Mazdutide Plus LNG-IUS for Fertility-Sparing Treatment of AEH or Early Endometrial Cancer

Eligible participants are premenopausal women with a strong desire to preserve fertility, diagnosed with AEH or FIGO grade 1 early-stage endometrioid endometrial cancer confined to the endometrium, and with overweight or obesity. All participants will receive LNG-IUS. Participants will be randomized 1:1 to receive either mazdutide or matching placebo by subcutaneous injection once weekly, using a dose-escalation regimen. Endometrial response will be assessed by hysteroscopic endometrial biopsy and pathology evaluation at prespecified time points. The study will compare pathological response, time to complete response, safety, body weight and metabolic changes, reproductive endocrine parameters, subsequent pregnancy outcomes, recurrence, patient-reported outcomes, and exploratory biomarker changes between the two treatment groups.

• Mazdutide(Dual GLP-1R/GCGR Agonist) (Drug), also known as IBI362: Mazdutide will be administered by subcutaneous injection once weekly. The starting dose is 2 mg once weekly for weeks 1-4, followed by 4 mg once weekly for weeks 5-8, and 6 mg once weekly from week 9 onward. If 6 mg is not tolerated, the dose may be reduced to 4 mg once weekly according to the protocol.
• Placebo (Drug): Matching placebo will be administered by subcutaneous injection once weekly using the same injection route, frequency, injection volume, appearance, packaging, labeling, injection device, and dose-escalation procedure as mazdutide.
• Levonorgestrel-releasing intrauterine system (Device), also known as LNG-IUS: The levonorgestrel-releasing intrauterine system will be placed in the uterine cavity according to standard clinical practice and will be used as the background fertility-sparing progestin therapy in both treatment groups.

Primary outcomes

• Complete response rate of endometrial lesions at 24 week [At 24 weeks after randomization]: The proportion of participants who achieve complete response of endometrial lesions at the week 24 assessment. Complete response is defined as no residual AEH or endometrioid endometrial cancer on evaluable endometrial pathology obtained by hysteroscopic endometrial biopsy.

Secondary outcomes

• Complete response rate at 12 weeks [At 12 weeks after randomization]: The proportion of participants who achieve complete response at the week 12 pathological assessment.
• Complete response rate at 36 weeks [At 36 weeks after randomization]: The proportion of participants who achieve complete response at the week 36 pathological assessment.
• Time to first complete response [From randomization to first documented complete response, up to 36 weeks]: Time from randomization to the date of the first pathological assessment confirming complete response.
• Pathological response status [At 12, 24, and 36 weeks after randomization]: Distribution of pathological response categories, including complete response, partial response, stable disease, progressive disease, and unevaluable specimens.
• Fertility-sparing treatment failure and radical surgery [From randomization through the end of study follow-up, up to 2 years after complete response]: Proportion of participants who discontinue fertility-sparing treatment due to disease progression, persistent non-response, intolerance, or other oncologic reasons, and the proportion undergoing radical surgery.
• Change in body weight [Baseline, 12 weeks, 24 weeks, and 36 weeks after randomization]: Change from baseline in body weight measured in kilograms.
• Percentage change in body weight [Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable]: Percentage change from baseline in body weight, calculated as: \[(body weight at visit - baseline body weight) / baseline body weight\] × 100%.
• Proportion of participants with at least 5% body weight reduction [At 12, 24, and 36 weeks after randomization]: The proportion of participants with body weight reduction of at least 5% from baseline. The outcome will be reported as a percentage of participants.
• Proportion of participants with at least 10% body weight reduction [At 12, 24, and 36 weeks after randomization]: The proportion of participants with body weight reduction of at least 10% from baseline. The outcome will be reported as a percentage of participants.
• Change in body mass index [Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in body mass index, measured in kg/m\^2.
• Change in waist circumference [Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in waist circumference, measured in centimeters.
• Change in fasting plasma glucose [Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in fasting plasma glucose, measured in mmol/L.
• Change in HbA1c [Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in glycated hemoglobin, measured as percentage.
• Change in fasting insulin [Baseline, 24 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in fasting insulin, measured in μIU/mL or mIU/L according to the local laboratory standard.
• Change in HOMA-IR [Baseline, 24 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in homeostatic model assessment of insulin resistance. HOMA-IR is calculated from fasting glucose and fasting insulin and is reported as a unitless index.
• Change in total cholesterol [Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in total cholesterol, measured in mmol/L.
• Change in triglycerides [Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in triglycerides, measured in mmol/L.
• Change in LDL cholesterol [Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in low-density lipoprotein cholesterol, measured in mmol/L.
• Change in HDL cholesterol [Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in high-density lipoprotein cholesterol, measured in mmol/L.
• Change in alanine aminotransferase [Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in alanine aminotransferase, measured in U/L.
• Change in aspartate aminotransferase [Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in aspartate aminotransferase, measured in U/L.
• Change in serum uric acid [Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable]: Change from baseline in serum uric acid, measured in μmol/L.

Sex: Female, ages: 18 Years to 45 Years

Inclusion Criteria:

* Female participants aged 18 to 45 years.
* Participants have a clear desire to preserve fertility, fully understand that fertility-sparing treatment is not the standard radical treatment for endometrial cancer, are willing to accept the potential risks of disease progression or recurrence associated with delayed radical surgery, and are able to comply with close follow-up as required by the protocol.
* Histologically confirmed disease meeting one of the following criteria: atypical endometrial hyperplasia; or FIGO grade 1 endometrioid endometrial cancer meeting FIGO 2023 stage IA1, with disease confined to the endometrium or an endometrial polyp and no myometrial invasion.
* Imaging confirms disease confined to the endometrium, with no evidence of myometrial invasion, adnexal involvement, extrauterine disease, or distant metastasis.
* Estrogen receptor-positive disease.
* Molecular pathology requirements are fulfilled for participants with endometrial cancer, including exclusion of the p53-abnormal molecular subtype. For participants with POLE-ultramutated or mismatch repair-deficient tumors, suitability for fertility-sparing treatment should be determined based on age, family history, genetic findings, and multidisciplinary assessment. Genetic counseling, germline testing, or additional molecular testing may be performed when clinically indicated.
* No contraindication to progestin therapy.
* Uterine cavity suitable for LNG-IUS placement.
* Completed baseline fertility assessment; after complete response, a specific pregnancy plan should be developed after evaluation by reproductive specialists.
* BMI ≥28 kg/m2, or BMI ≥24 kg/m2 with at least one weight-related comorbidity, such as hyperglycemia, hypertension, dyslipidemia, fatty liver disease, or obstructive sleep apnea.
* No contraindication to mazdutide.
* No contraindication to LNG-IUS.
* Able to understand and sign informed consent and willing to comply with all study treatments, assessments, and follow-up procedures.

Exclusion Criteria:

* Pathological diagnosis not consistent with atypical endometrial hyperplasia or eligible early endometrioid endometrial cancer; endometrioid carcinoma grade 2 or higher; or p53-abnormal molecular subtype.
* Imaging or pathological evidence of myometrial invasion, ovarian malignancy, extrauterine disease, or distant metastasis.
* Prior fertility-sparing drug therapy or intrauterine progestin therapy for atypical endometrial hyperplasia or endometrial cancer.
* Use of hormonal therapy or GLP-1 receptor agonists within 6 months before enrollment.
* Pregnancy or breastfeeding at enrollment.
* Request for hysterectomy or treatment other than conservative medical therapy.
* Active pelvic inflammatory disease, recurrent pelvic inflammatory disease, or lower genital tract infection.
* Cervical dysplasia or congenital or acquired uterine abnormalities, including fibroids that distort the uterine cavity.
* Uterine cavity too large for adequate LNG-IUS coverage or history of LNG-IUS expulsion.
* Known hypersensitivity to mazdutide, any of its excipients, or LNG-IUS materials.
* History of malignancy at another site.
* Uncontrolled clinically significant comorbidities or medical history that may increase study risk or interfere with study evaluation, including cardiovascular, cerebrovascular, thromboembolic, hepatic, renal, coagulation, endocrine, psychiatric, pancreatic, biliary, or severe gastrointestinal disorders.
* Diabetes diagnosed by oral glucose tolerance test.
* Secondary obesity or endocrine disorders that may affect body weight or metabolic assessment.
* Contraindications or major risk factors related to GLP-1 receptor agonist therapy, including pancreatitis, clinically significant gallbladder disease, severe gastrointestinal motility disorder, medullary thyroid carcinoma, or multiple endocrine neoplasia type 2.
* Participation in another interventional clinical trial.
* Any condition that, in the investigator's opinion, may increase risk during study treatment, interfere with safety assessment, or affect interpretation of study results.

• Gang Chen, Principal Investigator, Principal investigator, Tongji Hospital