Atypical Hyperplasia, Endometrial Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia, Endometrial Carcinoma, FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma, FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma
Conditions
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.
Interventions
DRUGExemestane
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacokinetic Study
Correlative studies
OTHERQuestionnaire Administration
Ancillary studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
45 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Tumor Proliferation | Baseline up to 2 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
| Measure | Time frame | Description |
|---|---|---|
| Changes in Circulating Serum Progesterone | Baseline up to 2 months | Circulating serum progesterone pre and post treatment to determine the effect of daily dose of 25mg of exemestane for 21-42 days. |
| Percent of Participants by Pathological Response Class at 2 Months | Up to 2 months | This measure assesses change in categories in pathological response. As pathological response is an ordered categorical variable with classes of No visible lesion, CAH/EIN, Grade I, Grade II, and Grade III in this study, a change in class from baseline to time of surgery represents a decrease or increase in disease severity. |
| Change From Baseline in Percent of Cells Positive for Tissue Markers | Up to 2 months | Assessment of change from baseline for apoptosis (cleaved caspase 3), proliferation (cyclin D1), insulin pathway (pAKT, IGF-1R), and endocrine regulation (estrogen receptor/progesterone receptor/androgen receptor). The units for absolute change in is % Positive. |
| Changes in Circulating Serum Estradiol | Baseline up to 2 months | Circulating serum estradiol pre and post treatment to determine the effect of daily dose of 25mg of exemestane for 21-42 days. |
| Protein Markers | Up to 2 months | Perform pre- and post-treatment proteomic analysis of vaginal proteins from tampon recovery to identify biomarkers that may predict response to exemestane treatment. |
| Ki-67 Expression With Historic Controls | Up to 2 months | Will compare Ki-67 expression between participants samples and historically matched samples. |
| Plasma Levels of Exemestane | Up to 2 months | Will evaluate plasma levels of exemestane pre and post treatment. |
| Deoxyribonucleic Acid (DNA) Mutational Analysis | Up to 2 months | Will be analyzed by next generation sequencing. |
Countries
United States
Participant flow
Recruitment details
We are aware that CTRP lists 46 as enrollment. PRS shall remain as 40 because: Potential participants who are screened for the purpose of determining eligibility for the study, but do not participate in the study, are not considered enrolled. Thus, 40 is the proper number because the other 6 were screened and found ineligible, therefore not considered enrolled.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Exemestane: Given PO
Laboratory Biomarker Analysis: Correlative studies
Pharmacokinetic Study: Correlative studies
Questionnaire Administration: Ancillary studies | 40 |
| Total | 40 |
Baseline characteristics
| Characteristic | Treatment (Exemestane) |
|---|---|
| Age, Customized 50-59 years | 13 Participants |
| Age, Customized 60-69 years | 18 Participants |
| Age, Customized 70-79 years | 7 Participants |
| Age, Customized Unknown | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 38 Participants |
| Region of Enrollment United States | 40 participants |
| Sex: Female, Male Female | 40 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 40 |
| other Total, other adverse events | 38 / 40 |
| serious Total, serious adverse events | 0 / 40 |
Outcome results
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.
Time frame: Baseline up to 2 months
Population: There was not enough tissue to analyze from the other two participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Exemestane) | Change in Tumor Proliferation | -0.17 percent (represented by mean) of cells | Standard Deviation 0.22 |
Secondary
Change From Baseline in Percent of Cells Positive for Tissue Markers
Assessment of change from baseline for apoptosis (cleaved caspase 3), proliferation (cyclin D1), insulin pathway (pAKT, IGF-1R), and endocrine regulation (estrogen receptor/progesterone receptor/androgen receptor). The units for absolute change in is % Positive.
Time frame: Up to 2 months
Population: N=37 for caspase because there was not enough tissue on slide for 2 and 1 block was not sent. N=36 for cyclin D1 because 3 were missing data and 1 block was not sent. N=35 for pAKT because 3 were missing data, 1 did not have enough tissue, and 1 block was not sent. N=22 for IGF-1R because 1 black was not sent, 5 did not have enough tissue, and the rest are missing data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment (Exemestane) | Change From Baseline in Percent of Cells Positive for Tissue Markers | Cleaved capsase | -0.17 % positive | Standard Deviation 0.18 |
| Treatment (Exemestane) | Change From Baseline in Percent of Cells Positive for Tissue Markers | Cyclin D1 | -0.07 % positive | Standard Deviation 0.22 |
| Treatment (Exemestane) | Change From Baseline in Percent of Cells Positive for Tissue Markers | pAKT | -0.12 % positive | Standard Deviation 0.27 |
| Treatment (Exemestane) | Change From Baseline in Percent of Cells Positive for Tissue Markers | IGF-1R | -2.50 % positive | Standard Deviation 3 |
Secondary
Changes in Circulating Serum Estradiol
Circulating serum estradiol pre and post treatment to determine the effect of daily dose of 25mg of exemestane for 21-42 days.
Time frame: Baseline up to 2 months
Population: Site did not collect data on the 3 participants omitted from the count
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Exemestane) | Changes in Circulating Serum Estradiol | 4.08 pg/mL | Standard Deviation 13.81 |
Secondary
Changes in Circulating Serum Progesterone
Circulating serum progesterone pre and post treatment to determine the effect of daily dose of 25mg of exemestane for 21-42 days.
Time frame: Baseline up to 2 months
Population: Site did not collect the relevant information for the omitted 3 participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Exemestane) | Changes in Circulating Serum Progesterone | 0.22 ng/mL | Standard Deviation 0.27 |
Secondary
Deoxyribonucleic Acid (DNA) Mutational Analysis
Will be analyzed by next generation sequencing.
Time frame: Up to 2 months
Population: Samples were collected from participants. After enrollment was completed, the intended laboratory was no longer available to process the samples. There are no data to report and there is no intent to analyze these samples in the future.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Exemestane) | Deoxyribonucleic Acid (DNA) Mutational Analysis | NA percentage of cells |
Secondary
Ki-67 Expression With Historic Controls
Will compare Ki-67 expression between participants samples and historically matched samples.
Time frame: Up to 2 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Exemestane) | Ki-67 Expression With Historic Controls | -0.07 percentage of cells | Standard Deviation 0.1 |
Secondary
Percent of Participants by Pathological Response Class at 2 Months
This measure assesses change in categories in pathological response. As pathological response is an ordered categorical variable with classes of No visible lesion, CAH/EIN, Grade I, Grade II, and Grade III in this study, a change in class from baseline to time of surgery represents a decrease or increase in disease severity.
Time frame: Up to 2 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Exemestane) | Percent of Participants by Pathological Response Class at 2 Months | No visible lesion | 2.5 Percent of participants |
| Treatment (Exemestane) | Percent of Participants by Pathological Response Class at 2 Months | CAH/EIN | 20 Percent of participants |
| Treatment (Exemestane) | Percent of Participants by Pathological Response Class at 2 Months | Grade I (Low) EC | 57.5 Percent of participants |
| Treatment (Exemestane) | Percent of Participants by Pathological Response Class at 2 Months | Grade II (Low) EC | 10 Percent of participants |
| Treatment (Exemestane) | Percent of Participants by Pathological Response Class at 2 Months | Grade III (High) EC | 10 Percent of participants |
Secondary
Plasma Levels of Exemestane
Will evaluate plasma levels of exemestane pre and post treatment.
Time frame: Up to 2 months
Population: 40th specimen was not collected by the site.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Exemestane) | Plasma Levels of Exemestane | 2.51 ng/mL | Standard Deviation 1.23 |
Secondary
Protein Markers
Perform pre- and post-treatment proteomic analysis of vaginal proteins from tampon recovery to identify biomarkers that may predict response to exemestane treatment.
Time frame: Up to 2 months
Population: Tampon submission was optional and not all participants submitted tampon samples.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Exemestane) | Protein Markers | 85 number of proteins |