Megestrol in Treating Patients With Endometrial Neoplasia or Endometrial Hyperplasia

Phase 2

Terminated

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

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

Registration Number: NCT00503581

Lead Sponsor: Gynecologic Oncology Group

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: Female

Target Recruitment: 9

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Regimen 1 (megestrol acetate, surgery)	Biopsy	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 1 (megestrol acetate, surgery)	Therapeutic Conventional Surgery	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 (megestrol acetate, surgery)	Biopsy	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 (surgery/biopsy)	Laboratory Biomarker Analysis	(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.
Regimen 3 (surgery/biopsy)	Therapeutic Conventional Surgery	(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.
Regimen 1 (megestrol acetate, surgery)	Laboratory Biomarker Analysis	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 1 (megestrol acetate, surgery)	Quality-of-Life Assessment	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 (megestrol acetate, surgery)	Laboratory Biomarker Analysis	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 1 (megestrol acetate, surgery)	Pharmacological Study	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 3 (surgery/biopsy)	Pharmacological Study	(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.
Regimen 2 (megestrol acetate, surgery)	Pharmacological Study	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 (surgery/biopsy)	Quality-of-Life Assessment	(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.
Regimen 2 (megestrol acetate, surgery)	Quality-of-Life Assessment	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 2 (megestrol acetate, surgery)	Therapeutic Conventional Surgery	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 (surgery/biopsy)	Biopsy	(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.
Regimen 1 (megestrol acetate, surgery)	Megestrol Acetate	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 (megestrol acetate, surgery)	Megestrol Acetate	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.

Primary Outcome Measures

Name	Time	Method
Number of Patients Who Experience a Response as Determined by a Central Blinded Review of the Three Post Treatment Endometrial	Up to 12 months after completion of treatment	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.

Secondary Outcome Measures

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

Trial Locations

Locations (50): Kaiser Permanente Los Angeles Medical Center
🇺🇸
Los Angeles, California, United States
Olive View-University of California Los Angeles Medical Center
🇺🇸
Sylmar, California, United States
Hartford Hospital
🇺🇸
Hartford, Connecticut, United States
Saint Francis Hospital and Medical Center
🇺🇸
Hartford, Connecticut, United States
The Hospital of Central Connecticut
🇺🇸
New Britain, Connecticut, United States
Memorial University Medical Center
🇺🇸
Savannah, Georgia, United States
Saint Anthony's Health
🇺🇸
Alton, Illinois, United States
Rush - Copley Medical Center
🇺🇸
Aurora, Illinois, United States
Northwestern University
🇺🇸
Chicago, Illinois, United States
Joliet Oncology-Hematology Associates Limited
🇺🇸
Joliet, Illinois, United States
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Kaiser Permanente Los Angeles Medical Center
🇺🇸Los Angeles, California, United States