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

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ClinicalTrials.gov Identifier: NCT03300557
Recruitment Status : Recruiting
First Posted : October 3, 2017
Last Update Posted : June 11, 2020
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Atypical Hyperplasia Endometrial 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.

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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 : December 1, 2021
Estimated Study Completion Date : December 1, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Exemestane

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




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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03300557


Locations
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United States, Alabama
University of Alabama at Birmingham Cancer Center Suspended
Birmingham, Alabama, United States, 35233
United States, Minnesota
University of Minnesota/Masonic Cancer Center Suspended
Minneapolis, Minnesota, United States, 55455
United States, Wisconsin
University of Wisconsin Hospital and Clinics Recruiting
Madison, Wisconsin, United States, 53792
Contact: Howard H. Bailey    608-263-8624    hhb@medicine.wisc.edu   
Principal Investigator: Howard H. Bailey         
Italy
Galliera Hospital Not yet recruiting
Genoa, Italy, 16128
Contact: Andrea De Censi    39 010 5634501    andrea.decensi@galliera.it   
Principal Investigator: Andrea De Censi         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Britt K Erickson University of Wisconsin, Madison
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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 Hospital and Clinics )
UWI2016-08-01 ( Other Identifier: DCP )
N01CN00033 ( U.S. NIH Grant/Contract )
P30CA014520 ( U.S. NIH Grant/Contract )
First Posted: October 3, 2017    Key Record Dates
Last Update Posted: June 11, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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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