Refining Fertility-sparing Treatment in Endometrial Carcinoma Based on Molecular Classification
Trial statusRecruiting
Trial phasePhase 2, Phase 3
Trial typeInterventional
Biological sexFemale
Age18-45
SponsorFudan University
About this trial
Endometrial cancer (EC) stands among the most common gynecological malignancies in developed countries and regions, with a notable trend toward younger age at onset. Correspondingly, the demand for fertility-sparing treatment (FST) has been increasingly prominent among young EC patients. High-potency progestogens remain the sole therapeutic option recommended by international guidelines for this patient population; however, approximately 30% of patients exhibit no response to such treatment.
The concept of EC molecular subtyping, proposed by The Cancer Genome Atlas (TCGA) in 2013, has revolutionized the diagnosis and management of EC. EC subtypes with distinct molecular features demonstrate substantial differences in biological behaviors and responses to pharmacotherapeutic interventions. Nevertheless, the role of molecular subtyping in guiding FST decision-making-both in terms of its applicability and specific mechanisms-remains an unmet research need worldwide.
Notably, the POLE-mutant and microsatellite instability-high (MSI-H) subtypes display the highest sensitivity to immune checkpoint inhibitors, underscoring the clinical value of exploring their utility in FST. The no specific molecular profile (NSMP) subtype is sensitive to progestogens but lacks reliable predictive biomarkers-accurate pre-treatment prediction would enable tailored treatment selection, shorten treatment duration, and enhance therapeutic outcomes. In contrast, the p53-abnormal (p53abn) subtype is associated with a poor prognosis, and FST is therefore not recommended for this subgroup.
Building on the aforementioned background and our research team's preliminary clinical findings, this project focuses on the field of FST for EC. To address the current challenges-including narrow indications, limited treatment options, suboptimal efficacy, and the absence of precise personalized regimens-we aim to conduct the world's first prospective multicenter umbrella trial based on EC molecular subtyping. Optimal novel diagnostic and therapeutic protocols will be developed for each molecular subtype, with the goals of optimizing existing FST strategies, improving FST efficacy and reproductive outcomes, expanding eligible indications, and providing high-quality clinical evidence for molecular subtype-guided FST in EC, thereby advancing the overall effectiveness of FST for EC patients.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Age ≥ 18 years and ≤ 45 years;
Strong willingness to preserve fertility/uterus: Patients who have fertility requirements and insist on preserving fertility; or patients who have no fertility requirements but insist on preserving the uterus;
Newly diagnosed endometrial cancer: Pathologically diagnosed as endometrial cancer via endometrial biopsy, diagnostic dilation and curettage, or hysteroscopic examination;
Recurrent patients: Patients with endometrial lesions who received conservative treatment previously and developed recurrent endometrial cancer, with an interval of more than 6 months from the last standardized treatment, or deemed eligible for enrollment by the researcher after evaluation;
Disqualifiers
Unclear molecular subtype or refusal to undergo molecular subtyping;
p53-abnormal molecular subtype;
ER-negative confirmed by pathological immunohistochemistry;
L1CAM-positive confirmed by pathological immunohistochemistry (L1CAM ≥ 10% positive cells);
Trial design
Design model
Factorial
Treatments tested in this trial
PD1 antibody
DrugAdministration: 200 mg via intravenous infusion, once every 3 weeks. After no lesions are detected in two consecutive pathological examinations, the patient enters the maintenance treatment phase. The maintenance treatment duration shall not exceed 6 months. During the maintenance period, 400 mg via intravenous infusion is administered once every 6 weeks, for 4 consecutive times.
Medroxyprogesterone Acetate 500 MG
Drug\- Medroxyprogesterone Acetate: 500 mg, orally once daily, continuously.
Megestrol Acetate 160 MG
Drug\- Megestrol Acetate: 160 mg, orally once daily, continuously.
GnRH agonist and Letrozole
Drug* Triptorelin Acetate for Injection (or similar drugs): 3.75 mg per vial, intramuscular injection once every 4 weeks as one treatment course. * Letrozole Tablets: 2.5 mg, orally once daily, continuously. In the clinical trial conducted at the same center, only the same drug from the same manufacturer shall be used as the trial medication.
Treatment groups
260 Participants
are divided into 3 treatment groupsGroup A: POLEmut Stage II Single-Arm Interventional StudyExperimental treatment 1 intervention
Group B: MMRd Stage II Single-Arm Interventional Study:Experimental treatment 3 interventions
Group C: NSMP Stage III Two-Arm Interventional StudyExperimental treatment 3 interventions
Trial outcomes
Primary outcomes
1
The complete response rate (CRR) at 32 weeks after initiating treatment.
This endpoint aims to assess the therapeutic response of patients stratified by molecular subtypes ( POLE-mutant, MSI-H, and NSMP). The complete response rate (CRR) is defined as the proportion of patients in each molecular subtype cohort who achieve complete disappearance of all detectable endometrial lesions, confirmed by a combination of hysteroscopic examination and endometrial biopsy (pathologically negative for cancer cells).
Time frame
32 full weeks following the first administration of fertility-preserving treatment for early-stage endometrial cancer patients.Secondary outcomes
1
the complete response rate (CRR) at 16 weeks after initiating treatment.
This endpoint aims to assess the 16 weeks' response of patients stratified by molecular subtypes ( POLE-mutant, MSI-H, and NSMP). The complete response rate (CRR) is defined as the proportion of patients in each molecular subtype cohort who achieve complete disappearance of all detectable endometrial lesions, confirmed by a combination of hysteroscopic examination and endometrial biopsy (pathologically negative for cancer cells).
Time frame
16 full weeks following the first administration of fertility-preserving treatment for early-stage endometrial cancer patients.2
Median treatment duration to achieve complete response in study cohorts with different molecular subtypes
The median duration is calculated using the Kaplan-Meier method, with the start time anchored to the first day of treatment and the end time marked as the date of the pathological report confirming complete response. Patients who do not achieve complete response by the end of the study (32 weeks) or who discontinue treatment early due to progression, adverse events, or personal reasons will be classified as "censored" in the statistical analysis, and their follow-up status will be clearly recorded.
Time frame
through study completion, an average of 1 year.3
Adverse Reactions and Safety Profiles of Different Fertility-Preserving Treatment Regimens
Safety is evaluated based on the incidence, severity, and resolution of adverse reactions (ARs) associated with each treatment regimen. ARs are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, including grade 1 (mild) to grade 5 (death).
Time frame
Throughout study completion, an average of 1year4
Impact of Different Treatment Regimens on Ovarian Function
Specific evaluation indicator: anti-Müllerian hormone (AMH) .The impact of treatment is defined as the relative change in AMH from baseline, with a focus on identifying whether the treatment causes reversible or irreversible damage to ovarian reserve.
Time frame
at four time points: (1) Baseline (within 1 week before treatment initiation); (2) 16 weeks after treatment; (3) 32 weeks after treatment; (4) The time point of complete response (if achieved earlier than 32 weeks).Sponsors and contacts
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Fudan University
Lead sponsor
Shanghai 10th People's Hospital
Sponsor institution
Source ClinicalTrials.gov