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

• ClinicalTrials.gov Identifier: NCT03300557
• Recruitment Status: Active, not recruiting
• First Posted: October 3, 2017
• Last Update Posted: July 28, 2022
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Atypical Hyperplasia; Endometrial Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia; FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma; FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma	Drug: Exemestane; Other: Laboratory Biomarker Analysis; Other: Pharmacokinetic Study; Other: Questionnaire Administration	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Pilot Study of Daily Exemestane in Women With Complex Atypical Hyperplasia of the Endometrium/Endometrial Intraepithelial Neoplasia or Low Grade Endometrial Cancer
• Actual Study Start Date: November 15, 2017
• Estimated Primary Completion Date: September 1, 2022
• Estimated Study Completion Date: September 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment (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.	Drug: Exemestane; Given PO; Other Names: Aromasin; FCE-24304; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacokinetic Study; Correlative studies; Other Names: PHARMACOKINETIC; PK Study; Other: Questionnaire Administration; Ancillary studies

Outcome Measures

Primary Outcome Measures :

1. Change in tumor proliferation [ Time Frame: 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 :

1. Changes in circulating serum estradiol [ Time Frame: Baseline up to 7 months ]
2. Changes in circulating serum progesterone [ Time Frame: Baseline up to 7 months ]
3. Pathological response to exemestane [ Time Frame: Up to 7 months ]
   Will assess regression of complex atypical hyperplasia/endometrial intraepithelial neoplasia and low grade (grade 1 and grade 2) endometrial carcinoma.
4. Tissue marker analysis [ Time Frame: 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).
5. Deoxyribonucleic acid (DNA) mutational analysis [ Time Frame: Up to 7 months ]
   Will be analyzed by next generation sequencing.
6. Methylation status of endometrial tumor [ Time Frame: Up to 7 months ]
7. Protein and DNA markers [ Time Frame: Up to 7 months ]
   Will be assessed via tampon recovery pre and post exemestane treatment.
8. Ki-67 expression [ Time Frame: Up to 7 months ]
   Will compare Ki-67 expression between participants samples and historically matched samples.
9. Plasma levels of exemestane [ Time Frame: Up to 7 months ]
   Will evaluate plasma levels of exemestane pre and post treatment.

Eligibility Criteria

• Ages Eligible for Study: 45 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, United States, 35233

United States, Minnesota

University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota, United States, 55455

United States, Wisconsin

University of Wisconsin Carbone Cancer Center

Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Britt K Erickson; University of Wisconsin, Madison

  Study Documents (Full-Text)

Documents provided by National Cancer Institute (NCI):

Study Protocol and Statistical Analysis Plan  [PDF] November 8, 2021

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT03300557
• Other Study ID Numbers: NCI-2017-01782; NCI-2017-01782 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); UW17010; N01-CN-2012-00033; 2016LS183 / UWI17010/UAB1788 ( Other Identifier: University of Wisconsin Carbone Cancer Center ); UWI2016-08-01 ( Other Identifier: DCP ); N01CN00033 ( U.S. NIH Grant/Contract ); P30CA014520 ( U.S. NIH Grant/Contract )
• First Posted: October 3, 2017
• Last Update Posted: July 28, 2022
• Last Verified: June 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Adenocarcinoma; Endometrial Neoplasms; Neoplasms; Carcinoma in Situ; Carcinoma, Endometrioid; Endometrial Hyperplasia; Hyperplasia; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Pathologic Processes; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Uterine Diseases; Ovarian Neoplasms; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine System Diseases; Exemestane; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists