Megestrol Acetate With or Without Pterostilbene in Treating Patients With Endometrial Cancer Undergoing Hysterectomy

Study Overview
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Brief Summary
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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
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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.

Official Title
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Open-Label Randomized Phase II Trial of Megestrol Acetate With or Without Pterostilbene in Patients With Endometrial Cancer Scheduled for Hysterectomy

Conditions
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Atypical Endometrial Hyperplasia, Endometrial Carcinoma

Intervention / Treatment
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* Drug: Megestrol Acetate
* Biological: Pterostilbene


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (pterostilbene, megestrol acetate)<br>Patients receive pterostilbene PO BID and megestrol acetate PO BID for 3 weeks in the absence of disease progression or unaccepted toxicity. | Drug: Megestrol Acetate<br>* Given PO<br>* Other names: SC-10363;Biological: Pterostilbene<br>* Given PO<br>* Other names: Trans-3,5-dimethoxy-4-hydroxystilbene;|
| Experimental: Arm II (megestrol acetate)<br>Patients receive megestrol acetate PO BID for 3 weeks in the absence of disease progression or unaccepted toxicity. | Drug: Megestrol Acetate<br>* Given PO<br>* Other names: SC-10363;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. We will compare treatment-associated change in Ki-67 proliferation index between the 2 study arms, using a 1-sided test with significance at p < 0.05. Ki-67 values will be assessed at two time-points during this study, prior to treatment with megace +/- pterostilbene (pre-treatment), and following completion of treatment (post-treatment). Using a generalized estimating equation to take into account the repeated assessment of subjects (pre and post treatment), analysis will use a generalized linear regression model of Ki-67 index. Adjustment for potential confounding factors will be made as appropriate. | Pre- and post-treatment up to 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms. | Up to 6 weeks | 
| 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). This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms. | Up to 6 weeks | 
| 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. This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms. | Up to 6 weeks | 
| Histologic response of eosinophilic cytoplasm | 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 cytoplasmic eosinophilia will be estimated as percentages, with < 10% considered negative and >= 10% as positive. This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms. | Up to 6 weeks | 
| 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. This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms. | Pre- and post-treatment up to 6 weeks | 
| 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. This secondary outcome measure will be entered into a generalized linear regression model (with Poisson distribution in the case of count data) to explore whether the effect of treatment differs between treatment arms. | Pre- and post-treatment up to 6 weeks |