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

FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03300557
• Other study ID #: NCI-2017-01782
• Secondary ID: NCI-2017-01782UW
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: November 15, 2017
• Est. completion date: June 30, 2024

Study information

• Verified date: December 2023
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 46
• Est. completion date: June 30, 2024
• Est. primary completion date: December 13, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 45 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Adenocarcinoma
• Atypical Hyperplasia
• Carcinoma in Situ
• Carcinoma, Endometrioid
• Endometrial Hyperplasia
• Endometrial Neoplasms
• FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma
• FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma
• Hyperplasia
• Neoplasms

Intervention

Drug:
• Exemestane
Given PO

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Pharmacokinetic Study
Correlative studies
• Questionnaire Administration
Ancillary studies

Locations

Country	Name	City	State
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	University of Wisconsin Carbone Cancer Center - University Hospital	Madison	Wisconsin
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Changes in circulating serum estradiol		Baseline up to 7 months
Secondary	Changes in circulating serum progesterone		Baseline up to 7 months
Secondary	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
Secondary	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
Secondary	Deoxyribonucleic acid (DNA) mutational analysis	Will be analyzed by next generation sequencing.	Up to 7 months
Secondary	Methylation status of endometrial tumor		Up to 7 months
Secondary	Protein and DNA markers	Will be assessed via tampon recovery pre and post exemestane treatment.	Up to 7 months
Secondary	Ki-67 expression	Will compare Ki-67 expression between participants samples and historically matched samples.	Up to 7 months
Secondary	Plasma levels of exemestane	Will evaluate plasma levels of exemestane pre and post treatment.	Up to 7 months