Weight-loss Drug for Fertility-Sparing Treatment of Atypical Hyperplasia and Grade 1 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 Glucagon-like Peptide-1 (GLP-1) 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, historically controlled, open-label phase 2 study to assess the safety and efficacy of the combination of semaglutide (GLP-1) and pIUD.

• Study Type: Interventional
• Enrollment (Estimated): 108
• 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:

1. People aged ≥ 18 and ≤ 41 years of age
2. BMI ≥ 27
3. Diagnosis of grade 1 or 2 endometrioid EC or AH made by either endometrial biopsy or dilation and curettage
4. Clinical FIGO 2009 stage 1A disease - no evidence of metastatic disease beyond the uterus and no evidence of myometrial invasion by imaging performed (MRI, CT)
5. ECOG status <2
6. Desire for fertility preservation
7. Have signed an approved informed consent form

Exclusion Criteria:

1. Evidence of myometrial invasion or extra-uterine disease on imaging
2. High grade or p53 mutated (p53mut) EC
3. Estrogen receptor (ER) EC
4. Mismatch repair deficient (MMRd) EC

5. History of other malignancies, except if:

   a. Curatively treated with no evidence of disease for >5 years

6. Previous surgical treatment of obesity
7. Current use of weight loss medication (no use in last 6 months)
8. Medical co-morbidity with end-organ dysfunction
9. Unable to understand and participate in the informed consent process
10. Currently pregnant or breastfeeding (negative serum bhCG at screening)
11. Contraindications to progestin intra-uterine device (pIUD)
12. History of chronic pancreatitis or acute pancreatitis within 180 days prior to screening

13. Contraindications to tirzepatide

    1. Personal or first-degree history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma
    2. Anaphylactic reaction

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Control Arm; pIUD	Drug: Mirena; Levonorgestrel-releasing Intrauterine System (52mg) to deliver up to 20 mcg levonorgestrel per day; Other Names: Progestin-releasing intra-uterine device (pIUD)
Experimental: Intervention Arm; tirzepatide + pIUD	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; Tirzepatide injection, starting dose is 2.5mg injected subcutaneously once weekly. After 4 weeks, dose should be increased to 5mg once weekly. The dose then can be increased in 2.5mg increments after no less than 4 weeks on current dose to maximum dose of 15mg once weekly.; Other Names: Tirzepatide

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Time Frame
Complete Response Rate (CRR) at 36 months	36 months
Time to achieve complete response: time it takes for the endometrium to return to normal (months)	36 months
Duration of response: duration of complete response (years)	7 years
Overall recurrence rate: proportion of patients who achieve pathological complete response but experience a recurrence (%)	7 years
Time to recurrence after complete response (months)	36 months
Overall progression/persistence rate: proportion of patients who experience progression or persistence (%)	36 months
Frequency of residual disease on definitive surgical specimens: proportion of patients with residual disease after they undergo completion hysterectomy (%)	7 years
Pregnancy rate (# of pregnancies/total attempting pregnancy)	7 years
Live birth rate (live births/total attempting pregnancy)	7 years
Pregnancy Complications	7 years
Incidence of Treatment-Emergent Adverse Events	36 months
Endometrial Cancer Specific Health Related Quality of Life Questionnaire (FACT-EN)	48 weeks
Impact of Weight on Quality of Life (IWQoL-Lite)	48 weeks
Generalized Anxiety Disorder 7-item (GAD-7)	48 weeks
Patient Health Questionnaire (PHQ-9)	48 weeks
Reproductive Concerns After Cancer (RCAC)	48 weeks
Adapted Illness Intrusiveness Scale (IIRS)	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): September 1, 2024
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2031

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): March 19, 2024
• Last Update Submitted That Met QC Criteria: March 17, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No