Exemestane in Treating Patients With Complex Atypical Hyperplasia of the Endometrium/Endometrial Intraepithelial Neoplasia or Low Grade Endometrial Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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Pilot Study of Daily Exemestane in Women With Complex Atypical Hyperplasia of the Endometrium/Endometrial Intraepithelial Neoplasia or Low Grade Endometrial Cancer

Conditions
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Atypical Hyperplasia, Endometrial Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia, FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma, FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma

Intervention / Treatment
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* Drug: Exemestane
* Other: Laboratory Biomarker Analysis
* Other: Pharmacokinetic Study
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 No prior treatment for CAH/EIN/EC 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 follicle stimulating hormone (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. Eastern Cooperative Oncology Group (ECOG) performance status =< 1 Hemoglobin >= 9 g/dL Serum creatinine =< 1.5 x upper limit of normal or calculated creatinine clearance >= 60 mL/min using Cockcroft-Gault equation for patients with creatinine levels > 1.5 x institutional upper limit of normal (ULN) Total bilirubin =< 1.5 x ULN OR direct bilirubin =< 1 x ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN White blood cell (WBC) >= 3000/mcl Platelets >= 100,000/mcl Able and willing to take oral medications Ability to understand and the willingness to sign a written informed consent document Body mass index (BMI) > 20 Exclusion Criteria: 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) Not a surgical candidate or surgery is not scheduled within 43 days from starting the study drug Receiving any other investigational agents Any gastrointestinal condition causing malabsorption or obstruction (e.g. celiac sprue, gastric bypass surgery, strictures, adhesions, history of small bowel resection, blind loop syndrome) Has been on any hormonal treatment (including progestin-containing intrauterine device [IUD]) for CAH/EIN or low grade (grade 1 or grade 2) endometrial carcinoma in last 3 months 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 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 Known hypersensitivity to exemestane or its excipients Known intercurrent illness or psychiatric illness/social situations that will limit compliance with study requirements Evidence or high suspicion of metastatic disease at enrollment 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) 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)

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (exemestane)<br>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. | Drug: Exemestane<br>* Given PO<br>* Other names: FCE-24304;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacokinetic Study<br>* Correlative studies<br>* Other names: PK Study;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in tumor proliferation | Will be measured by change in Ki-67 expression. 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. | Baseline up to 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in circulating serum estradiol |  | Baseline up to 7 months | 
| Changes in circulating serum progesterone |  | Baseline up to 7 months | 
| Pathological response to exemestane | Will assess regression of complex atypical hyperplasia/endometrial intraepithelial neoplasia and low grade (grade 1 and grade 2) endometrial carcinoma. | Up to 7 months | 
| Tissue marker analysis | Will assess apoptosis (cleaved caspase 3), proliferation (cyclin D1), insulin pathway (pAKT, IGF-1R), and endocrine regulation (estrogen receptor/progesterone receptor/androgen receptor). | Up to 7 months | 
| Deoxyribonucleic acid (DNA) mutational analysis | Will be analyzed by next generation sequencing. | Up to 7 months | 
| Methylation status of endometrial tumor |  | Up to 7 months | 
| Protein and DNA markers | Will be assessed via tampon recovery pre and post exemestane treatment. | Up to 7 months | 
| Ki-67 expression | Will compare Ki-67 expression between participants samples and historically matched samples. | Up to 7 months | 
| Plasma levels of exemestane | Will evaluate plasma levels of exemestane pre and post treatment. | Up to 7 months |