Orlistat Plus Progestin for Fertility-Sparing Treatment of Endometrial Cancer or Atypical Hyperplasia (PKUPH-ORLPP-EC)

A Single-Center, Randomized, Open-Label, Controlled Trial of Orlistat Combined With Progestin for Fertility-Sparing Treatment of Endometrial Cancer or Atypical Endometrial Hyperplasia With Low Progesterone Receptor Expression

This is a single-center, randomized, open-label, controlled clinical trial evaluating whether adding orlistat to standard progestin therapy can improve treatment response in patients receiving fertility-sparing treatment for early-stage endometrial cancer (grade 1-2) or atypical endometrial hyperplasia.

Progestin is the standard drug used to preserve the uterus and fertility in these patients, but about 30% of patients respond poorly because the progesterone receptor (PR) in the endometrium is lost or reduced. Laboratory studies by the research team have shown that orlistat, a widely used oral weight-loss drug that blocks fat absorption, can raise PR levels and restore sensitivity to progestin.

The study will enroll 48 patients (age 45 years or younger, body mass index 24 kg/m2 or higher) who still have residual disease and low PR expression after at least 3 months of first-line progestin therapy. Participants will be randomly assigned in a 1:1 ratio to receive either progestin plus orlistat (experimental group) or progestin alone (control group) for 3 months, followed by 24 months of follow-up. The main goal is to compare the change in PR expression from baseline after 3 months of treatment. The study will also assess how many patients achieve complete disease reversal, time to complete response, recurrence, pregnancy and live-birth rates, safety, and changes in body weight and metabolic measures.

Study Overview

• Status: Not yet recruiting
• Conditions: Atypical Endometrial Hyperplasia; Endometrial Neoplasms; Endometrial Cancer; Progestin Resistance
• Intervention / Treatment: Drug: Orlistat; Drug: Progestin

Detailed Description

Background and rationale:

Endometrial cancer (EC) is one of the most common gynecologic malignancies, and 14% to 25% of cases occur in women of reproductive age, many of whom wish to preserve fertility. Progestin is the first-line agent for fertility-sparing treatment of grade 1-2 endometrioid EC and atypical endometrial hyperplasia (AEH), with reported complete response (CR) rates up to 84%. However, approximately 30% of patients show primary or secondary progestin resistance, and loss or down-regulation of the progesterone receptor (PR) is a key mechanism. Obesity is both an independent risk factor for EC and associated with poor progestin response, while progestin itself commonly causes weight gain, creating a vicious cycle of obesity, reduced efficacy, and further weight gain.

Orlistat is an FDA-approved oral gastrointestinal lipase inhibitor widely used for weight management. Beyond weight loss, preclinical studies have shown antitumor activity across several cancer types through inhibition of fatty acid synthase (FASN). The research team previously established a lipid metabolism-FOXA2-PR transcriptional regulatory axis in EC (Liu et al., Oncogene 2025), demonstrating that orlistat stabilizes FOXA2 by inhibiting AKT phosphorylation, thereby up-regulating PR transcription and restoring progestin sensitivity in xenograft models. This trial is the first prospective randomized controlled trial to evaluate orlistat as a transcriptional sensitizer in fertility-sparing treatment of EC/AEH.

Study design:

This is a single-center, prospective, randomized, open-label, parallel-controlled trial conducted at Peking University People's Hospital. Forty-eight eligible patients with G1-G2 endometrioid EC or AEH who have low PR expression (positive cells 25% or less) and have not achieved CR after at least 3 months of first-line progestin therapy are randomized in a 1:1 ratio to the experimental group (progestin plus oral orlistat 120 mg three times daily) or the control group (progestin alone). High-potency progestin (medroxyprogesterone acetate 250-500 mg/day or megestrol acetate 160-320 mg/day) is individualized by the investigator according to body weight, liver function, and prior dose. Randomization uses a computer-generated sequence (SAS 9.4) concealed in sequentially numbered sealed opaque envelopes.

The treatment period is 3 months, followed by 24 months of follow-up. Endometrial biopsy by hysteroscopy is performed every 3 months to evaluate histopathologic response, with paired tissue sampling for translational endpoints (PR, FOXA2, and phospho-FOXA2 immunohistochemistry; bulk RNA sequencing; and peripheral blood lipid metabolomics). The primary endpoint is the relative change in PR expression from baseline at 3 months. A pre-planned interim futility analysis using an O'Brien-Fleming alpha-spending function is performed when 50% of participants are enrolled, overseen by a Data and Safety Monitoring Board.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jian liu Wang, MD; Phone Number: 861088324075; Email: wangjianliu1203@163.com
• Study Contact Backup: Name: Jie Liu, PhD; Phone Number: +8619801118612; Email: liu19801118612@163.com

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100044
      • Peking University People's Hospital
      • Contact: Jie Liu, PhD; Phone Number: +8619801118612; Email: liu19801118612@163.com
      • Contact: Jian liu W, MD; Phone Number: 86-10-88324075; Email: wangjianliu1203@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed grade 1-2 endometrioid endometrial adenocarcinoma or atypical endometrial hyperplasia (AEH), independently confirmed by two senior pathologists
• Lesion confined to the endometrium on MRI or transvaginal ultrasound; FIGO (2009) stage IA without myometrial invasion (for G1, superficial invasion less than one half is allowed; G2 must have no myometrial invasion)
• Age 45 years or younger
• Received first-line MPA 250-500 mg/day or MA 160-320 mg/day for at least 3 months, with hysteroscopy plus curettage confirming failure to achieve complete response (persistent EC/AEH lesion)
• PR-positive cell percentage 25% or less and intensity grade 1 or lower (0 negative, 1 weak, 2 moderate, 3 strong), independently judged by two senior pathologists with a third adjudicating any disagreement
• BMI 24 kg/m2 or higher; no severe comorbidity, specifically ALT/AST 2.5x ULN or lower, serum creatinine 1.5x ULN or lower, and no history of active gastrointestinal bleeding
• No contraindication to progestin therapy or to pregnancy
• No evidence of distant metastasis on pelvic MRI and chest/abdominal CT
• Clearly wishes to preserve fertility and provides signed informed consent
• No use of orlistat or other lipase inhibitors within the past 6 months
• Willing and able to comply with follow-up at this hospital

Exclusion Criteria:

• Tumor invading more than one half of the myometrium; FIGO (2009) stage IB or higher
• Grade G3 or non-endometrioid histology (serous, clear cell, carcinosarcoma, etc.)
• Coexisting other endometrial cancer or other reproductive-system malignancy; coexisting breast cancer or other hormone-dependent tumor precluding progestin use
• Allergy to orlistat or any formulation component, or prior severe adverse reaction (including severe hepatic injury) to orlistat
• Chronic malabsorption syndrome (Crohn disease, celiac disease, short bowel syndrome) or cholestasis
• Concurrent use of ciclosporin, warfarin, levothyroxine, antiepileptics (carbamazepine, phenytoin), or amiodarone that interact significantly with orlistat and cannot be replaced or dose-adjusted
• Planned bariatric surgery (gastric bypass, sleeve gastrectomy, etc.) during the study
• Pregnancy or lactation; unwilling to use reliable contraception during the study and for 3 months after study completion
• Poor compliance or unable to complete 24 months of follow-up

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Orlistat Plus Progestin; Participants receive high-potency progestin (medroxyprogesterone acetate 250-500 mg/day or megestrol acetate 160-320 mg/day, dose individualized by the investigator) combined with oral orlistat 120 mg three times daily, taken with meals or within 1 hour after a meal, for 3 months.	Drug: Orlistat; Oral orlistat 120 mg three times daily, taken with meals or within 1 hour after a meal, for 3 months. A dose may be omitted if a meal is skipped or contains no fat.; Drug: Progestin; High-potency progestin given orally as background therapy in both groups: medroxyprogesterone acetate 250-500 mg/day or megestrol acetate 160-320 mg/day, with the specific agent and dose individualized by the investigator based on body weight, liver function, and prior dose.
Active Comparator: Progestin Alone; Participants receive high-potency progestin alone (medroxyprogesterone acetate 250-500 mg/day or megestrol acetate 160-320 mg/day, dose individualized by the investigator) for 3 months.	Drug: Progestin; High-potency progestin given orally as background therapy in both groups: medroxyprogesterone acetate 250-500 mg/day or megestrol acetate 160-320 mg/day, with the specific agent and dose individualized by the investigator based on body weight, liver function, and prior dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative change in progesterone receptor (PR) expression from baseline at 3 months (delta PR%)	Relative change in PR expression measured by immunohistochemistry (H-score or percentage of PR-positive cells) in endometrial tissue obtained by hysteroscopic biopsy at 3 months versus baseline. An effective PR increase is defined as delta PR% >= 1%, calculated as (PR at 3 months minus PR at baseline) / PR at baseline x 100%.	Baseline and 3 months (90 +/- 7 days after randomization)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response rate at 3 months	Proportion of participants achieving complete response (CR), defined as complete reversal of the endometrium to normal proliferative or secretory endometrium with no residual endometrial cancer or atypical hyperplasia, assessed by hysteroscopic biopsy and curettage and judged independently by two blinded pathologists.	3 months (90 +/- 7 days after randomization)
Pathological complete response rate at 6 months	Proportion of participants achieving pathological complete response at 6 months, assessed by hysteroscopic biopsy and curettage.	6 months (180 +/- 7 days after randomization)
Relative change in PR expression from baseline at 6 months (delta PR%)	Relative change in PR immunohistochemistry H-score in paired endometrial tissue at 6 months versus baseline.	Baseline and 6 months

Collaborators and Investigators

• Sponsor: Peking University People's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: July 15, 2026
• First Submitted That Met QC Criteria: July 15, 2026
• First Posted (Actual): July 20, 2026

Study Record Updates

• Last Update Posted (Actual): July 20, 2026
• Last Update Submitted That Met QC Criteria: July 15, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: orlistat; Fertility Preservation; progesterone receptor; progestin; Fertility-Sparing Treatment
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Uterine Diseases; Genital Diseases, Female; Genital Neoplasms, Female; Uterine Neoplasms; Endometrial Neoplasms; Endometrial Hyperplasia; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Organic Chemicals; Pharmacologic Actions; Chemical Actions and Uses; Lactones; Orlistat; Progestins
• Other Study ID Numbers: 2026PHB495-001; 2025ZD0545900 (Other Grant/Funding Number: National Science and Technology)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data underlying the published results, together with the data dictionary, will be made available to qualified researchers whose proposed use has been approved by the study team.
• IPD Sharing Time Frame: Beginning 6 months and ending 36 months after publication of the primary results.
• IPD Sharing Access Criteria: Requests should be directed to the principal investigator. Requesters will be asked to sign a data access agreement, and each proposal will be reviewed and approved by the study team and the sponsor institution before data are released.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No