or low 
grade endometrial carcinoma. It is planned to enroll up to 40 participants over 12 to 18 months from the 
three participating clinical sites to ensure 30 evaluable patients. 
 
13.4 
Primary Objective, Endpoint(s), Analysis Plan 
The primary objective is to determine if there is a decrease in proliferation index, measured by percent Ki-
67 expression, in CAH/EIN or low grade endometrial cancer cells from baseline to post-exposure.  
Therefore, the primary endpoint is the absolute change in Ki-67 expression in endometrial cancer cells from 
baseline to post-exposure.  We will evaluate the change from baseline to post-exposure in absolute change 
in Ki-67 using one-sample Student’s t-test or Wilcoxon signed-rank test, as appropriate. In addition, we 
will evaluate the change relative to the change recorded in the historic cohort.  
 
Ki-67 values for patients with endometrial cancer are available in prior research44. When the patients from 
this paper are limited to those with low grade cancers, the mean (standard deviation) of the decrease from 
baseline was 7.2 (7.5) among the treated patients.  Given an SD of 7.5, the table below shows the detectable 
effect sizes (defined as the mean change divided by the standard deviation of the change) and mean changes 
for a one-sided test for significance level α=0.05 and various power (1-β) levels for the primary endpoint 
given the effective sample size of 30.  For example, using an 0.05 level one-sided one-sample Student t-
test, we would be able to detect an effect size of 0.50, which corresponds to a mean decrease of 3.8, with 
0.85 power. 
    
 
Power 
 
0.80 
0.85 
0.90 
Effect Size 
0.46 
0.50 
0.55 
Mean Decrease 
3.5 
3.8 
4.1 
 
The mean decreases in this table are smaller than the mean difference in the treatment group for those with 
low grade endometrial cancer in the prior research with letrozole44.  We are including CAH/EIN in addition 
to low grade endometrial cancer in the current study and therefore it is not unreasonable to expect a lesser 
treatment effect for these patients with a less severe form of the disease.  For these reasons, we feel there is 
a need to power for smaller differences.  
It is estimated that 50% of the patients will have CAH/EIN and 50% will have low grade endometrial 
cancer.  For subgroups each with 15 patients, using a 0.05 level one-sided one-sample Student t-test, and 
assuming the same standard deviation as above, there will be power of 0.8-0.9 to detect a mean decrease 
ranging from 5.1-6.0.  Because of the nature of the study being exploratory, we are not making adjustment 
for multiplicity of testing in subgroups defined by CAH/EIN vs low grade carcinoma.  
 
13.5 
Secondary Objectives, Endpoints, Analysis Plans 
The secondary objectives are to examine and test change in circulating serum estradiol and progesterone, 
histology, and tissue biomarkers. Additionally, we will correlate response with tumor DNA mutations, and 


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protein and DNA markers via tampon recovery.  Therefore, the secondary endpoints are the changes in 
circulating serum estradiol and progesterone levels, in tissue biomarkers such as apoptosis as measured by 
cleaved caspase 3 level, proliferation as measured by cyclin D1 level, and insulin pathway as measured by 
pAKT and IGF-1R levels, and hormone receptor changes as measured by ER, PR and AR.   
All tumors will be sequenced via Next Generation Sequencing panel testing and also be tested for 
microsatellite instability. Results of tumor genetic testing will be correlated with exemestane response as 
defined by the change in KI-67 expression.  
As an exploratory endpoint, we will attempt to identify the genetic mutation of the primary tumor by 
performing Next Generation Sequencing of tampon collected DNA. Additionally, vaginal proteomic 
analysis will also be performed via tampon collection and correlated with tumor response to exemestane as 
defined by the change in KI-67 expression45,46.  
To evaluate the reliability of methylation measurement assayed on the 850K EPIC chip, an intraclass 
correlation coefficient (ICC) will be calculated for each CpG site using the technical replicates (using 4 
blinded duplicate measurements). We aim to classify the CpG sites into multiple reliability groups, by 
modeling the distribution of ICC values using a mixture distribution. 
The degree of methylation will be determined using Illumina GenomeStudio software. The methylation 
score for each CpG will be represented as a beta (β) value calculated by dividing the fluorescence intensity 
of the methylated allele by the sum of the intensities of the methylated allele and unmethylated allele. β-
values may take any value between 0 (non-methylated) and 1 (completely methylated). Background 
subtraction will be conducted with the GenomeStudio software using built-in negative control bead types 
on the array. An average normalization will also applied in GenomeStudio to minimize scanner-to-scanner 
variation using ~90 normalization probe pairs included on the array, which target housekeeping regions 
with no underlying CpG sites. These probes will be used to independently calculate normalization values 
in the green and red channels so that all samples have the same average intensity. 
We will identify individual DNA methylation sites (β values as independent variables) in the 850K EPIC 
chip that are either overexpressed or underexpressed in endometrial tumor DNA by focusing on the tails of 
distribution of the β values. We will evaluate whether those individual methylation sites can be detected in 
the matched tampon DNA. We realize that this study is not powered to comprehensively identify all 
individual DNA methylation markers in endometrial cancer and will perform these analyses to potential 
targets that can be confirmed in future studies.  
Vaginal and tumor DNA methylation studies will be performed; the signals from methylated (M) and 
unmethylated (U) bead types will be used to calculate β = M/(U + M) for the 850,000CpG sites that the 
EPIC methylation chip evaluates.  Correlations will be tested between vaginal and tumor DNA methylation 
at each CpG site, adjusting for covariates, possibly including age.  Linear mixed models adjusting for 
covariates such as age and histology (CAH/EIN vs grade 1/2) will be used to test for relationships between 
vaginal DNA methylation at CpG sites and the primary endpoint, change in Ki-67.  A False Discovery Rate 
(FDR) q-value of 0.05 will be applied to adjust for multiplicity in these tests; where an FDR is not 
appropriate, a Bonferroni correction will be used. 
 
13.6 
Reporting and Exclusions 
As noted above, we anticipate that approximately 25% of patients will not have CAH/EIN or low grade 
endometrial carcinoma on central pathology review or  their tissue samples will not be adequate for 
measuring Ki-67 expression, thus making them unevaluable for final analysis43.  This will result in 30 
evaluable patients, the effective sample size for the study.  These cases will be considered random loss, and 
will be excluded from analysis.  Otherwise, all cases will be included in the analysis regardless of 


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compliance with the protocol treatment.  All cases that received any amount of exemestane will be included 
in the analysis of toxicity as indicated below. 
 
13.7 
Evaluation of Toxicity 
All participants will be evaluable for toxicity from the time of their first dose of exemestane using CTCAE 
version 4.0.  The incidence and severity of adverse events will be summarized with frequency and 
proportion. 
13.8 
Evaluation of Response 
Pathological response, i.e. regression of endometrial hyperplasia and carcinoma in pre-treatment biopsies 
to final surgical tissue samples, will be summarized with frequency and proportion. All of the participants 
who met the eligibility criteria, with the exception of those who did not receive study agent, will be included 
in the main analysis. Random dropouts will be excluded.  Data will be examined for non-random dropouts.  
An appropriate sensitivity analysis will be conducted in the case of missing data. 
 
13.9 
Interim Analysis 
There is no planned interim analysis of the primary endpoint of the study. Safety data will be monitored 
periodically by the consortium’s data and safety monitoring committee. 
 
13.10 Ancillary Studies 
Not Applicable 
 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
14.1 
Form FDA 1572 
Prior to initiating this study, the Protocol Lead Investigator at the Lead or Participating Organization(s) will 
provide a signed Form FDA 1572 stating that the study will be conducted in compliance with regulations 
for clinical investigations and listing the investigators, at each site that will participate in the protocol. All 
personnel directly involved in the performance of procedures required by the protocol and the collection of 
data should be listed on Form FDA 1572. 
 
14.2 
Other Required Documents 
14.2.1 Current (within two years) CV or biosketch for all study personnel listed on the Form FDA 1572 
and Delegation of Tasks form for the Lead Organization and all Participating Organizations.  
 
14.2.2 Current medical licenses (where applicable) for all study personnel listed on Form FDA 1572 and 
Delegation of Tasks form for the Lead Organization and all Participating Organizations. 
 
14.2.3 Lab certification (e.g., CLIA, CAP) and lab normal ranges for all labs listed on Form FDA 1572 
for the Lead Organization and all Participating Organizations. 
 
14.2.4 Documentation of training in “Protection of Human Research Subjects” for all study personnel 
listed on the FDA Form 1572 and Delegation of Tasks form for the Lead Organization and all Participating 
Organizations. 
 
14.2.5 Documentation of Federalwide Assurance (FWA) number for the Lead Organization and all 
Participating Organizations. 
 
14.2.6 Signed Investigator’s Brochure/Package Insert acknowledgement form 


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14.2.7 Delegation of Tasks form for the Lead Organization and all Participating Organizations signed by 
the Principal Investigator for each site and initialed by all study personnel listed on the form 
 
14.2.8 Signed and dated NCI, DCP Financial Disclosure Form for all study personnel listed on Form FDA 
1572 for the Lead Organization and all Participating Organizations 
 
14.3 
Institutional Review Board Approval 
Prior to initiating the study and receiving agent, the Investigators at the Lead Organization and the 
Participating Organization(s) must obtain written approval to conduct the study from the CIRB. Should 
changes to the study become necessary, protocol amendments will be submitted to the DCP PIO according 
to DCP Amendment Guidelines. The DCP-approved amended protocol must be approved by the CIRB 
prior to implementation 
 
14.4 
Informed Consent 
All potential study participants will be given a copy of the IRB-approved Informed Consent to review. The 
investigator will explain all aspects of the study in lay language and answer all questions regarding the 
study. If the participant decides to participate in the study, he/she will be asked to sign and date the Informed 
Consent document. The study agent(s) will not be released to a participant who has not signed the Informed 
Consent document. Subjects who refuse to participate or who withdraw from the study will be treated 
without prejudice. 
 
Participants must be provided the option to allow the use of blood samples, other body fluids, and tissues 
obtained during testing, operative procedures, or other standard medical practices for further research 
purposes. If applicable, statement of this option may be included within the informed consent document or 
may be provided as an addendum to the consent. A Model Consent Form for Use of Tissue for Research is 
available through a link in the DCP website. 
 
Prior to study initiation, the informed consent document must be reviewed and approved by NCI, DCP, the 
Consortium Lead Organization, and the IRB at each Organization at which the protocol will be 
implemented. Any subsequent changes to the informed consent must be approved by NCI, DCP, the 
Consortium Lead Organization’s IRB, and then submitted to each organization’s IRB for approval prior to 
initiation. 
 
14.5 
Submission of Regulatory Documents 
All regulatory documents are collected by the Consortia Lead Organization and reviewed for completeness 
and accuracy. Once the Consortia Lead Organization has received complete and accurate documents from 
a participating organization, the Consortium Lead Organization will forward the regulatory documents to 
DCP’s Regulatory Contractor: 
 
 
Paper Document/CD-ROM Submissions: 
 
Regulatory Affairs Department 
 
CCS Associates, Inc. 
 
2001 Gateway Place, Suite 350 West 
 
San Jose, CA 95110 
 
Phone: 650-691-4400 
 
Fax: 650-691-4410 
 
E-mail Submissions: 
 
regulatory@ccsainc.com 


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Regulatory documents that do not require an original signature may be sent electronically to the Consortium 
Lead Organization for review, which will then be electronically forwarded to DCP’s Regulatory Contractor. 
 
14.6 
Other 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and the 
applicable regulatory requirements. 
 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE 
The costs of all procedures for this protocol are paid for by the study contract with the exception of the 
costs associated with surgical treatment at the end of the study. In the event that a participant is physically 
injured as a result of participating in this research, there is no provision for compensation for medical care 
for the injury. Participants will be compensated $150.00 for additional time and effort associated with the 
endometrial biopsy and tampon collection. Since the regulations in Italy does not permit for research 
participants to be compensated with money, no compensation will be provided to the participants enrolled 
at E.O. Ospedali Galliera. 
 
According to Directive 2001/20/EC implemented in Italy with Law Decree 211/2003, this clinical trial is 
covered by a study specific insurance. The study drug will be provided by the E.O. Ospedali Galliera 
Pharmacy and will be covered by the study budget. 
 
  
 
 


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Goss PE, Ingle JN, Ales-Martinez JE, Cheung AM, Chlebowski RT, Wactawski-Wende J, 
McTiernan A, Robbins J, Johnson KC, Martin LW, Winquist E, Sarto GE, Garber JE, Fabian CJ, 
Pujol P, Maunsell E, Farmer P, Gelmon KA, Tu D, Richardson H, NCIC CTG MAP.3 Study 
Investigators. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 


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Protocol Version 1 
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2011;364:2381–91. 
51. 
Alvogen Inc. Exemestane tablets, for oral use. Full prescribing information. Rev. 10/2016.. 
52.  
PMID 25656898 Dienstmann R, Jang IS, Bot B, Friend S, Guinney J. Database of genomic 
biomarkers for cancer drugs and clinical targetability in solid tumors. Cancer Discov. 2015 
Feb;5(2):118-23. 
53.  
PMID  27684579   Ainscough BJ, Griffith M, Coffman AC, Wagner AH, Kunisaki J, Choudhary 
MN, McMichael JF, Fulton RS, Wilson RK, Griffith OL, Mardis ER. DoCM: a database of curated 
mutations in cancer. Nat Methods. 2016;13(10):806-7. 
54.  
PMID 26643039 Yang R, Nelson AC, Henzler C, Thyagarajan B, Silverstein KA. ScanIndel: a 
hybrid framework for indel detection via gapped alignment, split reads and de novo assembly. 
Genome Med. 2015 Dec 7;7:127. 
55. 
 Pmid 23303603 Kinde I, Bettegowda C, Wang Y, Wu J, Agrawal N, Shih IeM, Kurman R, Dao F, 
Levine DA, Giuntoli R, Roden R, Eshleman JR, Carvalho JP, Marie SK, Papadopoulos N, Kinzler 
KW, Vogelstein B, Diaz LA Jr. Evaluation of DNA from the Papanicolaou test to detect ovarian 
and endometrial cancers. Sci Transl Med. 2013 Jan 9;5(167). 
56. 
Scholten AN, Smit VT, Beerman H, van Putten WL et al. Prognostic Significance and Interobserver 
Variability of Histologic Grading Systems for Endometrial Carcinoma. Cancer. 2004;100:764-72. 
57. 
Alkushi A, Abdul-Rahman Z, Lim P, Schulzer M et al. Description of a Novel System for Grading 
of Endometrial Carcinoma and Comparison with Existing Grading Systems. Am J Surg Pathol 
2005;29:295-304. 
58. 
Nofech-Mozes S, Ghorab Z, Ismiil N et al. Endometrial Endometrioid Adenocarcinoma A 
Pathologic Analysis of 827 consecutive cases. Am J Clin Pathol. 2008; 129: 110-114. 
59. 
Piulats JM, Guerra E, Gil-Martin M, Roman-Canal B et al. Molecular approaches for classifying 
endometrial carcinoma. Gynecologic Oncology. Vol 145:1. April 2017, pages 200-207. 
 
 
 


UWI2016-08-01 
Protocol Version Number 10.0 
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DCP Protocol Template Version 8.4 
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Protocol Version 1 
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APPENDIX A 
Performance Status Criteria 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
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). 
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. 
3 
In bed >50% of the time. Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


UWI2016-08-01 
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DCP Protocol Template Version 8.4 
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APPENDIX B 
Telephone Consent 
 
Hello, my name is ____________ (name of person screening) and I am from the _____________ (insert 
institution name).   
 
☐ (For clinic patients) 
I am calling from Dr. __________ office whom you are visiting for a surgical consult. He / She wanted me 
to reach out to you and talk about a research study that you may qualify for. Would you be interested in 
learning about this study?  
 
If No: Thank you so much for your time.  
If Yes: This phone call may take up to 15-20mins. Is this a good time to talk to you about the study? 
 
☐ (For self-referrals through NCT’s website) 
I am calling regarding your enquiry for the research study being conducted at our site. I will be providing 
a short description of the study and will answer any questions you may have. This phone call may take up 
to 15-20mins. Is this a good time to talk to you about the study?  
 
If No: Is there a better time to speak to you about this research study? (Get time and best phone number to 
reach them).  If they aren’t interested in being called again, thank them and disconnect phone contact.  
Assure them that their information will be destroyed. 
If Yes: Continue with the script 
 
Participation in this call and participation in the study is voluntary and you can stop at any time without any 
consequences to any on-going care.  
Before I talk about the study, can you tell me a little bit about what you know about your diagnosis and 
why you are coming in so I can direct my conversation accordingly? 
 
Hysterectomy is currently the treatment for uterine cancer (or pre-cancer). To find a less invasive treatment 
option, researchers are contacting patients who are being scheduled for hysterectomy to take an oral 
medication until the day of their surgery. Researchers will then study the effects of the medication on the 
tissue samples collected during the study to understand if the medication has any effect on the uterine cells 
and thickness of the lining. The results of this study may lead to future research with this medication  to 
possibly prevent or treat uterine cancers. 
 
The medication that is given for this study is called exemestane, which you will take orally, once a day for 
3 to 6 weeks prior to your surgery, depending on when your surgery is scheduled. Exemestane is FDA 
approved medication primarily used in patients with breast cancer. It is an anti-estrogen drug that reduces 
the levels of the female hormone estrogen.  Researchers believe that the changes you have in your 
cervix/uterus are also to be related to estrogen. They want to find out if taking this medication has similar 
effect on uterine cells as it has on breast cells.  
 
For this research study, we will be  collecting tissue samples of your uterus before and after the treatment 
with exemestane. If you decide to participate, at your pre-operative visit we will be conducting an 
endometrial biopsy to obtain this tissue sample. Several tests will be done on the samples to see if changes 
can be detected. Part of the study also involves studying samples obtained from a vaginal tampon, which 
we will ask you to place 8-12 hours before your clinic visit.   
 


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If you decide to participate, we  will meet with you at your  pre-operative clinic visit and on the day of your 
surgery. No additional visits will be required. We will collect eligibility information including your medical 
history, diagnosis and lab tests during the visit.  Your doctor will be collecting a research biopsy of your 
uterine lining (called endometrial tissue) and the tampon sample you inserted if you agreed to this portion 
of the study during this pre-operative visit for research. You will not be charged for this procedure and will 
be paid $150 as compensation for your efforts. 
 
Your total duration of participation in this study will depend on when your surgery gets scheduled which 
may be about 6-9 weeks long. We will follow up after your surgery if any side-effects are ongoing. If this 
study sounds like something you might be interested in, we will mail you a copy of the consent form as 
well as a tampon kit with instructions for using the tampon the before your pre-operative clinic visit. You 
can change your decision to be in the study at any time and it will not affect the care you receive in any 
way.  
 
What questions do you have? Note down the questions if any:   __________________________________ 
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
Would you be interested in participating in the study?  
If No: If Patient DOES NOT agree: Thank her for the call and do not proceed further. 
If Yes: Continue with script to obtain consent for tampon insertion.  
 
If you choose to participate, would you be interested in participating in the tampon collection?  
☐ No: If Patient DOES NOT agree: That is ok, you can still participate in the main study. You will be 
receiving a copy of the informed consent form that will be mailed to you, for you to read prior to coming 
for your pre-operative clinic visit. The informed consent form will be discussed at length on the day of the 
clinic visit and you will have the chance to discuss this and to ask more questions you may have. In addition, 
it is advised that you bring a family member or friend with you to all study visits including the pre-operative 
clinic visit.  
☐ Yes: Please note that this will be documented as your verbal consent to provide you with the Tampon 
kit to insert the tampon prior to your visit. This is NOT considered a consent to participate in the full study 
I have described and you can change your mind and not participate in the tampon portion at any time. There 
are minimal risks in placing a tampon or having it removed during your exam. You will be receiving a copy 
of the informed consent form in the kit that will be mailed to you, for you to read prior to coming for your 
pre-operative clinic visit. The informed consent form will be discussed at length on the day of the clinic 
visit and you will have the chance to discuss this and to ask more questions you may have.  In addition, it 
is advised that you bring a family member or friend with you to all study visits including the pre-operative 
clinic visit.  
 
Document date and time of verbal consent given.  Person screening must also sign and date this form. 
Verbal consent given at ________am/pm on _____________ (date).  
Person obtaining verbal consent: _______________________________   Date: _______________ 
Obtain the following information from the participant or medical records: 
Name: ________________________________________________________________________ 
Address (for mailing the kit): ____________________________________________________ 
Diagnosis: ☐ CAH/EIN; ☐ EC grade 1 ☐  EC grade 2                  Age: __________________ 




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UWI2016-08-01 
Protocol Version Number 10.0 
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DCP Protocol Template Version 8.4 
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APPENDIX E 
UWI2016-08-01 Pilot Study of Daily Exemestane in Women with Complex 
Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial 
Neoplasia or Low Grade Endometrial Cancer 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
TOBACCO ASSESSMENT – BASELINE 
Instructions:  
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a 
range or fraction of a number.  
 
Section A. Basic Cigarette Use Information 
1. Have you smoked at least 100 cigarettes (5 packs = 100 cigarettes) in your entire life? 
 
 Yes  
 
 No → Skip to Section B 
 Don’t know/Not sure → Skip to Section B 
 
2. How old were you when you first smoked a cigarette (even one or two puffs)? 
 
_______ Years old 
 
 
3. How old were you when you first began smoking cigarettes regularly?   
 
 
_______ Years old 
 
 
 Check here if you have never smoked cigarettes regularly. 
 
4. How many total years have you smoked (or did you smoke) cigarettes? Do not count any time you 
may have stayed off cigarettes. 
 
 
______ Years (If you smoked less than one year, write “1.”) 
 
 
5. On average when you have smoked, about how many cigarettes do you (or did you) smoke a day? 
(A pack usually has 20 cigarettes in it).  
 
 
_____ Number of cigarettes per day 
 
6. Do you NOW smoke cigarettes?  
 Everyday 
 Some days 
 Not at all → Skip to question 8 
 
7.  How soon after you wake up do you smoke your first cigarette?  
 Within 30 minutes 
 After 30 minutes 
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Protocol Version Number 10.0 
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DCP Protocol Template Version 8.4 
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Protocol Version 1 
03/17/2016 
UWI2016-08-01 Pilot Study of Daily Exemestane in Women with Complex 
Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial 
Neoplasia or Low Grade Endometrial Cancer 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
8. How long has it been since you last smoked a cigarette (even one or two puffs)? 
 
First check which one of the following choices applies to you. Then, if applicable, write a number on the 
line for how many days, weeks, months, or years it has been since your last cigarette. 
 
 I smoked a cigarette today (at least one puff) 
 1-7 days → Number of days since last cigarette ________ 
 Less than 1 month → Number of weeks since last cigarette _________ 
 Less than 1 year → Number of months since last cigarette __________ 
 More than 1 year → Number of years since last cigarette ___________ 
 Don’t know/Don’t remember 
 
Section B. Use of Other Forms of Tobacco 
 
9.  Have you ever used other forms of tobacco, not including cigarettes? 
  
 Yes  
 No → Skip to Section C 
 
10. How often do you/did you use other forms of tobacco?  
 
 Every day → Number of times per day ________ 
 Some days → Number of days _______ per 
 Week 
 Month 
 Year 
 
11. Which of the following products have you ever used regularly? 
 Check all that apply  
 
 Cigarettes 
 E-cigarettes or other electronic nicotine delivery system 
 Traditional cigars, cigarillos or filtered cigars 
 Pipes 
 Waterpipe 
 Hookah 
 Clove cigarettes or kreteks 
 Bidis  
 Smokeless tobacco, like dip, chew, or snuff 
 Snus 
 Paan with tobacco, gutka, zarda, khaini 
 Other, Please specify:___________________________ 
 
TOBAS Page 2 of 4 
 
 
 
 
 
 
 
 
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UWI2016-08-01 
Protocol Version Number 10.0 
November 08,2021 
 
 
DCP Protocol Template Version 8.4 
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Protocol Version 1 
03/17/2016 
 
UWI2016-08-01 Pilot Study of Daily Exemestane in Women with Complex 
Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial 
Neoplasia or Low Grade Endometrial Cancer 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
12. If you do not currently use other forms of tobacco, but did in the past, how long has it been since 
you last used other forms of tobacco regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago 
 Don’t know/Not sure 
 Never used other forms of tobacco regularly 
 
Section C. Second-Hand Smoke Exposure 
 
13. Are you currently living with a smoker?   
 
 Yes  
 No  
 
14. In the past 30 days, have you lived in a place where other people smoked cigarettes indoors?  
 
 Yes  
 No  
 
15. In the past 30 days, have you worked in a place where other people smoked cigarettes indoors? 
 
 Yes  
 No  
 
16. Thinking of all your childhood and adult years, have you ever lived in a place where other people 
smoked cigarettes indoors? 
 
 Yes → In total, for about how many years? _______ If less than 1, write “1.”   
 No  
 
 
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Protocol Version Number 10.0 
November 08,2021 
 
 
DCP Protocol Template Version 8.4 
–60– 
Protocol Version 1 
03/17/2016 
 
UWI2016-08-01 Pilot Study of Daily Exemestane in Women with Complex 
Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial 
Neoplasia or Low Grade Endometrial Cancer 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
17. Thinking of all the years you have worked, have you ever worked in a place where other people 
smoked cigarettes indoors?    
 
 Yes → In total, for about how many years? ______ If less than 1, write “1.”    
 No 
 
This assessment was completed by:  
 Study Team Member    
 Participant 
 
Completed By: _______________________________________________   Date __ __ / __ __ / __ __ __ __ 
                                                          (Signature of person completing)                                         (MM/DD/YYYY) 
Completed By: _______________________________________________ 
                                                          (Printed name of person completing) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Version Number 10.0 
November 08,2021 
 
 
DCP Protocol Template Version 8.4 
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Protocol Version 1 
03/17/2016 
 
UWI2016-08-01 Pilot Study of Daily Exemestane in Women with Complex 
Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial 
Neoplasia or Low Grade Endometrial Cancer 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
TOBACCO ASSESSMENT - FOLLOW-UP 
Instructions:  
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a 
range or fraction of a number. 
1. Do you NOW smoke cigarettes?  
 
 Everyday 
 Some days 
 Not at all → Skip to Question 3. 
 Never Smoked → Skip to Question 4. 
 
2. On average, when you smoked, about how many cigarettes do you (or did you) smoke a day? (A 
pack usually has 20 cigarettes in it).    
 
 
 
_____ Number of cigarettes per day 
 
3. How long has it been since you last smoked a cigarette (even one or two puffs)?    
 
First check which one of the following choices applies to you. Then, if applicable, write a number on the 
line for how many days, weeks, months, or years it has been since your last cigarette. 
 
 I smoked a cigarette today (at least one puff) 
 1-7 days → Number of days since last cigarette ________ 
 Less than 1 month → Number of weeks since last cigarette _________ 
 Less than 1 year → Number of months since last cigarette __________ 
 More than 1 year → Number of years since last cigarette ___________ 
 Don’t know/Don’t remember 
 
4. Since your last visit, have you used other forms of tobacco, not including cigarettes?  
 
 Yes 
 No (End) 
 
5. How often do you/did you use other forms of tobacco?  
 Every day → Number of times per day ________ 
 Some days → Number of days _______ per 
 Week 
 Month 
 Year 
 
 
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Protocol Version 1 
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UWI2016-08-01 Pilot Study of Daily Exemestane in Women with Complex 
Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial 
Neoplasia or Low Grade Endometrial Cancer 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
6. Since your last visit, which of the following products have you used?  Check all that apply 
 
 Cigarettes 
 E-cigarettes or other electronic nicotine delivery system 
 Traditional cigars, cigarillos or filtered cigars 
 Pipes 
 Waterpipe 
 Hookah 
 Clove cigarettes or kreteks 
 Bidis  
 Smokeless tobacco, like dip, chew, or snuff 
 Snus 
 Paan with tobacco, gutka, zarda, khaini 
 Other, Specify ______________________________________________________________ 
 
7. If you do not currently use other forms of tobacco, but did in the past, how long has it been since you 
last used other forms of tobacco regularly?  
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago 
 Don’t know/Not sure 
 Never used other forms of tobacco regularly 
 
The following instructions pertain to questions 8 - 10.  During each of the following time frames, please 
indicate whether you smoked cigarettes every day, some days, or not at all. 
8.  During study treatment 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 Not applicable  
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Protocol Version Number 10.0 
November 08,2021 
 
 
DCP Protocol Template Version 8.4 
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Protocol Version 1 
03/17/2016 
UWI2016-08-01 Pilot Study of Daily Exemestane in Women with Complex 
Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial 
Neoplasia or Low Grade Endometrial Cancer 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
9.  After the end of study treatment 
 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 Not applicable (I have not completed the study treatment) 
 
10.  Since your last visit to this clinic 
 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 
 
 
This assessment was completed by:  
 Study Team Member    
 Participant 
 
Completed By: _______________________________________________   Date __ __ / __ __ / __ __ __ __ 
                                                          (Signature of person completing)                                                       (MM/DD/YYYY) 
Completed By: _______________________________________________ 
                                                          (Printed name of person completing) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Version Number 10.0 
November 08,2021 
 
 
DCP Protocol Template Version 8.4 
–64– 
Protocol Version 1 
03/17/2016 
UWI2016-08-01 Pilot Study of Daily Exemestane in Women with Complex 
Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial 
Neoplasia or Low Grade Endometrial Cancer 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
ALCOHOL ASSESSMENT – BASELINE 
 
Instructions: 
For the following questions about drinking alcoholic beverages, a drink means a 12 oz. beer, a 5 
oz. glass of wine, or one and a half ounces of liquor. 
 
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a 
range or fraction of a number.  
 
1. In your entire life, have you had at least 12 drinks of any kind of alcoholic beverage?  
 
 Yes 
 No (End) 
 Refused (End) 
 Don’t know/Not sure 
 
2. In the past 12 months, on average, how often did you drink any type of alcoholic beverage?  
 
________ (Enter the number of days you drank based on the timeframe checked below.  Enter 0 
if you never drank and skip to Question 6.) 
  
 Week  
 Month 
 Year 
 Refused 
 Don’t know/Not sure 
 
3. In the past 12 months, on those days that you drank alcoholic beverages, on average, how many 
drinks did you have per day?  
 
________ (Enter the average number of drinks per day) 
 
 Refused 
 Don’t know/Not sure 
 
4. In the past 12 months, on how many days did you have 5 or more drinks of any alcoholic beverage?  
 
 
 
_________ (Enter the number of days you had 5 or more drinks, or enter 0 if none.) 
 
 Refused 
 Don’t know/Not sure 
 
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DCP Protocol Template Version 8.4 
–65– 
Protocol Version 1 
03/17/2016 
UWI2016-08-01 Pilot Study of Daily Exemestane in Women with Complex 
Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial 
Neoplasia or Low Grade Endometrial Cancer 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
5. Was there ever a time or times in your life when you drank 5 or more drinks of any kind of alcoholic 
beverage almost every day?  
 
 Yes 
 No  
 Refused 
 Don’t know/Not sure 
 
6. If you do not currently drink alcoholic beverages, but did in the past, how long has it been since 
 
you last drank regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago  
 Don’t know/Not sure 
 Never drank regularly 
 
7. At the heaviest point, either now or in the past, on the days when you drank, about how many drinks 
did you drink a day on the average?  
 
 
 
__________ (Enter the number of drinks a day) 
  
 Refused 
 Don’t know/Not sure 
 
8. How many years have you been drinking (or did drink) regularly?  
 
 
 
______ years 
 
 Refused 
 Don’t know/Not sure  
 
 
 
 
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Protocol Version 1 
03/17/2016 
UWI2016-08-01 Pilot Study of Daily Exemestane in Women with Complex 
Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial 
Neoplasia or Low Grade Endometrial Cancer 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
9. At what age did you begin drinking regularly?  
 
 
______ years of age 
 
 
 Refused 
 Don’t know/Not sure  
 
10. What type(s) of alcohol do you drink? (Mark ALL that apply) 
 
 Wine 
 Liquor 
 Beer 
 Wine cooler 
 
This assessment was completed by:  
 Study Team Member    
 Participant 
 
Completed By: __________________________________________________   Date __ __ / __ __ / __ __ __ __ 
                                                          (Signature of person completing)                                              (MM/DD/YYYY) 
Completed By: __________________________________________________ 
                                                          (Printed name of person completing) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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UWI2016-08-01 
Protocol Version Number 10.0 
November 08,2021 
 
 
DCP Protocol Template Version 8.4 
–67– 
Protocol Version 1 
03/17/2016 
UWI2016-08-01 Pilot Study of Daily Exemestane in Women with Complex 
Atypical Hyperplasia of the Endometrium / Endometrial Intraepithelial 
Neoplasia or Low Grade Endometrial Cancer 
PID#: __ __ __ __ __ __ __ 
 
Date: __ __/__ __/__ __ __ __ 
 
ALCOHOL ASSESSMENT - FOLLOW-UP 
Instructions: 
For the following questions about drinking alcoholic beverages, a drink means a 12 oz. beer, a 5 
oz. glass of wine, or one and a half ounces of liquor. 
 
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a 
range or fraction of a number. 
 
1. During the past 30 days, did you drink any alcoholic beverages?  
 
 Yes 
 No (End) 
 Refused (End) 
 Don’t know/Not sure 
 
2. During the past 30 days, how many days per week or per month did you drink any alcoholic beverages, 
on the average?  
  ________ (Enter number of days you drank based on the timeframe checked below.  Enter 0 if you 
did not drink.)  
 
 Week  
 Month 
 Refused 
 Don’t know/Not sure 
 
3. On the days when you drank, on average, about how many drinks did you have?  
 
________ (Enter the average number of drinks you had per day.) 
 
 Refused 
 Don’t know/Not sure 
 
4. In the past 30 days, on how many days did you have 5 or more drinks per day?  
________(Enter the number of days you had 5 or more drinks, or enter 0 if none) 
 
 Refused  
 Do not know/Not sure 
This assessment was completed by:  
 Study Team Member    
 Participant 
 
Completed By: _____________________________________________   Date __ __ / __ __ / __ __ __ __ 
                                                    (Signature of person completing)                                    (MM/DD/YYYY) 
Completed By: _____________________________________________ 
  
 
       
 
                                            (Printed name of person completing) 
 
 
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