Semaglutide, Weight Loss, and LNG-IUD for Conservative Treatment of Endometrial Atypical Hyperplasia and Grade 1 Endometrial Cancer

• Semaglutide (Wegovy) weekly injection (Drug): Semaglutide 2.4 mg administered subcutaneously once weekly, following standard dose-escalation protocol, for the duration of the 6-month active treatment period. Used off-label in this trial for its metabolic effects in combination with LNG-IUD, rather than as monotherapy for weight loss.
• LNG-IUD (Progestin) (Device): Levonorgestrel-releasing intrauterine device inserted at study baseline and maintained through the active treatment and follow-up periods, providing continuous local progestin delivery to the endometrium in combination with systemic semaglutide.
• Structured Weight Loss Program (Behavioral): A structured, protocol-defined weight loss program combining dietary counseling and physical activity guidance, delivered concurrently with pharmacologic and device-based treatment to support metabolic response, distinct from weight loss achieved through semaglutide alone.

Primary outcomes

• Pathological Response Rate [6 months]: Pathological Response Rate (PRR) defined as the rate of regression of atypical hyperplasia or carcinoma on histopathological examination of the 6-month (end-of-treatment) hysteroscopic sample

Secondary outcomes

• Time to response [12 months]: Time to response in months from treatment initiation to first documented histopathological regression
• Adverse events [12 months]: Incidence and severity of adverse events, graded per NCI-CTCAE v5.0, including drug-related (semaglutide) and device-related (LNG-IUD) events
• Durable response rate [12 months]: The proportion of participants who achieve a complete pathological response and maintain that response, without evidence of disease recurrence or progression, through 12 months following treatment initiation. Durable response will be assessed via hysteroscopy with endometrial sampling.
• Disease progression rate [12 months]: The proportion of participants who experience disease progression, defined as an increase in histologic grade or stage of endometrial atypical hyperplasia or endometrial cancer, without ever achieving a complete pathological response, assessed through 12 months from treatment initiation. Disease status will be assessed via hysteroscopy with endometrial sampling.
• Recurrence rate [12 months]: The proportion of participants who experience recurrence of endometrial atypical hyperplasia or endometrial cancer following an initial complete pathological response, assessed through 12 months from treatment initiation. Disease status will be assessed via hysteroscopy with endometrial sampling.

Other outcomes

• Body weight change [12 months]: Change in body weight, measured in kilograms, from baseline to 6 and 12 months following treatment initiation.
• Body mass index (BMI) change [12 months]: Change in body mass index (BMI), reported as weight in kilograms divided by height in meters squared (kg/m2) \[normal values: 18.5-24.9 kg/m2\], from baseline to 6 and 12 months following treatment initiation.
• Waist circumference change [12 months]: Change in waist circumference, measured in centimeters, from baseline to 6 and 12 months following treatment initiation.
• Hip circumference change [12 months]: Change in hip circumference, measured in centimeters, from baseline to 6 and 12 months following treatment initiation.
• Waist-to-hip ratio change [12 months]: Change in waist-to-hip ratio, calculated as waist circumference divided by hip circumference, from baseline to 6 and 12 months following treatment initiation.
• Glycated Hemoglobin change [12 months]: Change in glycated hemoglobin (HbA1c), measured as a percentage, from baseline to 6 and 12 months following treatment initiation.
• Weight-Related Quality of Life (WRQOL) [12 months]: Change in weight-related quality of life, assessed using a validated questionnaire, from baseline to 6 and 12 months following treatment initiation. We will utilize the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT) questionnaire. The IWQOL-Lite-CT is a 20-item patient-reported questionnaire that measures weight-related quality of life over the past 7 days. Each item is answered on a 5-point scale. It yields a total score and three composite scores: Physical (7 items), Physical Function (5 items, a subset of Physical), and Psychosocial (13 items). All scores are transformed to a 0-100 scale. Higher scores indicate better weight-related quality of life; lower scores indicate worse quality of life.
• Health-Related Quality of Life [12 months]: Change in health-related quality of life, assessed using a validated Health-Related Quality of Life questionnaire, from baseline to 6 and 12 months following treatment initiation. Health-related quality of life will be assessed with the EORTC QLQ-C30 (30 items) and its endometrial cancer-specific module, the QLQ-EN24 (24 items). The QLQ-C30 includes a global health status/quality of life scale, five functional scales (physical, role, emotional, cognitive, social), and symptom scales and items such as fatigue, pain, and nausea. The QLQ-EN24 assesses endometrial cancer-related symptoms (e.g., lymphoedema, urological, gastrointestinal, sexual/vaginal) and sexual functioning. All scores are linearly transformed to a 0-100 scale. For global health status and functional scales, higher scores indicate better quality of life and functioning. For symptom scales and items, higher scores indicate greater symptom burden, which means worse outcomes.

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

1. Histological Diagnosis: Histologically confirmed endometrial atypical hyperplasia or FIGO grade 1 endometrioid Endometrial Cancer
2. Imaging eligibility (for patients with endometrial cancer):

   1. Depth of myometrial invasion <50% confirmed by MRI or disease limited to the endometrium
   2. No evidence of extrauterine or metastatic disease on imaging.
3. Treatment Rationale (at least one of the following must apply):

   1. Desire for future fertility: Patient expresses a documented desire to preserve the uterus and future reproductive function, with explicit acknowledgment that fertility-sparing treatment is not standard of care for endometrial cancer.
   2. Medical inoperability: patients are considered a poor surgical candidate due to:

   i. Class III obesity (BMI ≥40 kg/m²); or ii. ASA Physical Status Classification score ≥3.
4. Metabolic Profile: BMI ≥ 30 kg/m², or BMI 27-29.9 kg/m² with at least one weight-related comorbidity (hypertension, type 2 diabetes mellitus, dyslipidemia, obstructive sleep apnea, or non-alcoholic fatty liver disease).
5. Progestin washout: patients with prior progestin exposure are eligible provided the following minimum washout periods have been observed.

   1. Oral progestins: 7 days
   2. Injectable, short acting: 14 days
   3. Injectable, long acting: 6 months
   4. Contraceptive implant: 28 days
   5. LNG-IUD: 7 days after removal

Exclusion Criteria:

1. Age ≥18 years
2. Negative pregnancy test at screening
3. Ability to provide written informed consent and comply with study procedures
4. Willingness to undergo genetic counseling and MMR/IHC tumor profiling
5. Willingness and ability to participate in a structured weight loss program, including attendance at counseling sessions (in person or virtual) and adherence to dietary and physical activity goals.

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• Aparna A. Kamat, MD, Principal investigator, The Methodist Hospital Research Institute