Starting soon
Phase 2
Mazdutide Plus LNG-IUS for Fertility-Sparing Treatment of AEH or Early Endometrial Cancer
Condition(s) studied
ObesityOverweightAtypical Endometrial HyperplasiaEndometrial Carcinoma Stage IEndometrioid Endometrial Cancer
Investigational drug(s) / intervention(s)
Mazdutide(Dual GLP-1R/GCGR Agonist)PlaceboLevonorgestrel-releasing intrauterine system
Mazdutide(Dual GLP-1R/GCGR Agonist): 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: 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: 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.
Study summary
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.
Eligibility
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.
Primary outcome measure(s)
- 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.
Trial sites (6)
| Facility | City | Region | Status |
| The First Affiliated Hospital of Zhengzhou University |
Zhengzhou |
Henan |
|
| Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology |
Wuhan |
Hubei |
|
| The Second Hospital of Jilin University |
Changchun |
Jilin |
|
| Zhejiang Cancer Hospital |
Hangzhou |
Zhejiang |
|
| Shanghai Tenth People's Hospital |
Shanghai |
China |
|
| Tianjin Medical University General Hospital |
Tianjin |
China |
|
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