Orlistat Plus Progestin for Fertility-Sparing Treatment of Endometrial Cancer or Atypical Hyperplasia

NCT07714070 | Not Yet Recruiting Phase 2 DMC

• 2 other identifiers: 2026PHB495-0012025ZD0545900
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Endometrial Neoplasms; Endometrial Cancer; Atypical Endometrial Hyperplasia; Progestin Resistance

Keywords

Fertility Preservation; Fertility-Sparing Treatment; progestin; orlistat; progesterone receptor

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Pathological complete response rate at 3 months

  3 months (90 +/- 7 days after randomization)

• Pathological complete response rate at 6 months

  6 months (180 +/- 7 days after randomization)

• Relative change in PR expression from baseline at 6 months (delta PR%)

  Baseline and 6 months

Study Arms (2)

Orlistat Plus Progestin

EXPERIMENTAL

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; Drug: Progestin

Progestin Alone

ACTIVE COMPARATOR

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

Interventions

Orlistat DRUG

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.

Orlistat Plus Progestin

Progestin DRUG

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.

Orlistat Plus Progestin; Progestin Alone

Eligibility Criteria

• Age: Up to 46 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Peking University People's Hospital: lead

Study Sites (1)

Peking University People's Hospital

Beijing, Beijing Municipality, 100044, China

Location

MeSH Terms

Conditions

Endometrial Neoplasms; Endometrial Hyperplasia

Interventions

Orlistat; Progestins

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)

Lactones; Organic Chemicals; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses

Central Study Contacts

Jian liu Wang, MD

CONTACT

861088324075; wangjianliu1203@163.com

Jie Liu, PhD

CONTACT

+8619801118612; liu19801118612@163.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and Chief Physician, Department of Obstetrics and Gynecology

Study Record Dates

• First Submitted: July 15, 2026
• First Posted: July 20, 2026
• Study Start: July 1, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): December 1, 2029
• Last Updated: July 20, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Beginning 6 months and ending 36 months after publication of the primary results.
• 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.

Locations

CN (1)