Endometrial Atypical Hyperplasia, Endometrial Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia, Endometrial Cancer, Endometrial Cancer Stage I, Fertility-Sparing Treatment (FST), Obesity & Overweight
Conditions
Keywords
Endometrial atypical hyperplasia, Endometrial cancer, Endometrial cancer stage I, Endometrioid intraepithelial neoplasia, Fertility-sparing treatment, Obesity, Weight reduction, Semaglutide
Brief summary
The goal of this clinical trial is to learn if a combination treatment of a hormonal intrauterine device (LNG-IUD), semaglutide, and a structured weight loss program can treat endometrial atypical hyperplasia or grade 1 endometrioid endometrial cancer while preserving fertility in women of reproductive age with endometrial atypical hyperplasia (EAH) or FIGO grade 1 endometrioid endometrial cancer who wish to preserve their fertility. The main questions it aims to answer are: * What proportion of participants achieve a complete pathological response after treatment? * How durable is the response at 12 months? * What effect does the treatment have on metabolic outcomes (weight, BMI, HbA1c) and quality of life? Participants will: * Receive an LNG-IUD * Receive semaglutide 2.4mg * Participate in a structured weight loss program * Undergo hysteroscopy with endometrial sampling to assess treatment response * Complete quality-of-life assessments at baseline, 6 months, and 12 months
Interventions
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.
DEVICELNG-IUD (Progestin)
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.
BEHAVIORALStructured Weight Loss Program
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.
Sponsors
The Methodist Hospital Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A Bayesian adaptive design with early futility monitoring will guide accrual. The pilot phase will recruit 20 patients. If at least 11 patients achieve a pathological complete response, the study will continue to the expansion phase. In the expansion phase, a stopping rule will be applied such that if the posterior probability Pr(RR ≥ 70% \| data) falls below 0.05, the study will be terminated.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAparna A. Kamat, MD
The Methodist Hospital Research Institute
Outcome results
None listed