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

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)

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.

Study Overview

• Status: Withdrawn
• Conditions: Atypical Endometrial Hyperplasia; Recurrent Endometrial Carcinoma; Endometrial Adenocarcinoma; 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: Other: laboratory biomarker analysis; Other: questionnaire administration; Drug: megestrol acetate; Device: levonorgestrel-releasing intrauterine system

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 44 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm A (megestrol acetate); Patients receive megestrol acetate PO BID for up to 18 months in the absence of disease progression or unacceptable toxicity.	Other: laboratory biomarker analysis; Correlative studies; Other: questionnaire administration; Ancillary studies; Drug: megestrol acetate; Given PO; Other Names: Megace; BDH 1298; Maygace; Megestil; Niagestin
EXPERIMENTAL: Arm B (levonorgestrel-releasing IUS); Patients receive levonorgestrel-releasing IUS with continuous release for up to 18 months in the absence of disease progression or unacceptable toxicity.	Other: laboratory biomarker analysis; Correlative studies; Other: questionnaire administration; Ancillary studies; Device: levonorgestrel-releasing intrauterine system; Given IUD; Other Names: Mirena

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in levels of ER stress	The changes in the biomarker levels will be examined using scatter plots or tables and paired tests such McNemar test, paired t-test or repeated measures ANOVA whenever appropriate.	Baseline up to 6 months after completion of study treatment
Changes in levels of tumorigenic biomarkers	The changes in the biomarker levels will be examined using scatter plots or tables and paired tests such McNemar test, paired t-test or repeated measures ANOVA whenever appropriate.	Baseline up to 6 months after completion of study treatment

Collaborators and Investigators

• Sponsor: University of Southern California
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Yvonne Lin-Liu, University of Southern California

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (ANTICIPATED): October 1, 2016
• Study Completion (ANTICIPATED): October 1, 2017

Study Registration Dates

• First Submitted: September 11, 2013
• First Submitted That Met QC Criteria: September 11, 2013
• First Posted (ESTIMATE): September 16, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): September 10, 2014
• Last Update Submitted That Met QC Criteria: September 9, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Carcinoma; Hyperplasia; Endometrial Hyperplasia; Endometrial Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Contraceptives, Oral, Hormonal; Central Nervous System Stimulants; Appetite Stimulants; Levonorgestrel; Megestrol; Megestrol Acetate
• Other Study ID Numbers: 5U-12-1 (OTHER: USC Norris Comprehensive Cancer Center); P30CA014089 (U.S. NIH Grant/Contract); NCI-2013-01725 (REGISTRY: CTRP (Clinical Trial Reporting Program))