A Study of Weight Loss Intervention With Tirzepatide and Progestin Intrauterine Device to Treat Endometrial Hyperplasia and Grade 1 Endometrial Cancer

PRIMARY OBJECTIVE: I. To determine the proportion of pathological complete response (pCR) on endometrial biopsy (EMB) at 26 weeks among patients receiving combined treatment with tirzepatide (dosed weekly) and levonorgestrel intrauterine device (LNG-IUD) for management of endometrial atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) and grade 1 endometrioid endometrial cancer in overweight or obese women compared to historical controls who received LNG-IUD alone. SECONDARY OBJECTIVES: I. To determine the proportion of participants who achieve sustained pathologic complete response on EMB at 52 weeks (12 months) compared to historical controls. II. To estimate the time to complete response and duration of response, up to 52 weeks (12 months) compared to historical controls. III. To determine the rate of hyperplasia persistence and progression to endometrial cancer at 26 and 52 weeks (6 and 12 months) compared to historical controls. IV. To estimate percent change in cell proliferation (Ki-67+) at 12, 26, 39 and 52 weeks compared to historical controls and baseline. V. To estimate percent change in hemoglobin A1C (HbA1C) at 12, 26, 39 and 52 weeks compared to baseline. VI. To estimate percent weight change every 4 weeks up to week 20 and then at weeks 26, 39 and 52 compared to baseline. VII. To estimate percent change in fasting blood glucose every 4 weeks up to week 20 and then at weeks 26, 39, and 52 compared to baseline. EXPLORATORY OBJECTIVES: I. To investigate the effect of GLP-1 agonism on the endometrial immune microenvironment at 12, 26, 39 and 52 weeks compared to baseline. II. To investigate the effect of GLP-1 agonism on systemic inflammation and metabolic markers at 12 26, 39 and 52 weeks compared to baseline. III. To investigate weight independent effects of GLP-1 agonism on cell proliferation (Ki-67+) at 12, 26, 39 and 52 weeks compared to baseline. IV. To investigate the effect of tirzepatide and LNG-IUD on treatment response based on molecular ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) classification at 26 and 52 weeks. OUTLINE: After LNG-IUD placement at baseline or on day 0, participants then self-inject tirzepatide subcutaneously (SC) once a week (QW) for 26 weeks in the absence of disease progression or unacceptable toxicity. Patients who qualify for tirzepatide or another weight loss medication as determined by primary provider may continue to receive treatment beyond 26 weeks as per standard of care. After completion of study treatment, patients are followed up at weeks 30, 39, and 52.