This is a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial designed to evaluate the efficacy and safety of mazdutide combined with a levonorgestrel-releasing intrauterine system (LNG-IUS) for fertility-sparing treatment in overweight or obese patients with atypical endometrial hyperplasia (AEH) or early-stage endometrioid endometrial cancer. Eligible participants will be randomized in a 1:1 ratio to receive LNG-IUS plus mazdutide or LNG-IUS plus matching placebo. The primary outcome is the complete response rate of endometrial lesions at 24 weeks after randomization.
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.
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.
Parallel
Mazdutide(Dual GLP-1R/GCGR Agonist)
DrugMazdutide 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
DrugMatching 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
DeviceThe 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.
Complete response rate of endometrial lesions at 24 week
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.
Complete response rate at 12 weeks
The proportion of participants who achieve complete response at the week 12 pathological assessment.
Complete response rate at 36 weeks
The proportion of participants who achieve complete response at the week 36 pathological assessment.
Time to first complete response
Time from randomization to the date of the first pathological assessment confirming complete response.
Pathological response status
Distribution of pathological response categories, including complete response, partial response, stable disease, progressive disease, and unevaluable specimens.
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Tongji Hospital
Lead sponsor
Innovent Biologics, Inc.
Collaborator
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