Atypical Endometrial Hyperplasia, Endometrial Carcinoma
Conditions
Brief summary
This phase II trial studies how well megestrol acetate with or without pterostilbene works in treating patients with endometrial cancer undergoing hysterectomy. Drugs used in chemotherapy, such as megestrol acetate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Pterostilbene is an antioxidant found in blueberries or grapes, and it has been shown to be effective in killing tumor cells and reducing cancer burden. It is not yet known whether giving megestrol acetate with or without pterostilbene may work better in treating patients with endometrial cancer.
Detailed description
PRIMARY OBJECTIVE: I. Determine the effect of megestrol acetate (MA) plus pterostilbene (PTE) versus MA alone on tumor proliferation (Ki-67) during the preoperative window in patients with endometrial cancer (EC) who are scheduled for hysterectomy. EXPLORATORY OBJECTIVES: I. Determine the effect of MA plus PTE versus MA alone on histologic response during the preoperative window in patients with EC or endometrial complex atypical hyperplasia who are scheduled for hysterectomy. II. Explore biological characteristics of tumors to determine potential biomarkers which could select for treatment eligibility in future studies. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive pterostilbene orally (PO) twice daily (BID) and megestrol acetate PO BID for 3 weeks in the absence of disease progression or unaccepted toxicity. ARM II: Patients receive megestrol acetate PO BID for 3 weeks in the absence of disease progression or unaccepted toxicity. After completion of study treatment, patients are followed up at 6 weeks.
Interventions
DRUGMegestrol Acetate
Given PO
BIOLOGICALPterostilbene
Given PO
Sponsors
City of Hope Medical Center
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented informed consent of the participant and/or legally authorized representative * Willing to undergo an intraoperative biopsy/or standard of care tissue collection during surgery, following completion of treatment with MA +/- PTE * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Histologically confirmed EC or complex atypical hyperplasia of the endometrium * Candidate for a total hysterectomy with or without bilateral salpingo-oophorectomy * About to initiate preoperative window period, with planned hysterectomy scheduled * Platelets \>= 100,000/mm\^3 * NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement * Total bilirubin =\< 1.5 X upper limit of normal (ULN) * Aspartate aminotransferase (AST) =\< 1.5 x ULN * Alanine aminotransferase (ALT) =\< 1.5 x ULN * Creatinine clearance of \>= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula * Women of childbearing potential: negative urine or serum pregnancy test in premenopausal women. Postmenopausal women do not need to undergo a pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Exclusion criteria
* Pterostilbene supplements within 30 days prior to day 1 of protocol therapy * Any of the following phytochemical-based supplements within 30 days prior to day 1 of protocol therapy: resveratrol, genistein, and quercetin * Chemotherapy for EC * Allergic reaction/hypersensitivity to similar agents, excipients * Unstable cardiac disease as defined by one of the following: * Cardiac events such as myocardial infarction (MI) within the past 6 months * NYHA (New York Heart Association) heart failure class III-IV * Uncontrolled atrial fibrillation or hypertensive emergency/urgency (defined as systolic blood pressure \>= 180 mmHg and/or diastolic blood pressure \>= 120 mmHg) * Active or history of recent thromboembolism or stroke, within the past 6 months * Cushing's syndrome * Acute infection requiring systemic (intravenous) treatment * Known history of human immunodeficiency virus (HIV) infection * Known active hepatitis B or C infection * Inability to swallow tablets/capsules * Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Ki-67 Proliferation Index | Pre- and post-treatment up to 6 weeks | Ki-67 represents a specific nuclear marker for cell proliferation that is measured by staining with specific antibodies by immunohistochemical (IHC) staining. The Ki-67 proliferation index is defined as percent tumor cells staining positive, and measured on a continuous scale of 0-100%, with higher values indicating higher proliferation. Ki-67 hotspot values were assessed at two time-points during this study, prior to treatment with megace +/- pterostilbene (pre-treatment), and following completion of treatment (post-treatment). Descriptive statistics were used to compare treatment-associated percent change in Ki-67 proliferation index between the 2 study arms, using a 1-sided test with significance at p \< 0.05. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Histologic Response of Gland Cellularity | Up to 6 weeks | These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). Gland cellularity will be assessed by counting the number of cells in one quarter of a high-power field (HPF) (average of 3 fields). The number of patients with an improvement in gland cellularity were compared between study arms. |
| Histologic Response of Mitotic Index | Up to 6 weeks | These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). The mitotic index will be calculated as the number of mitoses per HPF (average of 3 fields). The number of patients with an improvement in mitotic index were compared between study arms. |
| Histologic Response of Metaplasia | Up to 6 weeks | These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). The percentages of tumor that display squamous or mucinous metaplasia will be estimated as percentages, with \< 10% considered negative and \>= 10% as positive. The number of patients with an improvement in metaplasia were compared between study arms. |
| Histologic Response of Eosinophilic Metaplasia | Up to 6 weeks | These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). The number of patients with an improvement in eosinophilic metaplasia were compared between study arms. |
| Immunohistochemical Expression of Bcl-2 to Assess Tumor Growth and Apoptosis | Pre- and post-treatment up to 6 weeks | Immunohistochemistry stains with antibodies directed against Bcl-2 will be performed on pre- and post-treatment endometrial samples. Samples will be scored on a continuous scale (0-100%) using the product of the intensity of cytoplasmic staining, and the proportion of cells staining based on the distribution of staining. Descriptive statistics were used to compare the percent change in scores from pre-treatment to post-treatment between the 2 study arms. |
| Immunohistochemical Expression of Casp3 to Assess Tumor Growth and Apoptosis | Pre- and post-treatment up to 6 weeks | Immunohistochemistry stains with antibodies directed against Casp3 to assess apoptosis will be performed on pre- and post-treatment endometrial samples. Samples will be scored by counting the number of positive staining nuclei per HPF. Descriptive statistics were used to compare the percent change in scores from pre-treatment to post-treatment between the 2 study arms. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORThanh H Dellinger
City of Hope Medical Center
Participant flow
Recruitment details
A total of 44 patients were accrued. Seven patients were not evaluable for various reasons: received \<10 days of study treatment (n = 5), disenrolled (n = 1), did not receive hysterectomy (n = 1). Consequently, 37 patients were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Pterostilbene, Megestrol Acetate) Patients receive 100mg pterostilbene BID and 80mg megestrol acetate PO BID for 3 weeks in the absence of disease progression or unaccepted toxicity.
Megestrol Acetate: Given PO
Pterostilbene: Given PO | 19 |
| Arm II (Megestrol Acetate) Patients receive megestrol acetate PO BID for 3 weeks in the absence of disease progression or unaccepted toxicity.
Megestrol Acetate: Given PO | 18 |
| Total | 37 |
Baseline characteristics
| Characteristic | Arm I (Pterostilbene, Megestrol Acetate) | Total | Arm II (Megestrol Acetate) |
|---|---|---|---|
| Age, Continuous | 61.3 years | 61.9 years | 63.9 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 16 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 21 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 17 Participants | 27 Participants | 10 Participants |
| Region of Enrollment United States | 19 participants | 37 participants | 18 participants |
| Sex: Female, Male Female | 19 Participants | 37 Participants | 18 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 18 |
| other Total, other adverse events | 16 / 19 | 15 / 18 |
| serious Total, serious adverse events | 0 / 19 | 0 / 18 |
Outcome results
Primary
Tumor Ki-67 Proliferation Index
Ki-67 represents a specific nuclear marker for cell proliferation that is measured by staining with specific antibodies by immunohistochemical (IHC) staining. The Ki-67 proliferation index is defined as percent tumor cells staining positive, and measured on a continuous scale of 0-100%, with higher values indicating higher proliferation. Ki-67 hotspot values were assessed at two time-points during this study, prior to treatment with megace +/- pterostilbene (pre-treatment), and following completion of treatment (post-treatment). Descriptive statistics were used to compare treatment-associated percent change in Ki-67 proliferation index between the 2 study arms, using a 1-sided test with significance at p \< 0.05.
Time frame: Pre- and post-treatment up to 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Pterostilbene, Megestrol Acetate) | Tumor Ki-67 Proliferation Index | -26.7 percent change | Standard Deviation 34.1 |
| Arm II (Megestrol Acetate) | Tumor Ki-67 Proliferation Index | -25.7 percent change | Standard Deviation 36.3 |
p-value: 0.9t-test, 1 sided
Secondary
Histologic Response of Eosinophilic Metaplasia
These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). The number of patients with an improvement in eosinophilic metaplasia were compared between study arms.
Time frame: Up to 6 weeks
Population: Only 36 patients had data for this endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Pterostilbene, Megestrol Acetate) | Histologic Response of Eosinophilic Metaplasia | 9 Participants |
| Arm II (Megestrol Acetate) | Histologic Response of Eosinophilic Metaplasia | 5 Participants |
Secondary
Histologic Response of Gland Cellularity
These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). Gland cellularity will be assessed by counting the number of cells in one quarter of a high-power field (HPF) (average of 3 fields). The number of patients with an improvement in gland cellularity were compared between study arms.
Time frame: Up to 6 weeks
Population: Only 36 patients had data for this endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Pterostilbene, Megestrol Acetate) | Histologic Response of Gland Cellularity | 13 Participants |
| Arm II (Megestrol Acetate) | Histologic Response of Gland Cellularity | 14 Participants |
Secondary
Histologic Response of Metaplasia
These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). The percentages of tumor that display squamous or mucinous metaplasia will be estimated as percentages, with \< 10% considered negative and \>= 10% as positive. The number of patients with an improvement in metaplasia were compared between study arms.
Time frame: Up to 6 weeks
Population: Only 36 patients had data for this endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Pterostilbene, Megestrol Acetate) | Histologic Response of Metaplasia | 8 Participants |
| Arm II (Megestrol Acetate) | Histologic Response of Metaplasia | 11 Participants |
Secondary
Histologic Response of Mitotic Index
These histologic changes represent measures of growth and apoptosis, and will be separately scored in the pretreatment endometrial sample and the section of tumor from the hysterectomy (post-treatment sample). The mitotic index will be calculated as the number of mitoses per HPF (average of 3 fields). The number of patients with an improvement in mitotic index were compared between study arms.
Time frame: Up to 6 weeks
Population: Only 36 patients had data for this endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Pterostilbene, Megestrol Acetate) | Histologic Response of Mitotic Index | 14 Participants |
| Arm II (Megestrol Acetate) | Histologic Response of Mitotic Index | 14 Participants |
Secondary
Immunohistochemical Expression of Bcl-2 to Assess Tumor Growth and Apoptosis
Immunohistochemistry stains with antibodies directed against Bcl-2 will be performed on pre- and post-treatment endometrial samples. Samples will be scored on a continuous scale (0-100%) using the product of the intensity of cytoplasmic staining, and the proportion of cells staining based on the distribution of staining. Descriptive statistics were used to compare the percent change in scores from pre-treatment to post-treatment between the 2 study arms.
Time frame: Pre- and post-treatment up to 6 weeks
Population: Only 33 patients had data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Pterostilbene, Megestrol Acetate) | Immunohistochemical Expression of Bcl-2 to Assess Tumor Growth and Apoptosis | 2.1 percent change | Standard Deviation 5.2 |
| Arm II (Megestrol Acetate) | Immunohistochemical Expression of Bcl-2 to Assess Tumor Growth and Apoptosis | 1.2 percent change | Standard Deviation 4.4 |
p-value: 0.6t-test, 1 sided
Secondary
Immunohistochemical Expression of Casp3 to Assess Tumor Growth and Apoptosis
Immunohistochemistry stains with antibodies directed against Casp3 to assess apoptosis will be performed on pre- and post-treatment endometrial samples. Samples will be scored by counting the number of positive staining nuclei per HPF. Descriptive statistics were used to compare the percent change in scores from pre-treatment to post-treatment between the 2 study arms.
Time frame: Pre- and post-treatment up to 6 weeks
Population: Only 25 patients had data for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Pterostilbene, Megestrol Acetate) | Immunohistochemical Expression of Casp3 to Assess Tumor Growth and Apoptosis | -46.4 percent change | Standard Deviation 48.7 |
| Arm II (Megestrol Acetate) | Immunohistochemical Expression of Casp3 to Assess Tumor Growth and Apoptosis | -8.8 percent change | Standard Deviation 79.7 |
p-value: 0.2t-test, 1 sided