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

Phase 2Not Yet RecruitingNCT07781150

Tongji Hospital128 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

128

Conditions

Obesity

Interventions

Mazdutide(Dual GLP-1R/GCGR Agonist)DRUG

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.

PlaceboDRUG

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 systemDEVICE

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.

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 45 Years

Medical Language ↔ Plain English

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.

Locations (6)

The First Affiliated Hospital of Zhengzhou University

Zhengzhou, Henan, China

Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Wuhan, Hubei, China

The Second Hospital of Jilin University

Changchun, Jilin, China

Zhejiang Cancer Hospital

Hangzhou, Zhejiang, China

Shanghai Tenth People's Hospital

Shanghai, China

Tianjin Medical University General Hospital

Tianjin, China

Outcomes

Primary Outcomes

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.

Time frame: At 24 weeks after randomization

Secondary Outcomes

Complete response rate at 12 weeks

The proportion of participants who achieve complete response at the week 12 pathological assessment.

Time frame: At 12 weeks after randomization

Complete response rate at 36 weeks

The proportion of participants who achieve complete response at the week 36 pathological assessment.

Time frame: At 36 weeks after randomization

Time to first complete response

Time from randomization to the date of the first pathological assessment confirming complete response.

Time frame: From randomization to first documented complete response, up to 36 weeks

Pathological response status

Distribution of pathological response categories, including complete response, partial response, stable disease, progressive disease, and unevaluable specimens.

Time frame: At 12, 24, and 36 weeks after randomization

Fertility-sparing treatment failure and radical surgery

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.

Time frame: From randomization through the end of study follow-up, up to 2 years after complete response

Change in body weight

Change from baseline in body weight measured in kilograms.

Time frame: Baseline, 12 weeks, 24 weeks, and 36 weeks after randomization

Percentage change in body weight

Percentage change from baseline in body weight, calculated as: \[(body weight at visit - baseline body weight) / baseline body weight\] × 100%.

Time frame: 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

The proportion of participants with body weight reduction of at least 5% from baseline. The outcome will be reported as a percentage of participants.

Time frame: At 12, 24, and 36 weeks after randomization

Proportion of participants with at least 10% body weight reduction

The proportion of participants with body weight reduction of at least 10% from baseline. The outcome will be reported as a percentage of participants.

Time frame: At 12, 24, and 36 weeks after randomization

Change in body mass index

Change from baseline in body mass index, measured in kg/m\^2.

Time frame: Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable

Change in waist circumference

Change from baseline in waist circumference, measured in centimeters.

Time frame: Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable

Change in fasting plasma glucose

Change from baseline in fasting plasma glucose, measured in mmol/L.

Time frame: Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable

Change in HbA1c

Change from baseline in glycated hemoglobin, measured as percentage.

Time frame: Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable

Change in fasting insulin

Change from baseline in fasting insulin, measured in μIU/mL or mIU/L according to the local laboratory standard.

Time frame: Baseline, 24 weeks, and at early discontinuation of study treatment if applicable

Change in HOMA-IR

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.

Time frame: Baseline, 24 weeks, and at early discontinuation of study treatment if applicable

Change in total cholesterol

Change from baseline in total cholesterol, measured in mmol/L.

Time frame: Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable

Change in triglycerides

Change from baseline in triglycerides, measured in mmol/L.

Time frame: Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable

Change in LDL cholesterol

Change from baseline in low-density lipoprotein cholesterol, measured in mmol/L.

Time frame: Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable

Change in HDL cholesterol

Change from baseline in high-density lipoprotein cholesterol, measured in mmol/L.

Time frame: Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable

Change in alanine aminotransferase

Change from baseline in alanine aminotransferase, measured in U/L.

Time frame: Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable

Change in aspartate aminotransferase

Change from baseline in aspartate aminotransferase, measured in U/L.

Time frame: Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable

Change in serum uric acid

Change from baseline in serum uric acid, measured in μmol/L.

Time frame: Baseline, 12 weeks, 24 weeks, 36 weeks, and at early discontinuation of study treatment if applicable

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

Overview

Conditions

Interventions

Eligibility

Locations (6)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts