Surgical window-of-opportunity study of megestrol acetate compared with megestrol acetate and metformin for endometrial intraepithelial neoplasia

TPS5601 Background: Endometrial Intraepithelial Neoplasia (EIN) is a precursor lesion to endometrial carcinoma (EC), the most common gynecologic cancer among women in the US. The current standard of care for women with EIN is hysterectomy. Non-surgical treatments are needed for women desiring fertility preservation, and for those who are medically unfit for a major surgical procedure. Progestin therapy is the cornerstone of current nonsurgical management of EIN. However, approximately 30% of patients with EIN do not respond to progestin therapy, or respond incompletely. EIN is closely related to insulin resistance and metabolic syndrome with evidence that increased insulin resistance is a significant risk factor for development of EC. Metformin, an inhibitor of insulin/PI3K/AKT pathway, has been demonstrated to reduce endometrial proliferation in vitro and in vivo. We hypothesize that the combination of metformin and progestin therapy may synergize to arrest EIN progression and prevent the development of EC. Methods: This is a randomized pre-surgical window of opportunity study, comparing a commonly used oral progestin, megestrol acetate (MA), to MA and metformin (M). Patients with pathologically confirmed EIN or complex atypical hyperplasia (CAH) who present for hysterectomy will be approached. After enrollment, participants will receive MA 80mg PO BID ± M 500mg BID for 4 ± 1 weeks pre-operatively. Post-therapy endometrial biopsy will be obtained in the operating room prior to the hysterectomy, and compared to the pre-therapy diagnostic endometrial biopsy sample. The primary endpoint is the change in the percentage (%) of Ki-67 expressing cells (%Ki-67) between the pre- and post-treatment biopsies. Based on a two-sample t-test comparing the pre- to post-treatment changes in %Ki-67 between the two arms, a sample size of 21 patients per arm achieves 80% power with two-sided α = 0.05 to detect an absolute reduction in %Ki-67 of 10% vs. 17.6% in the MA vs. MA + M arms. An interim analysis is planned after enrollment of 32 patients, and an internal pilot approach based on variance re-estimation will be used to increase the sample size if needed, to maintain the original planned power. Secondary endpoints will include comparison of changes in protein expression of ER, PR, PTEN/PAX2, markers of the PI3K/AKT/MTOR pathway, cell death and intratumoral insulin signaling. We will randomize 50 subjects at five sites: Northwestern University, Cedars-Sinai (Los Angeles), Duke University, University of Colorado, and University of North Carolina. Participants will be randomized 1:1 and stratified by menopausal status to ensure balance between the two arms. Since September 2021, four sites have opened and 22 patients have been pre-screened. Three participants were enrolled and two have completed intervention. The study is expected to complete accrual by the end of 2023. Clinical trial information: NCT04576104.