Trial Information

A Randomized, Controlled Phase II Evaluation of Megestrol (Megace®) in Different Dose and Sequence in the Treatment of Endometrial Intraepithelial Neoplasia (EIN) From a Referred Cohort of Atypical Endometrial Hyperplasia (AEH) or EIN

OBJECTIVES:

Primary

- To determine the frequency of complete of remission of a community biopsy diagnosis of
atypical endometrial hyperplasia (AEH) or endometrial intraepithelial neoplasia (EIN)
at the time of hysterectomy in patients treated with continuous versus interrupted
progestin therapy.

- To determine the frequency of complete remission of central pathology panel diagnosed
EIN patients treated with continuous versus interrupted progestin therapy. (Patients
who did not receive progestin treatment closed to accrual as of 8/3/2010)

Secondary

- To compare the quality-of-life (mood, concerns about weight, and bleeding) of patients
treated with these regimens.

- To assess the expression levels of PTEN in tumor tissue and its association with
response in patients treated with these regimens.

- To assess the expression levels of hormone receptors, estrogen and progesterone, in
tumor tissue, and their association with response in patients treated with these
regimens.

- To assess histomorphometry and karyometry characteristics of pre-treatment biopsy in
these patients.

- To identify patterns of protein and glycoprotein expression associated with invasive
cancer in serum specimens obtained from patients with a diagnosis of AEH or EIN.

- To assess differences in plasma concentrations of megestrol acetate among these
patients using high-performance liquid chromatography (HPLC).

- To assess patient compliance to their treatment regimen using HPLC to determine plasma
concentrations of megestrol.

- To explore the correlation between megestrol concentrations using HPLC and
pharmacodynamic response as assessed in hysterectomy specimens.

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.