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

NCT07349641 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 4 other identifiers: NCI-2026-00081MDA24-19-01P30CA016672UG1CA242609
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Endometrial Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia; FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma

Outcome Measures

Primary Outcomes (1)

• 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.

  At 26 weeks

Secondary Outcomes (7)

• Proportion of participants who achieve pCR on endometrial biopsy

  At 52 weeks

• Time to complete response and duration of response

  Up to 52 weeks

• Rate of hyperplasia persistence and progression to EC

  At 26 and 52 weeks

• Percent change in cell proliferation

  At baseline and 12, 26, 39, and 52 weeks

• Percent change in hemoglobin A1C

  At baseline and weeks 12, 26, 39, and 52

Other Outcomes (4)

• Change in the endometrial immune microenvironment

  At baseline and 12, 26, 39, and 52 weeks

• Change in systemic inflammation and metabolic markers

  At baseline and 12, 26, 39 and 52 weeks

• Weight-independent effects of glucagon-like peptide 1 on cell proliferation (Ki-67+)

  At baseline and 12, 26, 39 and 52 weeks

Study Arms (1)

Prevention (LNG-IUD, tirzepatide)

EXPERIMENTAL

After LNG-IUD placement at baseline or on day 0, participants then self-inject tirzepatide SC 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.

Other: Medical Device Usage and Evaluation; Drug: Tirzepatide

Interventions

Tirzepatide DRUG

Given SC

Prevention (LNG-IUD, tirzepatide)

Medical Device Usage and Evaluation OTHER

Undergo LNG-IUD placement

Prevention (LNG-IUD, tirzepatide)

Eligibility Criteria

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

You may qualify if:

• 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/m\^2) with a weight-related comorbidity (hypertension, type 2 diabetes, or high cholesterol) or obese (BMI ≥ 30 kg/m\^2) 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%)
• Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For participants with a history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load
• Participants on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible
• Ability to comply with EMB every 3 months
• Women currently using oral hypoglycemic agents (e.g., metformin) are eligible for the study
• Ability to understand and the willingness to sign a written informed consent document in English or Spanish

You may not qualify if:

• 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
• Uncontrolled intercurrent illness, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study. Because of this, a pregnancy test is part of the screening for the study and women who are pregnant or planning pregnancy within 6 months after the end of the study will be excluded. The LNG-IUD is an Food and Drug Administration (FDA)-approved contraceptive agent. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately.
• Because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with tirzepatide, breastfeeding should be discontinued if the mother is treated with tirzepatide
• Women who have any severe and/or uncontrolled medical conditions such as:
• Unstable angina pectoris, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease,
• Symptomatic congestive heart failure of New York Heart Association class III or IV,
• Active (acute or chronic) or uncontrolled severe infection (not responding to antibiotics), liver diseases such as cirrhosis and decompensated liver disease,
• Known severely impaired lung function (spirometry and diffusion capacity of the lung for carbon monoxide \[DLCO\] 50% or less of normal and oxygen \[O2\] saturation 88% or less at rest on room air), or
• Active, bleeding diathesis
• Other malignancies within the past 3 years except for basal or squamous cell carcinoma of the skin
• Active (acute or chronic) or uncontrolled severe infections (not responding to antibiotics), including acute pelvic inflammatory disease

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (3)

Northwestern University

Chicago, Illinois, 60611, United States

Location

Lyndon Baines Johnson General Hospital

Houston, Texas, 77026-1967, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Endometrial Hyperplasia

Interventions

Tirzepatide

Condition Hierarchy (Ancestors)

Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Proteins; Amino Acids, Peptides, and Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide

Study Officials

• Roni N Wilke

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 16, 2026
• First Posted: January 20, 2026
• Study Start (Estimated): July 6, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2029
• Last Updated: May 14, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share

Locations

US (3)