Megestrol Acetate or Levonorgestrel-Releasing Intrauterine System in Treating Patients With Atypical Endometrial Hyperplasia or Endometrial Cancer

PRIMARY OBJECTIVES:

I. To determine if the levonorgestrel-releasing intrauterine system (IUS) results in
histologic regression of the endometrial lesion (complex atypical hyperplasia [CAH] and
grade 1 endometrial cancer [EC]) comparable to that achieved with oral megestrol (megestrol
acetate).

SECONDARY OBJECTIVES:

I. To compare both the side effect profiles, such as weight gain and mood changes as well as
compliance with assigned treatment between the 2 treatment arms.

TERTIARY OBJECTIVES:

I. To describe fertility-related outcomes, ovulation, menstrual pattern and fertility
abnormalities determined during usual workup (e.g., semen analysis), pregnancy and delivery
within 18-months of treatment.

II. To characterize the incidence of endocrine comorbidities (e.g., hypothyroidism,
polycystic ovarian syndrome, and diabetes).

III. To characterize the association of levels of endoplasmic reticular (ER) stress and
protein kinase B (Akt)-activation in endometrial samples with clinicopathologic-response to
Progestin (therapeutic progesterone) therapy.

OUTLINE:

Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive megestrol acetate orally (PO) twice daily (BID) for up to 18 months
in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive levonorgestrel-releasing IUS with continuous release for up to 18
months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 and 6 months.

Inclusion Criteria:

- A histologic diagnosis of complex atypical hyperplasia or grade 1 endometrioid
adenocarcinoma of the endometrium diagnoses within 3 months of study enrollment who
strongly desire to maintain fertility

- A diagnosis of endometrioid adenocarcinoma will undergo a magnetic resonance imaging
(MRI) scan of the pelvis to rule out deep (> 50%) myometrial invasion and
extrauterine metastases

- A negative urine or serum pregnancy test at the time of enrollment

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 90 days following completion of therapy;
should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately; a female of
child-bearing potential is any woman (regardless of sexual orientation, having
undergone a tubal ligation, or remaining celibate by choice) who meets the following
criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy; or

- Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months)

- Willing and able to consent for treatment with office endometrial biopsies every 3
months

- Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

- A diagnosis of grade 1 endometrioid adenocarcinoma of the endometrium who does not
wish to maintain fertility

- MRI evidence of deep myometrial and/or extrauterine spread

- Congenital or other structural uterine or tubal abnormality

- An acute pelvic inflammatory disease or medical conditions, such as, but not limited
to acquired immunodeficiency syndrome (AIDS) and chronic immunosuppression, that may
be associated with an increased susceptibility to infections

- Current diagnosis of breast cancer or any other cancer

- Currently pregnant or breastfeeding

- Thromboembolic disease, deep vein thrombosis, hypercoagulable state