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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Endometrial Cancer, Atypical Hyperplasia

Intervention / Treatment
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* Drug: Ozempic
* Drug: Mirena


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: People aged ≥ 18 and ≤ 41 years of age BMI ≥ 27 Diagnosis of grade 1 endometrioid EC or AH 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) ECOG status <2 Desire for fertility preservation Have signed an approved informed consent form Exclusion Criteria: Evidence of myometrial invasion or extra-uterine disease on imaging High grade or p53 mutated (p53mut) EC Estrogen receptor (ER) EC Mismatch repair deficient (MMRd) MLH1 with methylation EC History of other malignancies, except if: a. Curatively treated with no evidence of disease for >5 years Previous bariatric surgery Current use of weight loss medication Medical co-morbidity with end-organ dysfunction Unable to understand and participate in the informed consent process Currently pregnant or breastfeeding (negative serum bhCG at screening) Contraindications to progestin intra-uterine device (pIUD) Self-reported change in body weight of >5kg within 90 days before screening Previous treatment with any medication for obesity within 90 days before screening History of chronic pancreatitis or acute pancreatitis within 180 days prior to screening Contraindications to semaglutide Personal or first-degree history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma Anaphylactic reaction to semaglutide

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 41 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a multicentre single arm, historically controlled, open-label phase 2 study to assess the safety and efficacy of the combination of semaglutide and pIUD
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm<br>Treatment offered as part of this study will be semaglutide in addition to pIUD for total of 12 months. | Drug: Ozempic<br>* Semaglutide injection, 2mg once weekly.<br>* Other names: Semaglutide;Drug: Mirena<br>* Levonorgestrel-releasing Intrauterine System (52mg) to deliver up to 20 mcg levonorgestrel per day<br>* Other names: Progestin-releasing intra-uterine device (pIUD);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate (CRR) at 6 months | Proportion of patients who achieve pathological complete response at 6 months after initiation of pIUD and semaglutide (%). | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CRR at 12 months: proportion of patients who achieve pathological complete response at 12 months after initiation of pIUD and semaglutide (%) |  | 60 months | 
| Time to achieve complete response: time it takes for the endometrium to return to normal (weeks) |  | 60 months | 
| Duration of response: duration of complete response (weeks) |  | 60 months | 
| Overall recurrence rate: proportion of patients who achieve pathological complete response but experience a recurrence (%) |  | 60 months | 
| Time to recurrence after complete response (weeks) |  | 60 months | 
| Overall progression/persistence rate: proportion of patients who experience progression or persistence (%) |  | 60 months | 
| Frequency of residual disease on definitive surgical specimens: proportion of patients with residual disease after they undergo completion hysterectomy (%) |  | 60 months | 
| Pregnancy rate (# of pregnancies/total attempting pregnancy) |  | 60 months | 
| Live birth rate (live births/total attempting pregnancy) |  | 60 months | 
| Incidence of Treatment-Emergent Adverse Events |  | 60 months | 
| Endometrial Cancer Specific Health Related Quality of Life Questionnaire (FACT-EN) |  | 60 months | 
| Impact of Weight on Quality of Life (IWQOL) scale |  | 60 months | 
| Generalized Anxiety Disorder 7-item (GAD-7) scale |  | 60 months | 
| Patient Health Questionnaire (PHQ-9) scale |  | 60 months | 
| Adapted Illness Intrusiveness Scale (IIRS) |  | 60 months | 
| Reproductive Concerns After Cancer (RCAC) scale |  | 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Semaglutide, pIUD