Weight-loss Drug for Fertility-Sparing Treatment of Atypical Hyperplasia and Low-grade Cancer of the Endometrium (WE-FiERCE)

Weight-loss Drug for Fertility-Sparing Treatment of Atypical Hyperplasia and Grade 1 Cancer of the Endometrium (WE-FiERCE)

The incidence of endometrial cancer is increasing at an alarming rate. This trend parallels the rising rate of obesity, the most significant risk factor for endometrial cancer. Young women with obesity and endometrial cancer or atypical hyperplasia who want to maintain their fertility are treated with progestin therapy, such as progestin intra-uterine device (pIUD), which is associated with a mediocre response rate and high recurrence rate, and does not address the underlying cause, obesity. Therefore, the investigators want to assess whether the addition of a weight-loss drug to pIUD will improve their oncologic, reproductive and metabolic outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Endometrial Cancer; Atypical Hyperplasia
• Intervention / Treatment: Drug: Mirena; Drug: Mounjaro

Detailed Description

The research aims to answer the question: "Does the addition of a Glucose-dependent Insulinotropic Polypeptide (GIP)/Glucagon-like Peptide-1 (GLP-1) co-agonist to standard progestin treatment lead to a higher complete response rate compared to historical response rates using progestin alone in young patients with endometrial cancer/atypical hyperplasia who wish to preserve their fertility?".

This is a multicentre single arm open-label phase II clinical trial to assess the complete pathologic response as determined by endometrial sampling after 48 weeks of tirzepatide (GIP/GLP-1 co-agonist) and progestin therapy in patients with BMI ≥ 27 who have endometrial cancer/atypical hyperplasia and desire fertility preservation.

• Study Type: Interventional
• Enrollment (Estimated): 71
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Vanessa Ballin; Phone Number: 3195 416-946-4501; Email: vanessa.ballin@uhn.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• BMI ≥ 27
• Diagnosis of grade 1 or 2 endometrioid endometrial cancer or atypical hyperplasia made by either endometrial biopsy or dilation and curettage
• For those with endometrial cancer, clinical FIGO 2009 stage 1A disease without evidence of metastatic disease beyond the uterus and no myometrial invasion by MRI or CT
• ECOG status <2
• Desire for fertility preservation
• Ability to understand and willing to sign a written informed consent document

Exclusion Criteria:

• Evidence of myometrial invasion or extra-uterine disease on imaging
• High grade or p53 mutated (p53mut) endometrial cancer
• Estrogen receptor negative endometrial cancer (positivity defined as moderate/strong staining>10%)
• Mismatch repair deficient (MMRd) endometrial cancer
• History of other malignancies except if curatively treated with no evidence of disease for >5 years
• Previous surgical treatment of obesity
• Current use of weight loss medication (no use in last 2 months)
• Medical co-morbidity with end-organ dysfunction
• Contraindications to pIUD or tirzepatide.
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tirzepatide and Progestin Intrauterine Device; All patients will receive a progestin intrauterine device and tirzepatide subcutaneous injections	Drug: Mirena; Levonorgestrel-releasing Intrauterine System (52mg) to deliver up to 20 mcg levonorgestrel per day; Other Names: Progestin-releasing intra-uterine device (pIUD); Drug: Mounjaro; Weekly subcutaneous injection of 2.5mg tirzepatide at baseline with dose escalation by 2.5mg every 4 weeks to reach 15mg or the maximum tolerated dose, by Week 20; Other Names: Tirzepatide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of Complete Pathologic Response	Proportion of patients (%) who achieve pathological complete response at 48 weeks after initiation of pIUD and tirzepatide.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of Safety and Tolerability	Adverse events during treatment period	48 weeks
Assessment of Feasibility	Rate of accrual; Patient compliance; Retention	2.5 years
Assessment of Secondary Oncologic Outcomes	Time to achieve complete response; Duration of response; Recurrence rate; Time to recurrence; Progression/persistence rate	6 years
Assessment of Reproductive Outcomes	Rate of pregnancy; Live birth; Miscarriage; Pregnancy complications	6 years
Assessment of Patient Reported Outcomes	Quality of Life; Psychological functioning and fertility concerns after cancer diagnosis	48 weeks
Assessment of Metabolic Outcomes	Weight; BMI; Waist/hip circumference; Serum biomarkers of obesity and insulin resistance	48 weeks

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Investigators: Principal Investigator: Sarah E Ferguson, MD, University Health Network, Toronto; Principal Investigator: Rachel Soyoun Kim, MD, University Health Network, Toronto

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2025
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2032

Study Registration Dates

• First Submitted: September 12, 2023
• First Submitted That Met QC Criteria: October 3, 2023
• First Posted (Actual): October 10, 2023

Study Record Updates

• Last Update Posted (Actual): June 10, 2025
• Last Update Submitted That Met QC Criteria: June 5, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Tirzepatide; pIUD
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Pathologic Processes; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Body Weight; Body Weight Changes; Uterine Diseases; Genital Diseases, Female; Genital Neoplasms, Female; Uterine Neoplasms; Weight Loss; Hyperplasia; Endometrial Neoplasms; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Tirzepatide; Progestins
• Other Study ID Numbers: 25-5042

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No