Mazdutide Plus Levonorgestrel-Releasing Intrauterine System for Fertility-Sparing Treatment in Overweight or Obese Patients With Atypical Endometrial Hyperplasia or Early Endometrioid Endometrial Cancer
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 128
- 试验地点
- 6
- 主要终点
- Complete response rate of endometrial lesions at 24 week
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Mazdutide and matching placebo will be identical or matched in appearance, packaging, labeling, injection device, injection volume, route, dosing frequency, and dose-escalation procedure. Participants, investigators, care providers, and outcome assessors will remain blinded to treatment allocation. Pathology assessment will be performed without knowledge of randomized treatment assignment.
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
- •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.
结局指标
主要结局
Complete response rate of endometrial lesions at 24 week
时间窗: 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.
次要结局
- Complete response rate at 12 weeks(At 12 weeks after randomization)
- Complete response rate at 36 weeks(At 36 weeks after randomization)
- Time to first complete response(From randomization to first documented complete response, up to 36 weeks)
- Pathological response status(At 12, 24, and 36 weeks after randomization)
- Fertility-sparing treatment failure and radical surgery(From randomization through the end of study follow-up, up to 2 years after complete response)
- Change in body weight(Baseline, 12 weeks, 24 weeks, and 36 weeks after randomization)
- Percentage change in body weight(Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable)
- Proportion of participants with at least 5% body weight reduction(At 12, 24, and 36 weeks after randomization)
- Proportion of participants with at least 10% body weight reduction(At 12, 24, and 36 weeks after randomization)
- Change in body mass index(Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable)
- Change in waist circumference(Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable)
- Change in fasting plasma glucose(Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable)
- Change in HbA1c(Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable)
- Change in fasting insulin(Baseline, 24 weeks, and at early discontinuation of study treatment if applicable)
- Change in HOMA-IR(Baseline, 24 weeks, and at early discontinuation of study treatment if applicable)
- Change in total cholesterol(Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable)
- Change in triglycerides(Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable)
- Change in LDL cholesterol(Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable)
- Change in HDL cholesterol(Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable)
- Change in alanine aminotransferase(Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable)
- Change in aspartate aminotransferase(Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable)
- Change in serum uric acid(Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable)
研究者
Gang Chen (101199)
Co-Principal Investigator
Tongji Hospital