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

Study Overview
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Brief Summary
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This randomized phase II trial studies how well megestrol acetate or levonorgestrel-releasing intrauterine system works in treating patients with atypical endometrial hyperplasia or endometrial cancer. Progesterone can cause the growth of endometrial cancer cells. Hormone therapy using megestrol acetate or levonorgestrel-releasing intrauterine system may fight endometrial cancer by lowering the amount of progesterone the body makes. It is not yet known whether megestrol acetate is more effective than levonorgestrel-releasing intrauterine system in treating atypical endometrial hyperplasia or endometrial cancer.

Detailed Description
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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.

Official Title
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A Phase II Head-to-Head Comparison of Fertility-Sparing Approaches to Treat Complex Atypical Hyperplasia of the Edometrium: Megestrol Versus Levonorgestrel-Releasing Intrauterine System (LNG-IUS)

Conditions
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Atypical Endometrial Hyperplasia, Endometrial Adenocarcinoma, Recurrent Endometrial Carcinoma, Stage IA Endometrial Carcinoma, Stage IB Endometrial Carcinoma, Stage II Endometrial Carcinoma, Stage IIIA Endometrial Carcinoma, Stage IIIB Endometrial Carcinoma, Stage IIIC Endometrial Carcinoma, Stage IVA Endometrial Carcinoma, Stage IVB Endometrial Carcinoma

Intervention / Treatment
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* Drug: megestrol acetate
* Device: levonorgestrel-releasing intrauterine system
* Other: laboratory biomarker analysis
* Other: questionnaire administration


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 44 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 A (megestrol acetate)<br>Patients receive megestrol acetate PO BID for up to 18 months in the absence of disease progression or unacceptable toxicity. | Drug: megestrol acetate<br>* Given PO<br>* Other names: Niagestin;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: questionnaire administration<br>* Ancillary studies<br>|
| Experimental: Arm B (levonorgestrel-releasing IUS)<br>Patients receive levonorgestrel-releasing IUS with continuous release for up to 18 months in the absence of disease progression or unacceptable toxicity. | Device: levonorgestrel-releasing intrauterine system<br>* Given IUD<br>* Other names: Mirena;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: questionnaire administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histologic regression from endometrioid adenocarcinoma or complex atypical hyperplasia to benign endometrium | Histologic regression will be dichotomized as a binary outcome variable, yes if patients have a confirmed histologic regression at the time of the scheduled biopsy, and no if the histologic regression is not observed regardless of compliance, lost-to-follow-up, or other issues. A contingency table and a bar plot will be used to show the histologic regression rate between the 2 arms. Two-group test of equivalence in proportions will be used to detect whether the histologic regression rate in Arm B is not significantly lower than that in Arm A. | Up to 6 months after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in weight | Weight gain will be recorded longitudinally at each 3-month clinic visit and body mass index (BMI) will be calculated and analyzed over time. Can be evaluated using chi squared tests, logistic regression, or repeated measures analysis of variance (ANOVA) whenever appropriate. | Baseline to up to 6 months after completion of study treatment | 
| Change in mood ascertained using the self-reported Beck Depression Inventory-Primary Care (BDI-PC) | Can be evaluated using chi squared tests, logistic regression, or repeated measures ANOVA whenever appropriate. | Baseline to up to 6 months after completion of study treatment | 
| Compliance | Can be evaluated using chi squared tests, logistic regression, or repeated measures ANOVA whenever appropriate. | Up to 6 months after completion of study treatment |