This phase II trial studies whether adding tirzepatide injections to a levonorgestrel intrauterine device (LNG-IUD) improves pathologic response (absence of cancer cells in tissue samples after treatment) in women with endometrial atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) or grade 1 endometrial cancer who are overweight or obese. Endometrial cancer occurrence has continued to rise in the United States. Over half of endometrial cancer cases are thought to be attributable to being overweight and obese, and the risk relationship appears to be weight dependent. AH/EIN is a precancerous condition of the endometrium (the uterus or womb) where the lining of the uterus grows abnormally thick, and the cells become abnormal. Women with this thickening have a higher-than-average risk of developing endometrial cancer if left untreated. The usual approach for patients who have AH/EIN and grade 1 endometrial cancer is the removal of the uterus. While surgical treatment is generally safe and effective, it may not be the best approach for some patients. The LNG-IUD is a small, T-shaped device inserted into the uterus that releases the hormone levonorgestrel, a progestin, which counteracts the effects of estrogen in the endometrium. Tirzepatide is a dual glucagon-like peptide 1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) agonist which has been shown to drive weight loss. Adding tirzepatide injections to LNG-IUD may help overweight or obese women with AH-EIN or grade 1 endometrial cancer lose weight, which may improve pathologic response.
Women who have a pathologic diagnosis of AH/EIN or grade 1 endometrioid endometrial cancer confirmed on dilation and curettage (D&C) and desire non-surgical management, who are overweight (body mass index [BMI] ≥ 27 kg/m²) with a weight-related comorbidity (hypertension, type 2 diabetes, or high cholesterol) or obese (BMI ≥ 30 kg/m²) with or without weight-related comorbidities
Prior progesterone treatment for conditions other than AH/EIN or endometrial cancer is allowed, but a 28-day washout period is required before levonorgestrel IUD placement. If archival tissue is available from prior to any progesterone treatment but after the diagnosis of AH/EIN/EC, the washout period is not needed
Age ≥ 18 years. Because no dosing or adverse event (AE) data are currently available on the use of tirzepatide in participants < 18 years of age, children and adolescents < 18 years of age are excluded from this study but will be eligible for future pediatric trials, if applicable
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
Women with grade 2-3 endometrioid, or women with serous, clear cell, mucinous, squamous, transitional cell, sarcomas, or carcinosarcoma histology
Evidence of extrauterine spread of disease on imaging or during surgical evaluation
Participants may not be receiving any other investigational agents or anticancer therapies (including chemotherapy, radiation therapy, hormonal, or antibody-based therapy). Prior treatment should have a minimum washout period of 14 days
History of allergic reactions attributed to compounds of similar chemical or biologic composition to the levonorgestrel IUD or any GLP-1 agonist
Single group
Medical Device Usage and Evaluation
Other interventionUndergo LNG-IUD placement
Tirzepatide
DrugGiven SC
Weighted pathological complete response (pCR)
Proportion of pCR at 26 weeks among patients receiving combined treatment with tirzepatide and levonorgestrel intrauterine device (LNG-IUD) compared to historical controls who received LNG-IUD alone.
Proportion of participants who achieve pCR on endometrial biopsy
Will be compared to historical controls.
Time to complete response and duration of response
Will be compared to historical controls.
Rate of hyperplasia persistence and progression to EC
Will be compared to historical controls as assessed by standard pathologic criteria.
Percent change in cell proliferation
Will assess Ki67 within pre-treatment biopsy and post-treatment biopsies. Will also compare with historical controls.
Change in the endometrial immune microenvironment
Changes pre- and post-treatment will be assessed.
Change in systemic inflammation and metabolic markers
Will summarize percent changes from baseline.
Weight-independent effects of glucagon-like peptide 1 on cell proliferation (Ki-67+)
Effect of intervention on treatment response
Will evaluate the effect of the intervention (combined treatment of tirzepatide and levonorgestrel intrauterine device) on treatment response.
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