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

NCT07820358 | Not Yet Recruiting Phase 2 FDA Drug FDA Device

• 1 other identifier: PRO00043004
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 4

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

Conditions

Endometrial Atypical Hyperplasia; Endometrial Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia; Endometrial Cancer Stage I; Endometrial Cancer; Fertility-Sparing Treatment (FST); Obesity & Overweight

Keywords

Endometrial atypical hyperplasia; Endometrial cancer; Endometrial cancer stage I; Endometrioid intraepithelial neoplasia; Fertility-sparing treatment; Obesity; Weight reduction; Semaglutide

Outcome Measures

Primary Outcomes (1)

• Pathological Response Rate

  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

  6 months

Secondary Outcomes (5)

• Time to response

  12 months

• Adverse events

  12 months

• Durable response rate

  12 months

• Disease progression rate

  12 months

• Recurrence rate

  12 months

Other Outcomes (8)

• Body weight change

  12 months

• Body mass index (BMI) change

  12 months

• Waist circumference change

  12 months

Study Arms (1)

Combination Fertility-Sparing Treatment

EXPERIMENTAL

Participants will receive a three-component combination intervention consisting of: (1) a levonorgestrel-releasing intrauterine device (LNG-IUD), inserted at baseline; (2) semaglutide 2.4 mg, administered per standard dosing schedule; and (3) a structured weight loss program. Participants will undergo hysteroscopy with endometrial sampling to assess pathological response. Treatment will be administered for 6 months of active intervention, followed by a 6-month follow-up period.

Drug: Semaglutide (Wegovy) weekly injection; Device: LNG-IUD (Progestin); Behavioral: Structured Weight Loss Program

Interventions

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.

Combination Fertility-Sparing Treatment

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.

Combination Fertility-Sparing Treatment

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.

Combination Fertility-Sparing Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological Diagnosis: Histologically confirmed endometrial atypical hyperplasia or FIGO grade 1 endometrioid Endometrial Cancer
• Imaging eligibility (for patients with endometrial cancer):
• Depth of myometrial invasion \<50% confirmed by MRI or disease limited to the endometrium
• No evidence of extrauterine or metastatic disease on imaging.
• Treatment Rationale (at least one of the following must apply):
• 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.
• 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.
• 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).
• Progestin washout: patients with prior progestin exposure are eligible provided the following minimum washout periods have been observed.
• Oral progestins: 7 days
• Injectable, short acting: 14 days
• Injectable, long acting: 6 months
• Contraceptive implant: 28 days
• LNG-IUD: 7 days after removal

You may not qualify if:

• Age ≥18 years
• Negative pregnancy test at screening
• Ability to provide written informed consent and comply with study procedures
• Willingness to undergo genetic counseling and MMR/IHC tumor profiling
• 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.

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead

Study Sites (4)

Houston Methodist at The Medical Center

Houston, Texas, 77030, United States

Location

Houston Methodist Sugar Land

Houston, Texas, 77030, United States

Location

Houston Methodist Willowbrook

Houston, Texas, 77030, United States

Location

Houston Methodist Woodlands

Houston, Texas, 77030, United States

Location

Related Publications (13)

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  PMID: 41329840 BACKGROUND

• Peevey JF, Seagle BL, Maniar KP, Kim JJ. Association of body mass index with ER, PR and 14-3-3sigma expression in tumor and stroma of type I and type II endometrial carcinoma. Oncotarget. 2017 Jun 27;8(26):42548-42559. doi: 10.18632/oncotarget.17209.

  PMID: 28476021 BACKGROUND

• Zhang Z, Dong L, Sui L, Yang Y, Liu X, Yu Y, Zhu Y, Feng Y. Metformin reverses progestin resistance in endometrial cancer cells by downregulating GloI expression. Int J Gynecol Cancer. 2011 Feb;21(2):213-21. doi: 10.1097/IGC.0b013e318207dac7.

  PMID: 21270604 BACKGROUND

• Burzawa JK, Schmeler KM, Soliman PT, Meyer LA, Bevers MW, Pustilnik TL, Anderson ML, Ramondetta LM, Tortolero-Luna G, Urbauer DL, Chang S, Gershenson DM, Brown J, Lu KH. Prospective evaluation of insulin resistance among endometrial cancer patients. Am J Obstet Gynecol. 2011 Apr;204(4):355.e1-7. doi: 10.1016/j.ajog.2010.11.033. Epub 2011 Feb 16.

  PMID: 21324431 BACKGROUND

• Zhu XX, Feng ZH, Liu LZ, Zhang Y. Liraglutide suppresses the proliferation of endometrial cancer cells through the adenosine 5'-monophosphate (AMP)-activated protein kinase signaling pathway. Chin Med J (Engl). 2021 Jan 19;134(5):576-578. doi: 10.1097/CM9.0000000000001363. No abstract available.

  PMID: 33470656 BACKGROUND

• Dai H, Li Y, Lee YA, Lu Y, George TJ, Donahoo WT, Lee KP, Nakshatri H, Allen J, Guo Y, Sun RC, Guo J, Bian J. GLP-1 Receptor Agonists and Cancer Risk in Adults With Obesity. JAMA Oncol. 2025 Oct 1;11(10):1186-1193. doi: 10.1001/jamaoncol.2025.2681.

  PMID: 40839273 BACKGROUND

• Wang L, Xu R, Kaelber DC, Berger NA. Glucagon-Like Peptide 1 Receptor Agonists and 13 Obesity-Associated Cancers in Patients With Type 2 Diabetes. JAMA Netw Open. 2024 Jul 1;7(7):e2421305. doi: 10.1001/jamanetworkopen.2024.21305.

  PMID: 38967919 BACKGROUND

• Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002. doi: 10.1056/NEJMoa2032183. Epub 2021 Feb 10.

  PMID: 33567185 BACKGROUND

• Wichmann IA, Cuello MA. Obesity and gynecological cancers: A toxic relationship. Int J Gynaecol Obstet. 2021 Oct;155 Suppl 1(Suppl 1):123-134. doi: 10.1002/ijgo.13870.

  PMID: 34669205 BACKGROUND

• Kailasam A, Cucinella G, Fought AJ, Cliby W, Mariani A, Glaser G, Langstraat C. Nonsurgical management of early-stage endometrial cancer due to obesity: a survey of the practice patterns of current Society of Gynecologic Oncology members. Gynecol Oncol Rep. 2023 Oct 4;50:101280. doi: 10.1016/j.gore.2023.101280. eCollection 2023 Dec.

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• Kong W, Deng B, Shen X, John C, Haag J, Sinha N, Lee D, Sun W, Chen S, Zhang H, Clontz A, Hursting SD, Zhou C, Bae-Jump V. Tirzepatide as an innovative treatment strategy in a pre-clinical model of obesity-driven endometrial cancer. Gynecol Oncol. 2024 Dec;191:116-123. doi: 10.1016/j.ygyno.2024.10.004. Epub 2024 Oct 10.

  PMID: 39388742 BACKGROUND

• Westin SN, Fellman B, Sun CC, Broaddus RR, Woodall ML, Pal N, Urbauer DL, Ramondetta LM, Schmeler KM, Soliman PT, Fleming ND, Burzawa JK, Nick AM, Milbourne AM, Yuan Y, Lu KH, Bodurka DC, Coleman RL, Yates MS. Prospective phase II trial of levonorgestrel intrauterine device: nonsurgical approach for complex atypical hyperplasia and early-stage endometrial cancer. Am J Obstet Gynecol. 2021 Feb;224(2):191.e1-191.e15. doi: 10.1016/j.ajog.2020.08.032. Epub 2020 Aug 15.

  PMID: 32805208 BACKGROUND

• Janda M, Robledo KP, Gebski V, Armes JE, Alizart M, Cummings M, Chen C, Leung Y, Sykes P, McNally O, Oehler MK, Walker G, Garrett A, Tang A, Land R, Nicklin JL, Chetty N, Perrin LC, Hoet G, Sowden K, Eva L, Tristram A, Obermair A. Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial. Gynecol Oncol. 2021 Apr;161(1):143-151. doi: 10.1016/j.ygyno.2021.01.029.

  PMID: 33762086 BACKGROUND

MeSH Terms

Conditions

Endometrial Hyperplasia; Endometrial Neoplasms; Obesity; Overweight; Weight Loss

Interventions

semaglutide

Condition Hierarchy (Ancestors)

Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Body Weight Changes

Study Officials

• Aparna A. Kamat, MD

  The Methodist Hospital Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: September 9, 2026
• First Posted: September 15, 2026
• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2031
• Last Updated: October 1, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data will become available beginning 12 months after publication of the primary study results and will remain available for 36 months thereafter.
• Access Criteria: De-identified individual participant data, including the study protocol, statistical analysis plan, and informed consent form, will be available to researchers who provide a scientifically sound proposal for data use. Requests should be directed to the principal investigator. Proposals will be reviewed to confirm that the intended use is consistent with the original trial objectives and applicable data protection regulations. Approved requesters will be required to sign a data access agreement prior to receiving data. Access will be granted for the purpose of achieving the aims outlined in the approved proposal.

Locations

US (4)