Refining Fertility-sparing Treatment in Endometrial Carcinoma Based on Molecular Classification

NCT07319429 | Recruiting Phase 2 DMC

• 2 other identifiers: 20250520SYYYRH2025010
• Study Type: interventional
• Target: 260
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Endometrial Cancer; Fertility

Keywords

Fertility-sparing Treatment; Molecular Classification

Outcome Measures

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).

  32 full weeks following the first administration of fertility-preserving treatment for early-stage endometrial cancer patients.

Secondary Outcomes (8)

• the complete response rate (CRR) at 16 weeks after initiating treatment.

  16 full weeks following the first administration of fertility-preserving treatment for early-stage endometrial cancer patients.

• Median treatment duration to achieve complete response in study cohorts with different molecular subtypes

  through study completion, an average of 1 year.

• Adverse Reactions and Safety Profiles of Different Fertility-Preserving Treatment Regimens

  Throughout study completion, an average of 1year

• Impact of Different Treatment Regimens on Ovarian Function

  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).

• Quality of Life of Patients Receiving Different Treatment Regimens

  Assessments are conducted at the same four time points as ovarian function evaluation (baseline, through study completion, an average of 1year).

Study Arms (3)

POLEmut Stage II Single-Arm Interventional Study

EXPERIMENTAL

Enroll patients with FIGO 2023 Stage IA POLE-mutant endometrial carcinoma to evaluate the CR rate, CR duration, and reproductive outcomes of ICI monotherapy in FST with expanded indications. Enrolled patients will receive ICI monotherapy.

Drug: PD1 antibody

MMRd Stage II Single-Arm Interventional Study:

EXPERIMENTAL

Stratify patients based on MLH1 methylation status/MMR coding gene mutation status. Patients with MMR coding gene mutations (somatic/germline) will receive ICI monotherapy; MMRd patients with MLH1 promoter methylation will receive ICI combined with high-dose potent progestogens (PD-1 + MPA/MA). The study will evaluate the CR rate, CR duration, and reproductive outcomes of FST with expanded indications.

Drug: PD1 antibody; Drug: Medroxyprogesterone Acetate 500 MG; Drug: Megestrol Acetate 160 MG

NSMP Stage III Two-Arm Interventional Study

EXPERIMENTAL

Based on the prediction model, progestogen-sensitive patients will receive high-dose potent progestogens (MA/MPA); progestogen-insensitive patients will receive "GnRHa combined with letrozole". The study will evaluate FST efficacy and reproductive outcomes while further validating the predictive value of the model.Exclusion from FST: NSMP EC with ER negativity and/or L1CAM positivity (≥10%) or p53abn endometrial carcinoma.

Drug: Medroxyprogesterone Acetate 500 MG; Drug: Megestrol Acetate 160 MG; Drug: GnRH agonist and Letrozole

Interventions

Megestrol Acetate 160 MG DRUG

\- Megestrol Acetate: 160 mg, orally once daily, continuously.

MMRd Stage II Single-Arm Interventional Study:; NSMP Stage III Two-Arm Interventional Study

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.

NSMP Stage III Two-Arm Interventional Study

PD1 antibody DRUG

Administration: 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.

Also known as: Sintilimab Injection

MMRd Stage II Single-Arm Interventional Study:; POLEmut Stage II Single-Arm Interventional Study

Medroxyprogesterone Acetate 500 MG DRUG

\- Medroxyprogesterone Acetate: 500 mg, orally once daily, continuously.

MMRd Stage II Single-Arm Interventional Study:; NSMP Stage III Two-Arm Interventional Study

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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;
• Imaging examinations (including pelvic enhanced MRI, upper abdominal enhanced CT/MRI, chest non-contrast CT, or PET/CT-MR) performed within 2 weeks before enrollment treatment initiation to confirm that the lesions are confined to the uterus without extrauterine involvement; for patients allergic to iodine contrast agents, MRI can be used instead of CT;
• Clear molecular subtypes: POLE-mutant, NSMP (no specific molecular profile), or MSI-H (microsatellite instability-high);
• Provide informed consent and sign the informed consent form;
• Good compliance and follow-up conditions, willing and able to complete scheduled follow-up visits at our hospital;
• No significant abnormalities in major organ functions, with relevant test values meeting the following requirements:White blood cell count ≥ 3×10⁹/L or absolute neutrophil count ≥ 1.5×10⁹/L; Platelet count ≥ 100×10⁹/L; AST and/or ALT \< 2× upper limit of normal (ULN); Serum creatinine \< 2× ULN;
• Karnofsky Performance Status (KPS) score ≥ 90; Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2;
• Concurrent use of thyroid medications, calcium tablets, vitamin D, bisphosphonates, metformin, aspirin, etc., is permitted;
• Multidisciplinary Team (MDT) discussion is required before treatment initiation.

You may not qualify if:

• 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);
• Received any of the following treatments within 6 months before enrollment: high-dose potent progestins (megestrol acetate or medroxyprogesterone acetate) for consecutive ≥ 3 months; GnRHa ± letrozole for consecutive ≥ 3 months; immune checkpoint inhibitors for consecutive ≥ 3 months; levonorgestrel-releasing intrauterine system (Mirena) for consecutive ≥ 3 months; other treatments that may affect efficacy evaluation;
• Contraindications to therapeutic drugs (immune checkpoint inhibitors, progestins, GnRHa, letrozole);
• Complicated with severe medical diseases or severe liver dysfunction;
• History of major organ transplantation;
• History of severe mental illness or cerebral functional disorders;
• History of autoimmune diseases requiring immunosuppressant therapy;
• History of substance abuse or drug addiction;
• Request for hysterectomy or other treatments except conservative drug therapy;
• Inability to comply with the study protocol;
• POLE-mutant/NSMP endometrial cancer: Complicated with other gynecological malignancies; For non-gynecological malignancies, enrollment is permitted if MDT evaluation confirms no impact on fertility-preserving treatment, and excluded if it affects fertility-preserving treatment or efficacy evaluation;
• dMMR/MSI-H endometrial cancer (non-Lynch syndrome): Complicated with other malignancies, and MDT evaluation confirms impact on the selection of fertility-preserving treatment regimens or efficacy evaluation.

Sponsors & Collaborators

• Fudan University: lead

Study Sites (2)

Shanghai Tenth People's Hospital

Shanghai, Shanghai Municipality, 200090, China

NOT YET RECRUITING

Shanghai Tenth People's Hospital

Shanghai, Shanghai Municipality, 200090, China

RECRUITING

MeSH Terms

Conditions

Endometrial Neoplasms

Interventions

spartalizumab; sintilimab; Medroxyprogesterone Acetate; Megestrol Acetate; Gonadotropin-Releasing Hormone; Letrozole

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Medroxyprogesterone; Hydroxyprogesterones; Progesterone; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Megestrol; Pregnadienes; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• XIAOJUN CHEN, PhD. MD.

  Shanghai 10th People's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

WEIWEI SHAN, PhD. MD.

CONTACT

86-13817813106; fdsww1024@sina.cn

YU XUE, PhD. MD.

CONTACT

86-13918803650

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Phd.MD. vice President

Model Details: This is a non-randomized controlled, prospective, multi-center, umbrella clinical trial implementing stratified management based on molecular subtypes.

Study Record Dates

• First Submitted: December 8, 2025
• First Posted: January 6, 2026
• Study Start: January 25, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2029
• Last Updated: March 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

CN (2)