PROfiling Based Endometrial Cancer Adjuvant Therapy (PROBEAT)

Randomized Phase III Trial of Molecular Profile-based Versus Standard Recommendations for Adjuvant Therapy for Women With Early Stage Endometrioid Adenocarcinoma

This is a prospective, multicenter, randomized phase III trial among women with endometrioid adenocarcinoma with high-intermediate and intermediate risk features to investigate the role of integrated genomic-pathologic classification to determine if participants should receive no adjuvant therapy, vaginal brachytherapy, external beam radiotherapy or chemo-radiation therapy based on molecular features as compared to standard radiation therapy.

Study Overview

• Status: Recruiting
• Conditions: Endometrial Cancer Stage I; Endometrial Cancer Stage II
• Intervention / Treatment: Radiation: Vaginal brachytherapy; Other: Observation; Combination product: Chemoradiation therapy; Radiation: External beam radiotherapy

Detailed Description

Adjuvant therapy for women with endometrial cancer has increasingly been tailored to prognostic factors to prevent overtreatment and select those women for adjuvant treatment who will have a clinically relevant reduction of the risk of relapse by the adjuvant treatment. Risk profiles have traditionally been based on clinicopathological factors such as age, stage, grade, Lymph-Vascular Space Invasion (LVSI) and depth of invasion. Newer, both molecular-genetic (the cancer genome atlas subgroups) have become available which are strongly related to outcomes and risk of cancer spread. Based on 2022 National Comprehensive Cancer Network (NCCN) guideline and the ongoing "Portec-4a" trial, this randomized trial using integrated genomic-pathologic classification to assign adjuvant treatment for women with stage I-II high-intermediate and intermediate risk endometrioid adenocarcinoma.

• Study Type: Interventional
• Enrollment (Estimated): 590
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Xinyu Wang, MD; Phone Number: +86-571-87061501; Email: wangxinyu@zju.edu.cn
• Study Contact Backup: Name: Yang Li, PhD; Phone Number: +86-571-87061501; Email: li_yang@zju.edu.cn

Study Locations

• China
  • Beijing, China
    • Not yet recruiting
    • Peking University Peoples Hospital
    • Contact: Zhiqi Wang
    • Principal Investigator: Zhiqi Wang
  • Changsha, China
    • Recruiting
    • Xiangya Hospital of Central South University
    • Contact: Yu Zhang, MD
  • Guangzhou, China
    • Not yet recruiting
    • Sun Yat-sen University Cancer Hospital
    • Contact: Yanling Feng
    • Principal Investigator: Jihong Liu
  • Ningbo, China
    • Recruiting
    • Ningbo First Hospital
    • Contact: Yutao Guan
  • Ningbo, China
    • Recruiting
    • Ningbo Women and Children's Hospital
    • Contact: Lingjun Zhao
  • Shanghai, China
    • Not yet recruiting
    • Obstetrics & Gynecology Hospital of Fudan University
    • Contact: Xiaojun Chen; Email: cxjlhjj@163.com
    • Principal Investigator: Xiaojun Chen
  • Shanghai, China
    • Not yet recruiting
    • Shanghai First Maternity and Infant Hospital
    • Contact: Xiaoping Wan
    • Principal Investigator: Xiaoping Wan
  • Hubei
    • Wuhan, Hubei, China
      • Recruiting
      • Tongji Hospital, Huazhong University of Science and Technology
      • Contact: Gang Chen; Email: gumpc@126.com
      • Principal Investigator: Ding Ma
  • Shandong
    • Jinan, Shandong, China
      • Recruiting
      • Qilu Hospital of Shandong University
      • Contact: Jie Jiang; Email: qljiangjie@aliyun.com
      • Principal Investigator: Beihua Kong
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310000
      • Recruiting
      • Women's Hospital School of Medicine Zhejiang University
      • Contact: Xinyu Wang, MD; Phone Number: +86-571-87061501; Email: wangxinyu@zju.edu.cn
      • Contact: Yang Li; Phone Number: +86-571-87061501; Email: li_yang@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Surgery consisting of a total abdominal or laparoscopic hysterectomy, bilateral salpingectomy, pelvic lymphadenectomy or sentinel lymph node mapping and dissection, with or without para-aortic lymphadenectomy, oophorectomy

2. Histologically confirmed endometrioid type endometrial carcinoma, International Federation of Gynecology and Obstetrics (FIGO) 2009 stage I, with one of the following combinations of stage and grade:

   Stage I A, grade 3 Stage I B, grade 1 or 2 Stage I B, grade 3 Stage II

3. World Health Organization (WHO)-performance status 0-2
4. Written informed consent

Exclusion Criteria:

1. With residual disease
2. Any other stage and type of endometrial carcinoma
3. Histological types serous carcinoma or clear cell carcinoma (at least 10% if mixed type), or undifferentiated or neuroendocrine carcinoma
4. Uterine sarcoma (including carcinosarcoma)
5. Previous malignancy (except for non-melanomatous skin cancer)
6. Previous pelvic radiotherapy
7. Expected interval between the operation and start of radiotherapy exceeding 8 weeks

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: Molecular profile based treatment; Determination of the integrated genomic-pathologic profile to determine adjuvant treatment: observation for POLE-mutated profile; vaginal brachytherapy for intermediate profile; chemo-radiotherapy for p53-abnormal profile.	Radiation: Vaginal brachytherapy; Internal radiation of the vaginal vault using a vaginal cylinder. For brachytherapy administered alone it is recommended: suggested dose is either 3 fractions of 7 Gy or 5 fractions of 6 Gy. For brachytherapy administered after completion of External beam radiotherapy (EBRT): Total dose should aim to be 65 Gy, and suggested dose is 2-3 fractions of 5-6 Gy; Other: Observation; No adjuvant therapy, but active follow-up and quality of life questionnaires as in the groups who have adjuvant treatment; Combination product: Chemoradiation therapy; 4 adjuvant cycles carboplatin and paclitaxel followed by External beam pelvic radiotherapy (45-50 Gy )
Active Comparator: Radiotherapy; Adjuvant vaginal brachytherapy for intermediate risk (stage I A with G3 or stage I B with G1-2) and external beam pelvic radiotherapy for high-intermediate risk (stage I B with G3, or stage II) (standard treatment)	Radiation: Vaginal brachytherapy; Internal radiation of the vaginal vault using a vaginal cylinder. For brachytherapy administered alone it is recommended: suggested dose is either 3 fractions of 7 Gy or 5 fractions of 6 Gy. For brachytherapy administered after completion of External beam radiotherapy (EBRT): Total dose should aim to be 65 Gy, and suggested dose is 2-3 fractions of 5-6 Gy; Radiation: External beam radiotherapy; External beam pelvic radiotherapy on a linear accelerator, 45-50 Gy in 25-28 out-patients sessions

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total recurrence	Vaginal, pelvic or distant recurrence as first failure	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse-free survival	Relapse-free survival (survival without relapse)	3 years, 5 years
Survival	Overall survival (all-cause death)	3 years, 5 years
Adverse events	Treatment-related symptoms according to CTCAE v 5.0	3 years, 5 years
Health-related cancer-specific quality of life	Quality of Life Core Questionnaire (QLQC-30) - clinically relevant changes on Quality of Life Core Questionnaire-30 functioning scales, general quality of life and general cancer symptoms, quite a bit/very much vs no or mild symptoms	3 years, 5 years
Endometrial cancer related health care costs	All hospital based health care costs used with primary treatment or during followup for treatment of adverse events and/or treatment for relapse	3 years, 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence (vaginal and total) per risk profile	Vaginal, pelvic and distant relapse split by risk profile and compared between the 2 arms	3 years, 5 years

Collaborators and Investigators

• Sponsor: Women's Hospital School Of Medicine Zhejiang University
• Collaborators: Xiangya Hospital of Central South University; Peking University People's Hospital; Sun Yat-sen University; Tongji Hospital; Qilu Hospital of Shandong University; Anhui Provincial Cancer Hospital; Obstetrics & Gynecology Hospital of Fudan University; Shanghai First Maternity and Infant Hospital; Ningbo No. 1 Hospital; Ningbo Women & Children's Hospital
• Investigators: Principal Investigator: Xinyu Wang, MD, Women's Hospital School of Medicine Zhejiang University

Publications and helpful links

General Publications

• Concin N, Matias-Guiu X, Vergote I, Cibula D, Mirza MR, Marnitz S, Ledermann J, Bosse T, Chargari C, Fagotti A, Fotopoulou C, Gonzalez Martin A, Lax S, Lorusso D, Marth C, Morice P, Nout RA, O'Donnell D, Querleu D, Raspollini MR, Sehouli J, Sturdza A, Taylor A, Westermann A, Wimberger P, Colombo N, Planchamp F, Creutzberg CL. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer. 2021 Jan;31(1):12-39. doi: 10.1136/ijgc-2020-002230. Epub 2020 Dec 18.
• Leon-Castillo A, de Boer SM, Powell ME, Mileshkin LR, Mackay HJ, Leary A, Nijman HW, Singh N, Pollock PM, Bessette P, Fyles A, Haie-Meder C, Smit VTHBM, Edmondson RJ, Putter H, Kitchener HC, Crosbie EJ, de Bruyn M, Nout RA, Horeweg N, Creutzberg CL, Bosse T; TransPORTEC consortium. Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy. J Clin Oncol. 2020 Oct 10;38(29):3388-3397. doi: 10.1200/JCO.20.00549. Epub 2020 Aug 4.
• Wortman BG, Bosse T, Nout RA, Lutgens LCHW, van der Steen-Banasik EM, Westerveld H, van den Berg H, Slot A, De Winter KAJ, Verhoeven-Adema KW, Smit VTHBM, Creutzberg CL; PORTEC Study Group. Molecular-integrated risk profile to determine adjuvant radiotherapy in endometrial cancer: Evaluation of the pilot phase of the PORTEC-4a trial. Gynecol Oncol. 2018 Oct;151(1):69-75. doi: 10.1016/j.ygyno.2018.07.020. Epub 2018 Aug 3.
• Leon-Castillo A, Britton H, McConechy MK, McAlpine JN, Nout R, Kommoss S, Brucker SY, Carlson JW, Epstein E, Rau TT, Bosse T, Church DN, Gilks CB. Interpretation of somatic POLE mutations in endometrial carcinoma. J Pathol. 2020 Mar;250(3):323-335. doi: 10.1002/path.5372. Epub 2020 Jan 29.
• de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, Colombo A, Fyles A, Baron MH, Jurgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Carinelli S, Provencher D, Hanzen C, Lutgens LCHW, Smit VTHBM, Singh N, Do V, D'Amico R, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC study group. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Mar;19(3):295-309. doi: 10.1016/S1470-2045(18)30079-2. Epub 2018 Feb 12. Erratum In: Lancet Oncol. 2018 Apr;19(4):e184. doi: 10.1016/S1470-2045(18)30212-2.

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: December 16, 2021
• First Submitted That Met QC Criteria: December 16, 2021
• First Posted (Actual): January 5, 2022

Study Record Updates

• Last Update Posted (Actual): April 1, 2025
• Last Update Submitted That Met QC Criteria: March 26, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• 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
• Other Study ID Numbers: IRB-20210340-R

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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