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

Phase 2

Active, not recruiting

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

Interventions: Drug: Exemestane
Other: Laboratory Biomarker Analysis
Other: Pharmacokinetic Study
Other: Questionnaire Administration

Registration Number: NCT03300557

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: Female

Target Recruitment: 40

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (exemestane)	Pharmacokinetic Study	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.
Treatment (exemestane)	Exemestane	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.
Treatment (exemestane)	Laboratory Biomarker Analysis	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.
Treatment (exemestane)	Questionnaire Administration	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.

Primary Outcome Measures

Name	Time	Method
Change in tumor proliferation	Baseline up to 7 months	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.

Secondary Outcome Measures

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

Trial Locations

Locations (3): University of Alabama at Birmingham Cancer Center
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Birmingham, Alabama, United States
University of Minnesota/Masonic Cancer Center
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Minneapolis, Minnesota, United States
University of Wisconsin Carbone Cancer Center - University Hospital
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Madison, Wisconsin, United States