Megestrol in Treating Patients With Endometrial Neoplasia or Endometrial Hyperplasia

Study Overview
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Brief Summary
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This randomized phase II trial is studying how well megestrol works in treating patients with endometrial neoplasia or endometrial hyperplasia. Estrogen can cause the growth of endometrial cancer cells. Hormone therapy using megestrol may fight endometrial cancer by blocking the use of estrogen by the abnormal cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the frequency of complete remission by a central pathology review panel in diagnosed endometrial intraepithelial neoplasia (EIN) patients treated for 24 weeks with oral continuous versus interrupted progestin therapy. SECONDARY OBJECTIVES: I. To evaluate whether quality of life is superior in patients who take continuous megestrol versus sequential megestrol by evaluating mood, concerns about weight changes and bleeding. TERTIARY: I. To assess the expression levels of PTEN using immunohistochemistry and to explore the association of PTEN expression levels with patient response to treatment. II. To assess the expression levels of the hormone receptors ER and PR using immunohistochemistry and to explore the association of ER/PR expression levels with patient response to treatment. III. To assess histomorphometry and karyometry characteristics of the pre-treatment biopsy in this patient population. IV. To identify patterns of protein and glycoprotein expression associated with invasive cancer in serum specimens obtained from patients with a diagnosis of atypical endometrial hyperplasia (AEH) or EIN. V. To assess differences in plasma concentrations of megestrol acetate HPLC in this patient population. VI. To assess patient compliance to their treatment regimen using HPLC. OUTLINE: Patients are stratified according to the collection method of the initial/intake biopsy (dilatation and curettage vs all other methods). Patients are randomized to 1 of the following treatment regimens: REGIMEN 1: Patients receive oral megestrol twice daily every day for 24 weeks. Approximately twelve weeks after treatment starts, clinical blood tests are obtained and research serum and plasma collected. Twenty-four weeks constitutes one course of treatment and a pill count is performed during the 12-week f/u visit and at the completion of the treatment course to determine compliance. After progestin therapy the patient has an induced-withdrawal bleed. Patients in this arm undergo a re-evaluation biopsy and hysterectomy a minimum of two weeks and a maximum of eight weeks after completing the megestrol treatment. REGIMEN 2: Patients receive oral megestrol twice daily for two weeks continuously followed by no treatment for two weeks. This course is repeated for a total of 24 weeks. Approximately twelve weeks after treatment starts, clinical blood tests are obtained and research serum and plasma collected. Twenty-four weeks constitutes one course of treatment and a pill count is performed during the 12-week f/u visit and at the completion of the treatment course to determine compliance. After progestin therapy the patient has an induced-withdrawal bleed. Patients in this arm undergo a re-evaluation biopsy and hysterectomy a minimum of two weeks and a maximum of eight weeks after the megestrol treatment. REGIMEN 3: (Closed as of 6/3/2010) Patients do not receive megestrol. At the discretion of the managing physician, patients undergo the re-evaluation biopsy and hysterectomy anytime between 2-20 weeks after enrollment and randomization. Patients undergo biopsy and blood sample collection periodically for immunological and pharmacodynamic studies. Samples are analyzed for presence or absence of myoinvasion or deep myoinvasion in hysterectomy specimens, hormone receptivity status, and to compare PTEN status against treatment via karyometry or morphometry, expression of VEGF and tenascin-C (TN-C) via ELISA, presence of TN-C fragmentation via western immunoblots, additional biomarkers via proteomic analysis, protein and glycoprotein expression patterns via electrophoresis and image analysis, and plasma megestrol concentrations via high-performance liquid chromatography (HPLC). Patients complete the Hospital Anxiety and Depression Scale (HADS) and two items on bleeding and weight gain at baseline and periodically during study. A Treatment Decision Assessment is completed at baseline, and for patients withdrawing from the study, a Study Withdraw Assessment is also completed. There will be no additional follow-up on this study after the patient's hysterectomy.

Official Title
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A Randomized Phase II Evaluation of Continuous Progestin Therapy vs. Sequential Progestin Therapy in the Treatment of Endometrial Intraepithelial Neoplasia (EIN) From a Referred Cohort of Atypical Endometrial Hyperplasia (AEH) or EIN Patients That Desire Uterine Preservation

Conditions
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High Grade Squamous Intraepithelial Neoplasia, Stage 0 Uterine Corpus Cancer

Intervention / Treatment
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* Procedure: Biopsy
* Other: Laboratory Biomarker Analysis
* Drug: Megestrol Acetate
* Other: Pharmacological Study
* Other: Quality-of-Life Assessment
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a diagnosis of atypical endometrial hyperplasia (AEH) or endometrial intraepithelial neoplasia (EIN) diagnosed by dilatation and curettage (D&C), Novak curettage, Vabra aspirate, or Pipelle endometrial biopsy at the enrolling institution within 12 weeks of enrollment Patients must desire uterine retention for duration of study (18 months or after 3rd biopsy) if they remain EIN negative (-); patients are allowed to attempt pregnancy after their initial post-treatment biopsy without it being a major protocol violation Patients must have a GOG performance status of 0, 1, or 2 White blood cell (WBC) >= 3000 Platelets >= 100,000 Granulocytes >= 1,500 Creatinine =< 2 Bilirubin =< 1.5 x institutional upper limit normal Serum glutamic oxaloacetic transaminase (SGOT) =< 3 x institutional upper limit normal Alkaline phosphatase =< 3 x institutional upper limit normal Patients of child-bearing potential must have a negative serum pregnancy test prior to starting study drug and prior to each biopsy if capable of becoming pregnant (and at the discretion of the referring physician) Patients of childbearing potential must use appropriate non-hormonal contraception while on study medication Patients who have met the pre-entry requirements Patients must have signed an approved informed consent and authorization permitting release of personal health information Exclusion Criteria: Patients with a GOG performance status of 3 or 4 Patients with recognized endometrial carcinoma Patients with current or prior history of breast cancer Patients with invasive malignancies, with the exception of nonmelanoma skin cancer who had (or have) any evidence of the other cancer present within the past 5 years or whose previous cancer treatment contraindicates this protocol therapy Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded Patients who have received prior chemotherapy for any abdominal or pelvic tumor are excluded Patients who are pregnant or lactating Patients with a history of thrombophlebitis, thromboembolic phenomena, or cerebrovascular disorders within the past 5 years Patients under 18 years of age

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: Regimen 1 (megestrol acetate, surgery)<br>Patients receive oral megestrol twice daily every day for 24 weeks. Approximately twelve weeks after treatment starts, clinical blood tests are obtained and research serum and plasma collected. Twenty-four weeks constitutes one course of treatment and a pill count is performed during the 12-week f/u visit and at the completion of the treatment course to determine compliance. After progestin therapy the patient has an induced-withdrawal bleed. Patients in this arm undergo a re-evaluation biopsy and hysterectomy a minimum of two weeks and a maximum of eight weeks after completing the megestrol treatment. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Megestrol Acetate<br>* given orally<br>* Other names: SC-10363;Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Procedure: Therapeutic Conventional Surgery<br>* undergo hysterectomy<br>|
| Experimental: Regimen 2 (megestrol acetate, surgery)<br>Patients receive oral megestrol twice daily for two weeks continuously followed by no treatment for two weeks. This course is repeated for a total of 24 weeks. Approximately twelve weeks after treatment starts, clinical blood tests are obtained and research serum and plasma collected. Twenty-four weeks constitutes one course of treatment and a pill count is performed during the 12-week f/u visit and at the completion of the treatment course to determine compliance. After progestin therapy the patient has an induced-withdrawal bleed. Patients in this arm undergo a re-evaluation biopsy and hysterectomy a minimum of two weeks and a maximum of eight weeks after the megestrol treatment. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Megestrol Acetate<br>* given orally<br>* Other names: SC-10363;Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Procedure: Therapeutic Conventional Surgery<br>* undergo hysterectomy<br>|
| Active Comparator: Regimen 3 (surgery/biopsy)<br>(Closed as of 6/3/2010) Patients do not receive megestrol. At the discretion of the managing physician, patients undergo the re-evaluation biopsy and hysterectomy anytime between 2-20 weeks after enrollment and randomization. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Procedure: Therapeutic Conventional Surgery<br>* undergo hysterectomy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Experience a Response as Determined by a Central Blinded Review of the Three Post Treatment Endometrial | Treated and eligible participants. This study had 0 participants that completed treatment, therefore no analysis was done. Study closed prior to completion. Central blinded review was not performed for any participants in the study. | Up to 12 months after completion of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Quality of Life (QOL) Evaluated Using the Hospital Anxiety and Depression Scale (HADS) and the Two Items on Bleeding and Weight Gain | Eligible and Treated patients. This study had 0 participants that completed study. | Baseline to up to 12 months |